EA045949B1 - ANTIPROLIFERATIVE COMPOUNDS AND SECOND ACTIVE AGENTS FOR COMBINED USE - Google Patents

Description

This invention claims benefit from US Provisional Application No. 62/790326, filed January 9, 2019, which is incorporated herein by reference in its entirety.

1. Technical field

Presented herein are methods of using 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)- 3-fluorobenzonitrile or an enantiomer thereof, a mixture of enantiomers, a tautomer or a pharmaceutically acceptable salt, in combination with a second active agent for the treatment, prevention or control of multiple myeloma.

2. State of the art

Multiple myeloma (MM) is a cancer of the plasma cells in the bone marrow. Plasma cells typically produce antibodies and play a key role in immune function. However, uncontrolled growth of these cells leads to bone pain and fractures, anemia, infections and other complications. Multiple myeloma is the second most common hematologic malignancy, although the exact causes of multiple myeloma remain unknown. Multiple myeloma causes high levels of proteins in the blood, urine, and organs, including but not limited to M protein and other immunoglobulins (antibodies), albumin, and beta-2 microglobulin, except in some patients (estimated at 1% to 5% ), myeloma cells which do not secrete these proteins (so-called non-secretory myeloma). M protein, short for monoclonal protein, also known as paraprotein, is a particularly abnormal protein produced by myeloma plasma cells and can be found in the blood or urine of almost all patients with multiple myeloma, except patients with nonsecretory myeloma or whose myeloma cells produce immunoglobulin light chains with a heavy chain.

Skeletal symptoms, including bone pain, are among the most clinically significant symptoms of multiple myeloma. Malignant plasma cells secrete osteoclast-stimulating factors (including IL-1, IL-6, and TNF), which cause calcium to be leached from bone, causing lytic lesions; hypercalcemia is another symptom. Osteoclast stimulating factors, also called cytokines, can prevent apoptosis or death of myeloma cells. Fifty percent of patients have radiologically detectable skeletal lesions associated with myeloma at the time of diagnosis. Other common clinical symptoms of multiple myeloma include polyneuropathy, anemia, hyperviscosity, infections and kidney failure.

Current therapy for multiple myeloma may involve one or more of surgery, stem cell transplant, chemotherapy, immunotherapy, and/or radiation therapy to destroy a patient's multiple myeloma cells. All current therapeutic approaches present significant disadvantages for the patient.

In the last decade, new therapeutic agents, particularly immunomodulatory drugs such as lenalidomide and pomalidomide, have significantly increased response rates and prolonged progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma. However, persistent levels of residual disease that are below the sensitivity of bone marrow (BM) morphology, immunofixation protein electrophoresis, and light chain quantitation exist in many patients with multiple myeloma even after these patients achieve a complete response (CR), and over time will cause a relapse of the disease. Minimal residual disease (MRD) in myeloma is an independent predictor of progression-free survival (PFS) and is being considered as a surrogate trial endpoint to improve identification of effective treatments, especially for exploratory trials, which currently require 5 to 10 years of follow-up for identifying differences in survival. Thus, minimal residual disease (MRD) monitoring in patients with multiple myeloma provides prognostic value for predicting PFS and OS and making treatment decisions. To detect minimal residual disease (MRD) in myeloma, a threshold of 0.01% (10 ^-4 ) after treatment can be used, i.e. having 10 ^-4 cells or fewer multiple myeloma cells as a percentage of total bone marrow mononuclear cells is considered MRD negative and having 10 ^-4 cells or more MRD positive. The 10 ^-4 MRD threshold was originally based on technical feasibility, but it is now possible to quantify MRD at 10 ^-5 using flow cytometry and 10 ^-6 using high-throughput sequencing. (Rawstron et al., Blood 2015;125(12):1932-1935). Methods for measuring MRD include VDJ DNA sequencing, polymerase chain reaction (PCR) (including allele-specific PCR, ASO-PCR), and multiparameter flow cytometry (MPF). MRD assays, for example based on clonotype profile measurements, are also described in US Pat. No. 8,628,927 to Faham et al., which is incorporated herein by reference.

There is a significant need for safe and effective compounds and methods for the treatment, prevention and management of multiple myeloma, including for patients who are newly diagnosed with multiple myeloma or who are refractory to standard treatment, while

- 1 045949 temporary reduction or prevention of toxicity and/or side effects associated with conventional treatments.

The citation or identification of any reference in Section 2 of this invention should not be construed as an admission that the reference is prior art to this invention.

3. Essence of the invention

Presented herein are methods of using the compound 4-(4-(4-(((2-(2,6-dioxopiperidin3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl) -3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof, in combination with a second active agent for the treatment, prevention or control of multiple myeloma, where the second active agent is one or more of a BTK inhibitor (e.g., ibrutinib) , mTOR inhibitor (eg, everolimus), PIM inhibitor (eg, LGH-447), IGF-1R inhibitor (eg, linsitinib), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999 or CPI-1205), JAK2 inhibitor (eg, fedratinib), BRD4 inhibitor (eg, JQ1), PLK1 inhibitor (eg, BI2536), NEK2 inhibitor (eg, JH295) , an AURKB inhibitor (eg, AZD1152), a BIRC5 inhibitor (eg, YM155), a BET inhibitor (eg, Compound C), or a DNA methyltransferase inhibitor (eg, azacitidine).

Also provided for use in the methods described herein are pharmaceutical compositions formulated for administration by appropriate route and means, containing effective concentrations of the compounds provided herein, for example, compound 1, compound 2 or compound 3, or an enantiomer thereof, a mixture of enantiomers , tautomer, isotopologue or pharmaceutically acceptable salt, and optionally containing at least one pharmaceutical carrier. Also provided for use in the methods provided herein are pharmaceutical compositions formulated for administration by a suitable route and means containing effective concentrations of the second active agents provided herein, e.g., ibrutinib, everolimus, LGH-447, linsitinib, trametinib, dimethyl sulfoxide trametinib, selinexor, SGC0946, pinometostat, tazemetostat, UNC1999, CPI-1205, fedratinib, JQ1, BI2536, JH295, barasertib, AZD1152-HQPA, YM155, compound C, or azacitidine, or stereoisomer thereof, mixture of stereoisomers, tautomer, isotopologue pharmaceutically acceptable salt.

In one embodiment, the pharmaceutical compositions deliver amounts effective to treat multiple myeloma. In one embodiment, the pharmaceutical compositions deliver amounts effective to prevent multiple myeloma. In one embodiment, the pharmaceutical compositions deliver amounts effective to eliminate multiple myeloma.

Also provided herein are combination therapies using the compounds or compositions provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, as well as a second active agent provided herein (e.g., ibrutinib, everolimus, LGH-447, lensitinib, trametinib, trametinib dimethyl sulfoxide, selinexor, SGC0946, pinometostat, tazemetostat, UNC1999, CPI1205, fedratinib, JQ1, BI2536, JH295, barasertib, AZD1152-HQPA, YM155, compound C or azacitidine, their stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt) in an additional combination (eg, triple therapy) with therapy, for example, another pharmaceutical agent with activity against multiple myeloma or its symptoms. Examples of therapies within the methods include, but are not limited to, surgery, chemotherapy, radiation therapy, biological therapy, stem cell transplantation, cell therapy, and combinations thereof.

The compounds or compositions provided herein, or pharmaceutically acceptable derivatives thereof, may be administered concomitantly with, before, or after the administration of any other and one or more of the above therapeutic agents. Also provided are pharmaceutical compositions containing a compound provided herein and one or more of the above therapies.

In one embodiment of the methods presented herein, effective amounts of compounds or compositions containing therapeutically effective concentrations of compounds are administered to a subject exhibiting symptoms of multiple myeloma to be treated. These amounts are effective in relieving or eliminating one or more symptoms of multiple myeloma.

Also provided is a pharmaceutical package or kit including one or more containers filled with one or more ingredients of the pharmaceutical compositions. Such container(s) may not necessarily be accompanied by a notice in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical or biological products, the notice reflecting the agency's approval of the manufacture, use, and sale for administration to humans. The packaging or kit may contain information about the route of administration, the sequence of administration of the drug (for example, from

- 2 045949 separately, sequentially or simultaneously) or the like.

These and other aspects of the subject matter described herein will become apparent upon reference to the following detailed description.

4. Detailed description of the invention

A. Definitions.

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. If there are multiple definitions of a term mentioned in this document, the definition provided in this section should be used unless otherwise noted.

As used herein, the terms containing and including may be used interchangeably. The terms containing and including should be interpreted as indicating the presence of specified features or components, but do not exclude the presence or addition of one or more features or components, or groups thereof. Additionally, the terms containing and including are intended to include examples covered by the term consisting of. Therefore, the term consisting of may be used in place of the terms containing and including to provide more specific embodiments of the invention.

The term consisting of means that an object contains at least 90%, 95%, 97%, 98%, or 99% of the stated functions or components of which it is composed. In another embodiment, the term consisting of excludes from the scope of any subsequent listing any other features or components other than those that are not essential to the technical effect to be achieved.

As used herein, the term or should be interpreted to include or to mean any one or any combination. Therefore, A, B or C means any of the following: A; B; C; A and B; A and C; B and C; A, B and C. An exception to this definition will occur only when the combination of elements, functions, stages or activities are in some way inherently exclusive of each other.

IC ₅₀ refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximum response, such as receptor binding, receptor activity, cell growth or proliferation, as measured by any of the in vitro assays or cell-based assays described in this document.

Pharmaceutically acceptable salts include, but are not limited to, amine salts such as, but not limited to, N.N-dibenzylethylenediamine. chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-parachlorobenzyl-2-pyrrolidin-1-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts such as, but not limited to, lithium, potassium and sodium; alkaline earth metal salts such as, but not limited to, barium, calcium and magnesium; transition metal salts such as, but not limited to, zinc; and other metal salts such as, but not limited to, sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids such as, but not limited to, hydrochlorides and sulfates; and salts of organic acids such as, but not limited to, acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, fumarates and organic sulfonates.

Unless specifically stated otherwise, when a compound can be expected to have alternative tautomeric, regioisomeric and/or stereoisomeric forms, all alternative isomers are embraced within the scope of the claimed subject matter. For example, where a compound may have one of two tautomeric forms, it is intended that both tautomers be included herein.

Thus, the compounds provided herein may be enantiomerically pure or be stereoisomeric or diastereomeric mixtures. As used herein and unless otherwise indicated, the term stereoisomerically pure or optically pure means a composition that contains one stereoisomer of a compound and substantially no other stereoisomers of the compound. For example, a stereoisomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound, more preferably more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight by weight of the other stereoisomers of the compound, even more preferably, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably, more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. How is it used in this

- 3 045949 document, a stereoisomerically pure compound contains more than about 80% by weight of one stereoisomer of the compound, more preferably, more than about 90% by weight of one stereoisomer of the compound, even more preferably, more than about 95% by weight of one stereoisomer of the given compound compounds, and most preferably, more than about 97% by weight of one stereoisomer of the compound. As used herein and unless otherwise indicated, the term stereoisomerically enriched means a composition that contains more than about 60% by weight of one stereoisomer of a compound, preferably more than about 70% by weight, more preferably more than about 80% by weight one stereoisomer of a compound. As used herein and unless otherwise indicated, the term enantiomerically pure means a stereoisomerically pure composition of a compound having a single chiral center. Likewise, the term stereoisomerically enriched means a stereoisomerically enriched compound having a single chiral center. As used herein, mixtures of stereoisomers or diastereomers means a composition that contains more than one stereoisomer of a compound. A typical mixture of stereoisomers of a compound contains about 50% by weight of one stereoisomer of the compound and about 50% by weight of the other stereoisomers of the compound, or contains more than about 50% by weight of one stereoisomer of the compound and less than about 50% by weight of the other stereoisomers of the compound. or contains more than about 45% by weight of one stereoisomer of a given compound and less than about 55% by weight of other stereoisomers of a given compound, or contains more than about 40% by weight of one stereoisomer of a given compound and less than about 60% by weight of other stereoisomers of a given compound compounds, or contains more than about 35% by weight of one stereoisomer of the compound and less than about 65% by weight of the other stereoisomers of the compound.

It should be understood that the compounds presented herein may contain chiral centers. Such chiral centers may have either the (R) or (S) configuration, or may be a mixture of both. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Thus, one skilled in the art will appreciate that administering a compound in its (R) form is equivalent, in the case of compounds that undergo epimerization in vivo, to administering the compound in its (S) form.

Optically active (+) and (-), (R)- and (S)-, or (D)- and (b)-isomers can be prepared using chiral synthons or chiral reagents or separated using traditional technologies such as chromatography in a chiral stationary phase.

As used herein, isotopologue means an isotopically enriched compound. The term isotopically enriched refers to an atom having an isotopic composition different from the natural isotopic composition of that atom. Isotopically enriched may also refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of that atom. The term isotopic composition refers to the amount of each isotope present in a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, for example, therapeutic agents for multiple myeloma, research reagents, for example, binding assay reagents, and diagnostic agents, for example, in vivo imaging agents. All isotopic variations of the compounds described herein, whether radioactive or not, are intended to be within the scope of these embodiments proposed herein. In some embodiments, compound isotopologues are provided, for example, the isotopologues of compound 1, compound 2, or compound 3 are compounds enriched in deuterium, carbon-13, or nitrogen-15. In some embodiments, the isotopologues provided herein are deuterium-enriched compounds. In some embodiments, the isotopologues provided herein are deuterium-enriched compounds, where the deuterium enrichment occurs at a chiral center.

In the description given herein, if there is any discrepancy between the chemical name and the chemical structure, the structure takes precedence.

As used herein, the term multiple myeloma refers to hematological conditions characterized by malignant plasma cells and includes the following disorders: monoclonal gammopathy of undetermined significance (MGUS); low, intermediate and high risk multiple myeloma; newly diagnosed multiple myeloma (including newly diagnosed low-, intermediate-, and high-risk multiple myeloma); transplant eligible and transplant ineligible multiple myeloma; smoldering (sluggish) multiple myeloma (including smoldering multiple myeloma of low, intermediate and high risk); active multiple myeloma; solitary plasmacytoma; extramedullary plasmacytoma; plasma cell leukemia; multiple myeloma of the central nervous system; light chain myeloma; nonsecretory myeloma; Immunoglobulin D myeloma; and immunoglobulin E myeloma; and multiple myeloma, characterized by genetic abnormalities such as cyclin D translocations (eg, t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32) ); or t (6; 20);); MMSET translocations (e.g. t(4;14)(p16;q32)); MAF translocations (e.g. t(14;16)(q32;q32);t(20;22);t

- 4 045949 (16; 22) (q11; q13); or t (14; 20) (q32; q11)); or other chromosomal factors (eg, deletion of 17p13 or chromosome 13; del(17/17p), non-hyperdiploidy, and amplification (1q)). In one embodiment, multiple myeloma is characterized according to the International Multiple Myeloma Definition System (ISS). In one embodiment, the multiple myeloma is stage I multiple myeloma, which is characterized by ISS (eg, serum β2microglobulin level <3.5 mg/L and serum albumin >3.5 g/dL). In one embodiment, the multiple myeloma is stage III multiple myeloma that is characterized by ISS (eg, serum β2-microglobulin level >5.4 mg/L). In one embodiment, the multiple myeloma is stage II multiple myeloma, as characterized by ISS (eg, not stage I or III).

As used herein and unless otherwise noted, the terms treat, therapy and treatment refer to the alleviation or reduction in severity of a symptom associated with the disease or condition being treated, such as multiple myeloma.

The term prevention includes suppression of a symptom of a specific disease or disorder, such as multiple myeloma. In some embodiments, patients with a family history of multiple myeloma are candidates for prophylactic regimens. Typically, the term prevention refers to administering a drug before symptoms appear, especially in patients at risk for multiple myeloma.

As used herein, unless otherwise specified, the term management includes preventing relapse of a particular disease or disorder, such as multiple myeloma, in a patient who has suffered from it, prolonging the time a patient has suffered from that disease or disorder, reducing the level of patient mortality and/or maintaining reduction in severity or avoidance of a symptom associated with the disease or condition being treated.

As used herein, a subject or patient means an animal, typically a mammal, including a human, such as a human patient.

The term relapse refers to a situation where patients who have had multiple myeloma in remission after therapy experience a return of myeloma cells and/or a decrease in normal cells in the bone marrow.

The term refractory or resistant refers to circumstances where patients, even after intensive treatment, have residual myeloma cells and/or reduced normal cells in the bone marrow.

As used herein, the term induction therapy refers to the first treatment of a disease or the first treatment to induce complete remission of a disease, such as cancer. Induction therapy itself is considered the best treatment available. If residual cancer is found, patients are treated with another therapy called re-induction. If the patient is in complete remission after induction therapy, additional consolidation and/or maintenance therapy is given to prolong remission or potentially cure the patient.

As used herein, the term consolidation therapy refers to the treatment of a disease after remission has first been achieved. For example, consolidation therapy for cancer is treatment given after the cancer has disappeared after initial therapy. Consolidation therapy may include radiation therapy, a stem cell transplant, or treatment with cancer drugs. Consolidation therapy is also called intensification therapy and post-remission therapy.

As used herein, the term maintenance therapy refers to the treatment of a disease after remission or best response has been achieved to prevent or delay relapse. Maintenance therapy may include chemotherapy, hormonal therapy, or targeted therapy.

Remission as used herein means a reduction or disappearance of the signs and symptoms of a cancer, such as multiple myeloma. In partial remission, some, but not all, signs and symptoms of cancer disappear. In complete remission, all signs and symptoms of cancer have disappeared, although cancer may still be present in the body.

As used herein, the term transplant refers to high-dose therapy for the purpose of stem cell salvage. Hematopoietic (blood) or bone marrow stem cells are used not for treatment, but to save the patient after high-dose therapy, such as chemotherapy and/or high-dose radiation. The transplant includes an autologous stem cell transplant (ASCT), which refers to the use of the patient's own stem cells, which are collected and used as replacement cells. In some embodiments, the graft also includes a tandem graft or multiple grafts.

As used herein, unless otherwise indicated, the terms a therapeutically effective amount and an effective amount of a compound refer to an amount sufficient to provide a therapeutic effect in the treatment, prevention and/or management of a disease, e.g.

- 5 045949 venous myeloma or to delay or minimize one or more symptoms associated with a disease or disorder that needs to be treated. The terms therapeutically effective amount and effective amount can encompass an amount that improves overall therapy, reduces or eliminates symptoms or causes of a disease or disorder, or increases the therapeutic effectiveness of another therapeutic agent.

The terms co-administration and in combination with include the administration of one or more therapeutic agents (for example, a compound provided herein and another anti-multiple myeloma agent, anti-cancer agent or supportive care agent) either simultaneously, concurrently or sequentially without any specific deadlines. In one embodiment, the agents are present in the cell or body of the patient at the same time or exert their biological or therapeutic effects at the same time. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In another embodiment, the therapeutic agents are in separate compositions or unit dosage forms.

The term maintenance agent refers to any substance that treats, prevents or controls the adverse effect of treatment with Compound 1, Compound 2 or Compound 3 or an enantiomer thereof, or a mixture of enantiomers, a tautomer, an isotopologue or a pharmaceutically acceptable salt.

The term biological therapy refers to the administration of biological therapeutics such as umbilical cord blood, stem cells, growth factors and the like.

In the context of a cancer such as multiple myeloma, inhibition can be assessed by inhibition of disease progression, inhibition of tumor growth, shrinkage of the primary tumor, relief of tumor-associated symptoms, inhibition of factors secreted by the tumor, delay in the appearance of primary or secondary tumors, delayed development of primary or secondary tumors. tumors, reducing the incidence of primary or secondary tumors, slowing or reducing the severity of secondary effects of the disease, delaying tumor growth and regression, increasing time to progression (TTP), increasing progression-free survival (PFS), increasing overall survival (OS), among others. As used herein, OS refers to the time from the start of treatment to death from any cause. TTP, as used herein, refers to the time from initiation of treatment to tumor progression; The TTP does not include deaths. In one embodiment, PFS means the time from the start of treatment to tumor progression or death. In one embodiment, PFS means the time from the first dose of a compound to the first occurrence of disease progression or death from any cause. In one implementation of PFS, scores will be calculated using Kaplan-Meier estimates. Event-free survival (EFS) refers to the time from the start of treatment to any treatment failure, including disease progression, discontinuation of treatment for any reason, or death. In one embodiment, the overall response rate (ORR) means the percentage of patients who achieve a response. In one embodiment, ORR means the sum of the percentage of patients who achieve a complete response and a partial response. In one embodiment, ORR means the percentage of patients who have best response > partial response (PR), according to the IMWG Unified Response criteria. In one embodiment, duration of response (DoR) is the time from achieving response to disease relapse or progression. In one embodiment, DoR is the time from achieving response > partial response (PR) to disease relapse or progression. In one embodiment, the DoR is the time from the first documentation of a response to the first documentation of progressive disease or death. In one embodiment, the DoR is the time from first documentation of response > partial response (PR) to first documentation of progressive disease or death. In one embodiment, time to response (TTR) means the time from the first dose of a compound to the first confirmation of a response. In one embodiment, TTR means the time from the first dose of a compound to the first confirmation of response > partial response (PR). In extreme cases, complete inhibition is referred to herein as prophylaxis or chemoprevention. As used herein, the term prevention includes either completely preventing the occurrence of clinically obvious cancer or preventing the occurrence of preclinically obvious cancer. This definition is also intended to include preventing transformation into malignant cells or stopping or reversing the development of precancerous cells into malignant cells. This includes preventive treatment for individuals at risk of developing cancer.

In some embodiments, treatment for multiple myeloma can be assessed using the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie BGM, Harousseau J-L, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006; (10 ) 10:1-7), using the response and endpoint definitions shown below.

- 6 045949

Response subcategory Answer Criteria ³ sCR CR as defined below plus Normal FLC ratio and Absence of clonal cells in bone marrow ¹¹ by immunohistochemistry or immunofluorescence ¹ CR Negative immunofixation in serum and urine and disappearance of any soft tissue plasma cells and <5% of plasma cells in the bone marrow ^b VGPR Serum and urinary M protein detected by immunofixation but not electrophoresis, or a 90% or greater decrease in serum M protein plus urinary M protein <100 mg in 24 hours PR >50% reduction in serum M-protein and >90% reduction in 24-hour urine M-protein or to <200 mg per day If serum and urine M-protein are not measurable, ^a >50% reduction is required differences between levels of involved and uninvolved FLC instead of Mprotein criteria. If serum and urine M protein are not measurable and the serum-free light assay is also not measurable, a >50% reduction in plasma cells is required instead of M protein, provided that the baseline percentage of bone marrow plasma cells was >30%. In addition to the above criteria, if present at baseline, a >50% reduction in the size of soft tissue plasmacytomas is also required. SD (not recommended for use as an indicator of response; disease stability is better describe everything, indicating the time for assessing progression) Not meeting criteria for CR, VGPR, PR or progressive disease

Abbreviations: CR - complete answer; FLC, free light chain; PR - partial response; SD - stable disease; sCR=strict complete response; VGPR is a very good partial answer.

^a All response categories require two consecutive assessments made at any time before the start of any new therapy; All categories also do not require known evidence of progressive or new bone disease if radiographic studies were performed. Radiographic examinations are not required to satisfy these response requirements.

^b Confirmation by repeat bone marrow biopsy is not required.

^c The presence/absence of clonal cells is based on the κ/λ ratio. An abnormal κ/λ ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. The abnormal ratio, reflecting the presence of an abnormal clone, is κ/λ > 4:1 or <1:2.

^d Measurable disease defined by at least one of the following: bone marrow plasma cells >30%; Serum M-protein >1 g/dL (>10 g/L) [10 g/L]; M-protein in urine >200 mg/24 h; Serum FLC assay: involved FLC level >10 mg/dL

- 7 045949 (>100 mg/l); provided that the serum FLC ratio is abnormal.

In this context, ECOG status refers to the Eastern Cooperative Oncology Group (ECOG) performance status (Oken M, et al Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649655), as shown below .

Scale estimates External characteristics 0 Fully active, able to perform all pre-disease activities without restrictions. 1 Limited in physically strenuous activities, but ambulatory and able to perform light or sedentary work, such as light housework, office work. 2 Ambulatory and capable of self-care, but unable to perform any work. Wakeful and more than 50% of the time awake. 3 Capable of only limited self-care and confined to bed or chair more than 50% of waking hours. 4 Completely disabled. Can't study self-service. Completely confined to a bed or chair 5 Dead

The term about, as used herein, unless otherwise noted, refers to a value that is no more than 10% higher or lower than the value modified by the term. For example, the term about 10 mg/m ² means a range from 9 mg/m ² to 11 mg/m ² .

B. Brief description of graphic materials.

Fig. 1 shows the effect of treating MM cells with compound 2 in combination with 9 small molecule inhibitors. Synergy calculations were performed for treatment with compound 2 in combination with 9 small molecule inhibitors in a panel of MM cell lines. Shaded boxes indicate the percentage of wells that exhibited synergistic activity after combination treatment with compound 2. * represents the significance of the difference in surface response from the null model.

Fig. 2A shows the effect of treating MM RPMI cells with compound 2 in combination with ibrutinib; fig. 2B shows the effect of treating MM RPMI cells with Compound 2 in combination with everolimus; fig. 2C shows the effect of treating MM RPMI cells with Compound 2 in combination with LGH-447; fig. 2D shows the effect of treating MM RPMI cells with compound 2 in combination with linsitinib; fig. 2E shows the effect of treating MM RPMI cells with Compound 2 in combination with SGC0946; fig. 2F shows the effect of treating MM RPMI cells with Compound 2 in combination with EPZ-6438; fig. 2G shows the effect of treating MM H929 cells with Compound 2 in combination with trametinib; fig. 2H shows the effect of treating MM H929 cells with Compound 2 in combination with fedratinib; and figs. 2I shows the effect of treating L363 MM cells with Compound 2 in combination with selinexor.

Fig. 3A shows the effect of treating K12PE cell lines with Compound 2 in combination with JQ1; fig. 3B shows the corresponding additivity index values; fig. 3C shows the effect of treating K12PE-PR cell lines with Compound 2 in combination with JQ1; and figs. 3D shows the corresponding values of the additivity index.

Fig. 4A shows treatment of AMO1 cell lines with Compound 2 in combination with trametinib; fig. 4B shows the corresponding additivity index values; fig. 4C shows the effect of treating AMO1-PR cell lines with Compound 2 in combination with trametinib; and figs. 4D shows the corresponding additivity index values.

Fig. 5A shows the effect of treating H929 cell lines with Compound 2 in combination with UNC1999; and figs. 5B shows the corresponding additivity index values.

Fig. 6A shows the effect of treating AMO1 cell lines with Compound 2 in combination with BI2536; fig. 6B shows the corresponding additivity index values; fig. 6C shows the effect of treating AMO1-PR cell lines with Compound 2 in combination with BI2536; and figs. 6D shows the corresponding additivity index values.

Fig. 7A shows the efficacy rate for treating AMO1 cell lines with Compound 2 in combination with JH295; and figs. 7B shows the efficacy rate for treatment of AMO1-PR cell lines with Compound 2 in combination with JH295.

Fig. 8A shows the efficacy rate for treatment of AMO1 cell lines with compound 2b

- 8 045949 combination with AZD1152; fig. 8B shows the efficacy rate for treatment of K12PE cell lines with Compound 2 in combination with AZD1152; fig. 8C shows the efficacy rate for treatment of AMO1-PR cell lines with Compound 2 in combination with AZD1152; and fig. 8D shows the efficacy rate for treatment of K12PE-PR cell lines with Compound 2 in combination with AZD1152.

Fig. 9A shows the effect of treating AMO1 cell lines with Compound 2 in combination with YM155; fig. 9B shows the corresponding additivity index values; fig. 9C shows the effect of treating AMO1-PR cell lines with Compound 2 in combination with YM155; and fig. 9D shows the corresponding additivity index values.

Fig. 10A and FIG. 10B shows the effect of treatment with Compound 2 in combination with Compound C on OPM.2-P10 and H929-1051 MM cells, respectively.

Fig. 11A, FIG. 11B, FIG. 11C and FIG. 11D shows the effect of treatment with Compound 2 in combination with azacitidine in OPM.2-P10, H929-1051, L363 and JJN3 MM cells, respectively.

Fig. 12A, FIG. 12B, FIG. 12C and FIG. 12D shows the effect of treatment with Compound 2 in combination with tazemetostat in OPM.2-P10, H929-1051, L363 and JJN3 MM cells, respectively.

Fig. 13A, FIG. 13B, FIG. 13C and FIG. 13D shows the effect of treatment with Compound 2 in combination with CPI-1205 in OPM.2-P10, H929-1051, L363 and JJN3 MM cells, respectively.

Fig. 14A and FIG. 14B shows the effect of treatment in KMS12BM PR cells with Compound 2 in combination with tazemetostat and CPI-1205, respectively.

Fig. 15A, FIG. 15B, FIG. 15C and FIG. 15D shows the effect of treatment with Compound 2 in combination with pinometostat in OPM.2-P10, H929-1051, L363 and JJN3 MM cells, respectively.

C. Connections.

For use in the methods proposed herein, the compound 4-(4-(4(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl) is provided. piperazin-1-yl)-3fluorobenzonitrile, referred to as compound 1:

ABOUT

I

NC^^ 'F or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof.

Also provided for use in the methods provided herein is the compound (S)4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy )methyl)benzyl)piperazin-1-yl)-3fluorobenzonitrile, referred to as compound 2:

or a tautomer, isotopologue or pharmaceutically acceptable salt thereof.

Also provided for use in the methods provided herein is the compound ^)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy )methyl)benzyl)piperazin-1-yl)3-fluorobenzonitrile, referred to as compound 3:

ABOUT

s or a tautomer, isotopologue or pharmaceutically acceptable salt thereof.

In one embodiment, Compound 1 is used in the methods presented herein. In one embodiment, the tautomer of compound 1 is used in the methods presented herein. In one embodiment, the enantiomer of compound 1 is used in

- 9 045949 methods presented in this document. In one embodiment, a mixture of enantiomers of compound 1 is used in the methods presented herein. In one embodiment, a pharmaceutically acceptable salt of Compound 1 is used in the methods presented herein.

In one embodiment, compound 2 is used in the methods presented herein. In one embodiment, the tautomer of compound 2 is used in the methods presented herein. In one embodiment, a pharmaceutically acceptable salt of compound 2 is used in the methods presented herein.

In one embodiment, compound 3 is used in the methods presented herein. In one embodiment, the tautomer of compound 3 is used in the methods presented herein. In one embodiment, a pharmaceutically acceptable salt of compound 3 is used in the methods presented herein.

In one embodiment, isotopically enriched analogues of the compounds are used in the methods provided herein. In one embodiment, isotope-enriched analogues of the compounds used in the methods provided herein include those described in US application No. 16/030695, which is incorporated herein by reference in its entirety.

D. Preparation of compound 1, compound 2 or compound 3.

Compounds for use in the methods proposed herein can be prepared by methods known to one skilled in the art and by the following procedures similar to those described in the Examples section herein and usual modifications thereof. An exemplary reaction scheme for preparing the compounds is shown below in Scheme 1 for Compound 2.

Reaction of the intermediate methyl 2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxybenzoate with chiral tert-butyl-(4S)-4,5-diamino-5-oxopentanoate (also called HLGlu(OtBu)- NH ₂ ; reaction with HD-Glu(OtBu)-NH ₂ gives the opposite enantiomer), in the presence of a base (such as DIEA) leads to the formation of derivatized isoindoline, followed by deprotection of TBS using tetrabutylammonium fluoride. Reaction of the substituted isoindoline with 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile in the presence of a base (such as potassium carbonate) was followed by deprotection and formation of glutarimide, yielding the title compound 2. Compound 1 and Compound 3 can be prepared according to Scheme 1, but with the appropriate racemate or R-enantiomer starting material, respectively. The preparation of compound 1, compound 2 and compound 3 is also described in US application No. 16/030695, which is incorporated herein by reference in its entirety.

Scheme 1.

One skilled in the art will appreciate how to modify the procedures set forth in the illustrative diagrams and examples to obtain the desired products.

E. Second active agents.

In one embodiment, the second active agent used in the methods presented herein is a Bruton's tyrosine kinase (BTK) inhibitor. In one embodiment, the BTK inhibitor is ibrutinib, or acalabrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BTK inhibitor is ibrutinib or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BTK inhibitor is ibrutinib. In one embodiment, the BTK inhibitor is acalabrutinib. Ibrutinib has the chemical name 1-[(3R)-3-[4-amino-3-(4phenoxyphenyl)-III-pyrazolo[3,4^]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1 - it has the structure:

In one embodiment, the second active agent used in the methods presented herein is a mammalian target of rapamycin (mTOR) inhibitor. In one embodiment, the mTOR inhibitor is rapamycin or an analogue thereof (also called rapalog). In one embodiment, the mTOR inhibitor is everolimus or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the mTOR inhibitor is everolimus. Everolimus has the chemical name 40-O-(2-hydroxyethyl)rapamycin and has the structure:

In one embodiment, the second active agent used in the methods presented herein is a Moloney murine leukemia kinase proviral integration site inhibitor (PIM). In one embodiment, the PIM inhibitor is a pan-PIM inhibitor. In one embodiment, the PIM inhibitor is LGH-447, AZD1208, SGI-1776, or TP-3654, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the PIM inhibitor is LGH-447 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the PIM inhibitor is LGH-447. In one embodiment, the PIM inhibitor is a pharmaceutically acceptable salt of LGH-447. In one embodiment, the PIM inhibitor is the hydrochloride salt of LGH-447. In one embodiment, the hydrochloride salt of LGH-447 is a hydrochloride salt. In one embodiment, the hydrochloride salt of LGH-447 is a monohydrochloride salt. In one embodiment, the PIM inhibitor is AZD1208. In one embodiment, the PIM inhibitor is SGI-1776. In one embodiment, the PIM inhibitor is TP-3654. LGH-447 has the chemical name N-[4[(1R,3S,5S)-3-amino-5-methylcyclohexyl]-3-pyridinyl]-6-(2,6-difluorophenyl)-5-fluoro-2pyridinecarboxamide and has structure:

In one embodiment, the second active agent used in the methods presented herein is an inhibitor of the insulin-like growth factor 1 receptor (IGF-1R). In one embodiment, the IGF-1R inhibitor is linsitinib or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the IGF-1R inhibitor is linsitinib. Linzitinib has the chemical name cis-3-[8-amino-1-(2-phenyl-7-quinolinyl)imidazo[1,5-a]pyrazin-3-yl]-1-11 045949 methylcyclobutanol and has the structure:

In one embodiment, the second active agent used in the methods presented herein is an extracellular signal-regulated mitogen-activated kinase (MEK) inhibitor. In one embodiment, the MEK inhibitor is trametinib, trametinib dimethyl sulfoxide, cobimetinib, binimetinib, or selumetinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the MEK inhibitor is trametinib or trametinib dimethyl sulfoxide, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the MEK inhibitor is trametinib. In one embodiment, the MEK inhibitor is trametinib dimethyl sulfoxide. In one embodiment, the MEK inhibitor is cobimetinib. In one embodiment, the MEK inhibitor is binimetinib. In one embodiment, the MEK inhibitor is selumetinib. Trametinib dimethyl sulfoxide has the chemical name X-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4. 7trioxo11irido[4,3-с1]11irimidin-1(211)-yl]phenyl]-ap.etamide, compound with dimethyl sulfoxide (1:1). Trametinib dimethyl sulfoxide has the structure:

In one embodiment, the second active agent used in the methods presented herein is an inhibitor of exportin 1 (XPO1). In one embodiment, the XPO1 inhibitor is selinexor or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the XPO1 inhibitor is selinexor. Selinexor has the chemical name (2Z)-3-{3-[3,5bis(trifluoromethyl)phenyl]-III-1,2,4-triazol-1-yl}-N-(pyrazin-2-yl)prop-2 -enhydrazide and has the structure:

In one embodiment, the second active agent used in the methods presented herein is an inhibitor of telomere silencing interrupter 1 (DOT1L) protein. In one embodiment, the DOT1L inhibitor is SGC0946 or pinometostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the DOT1L inhibitor is SGC0946 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the DOT1L inhibitor is SGC0946. SGC0946 has the chemical name 5-bromo-7-[5-deoxy-5-[[3-[[[[4-(1,1-dimethylethyl)phenyl]amino]carbonyl]amino]propyl](1methylethyl)amino]- β-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine and has the structure:

- 12 045949

In one embodiment, the DOT1L inhibitor is pinometostat or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the DOT1L inhibitor is pinometostat. Pinometostat (also known as EPZ-5676) has the chemical name (2R,3R,4S,5R)-2-(6-αmino-9H-purin-9-yl)-5-((((1r,3S)-3 -(2-(5-(tert-butyl)-III-benzo^]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol and has the structure:

In one embodiment, the second active agent used in the methods presented herein is an enhancer of zeste homolog 2 (EZH2) inhibitor. In one embodiment, the EZH2 inhibitor is tazemetostat, 3-deazaneplanocin A (DZNep), EPZ005687, EI1, GSK126, UNC1999, CPI-1205, or sinefungin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the EZH2 inhibitor is tazemetostat or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the EZH2 inhibitor is tazemetostat. In one embodiment, the EZH2 inhibitor is 3-deazaneplanocin A. In one embodiment, the EZH2 inhibitor is EPZ005687. In one embodiment, the EZH2 inhibitor is EI1. In one embodiment, the EZH2 inhibitor is GSK126. In one embodiment, the EZH2 inhibitor is sinefungin. Tazemetostat (also known as EPZ-6438) has the chemical name N-[(1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-5-[ethyl(tetrahydro-2H-pyran4- yl)amino]-4-methyl-4'-(4-morpholinylmethyl)-[1,1'-biphenyl]-3-carboxamide and has the structure:

In one embodiment, the EZH2 inhibitor is UNC1999 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the EZH2 inhibitor is UNC1999. UNC1999 has the chemical name 1-isopropyl-6-(6-(4isopropylpiperazin-1-yl)pyridin-3-yl)-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3yl )methyl)-III-indazole-4-carboxamide and has the structure:

In one embodiment, the EZH2 inhibitor is CPI-1205 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the EZH2 inhibitor is CPI-1205. CPI-1205 has the chemical name (K.)^(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-( 2,2,2

- 13 045949 trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide and has the structure:

In one embodiment, the second active agent used in the methods presented herein is a Janus kinase 2 (JAK2) inhibitor. In one embodiment, the JAK2 inhibitor is fedratinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, momelotinib, or pacritinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the JAK2 inhibitor is fedratinib or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the JAK2 inhibitor is fedratinib. In one embodiment, the JAK2 inhibitor is ruxolitinib. In one embodiment, the JAK2 inhibitor is baricitinib. In one embodiment, the JAK2 inhibitor is gandotinib. In one embodiment, the JAK2 inhibitor is lestaurtinib. In one embodiment, the JAK2 inhibitor is momelotinib. In one embodiment, the JAK2 inhibitor is pacritinib. Fedratinib has the chemical name tert-butyl-3-[(5-methyl-2-{4-[2-(pyrrolidin-1-yl)ethoxy]anilino}pyrimidin-4yl)amino]benzenesulfonamide and has the structure:

In one embodiment, the second active agent used in the methods presented herein is a bromodomain 4 (BRD4) inhibitor. In one embodiment, the BRD4 inhibitor is JQ1 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BRD4 inhibitor is JQ1. JQ1 has the chemical name ^)-tert-butyl-2-(4-(4-chlorophenyl)-2,3,9trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3 -a][1,4]diazepin-6-yl)acetate and has the structure:

In one embodiment, the second active agent used in the methods presented herein is a Polo-like kinase 1 (PLK1) inhibitor. In one embodiment, the PLK1 inhibitor is BI2536 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the PLK1 inhibitor is BI2536. BI2536 has the chemical name (K)-4((8-cyclopentyl-7ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-I-(1 -methylpiperidin-4yl)benzamide and has the structure:

In one embodiment, the second active agent used in the methods presented herein is a serine/threonine protein kinase (NEK2) inhibitor. In one

- 14 045949 In an embodiment, the NEK2 inhibitor is JH295 or a tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, the NEK2 inhibitor is JH295. JH295 has the chemical name ^)-N-(3-((2-ethyl-4-methyl-N-imidazol-5-yl)methylene)-2oxoindolin-5-yl)propiolamide and has the structure:

In one embodiment, the second active agent used in the methods presented herein is an Aurora kinase B (AURKB) inhibitor. In one embodiment, the AURKB inhibitor is barasertib (also known as AZD1152) or AZD1152-HQPA, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the AURKB inhibitor is barasertib. In one embodiment, the AURKB inhibitor is AZD1152-HQPA. AZD1152-HQPA has the chemical name 2-(3((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)quinazolin-4-yl)amino)-N-pyrazol-5-yl)-N-(3fluorophenyl )acetamide and has the structure:

Barasertib is a dihydrogen phosphate prodrug of AZD1152-HQPA and has the structure:

In one embodiment, the second active agent used in the methods presented herein is a survivin inhibitor (also called baculovirus inhibitor of apoptosis repeat 5, or BIRC5). In one embodiment, the BIRC5 inhibitor is YM155 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BIRC5 inhibitor is YM155. YM155 has the chemical name 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-N-naphtho[2,3d]imidazol-3- ia bromide and has the structure:

In one embodiment, the second active agent used in the methods presented herein is a bromodomain and extra-terminal motif (BET) protein inhibitor. In one embodiment, the BET inhibitor is birabresib, or compound C, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof.

In one embodiment, the BET inhibitor is birabresib or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BET inhibitor is birabresib. Birabresib (also known as OTX015 or MK-8628) has the chemical name (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6Hthieno[3,2-f][1,2. 4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-hydroxyphenyl)acetamide and has the structure:

- 15 045949

In one embodiment, the BET inhibitor is Compound C or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BET inhibitor is Compound C. Compound C has the chemical name 4-[2(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one and has the structure:

In one embodiment, the second active agent used in the methods presented herein is a DNA methyltransferase inhibitor. In one embodiment, the DNA methyltransferase inhibitor is azacitidine or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the hypomethylating agent is azacitidine. Azacitidine (also known as azacitidine or 5-azacytidine) has the chemical name 4-amino-1-β-O-ribofuranosyl1,3,5-triazin-2(III)-one and has the structure:

F. Methods of treatment and prevention.

In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt in combination with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (eg, ibrutinib), mTOR inhibitor (eg, everolimus), PIM inhibitor (eg, LGH-447), IGF-1R inhibitor (eg, linsitinib), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg e.g. selinexor), DOT1L inhibitor (e.g. SGC0946 or pinometostat), EZH2 inhibitor (e.g. tazemetostat, UNC1999 or CPI-1205), JAK2 inhibitor (e.g. fedratinib), BRD4 inhibitor (e.g. JQ1), PLK1 inhibitor (e.g. BI2536), NEK2 inhibitor (eg, JH295), AURKB inhibitor (eg, AZD1152), BIRC5 inhibitor (eg, YM155), BET inhibitor (eg, Compound C), or DNA methyltransferase inhibitor (eg, azacitidine). In one embodiment, provided herein is Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, for use in a method of treating multiple myeloma, wherein the method includes administering to a patient a therapeutically effective amount of said compound in combination with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (eg, ibrutinib), an mTOR inhibitor (eg, everolimus), a PIM inhibitor (eg, LGH-447), an IGF-1R inhibitor (eg, linsitinib), a MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999, or CPI-1205), JAK2 inhibitor (eg, fedratinib), BRD4 inhibitor (eg, JQ1) , PLK1 inhibitor (eg, BI2536), NEK2 inhibitor (eg, JH295), AURKB inhibitor (eg, AZD1152), BIRC5 inhibitor (eg, YM155), BET inhibitor (eg, Compound C), or DNA methyltransferase inhibitor (eg, azacitidine ).

In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (eg ibrutinib), mTOR inhibitor (eg everolimus), PIM inhibitor (eg

- 16 045949

LGH-447), IGF-1R inhibitor (eg, linsitinib), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999 or CPI-1205), JAK2 inhibitor (eg, fedratinib), BRD4 inhibitor (eg, JQ1), PLK1 inhibitor (eg, BI2536), NEK2 inhibitor (eg, JH295), AURKB inhibitor (eg, AZD1152), BIRC5 inhibitor (eg, YM155), a BET inhibitor (eg Compound C) or a DNA methyltransferase inhibitor (eg azacitidine). In one embodiment, provided herein is Compound 2, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, for use in a method of treating multiple myeloma, wherein the method includes administering to a patient a therapeutically effective amount of said compound in combination with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (eg, ibrutinib), mTOR inhibitor (eg, everolimus), PIM inhibitor (eg, LGH-447), IGF-1R inhibitor (eg, linsitinib), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg selinexor), DOT1L inhibitor (eg SGC0946 or pinometostat), EZH2 inhibitor (eg tazemetostat, UNC1999 or CPI-1205), JAK2 inhibitor (eg fedratinib), BRD4 inhibitor (eg JQ1), PLK1 inhibitor (eg , BI2536), NEK2 inhibitor (eg, JH295), AURKB inhibitor (eg, AZD1152), BIRC5 inhibitor (eg, YM155), BET inhibitor (eg, Compound C), or DNA methyltransferase inhibitor (eg, azacitidine).

In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 3 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (eg, ibrutinib), mTOR inhibitor (eg, everolimus), PIM inhibitor (eg, LGH-447), IGF-1R inhibitor (eg, linsitinib), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999, or CPI-1205), JAK2 inhibitor (eg, fedratinib), BRD4 inhibitor (eg, JQ1), PLK1 inhibitor (eg, BI2536), NEK2 inhibitor (eg, JH295), an AURKB inhibitor (eg, AZD1152), a BIRC5 inhibitor (eg, YM155), a BET inhibitor (eg, Compound C), or a DNA methyltransferase inhibitor (eg, azacitidine). In one embodiment, provided herein is Compound 3, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, for use in a method of treating multiple myeloma, wherein the method comprises administering to a patient said compound in combination with a second active agent, wherein the second active agent is one or more of BTK inhibitor (eg, ibrutinib), mTOR inhibitor (eg, everolimus), PIM inhibitor (eg, LGH-447), IGF-1R inhibitor (eg, linsitinib), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999, or CPI-1205), JAK2 inhibitor (eg, fedratinib), BRD4 inhibitor (eg, JQ1), PLK1 inhibitor (eg, BI2536) , NEK2 inhibitor (eg, JH295), AURKB inhibitor (eg, AZD1152), BIRC5 inhibitor (eg, YM155), BET inhibitor (eg, Compound C), or DNA methyltransferase inhibitor (eg, azacitidine).

In one embodiment, provided herein is a method of preventing multiple myeloma, which includes administering to a patient a compound provided herein, for example, Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combinations with a second active agent, where the second active agent is one or more of a BTK inhibitor (eg, ibrutinib), an mTOR inhibitor (eg, everolimus), a PIM inhibitor (eg, LGH447), an IGF-1R inhibitor (eg, linsitinib), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999, or CPI-1205), JAK2 inhibitor (eg, fedratinib), BRD4 inhibitor (eg, JQ1), PLK1 inhibitor (eg, BI2536), NEK2 inhibitor (eg, JH295), AURKB inhibitor (eg, AZD1152), BIRC5 inhibitor (eg, YM155), BET inhibitor (eg, Compound C), or DNA inhibitor methyltransferases (for example, azacitidine). In one embodiment, provided herein is a compound, such as Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, for use in a method of preventing multiple myeloma, wherein the method includes administering said compound to a patient at combinations with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (e.g., ibrutinib), an mTOR inhibitor (e.g., everolimus), a PIM inhibitor (e.g., LGH-447), an IGF-1R inhibitor (e.g., linsitinib ), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999 or CPI-1205), JAK2 inhibitor (eg, fedratinib), BRD4 inhibitor (eg JQ1), PLK1 inhibitor (eg BI2536), NEK2 inhibitor (eg JH295), AURKB inhibitor (on

- 17 045949 example, AZD1152), a BIRC5 inhibitor (eg YM155), a BET inhibitor (eg Compound C) or a DNA methyltransferase inhibitor (eg azacitidine).

In another embodiment, provided herein is a method of controlling multiple myeloma, which includes administering to a patient a compound provided herein, for example, Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combinations with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (e.g., ibrutinib), an mTOR inhibitor (e.g., everolimus), a PIM inhibitor (e.g., LGH-447), an IGF-1R inhibitor (e.g., linsitinib ), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999 or CPI-1205), JAK2 inhibitor (eg, fedratinib), BRD4 inhibitor (eg, JQ1), PLK1 inhibitor (eg, BI2536), NEK2 inhibitor (eg, JH295), AURKB inhibitor (eg, AZD1152), BIRC5 inhibitor (eg, YM155), BET inhibitor (eg, Compound C), or DNA methyltransferases (for example, azacitidine). In one embodiment, provided herein is a compound, such as Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, for use in a method of controlling multiple myeloma, wherein the method includes administering said compound to a patient at combinations with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (e.g., ibrutinib), an mTOR inhibitor (e.g., everolimus), a PIM inhibitor (e.g., LGH-447), an IGF-1R inhibitor (e.g., linsitinib ), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999 or CPI-1205), JAK2 inhibitor (eg, fedratinib), BRD4 inhibitor (eg, JQ1), PLK1 inhibitor (eg, BI2536), NEK2 inhibitor (eg, JH295), AURKB inhibitor (eg, AZD1152), BIRC5 inhibitor (eg, YM155), BET inhibitor (eg, Compound C), or DNA methyltransferases (for example, azacitidine).

In one embodiment, this document also provides methods for inducing a therapeutic response assessed using the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie BGM, Harousseau J-L, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006;(10)10:1-7) to a patient, which involve administering to a patient with multiple myeloma an effective amount of a compound provided herein, for example, Compound 1, Compound 2, or Compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, isotopologue, or pharmaceutically acceptable salt in combination with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (eg, ibrutinib), an mTOR inhibitor (eg, everolimus), a PIM inhibitor (eg, LGH447), an IGF inhibitor -1R (eg, linsitinib), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999, or CPI-1205), JAK2 inhibitor (eg fedratinib), BRD4 inhibitor (eg JQ1), PLK1 inhibitor (eg BI2536), NEK2 inhibitor (eg JH295), AURKB inhibitor (eg AZD1152), BIRC5 inhibitor (eg YM155), BET inhibitor (eg , compound C) or a DNA methyltransferase inhibitor (eg, azacitidine).

In another embodiment, provided herein are methods of achieving a stringent complete response, a complete response, or a very good partial response, as defined by the International Uniform Response Criteria for Multiple Myeloma (IURC) in a patient, which comprises administering to the multiple myeloma patient an effective amount of a compound provided in herein, for example, Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (e.g., ibrutinib), mTOR inhibitor (eg, everolimus), PIM inhibitor (eg, LGH-447), IGF-1R inhibitor (eg, linsitinib), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg e.g., SGC0946 or pinometostat), EZH2 inhibitor (e.g., tazemetostat, UNC1999, or CPI-1205), JAK2 inhibitor (e.g., fedratinib), BRD4 inhibitor (e.g., JQ1), PLK1 inhibitor (e.g., BI2536), NEK2 inhibitor (e.g., JH295), an AURKB inhibitor (eg, AZD1152), a BIRC5 inhibitor (eg, YM155), a BET inhibitor (eg, Compound C), or a DNA methyltransferase inhibitor (eg, azacitidine).

In another embodiment, provided herein are methods of achieving an increase in overall survival, progression-free survival, event-free survival, time to disease progression, or disease-free survival of a patient, which comprises administering to a patient with multiple myeloma an effective amount of a compound provided herein, for example , compound 1, compound 2 or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is

- 18 045949 one or more of a BTK inhibitor (eg ibrutinib), mTOR inhibitor (eg everolimus), PIM inhibitor (eg LGH-447), IGF-1R inhibitor (eg linsitinib), MEK inhibitor (eg trametinib) , XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999, or CPI-1205), JAK2 inhibitor (eg, fedratinib), BRD4 inhibitor (eg, JQ1), inhibitor PLK1 (eg, BI2536), NEK2 inhibitor (eg, JH295), AURKB inhibitor (eg, AZD1152), BIRC5 inhibitor (eg, YM155), BET inhibitor (eg, compound C), or DNA methyltransferase inhibitor (eg, azacitidine).

In another embodiment, provided herein are methods of achieving an increase in overall survival of a patient, which comprise administering to a patient with multiple myeloma an effective amount of a compound provided herein, for example, Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer thereof , an isotopologue, or a pharmaceutically acceptable salt in combination with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (e.g., ibrutinib), an mTOR inhibitor (e.g., everolimus), a PIM inhibitor (e.g., LGH-447), an IGF-1R (eg, linsitinib), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999, or CPI-1205), inhibitor JAK2 inhibitor (eg fedratinib), BRD4 inhibitor (eg JQ1), PLK1 inhibitor (eg BI2536), NEK2 inhibitor (eg JH295), AURKB inhibitor (eg AZD1152), BIRC5 inhibitor (eg YM155), BET inhibitor (eg eg Compound C) or a DNA methyltransferase inhibitor (eg azacitidine).

In another embodiment, provided herein are methods of achieving increased progression-free survival of a patient, which comprise administering to a patient with multiple myeloma an effective amount of a compound provided herein, for example, Compound 1, Compound 2, or Compound 3, or an enantiomer thereof, a mixture of enantiomers , tautomer, isotopologue, or pharmaceutically acceptable salt in combination with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (e.g., ibrutinib), an mTOR inhibitor (e.g., everolimus), a PIM inhibitor (e.g., LGH-447) , IGF-1R inhibitor (eg, linsitinib), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999, or CPI-1205) , JAK2 inhibitor (eg, fedratinib), BRD4 inhibitor (eg, JQ1), PLK1 inhibitor (eg, BI2536), NEK2 inhibitor (eg, JH295), AURKB inhibitor (eg, AZD1152), BIRC5 inhibitor (eg, YM155), inhibitor BET (eg Compound C) or DNA methyltransferase inhibitor (eg azacitidine).

In another embodiment, provided herein are methods of achieving increased event-free survival of a patient which comprise administering to a patient with multiple myeloma an effective amount of a compound provided herein, e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer thereof , an isotopologue, or a pharmaceutically acceptable salt in combination with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (e.g., ibrutinib), an mTOR inhibitor (e.g., everolimus), a PIM inhibitor (e.g., LGH-447), an IGF-1R (eg, linsitinib), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999, or CPI-1205), inhibitor JAK2 inhibitor (eg fedratinib), BRD4 inhibitor (eg JQ1), PLK1 inhibitor (eg BI2536), NEK2 inhibitor (eg JH295), AURKB inhibitor (eg AZD1152), BIRC5 inhibitor (eg YM155), BET inhibitor (eg eg Compound C) or a DNA methyltransferase inhibitor (eg azacitidine).

In another embodiment, provided herein are methods of achieving an increase in time to disease progression in a patient, which comprise administering to a patient with multiple myeloma an effective amount of a compound provided herein, for example, Compound 1, Compound 2, or Compound 3, or an enantiomer thereof, a mixture an enantiomer, tautomer, isotopologue, or pharmaceutically acceptable salt in combination with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (e.g., ibrutinib), an mTOR inhibitor (e.g., everolimus), a PIM inhibitor (e.g., LGH-447 ), IGF-1R inhibitor (eg, linsitinib), MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999, or CPI-1205 ), JAK2 inhibitor (eg fedratinib), BRD4 inhibitor (eg JQ1), PLK1 inhibitor (eg BI2536), NEK2 inhibitor (eg JH295), AURKB inhibitor (eg AZD1152), BIRC5 inhibitor (eg YM155), a BET inhibitor (eg Compound C) or a DNA methyltransferase inhibitor (eg azacitidine).

In another embodiment, provided herein are methods of achieving increased disease-free survival of a patient, which include administering to the patient a multi

- 19 045949 with female myeloma an effective amount of a compound provided herein, for example, compound 1, compound 2 or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is one or more of a BTK inhibitor (eg, ibrutinib), an mTOR inhibitor (eg, everolimus), a PIM inhibitor (eg, LGH-447), an IGF-1R inhibitor (eg, linsitinib), a MEK inhibitor (eg, trametinib), XPO1 inhibitor (eg, selinexor), DOT1L inhibitor (eg, SGC0946 or pinometostat), EZH2 inhibitor (eg, tazemetostat, UNC1999, or CPI-1205), JAK2 inhibitor (eg, fedratinib), BRD4 inhibitor (eg, JQ1), PLK1 inhibitor (eg, BI2536), NEK2 inhibitor (eg, JH295), AURKB inhibitor (eg, AZD1152), BIRC5 inhibitor (eg, YM155), BET inhibitor (eg, Compound C), or DNA methyltransferase inhibitor (eg, azacitidine).

In one embodiment, the second active agent used in the methods presented herein is a BTK inhibitor. In one embodiment, the BTK inhibitor is ibrutinib, or acalabrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BTK inhibitor is ibrutinib or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BTK inhibitor is ibrutinib. In one embodiment, the BTK inhibitor is acalabrutinib. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is ibrutinib or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is ibrutinib. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is an mTOR inhibitor. In one embodiment, the mTOR inhibitor is rapamycin or an analogue thereof (also called rapalog). In one embodiment, the mTOR inhibitor is everolimus or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the mTOR inhibitor is everolimus. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is everolimus or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is everolimus. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is a PIM inhibitor. In one embodiment, the PIM inhibitor is a pan-PIM inhibitor. In one embodiment, the PIM inhibitor is LGH-447, AZD1208, SGI-1776, or TP-3654, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the PIM inhibitor is LGH-447 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the PIM inhibitor is LGH-447. In one embodiment, the PIM inhibitor is a pharmaceutically acceptable salt of LGH-447. In one embodiment, the PIM inhibitor is the hydrochloride salt of LGH-447. In one embodiment, the hydrochloride salt of LGH-447 is a hydrochloride salt. In one embodiment, the hydrochloride salt of LGH-447 is a monohydrochloride salt. In one embodiment, the PIM inhibitor is AZD1208. In one embodiment, the PIM inhibitor is SGI-1776. In one embodiment, the PIM inhibitor is TP-3654. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharmaceutically acceptable salt in combination

- 20 045949 with a second active agent, where the second active agent is LGH-447 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue or pharmaceutically acceptable salt. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is LGH-447. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is an IGF-1R inhibitor. In one embodiment, the IGF-1R inhibitor is linsitinib or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the IGF-1R inhibitor is linsitinib. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is linsitinib or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is linsitinib. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is a MEK inhibitor. In one embodiment, the MEK inhibitor is trametinib, trametinib dimethyl sulfoxide, cobimetinib, binimetinib, or selumetinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the MEK inhibitor is trametinib or trametinib dimethyl sulfoxide, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the MEK inhibitor is trametinib. In one embodiment, the MEK inhibitor is trametinib dimethyl sulfoxide. In one embodiment, the MEK inhibitor is cobimetinib. In one embodiment, the MEK inhibitor is binimetinib. In one embodiment, the MEK inhibitor is selumetinib. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is trametinib or trametinib dimethyl sulfoxide, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is trametinib. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is trametinib dimethyl sulfoxide. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is an XPO1 inhibitor. In one embodiment, the XPO1 inhibitor is selinexor or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the XPO1 inhibitor is selinexor. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is selinexor or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is selinexor. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

- 21 045949

In one embodiment, the second active agent used in the methods presented herein is a DOT1L inhibitor. In one embodiment, the DOT1L inhibitor is SGC0946 or pinometostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the DOT1L inhibitor is SGC0946 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the DOT1L inhibitor is SGC0946. In one embodiment, the DOT1L inhibitor is pinometostat or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the DOT1L inhibitor is pinometostat. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is SGC0946 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is SGC0946. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is pinometostat or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is pinometostat. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is an EZH2 inhibitor. In one embodiment, the EZH2 inhibitor is tazemetostat, 3-deazaneplanocin A (DZNep), EPZ005687, EI1, GSK126, UNC1999, CPI-1205, or sinefungin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the EZH2 inhibitor is tazemetostat or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the EZH2 inhibitor is tazemetostat. In one embodiment, the EZH2 inhibitor is 3-deazaneplanocin A. In one embodiment, the EZH2 inhibitor is EPZ005687. In one embodiment, the EZH2 inhibitor is EI1. In one embodiment, the EZH2 inhibitor is GSK126. In one embodiment, the EZH2 inhibitor is UNC1999 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the EZH2 inhibitor is UNC1999. In one embodiment, the EZH2 inhibitor is CPI-1205 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the EZH2 inhibitor is CPI-1205. In one embodiment, the EZH2 inhibitor is sinefungin. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is tazemetostat or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is tazemetostat. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is UNC1999 or a tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is UNC1999. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiome thereof

- 22 045949 pa, a mixture of enantiomers, a tautomer, an isotopologue or a pharmaceutically acceptable salt in combination with a second active agent, where the second active agent is CPI-1205 or a stereoisomer, a mixture of stereoisomers, a tautomer, an isotopologue or a pharmaceutically acceptable salt. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is CPI-1205. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is a JAK2 inhibitor. In one embodiment, the JAK2 inhibitor is fedratinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, momelotinib, or pacritinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the JAK2 inhibitor is fedratinib or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the JAK2 inhibitor is fedratinib. In one embodiment, the JAK2 inhibitor is ruxolitinib. In one embodiment, the JAK2 inhibitor is baricitinib. In one embodiment, the JAK2 inhibitor is gandotinib. In one embodiment, the JAK2 inhibitor is lestaurtinib. In one embodiment, the JAK2 inhibitor is momelotinib. In one embodiment, the JAK2 inhibitor is pacritinib. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is fedratinib or a tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is fedratinib. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is a BRD4 inhibitor. In one embodiment, the BRD4 inhibitor is JQ1 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BRD4 inhibitor is JQ1. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is JQ1 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is JQ1. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is a PLK1 inhibitor. In one embodiment, the PLK1 inhibitor is BI2536 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the PLK1 inhibitor is BI2536. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is BI2536 or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is BI2536. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is an NEK2 inhibitor. In one embodiment, the NEK2 inhibitor is JH295 or a tautomer, isotopologue, or pharmaceutically acceptable

- 23 045949 salt. In one embodiment, the NEK2 inhibitor is JH295. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is JH295 or a tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is JH295. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is an AURKB inhibitor. In one embodiment, the AURKB inhibitor is barasertib (AZD1152) or AZD1152-HQPA, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the AURKB inhibitor is barasertib. In one embodiment, the AURKB inhibitor is AZD1152-HQPA. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is barasertib or AZD1152-HQPA or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is barasertib. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is AZD1152-HQPA. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is a BIRC5 inhibitor. In one embodiment, the BIRC5 inhibitor is YM155 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BIRC5 inhibitor is YM155. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is YM155 or a tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is YM155. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is a BET inhibitor. In one embodiment, the BET inhibitor is birabresib, or compound C, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BET inhibitor is birabresib or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BET inhibitor is birabresib. In one embodiment, the BET inhibitor is Compound C or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BET inhibitor is Compound C. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is birabresib or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or a pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is birabresib. In one embodiment, provided herein is a method of treating multiple myeloma, which includes administering

- 24 045949 to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt in combination with a second active agent, wherein the second active agent is Compound C or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is Compound C. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

In one embodiment, the second active agent used in the methods presented herein is a DNA methyltransferase inhibitor. In one embodiment, the DNA methyltransferase inhibitor is azacitidine or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the DNA methyltransferase inhibitor is azacitidine. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent, wherein the second active agent is azacitidine or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating multiple myeloma that includes administering to a patient a therapeutically effective amount of Compound 2 in combination with a second active agent, wherein the second active agent is azacitidine. In one embodiment, the method further includes administering dexamethasone to the patient. In one embodiment, the method further includes administering bortezomib to the patient.

This document also provides treatments for patients who have previously been treated for multiple myeloma but do not respond to standard treatments, as well as for patients who have not previously been treated. It also covers treatments for patients who have undergone surgery to attempt treatment for multiple myeloma, as well as those who have not. This document also presents treatments for patients who have previously undergone transplant therapy, as well as those who have not.

The methods provided herein include the treatment of multiple myeloma that is relapsed, refractory or refractory. Methods provided herein include the prevention of multiple myeloma that is relapsed, refractory or resistant. The methods provided herein include the treatment of multiple myeloma that is relapsed, refractory or refractory. In some such embodiments, the myeloma is primary, secondary, tertiary, quadruple, or quintuple multiple myeloma. In one embodiment, the methods presented herein reduce, maintain, or eliminate minimal residual disease (MRD). In one embodiment, provided herein is a method of increasing the rate and/or duration of MRD negativity in patients with multiple myeloma, comprising administering a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent presented in this document. In one embodiment, provided herein is a method of increasing the rate and/or duration of MRD negativity in patients with multiple myeloma, comprising administering a therapeutically effective amount of compound 2 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein . In one embodiment, the methods provided herein include the treatment, prevention, or management of various types of multiple myeloma, such as monoclonal gammopathy of undetermined significance (MGUS), low-, intermediate-, and high-risk multiple myeloma, newly diagnosed multiple myeloma (including newly diagnosed multiple myeloma). low-intermediate and high-risk myeloma), transplant-eligible and transplant-ineligible multiple myeloma, smoldering (smoldering) multiple myeloma (including low-, intermediate- and high-risk smoldering multiple myeloma), active multiple myeloma, solitary plasmacytoma, extramedullary plasmacytoma, plasma cell leukemia , multiple myeloma of the central nervous system, light chain myeloma, non-secretory myeloma, immunoglobulin D myeloma and immunoglobulin E myeloma by administering a therapeutically effective amount of a compound provided herein. In another embodiment, the methods provided herein include the treatment, prevention, or management of multiple myeloma characterized by genetic abnormalities such as cyclin D translocations (e.g., t(11;14)(q13;q32); t(6;14) (p21; 32); t (12; 14) (p13; q32); or t (6; 20);); MMSET translocations (e.g. t(4;14)(p16;q32)); MAF translocations (e.g. t(14;16)(q32;q32); t(20;22); t(16;22)(q11;q13); or t(14;20)(q32;q11)); or other chromosomal

- 25 045949 factors (eg, deletion of 17p13 or chromosome 13; del (17/17p), non-hyperdiploidy and amplification (1q)) by administering a therapeutically effective amount of a compound provided herein. In one embodiment, multiple myeloma is characterized according to the International Multiple Myeloma Definition System (ISS). In one embodiment, the multiple myeloma is stage I multiple myeloma, which is characterized by ISS (eg, serum β2-microglobulin level <3.5 mg/L and serum albumin >3.5 g/dL). In one embodiment, the multiple myeloma is stage III multiple myeloma that is characterized by ISS (eg, serum β2-microglobulin level >5.4 mg/L). In one embodiment, the multiple myeloma is stage II multiple myeloma, as characterized by ISS (eg, not stage I or III).

In one embodiment, the methods include administering a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein. In another embodiment, the methods comprise administering a therapeutically effective amount of Compound 2, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein. In another embodiment, the methods comprise administering a therapeutically effective amount of Compound 3 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein.

In some embodiments, the methods include administering a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein as induction therapy. In another embodiment, the methods comprise administering a therapeutically effective amount of Compound 2 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein as induction therapy. In another embodiment, the methods comprise administering a therapeutically effective amount of Compound 3 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein as induction therapy. In some embodiments, the methods include administering a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein as consolidation therapy. In another embodiment, the methods comprise administering a therapeutically effective amount of Compound 2 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein as consolidation therapy. In another embodiment, the methods comprise administering a therapeutically effective amount of Compound 3 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein as consolidation therapy. In some embodiments, the methods include administering a therapeutically effective amount of Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein as maintenance therapy. In another embodiment, the methods comprise administering a therapeutically effective amount of Compound 2 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein as maintenance therapy. In another embodiment, the methods comprise administering a therapeutically effective amount of Compound 3 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein as maintenance therapy.

In one specific embodiment of the methods described herein, multiple myeloma is a plasma cell leukemia.

In one embodiment of the methods described herein, the multiple myeloma is high-risk multiple myeloma. In some such embodiments, the high-risk multiple myeloma is relapsed or refractory. In one embodiment, high-risk multiple myeloma is multiple myeloma that recurs within 12 months of initial treatment. In yet another embodiment, high-risk multiple myeloma is multiple myeloma that is characterized by genetic abnormalities, such as one or more of del(17/17p) and t(14;16)(q32;q32). In some such embodiments, the high-risk multiple myeloma has relapsed or is resistant to one, two, or three previous courses of treatment.

In one embodiment, multiple myeloma is characterized by a p53 mutation. In one embodiment, the p53 mutation is a Q331 mutation. In one embodiment, muta

- 26 045949 p53 mutation is the R273H mutation. In one embodiment, the p53 mutation is a K132 mutation. In one embodiment, the p53 mutation is a K132N mutation. In one embodiment, the p53 mutation is an R337 mutation. In one embodiment, the p53 mutation is the R337L mutation. In one embodiment, the p53 mutation is a W146 mutation. In one embodiment, the p53 mutation is an S261 mutation. In one embodiment, the p53 mutation is an S261T mutation. In one embodiment, the p53 mutation is an E286 mutation. In one embodiment, the p53 mutation is an E286K mutation. In one embodiment, the p53 mutation is an R175 mutation. In one embodiment, the p53 mutation is the R175H mutation. In one embodiment, the p53 mutation is an E258 mutation. In one embodiment, the p53 mutation is an E258K mutation. In one embodiment, the p53 mutation is an A161 mutation. In one embodiment, the p53 mutation is an A161T mutation.

In one embodiment, multiple myeloma is characterized by a homozygous deletion of p53. In one embodiment, multiple myeloma is characterized by a homozygous deletion of wild-type p53.

In one embodiment, multiple myeloma is characterized by wild-type p53.

In one embodiment, multiple myeloma is characterized by activation of one or more oncogenic factors. In one embodiment, the one or more oncogenic drivers are selected from the group consisting of C-MAF, MAFB, FGFR3, MMset, Cyclin D1, and Cyclin D. In one embodiment, multiple myeloma is characterized by activation of C-MAF. In one embodiment, multiple myeloma is characterized by activation of MAFB. In one embodiment, multiple myeloma is characterized by activation of FGFR3 and MMset. In one embodiment, multiple myeloma is characterized by activation of C-MAF, FGFR3, and MMset. In one embodiment, multiple myeloma is characterized by activation of cyclin D1. In one embodiment, multiple myeloma is characterized by activation of MAFB and cyclin D1. In one embodiment, multiple myeloma is characterized by activation of cyclin D.

In one embodiment, multiple myeloma is characterized by one or more chromosomal translocations. In one embodiment, the chromosomal translocation is t(14;16). In one embodiment, the chromosomal translocation is t(14;20). In one embodiment, the chromosomal translocation is t(4;14). In one embodiment, the chromosomal translocations are t(4;14) and t(14;16). In one embodiment, the chromosomal translocation is t(11;14). In one embodiment, the chromosomal translocation is t(6;20). In one embodiment, the chromosomal translocation is t(20;22). In one embodiment, the chromosomal translocations are t(6;20) and t(20;22). In one embodiment, the chromosomal translocation is t(16;22). In one embodiment, the chromosomal translocations are t(14;16) and t(16;22). In one embodiment, the chromosomal translocations are t(14;20) and t(11;14).

In one embodiment, multiple myeloma is characterized by a p53 Q331 mutation, C-MAF activation, and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma is characterized by a homozygous p53 deletion, C-MAF activation, and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma is characterized by a p53 K132N mutation, MAFB activation, and a chromosomal translocation at t(14;20). In one embodiment, multiple myeloma is characterized by wild-type p53, FGFR3 and MMset activation, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by wild-type p53, C-MAF activation, and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma is characterized by homozygous deletion of p53, activation of FGFR3, MMset and C-MAF, and chromosomal translocations at t(4;14) and t(14;16). In one embodiment, multiple myeloma is characterized by a homozygous p53 deletion, cyclin D1 activation, and a chromosomal translocation at t(11;14). In one embodiment, multiple myeloma is characterized by a p53 R337L mutation, cyclin D1 activation, and a chromosomal translocation at t(11;14). In one embodiment, multiple myeloma is characterized by a p53 W146 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by the S261T p53 mutation, MAFB activation, and chromosomal translocations at t(6;20) and t(20;22). In one embodiment, multiple myeloma is characterized by a p53 E286K mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by a p53 R175H mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by a p53 E258K mutation, CMAF activation, and chromosomal translocations at t(14;16) and t(16;22). In one embodiment, multiple myeloma is characterized by wild-type p53, activation of MAFB and cyclin D1, and chromosomal translocations at t(14;20) and t(11;14). In one embodiment, multiple myeloma

- 27 045949 is characterized by the A161T p53 mutation, activation of cyclin D and chromosomal translocation at t(ii;i4).

In some embodiments of the methods described herein, the multiple myeloma is a newly diagnosed multiple myeloma suitable for transplantation. In another embodiment, the multiple myeloma is a newly diagnosed multiple myeloma ineligible for transplantation.

In yet other embodiments, multiple myeloma is characterized by early progression (eg, less than 12 months) after initial treatment. In other embodiments, multiple myeloma is characterized by early progression (eg, less than i2 months) after autologous stem cell transplantation. In another embodiment, the multiple myeloma is resistant to lenalidomide. In another embodiment, multiple myeloma is refractory to pomalidomide. In some such embodiments, the multiple myeloma is assumed to be resistant to pomalidomide (eg, based on molecular characteristics). In another embodiment, the multiple myeloma is recurrent or resistant to 3 or more treatments and has been exposed to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprosomib, or marizomib) and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide), or doubly resistant to a proteasome inhibitor and an immunomodulatory compound. In still other embodiments, the multiple myeloma is relapsed or refractory to 3 or more prior treatments, including, for example, a CD38 monoclonal antibody (CD38 mAb, e.g., daratumumab or isatuximab), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or marizomib) and an immunomodulatory compound (eg, thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide) or dual resistance to a proteasome inhibitor or immunomodulatory compound and a CD38 mAb. In other embodiments, the multiple myeloma is triple refractory, e.g., the multiple myeloma is resistant to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprosomib, or marizomib), an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide), and another active agent as described herein.

In some embodiments, provided herein are methods of treating, preventing, and/or controlling multiple myeloma, including relapsed/refractory multiple myeloma in patients with renal impairment or symptom thereof, comprising administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharmaceutically acceptable salt in combination with a second active agent provided herein in a patient with relapsed/refractory multiple myeloma with impaired renal function.

In some embodiments, provided herein are methods of treating, preventing and/or controlling multiple myeloma, including relapsed or refractory multiple myeloma in frail patients or a symptom thereof, comprising administering a therapeutically effective amount of compound i, compound 2 or compound 3 or an enantiomer thereof, a mixture enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt in combination with a second active agent provided herein in a frail patient with multiple myeloma. In some such embodiments, the frail patient is characterized by being unsuitable for induction therapy or intolerant to dexamethasone treatment. In some such embodiments, the frail patient is elderly, such as over 65 years of age.

In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of compound i, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein, wherein the multiple myeloma is is a fourth-line relapsed/refractory multiple myeloma. In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 2, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein, wherein the multiple myeloma is is a fourth-line relapsed/refractory multiple myeloma. In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 3, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein, wherein the multiple myeloma is is a fourth-line relapsed/refractory multiple myeloma.

In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutic

- 28 045949 highly effective amount of compound 1 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein as induction therapy, wherein multiple myeloma is newly diagnosed, transplantable multiple myeloma. In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 2, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein as induction therapy , wherein multiple myeloma is newly diagnosed, transplant-eligible multiple myeloma. In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 3 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein as induction therapy , wherein multiple myeloma is newly diagnosed, transplant-eligible multiple myeloma.

In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 1, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein as maintenance therapy after another therapy or transplantation, where multiple myeloma is newly diagnosed, transplant-eligible multiple myeloma before another therapy or transplantation. In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 2, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein as maintenance therapy after another therapy or transplantation, where multiple myeloma is newly diagnosed, transplant-eligible multiple myeloma before another therapy or transplantation. In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 3, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein as maintenance therapy after another therapy or transplantation, where multiple myeloma is newly diagnosed, transplant-eligible multiple myeloma before another therapy or transplantation.

In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 1, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein as maintenance therapy after other therapy or transplantation. In some embodiments, multiple myeloma is newly diagnosed multiple myeloma eligible for transplantation, prior to other therapy and/or transplantation. In some embodiments, the other pre-transplant therapy is treatment with chemotherapy or Compound 1, Compound 2, and Compound 3. In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 2 or a tautomer thereof , isotopologue or pharmaceutically acceptable salt in combination with a second active agent provided herein as maintenance therapy after other therapy or transplantation. In some embodiments, multiple myeloma is newly diagnosed multiple myeloma eligible for transplantation, prior to other therapy and/or transplantation. In some embodiments, the other pre-transplant therapy is treatment with chemotherapy or Compound 1, Compound 2, and Compound 3. In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 3 or a tautomer thereof , isotopologue or pharmaceutically acceptable salt in combination with a second active agent provided herein as maintenance therapy after other therapy or transplantation. In some embodiments, multiple myeloma is newly diagnosed multiple myeloma eligible for transplantation, prior to other therapy and/or transplantation. In some embodiments, the other pre-transplant therapy is treatment with chemotherapy or Compound 1, Compound 2, and Compound 3.

In certain embodiments, provided herein are methods of treatment,

- 29 045949 for the prevention or control of multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 1 or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided herein, wherein the multiple myeloma is a high-risk, relapsing multiple myeloma /refractory to one, two or three previous therapies. In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 2, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein, wherein the multiple myeloma is is a high-risk multiple myeloma relapsed/refractory to one, two or three previous therapies. In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 3, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein, wherein the multiple myeloma is is a high-risk multiple myeloma relapsed/refractory to one, two or three previous therapies.

In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 1, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein, wherein the multiple myeloma is a newly diagnosed, transplant-ineligible multiple myeloma. In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 2, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein, wherein the multiple myeloma is a newly diagnosed, transplant-ineligible multiple myeloma. In certain embodiments, provided herein are methods of treating, preventing, or controlling multiple myeloma, comprising administering to a patient a therapeutically effective amount of Compound 3, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein, wherein the multiple myeloma is a newly diagnosed, transplant-ineligible multiple myeloma.

In certain embodiments, the patient being treated with one of the methods presented herein has not been treated with multiple myeloma therapy prior to administration of Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt in combination with the second active agent provided herein. In certain embodiments, the patient being treated with one of the methods presented herein has been treated with multiple myeloma therapy prior to administration of Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof in combination with a second active agent provided for herein. In some embodiments, a patient being treated with one of the methods presented herein has developed drug resistance to therapy against multiple myeloma. In some such embodiments, the patient has developed resistance to one, two, or three multiple myeloma drugs, wherein the treatments are selected from an anti-CD38 monoclonal antibody (CD38 mAb, e.g., daratumumab or isatuximab), a proteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib or marizomib) and an immunomodulatory compound (eg thalidomide, lenalidomide, pomalidomide, iberdomide or avadomide).

The methods presented herein cover treatment of the patient regardless of the patient's age. In some embodiments, the subject is 18 years of age or older. In other embodiments, the subject is over 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years of age. In other embodiments, the subject is under 65 years of age. In other embodiments, the subject is over 65 years of age. In one embodiment, the subject is an elderly subject with multiple myeloma, such as a subject over 65 years of age. In one embodiment, the subject is an elderly subject with multiple myeloma, such as a subject over 75 years of age.

G. Dosing of Compound 1, Compound 2 or Compound 3.

In certain embodiments, the therapeutically or prophylactically effective amount of Compound 1, Compound 2, or Compound 3 is from about 0.01 to about 25 mg per day, from about 0.01 to about 10 mg per day, from about 0.01 to about 5 mg per day, about 0.01 to about 2 mg per day, about 0.01 to about 1 mg per day, about 0.01 to about 0.5 mg per day, about 0.01 to about 0 .25 mg per day, about 0.1 to about 25 mg per day, about 0.1 to about 10 mg per day, about 0.1 to about 5 mg per day

- 30 045949 day, from about 0.1 to about 2 mg per day, from about 0.1 to about 1 mg per day, from about 0.1 to about 0.5 mg per day, from about 0.1 to about 0.25 mg per day, about 0.5 to about 25 mg per day, about 0.5 to about 10 mg per day, about 0.5 to about 5 mg per day, about 0.5 to about 2 mg per day, about 0.5 to about 1 mg per day, about 1 to about 25 mg per day, about 1 to about 10 mg per day, about 1 to about 5 mg per day, about 1 up to about 2.5 mg per day or from about 1 to about 2 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of Compound 1, Compound 2, or Compound 3 is from about 0.1 mg per day to about 0.4 mg per day.

In some embodiments, the therapeutically or prophylactically effective amount of Compound 1, Compound 2, or Compound 3 is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0 .7, about 0.8, about 0.9, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20 or about 25 mg per day. In some such embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, or about 0.7 mg per day.

In one embodiment, the recommended daily dosage range of Compound 1, Compound 2, or Compound 3 for the conditions described herein is in the range of about 0.1 mg to about 25 mg per day, preferably administered as a single dose once daily or in divided doses throughout the day. In other embodiments, the dosage is from about 0.1 to about 10 mg per day. Specific daily doses include 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 mg per day. More specific daily doses include 0.1, 0.2, 0.3, 0.4, or 0.5 mg per day.

In a particular embodiment, the recommended starting dose of Compound 1, Compound 2, or Compound 3 may be 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 15 , 20 or 25 mg per day. In another embodiment, the recommended starting dose may be 0.1, 0.2, 0.3, 0.4, or 0.5 mg per day. The dose can be increased to 1, 2, 3, 4 or 5 mg per day.

In some embodiments, the therapeutically or prophylactically effective amount of Compound 1, Compound 2, or Compound 3 is from about 0.001 to about 5 mg/kg/day, from about 0.001 to about 4 mg/kg/day, from about 0.001 to about 3 mg/day kg/day, from about 0.001 to about 2 mg/kg/day, from about 0.001 to about 1 mg/kg/day, from about 0.001 to about 0.05 mg/kg/day, from about 0.001 to about 0.04 mg/kg/day, from about 0.001 to about 0.03 mg/kg/day, from about 0.001 to about 0.02 mg/kg/day, from about 0.001 to about 0.01 mg/kg/day or from about 0.001 to about 0.005 mg/kg/day.

The dose administered may also be expressed in units other than mg/kg/day. For example, doses for parenteral administration may be expressed in mg/m ² /day. One skilled in the art will readily recognize how to convert doses from mg/kg/day to mg/m ² /day based on the subject's height or weight, or both (see www.fda.gov/cder/cancer/animalframe .htm). For example, a dose of 1 mg/kg/day for a 65 kg person is approximately 38 mg/ ^m2 /day.

Depending on the condition of the disease being treated and the condition of the subject, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, can be administered by an oral, parenteral route (eg , intramuscular, intraperitoneal, intravenous, IV, intracisternal injection or infusion, subcutaneous injection or implant), by inhalation, nasal, vaginal, rectal, sublingual or topical (eg, transdermal or topical) route of administration. Compound 1, Compound 2 or Compound 3 as provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof may be formulated, alone or together, into a suitable unit dosage form with pharmaceutically acceptable excipients, carriers, adjuvants and liquid media suitable for each route of administration.

In one embodiment, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administered orally. In another embodiment, a compound of Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administered parenterally. In yet another embodiment, a compound of Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is administered intravenously.

Compound 1, Compound 2, or Compound 3 as provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, can be delivered in a single dose, such as, for example, a single bolus injection or oral tablets or pills; or over a specified period of time, for example, by continuous infusion over a specified time or in divided bolus doses over a specified time. The compounds described herein may be re-administered as necessary, for example, until the patient exhibits stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. Stable disease or

- 31 045949 absence is determined by methods known in the art, such as assessment of the patient's symptoms, physical examination, imaging of the tumor, which has been visualized using X-ray, computed tomography, PET or MRI, and other conventional assessment methods.

Compound 1, Compound 2, or Compound 3 as provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, may be independently administered once daily (QD) or may be divided into multiple daily doses, such as for dosing twice daily (BID), three times daily (TID) and four times daily (QID). In addition, administration may be continuous (rn.e. daily for consecutive days or every day), intermittent, such as cyclic (rn.e. including days, weeks or months of rest without drug). As used herein, the term daily means that a therapeutic compound, such as Compound 1, Compound 2, or Compound 3 as provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is administered one or more times per day, for example, over a period of time. The term continuous means that a therapeutic compound, such as Compound 1, Compound 2 or Compound 3 as provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof is administered daily for a continuous period of at least 7 days to 52 weeks. The term intermittent or intermittent as used in this document is intended to mean stopping and starting at regular or irregular intervals. For example, periodic administration of Compound 1, Compound 2, or Compound 3 as provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administration for one to six days per week, administration in cycles (e.g. , daily administration for two to eight consecutive weeks, followed by a rest period without administration for up to one week) or administration every other day. As used herein, the term cyclic means that a therapeutic compound, such as Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is administered daily or continuously, but with rest period. In some such embodiments, administration is once daily for two to six days, followed by a rest period without administration for five to seven days.

In some embodiments, the frequency of administration of Compound 1, Compound 2, or Compound 3 ranges from about a daily dose to about a monthly dose. In some embodiments, administration is once daily, twice daily, three times daily, four times daily, once every other day, twice weekly, once weekly, once every two weeks, once every three weeks or once every four weeks. In one embodiment, Compound 1, Compound 2, or Compound 3 described herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administered once daily. In another embodiment, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administered twice daily. In yet another embodiment, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administered three times daily. In yet another embodiment, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is administered four times daily.

In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes an administration period of up to 21 days followed by a rest period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes an administration period of up to 20 days followed by a rest period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes an administration period of up to 15 days followed by a rest period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes an administration period of up to 10 days followed by a rest period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes an administration period of up to 7 days followed by a rest period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes an administration period of up to 5 days followed by a rest period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes an administration period of up to 4 days followed by a rest period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes an administration period of up to 3 days followed by a rest period.

In one embodiment, a treatment cycle with Compound 1, Compound 2, or Compound 3

- 32 045949 includes an administration period of up to 14 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 7 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 5 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 4 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 3 days followed by a rest period.

In one embodiment, the rest period ranges from about 2 days to about 11 days. In one embodiment, the rest period ranges from about 2 days to about 10 days. In one embodiment, the rest period is about 2 days. In one embodiment, the rest period is about 3 days. In one embodiment, the rest period is about 4 days. In one embodiment, the rest period is about 5 days. In one embodiment, the rest period is about 6 days. In another embodiment, the rest period is about 7 days. In another embodiment, the rest period is about 8 days. In another embodiment, the rest period is about 9 days. In another embodiment, the rest period is about 10 days. In another embodiment, the rest period is about 11 days.

In one embodiment, a treatment cycle with Compound 1, Compound 2, or Compound 3 includes an administration period of up to 15 days, followed by a rest period of about 2 days to about 10 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days, followed by a rest period of about 2 days to about 10 days. In one embodiment, the treatment cycle includes an administration period of up to 7 days, followed by a rest period of about 2 days to about 10 days. In one embodiment, the treatment cycle includes an administration period of up to 5 days, followed by a rest period of about 2 days to about 10 days. In one embodiment, the treatment cycle includes an administration period of up to 3 days, followed by a rest period of about 10 days to about 15 days. In one embodiment, the treatment cycle includes an administration period of up to 3 days, followed by a rest period of about 3 days to about 15 days.

In one embodiment, a treatment cycle with Compound 1, Compound 2, or Compound 3 includes an administration period of up to 15 days followed by a rest period of 7 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period of 5 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period of 4 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period of 3 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period of 2 days. In one embodiment, the treatment cycle includes an administration period of up to 7 days followed by a rest period of 7 days. In one embodiment, the treatment cycle includes an administration period of up to 5 days followed by a rest period of 5 days. In one embodiment, the treatment cycle includes an administration period of up to 3 days followed by a rest period of 11 days. In another embodiment, the treatment cycle includes an administration period of up to 5 days followed by a rest period of 9 days. In another embodiment, the treatment cycle includes an administration period of up to 5 days followed by a rest period of 2 days. In another embodiment, the treatment cycle includes an administration period of up to 3 days followed by a rest period of 4 days.

In one embodiment, a treatment cycle with Compound 1, Compound 2, or Compound 3 comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 through 5 of a 28-day cycle. In another embodiment, the treatment cycle includes administration of Compound 1, Compound 2, or Compound 3 on days 1 to 10 of a 28-day cycle. In one embodiment, a treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 21 of a 28-day cycle. In another embodiment, a treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 5 of a 7-day cycle. In another embodiment, a treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 7 of a 7-day cycle. In one embodiment, the treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 10 and days 15 to 24 of a 28-day cycle (herein referred to as a 20/28 dosing cycle). In one embodiment, the treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 3 and days 15 to 18 of a 28-day cycle. In one embodiment, the treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2 or compound 3 on days 1 to 7 and days 15 to 21 of a 28-day cycle (herein referred to as the 14/28 dosing cycle). In one embodiment, a treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 5 and days 15 to 19 of a 28-day cycle (herein referred to as a 10/28 dosing cycle). In one embodiment, the treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 3 and days 15 to 17 of a 28-day cycle (in this case, to

- 33 045949 document called dosing cycle 6/28).

In one embodiment, a treatment cycle with Compound 1, Compound 2, or Compound 3 comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 through 14 of a 21-day cycle. In another embodiment, a treatment cycle includes administration of Compound 1, Compound 2, or Compound 3 on days 1 to 4 and 8 to 11 of a 21-day cycle. In one embodiment, a treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 5 and 8 to 12 of a 21-day cycle. In one embodiment, the treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 5 and 11 to 15 of a 21-day cycle. In another embodiment, a treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 5, 8 to 12, and 15 to 19 of a 21-day cycle. In another embodiment, the treatment cycle includes administration of a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 through 4, 8 through 11, and 15 through 18 of a 21-day cycle. In another embodiment, a treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 4, 8 to 10, and 15 to 17 of a 21-day cycle. In another embodiment, a treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 3 and 8 to 11 of a 21-day cycle. In one embodiment, a treatment cycle includes administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on days 1 to 3 and 11 to 13 of a 21-day cycle.

Any treatment cycle described herein may be repeated for at least 2, 3, 4, 5, 6, 7, 8 or more cycles. In some cases, a treatment cycle as described herein comprises from 1 to about 24 cycles, from about 2 to about 16 cycles, or from about 2 to about 4 cycles. In some cases, a treatment cycle as described herein comprises from 1 to about 4 cycles. In some embodiments, cycles 1 through 4 are all 28-day cycles. In some embodiments, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered over 1 to 13 cycles of 28 days (eg, about 1 year). In some cases, cyclic therapy is not limited to the number of cycles, and therapy continues until the disease progresses. Cycles may in some cases include varying the length of the administration periods and/or rest periods described herein.

In one embodiment, the treatment cycle includes administration of Compound 1, Compound 2, or Compound 3 at a dosage of about 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day, 0.7 mg/day, 0.8 mg/day, 0.9 mg/day, 1.0 mg/day, 2.0 mg/day, 5.0 mg /day or 10 mg/day administered once daily. In one embodiment, the treatment cycle includes administration of Compound 1, Compound 2, or Compound 3 at a dosage of about 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, 0.4 mg/day, 0.5 mg/day, 0.6 mg/day, 0.7 mg/day, or 0.8 mg/day administered once daily. In some such embodiments, the treatment cycle includes administering Compound 1, Compound 2, or Compound 3 once daily at a dosage of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg per days from 1 to 10 of the 28-day cycle. In some such embodiments, the treatment cycle includes administering Compound 1, Compound 2, or Compound 3 once daily at a dosage of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg per days from 1 to 10 and from 15 to 24 of the 28-day cycle. In some such embodiments, the treatment cycle includes administering Compound 1, Compound 2, or Compound 3 once daily at a dosage of about 0.1 mg on days 1 to 10 and 15 to 24 of a 28-day cycle. In other embodiments, the treatment cycle includes administration of Compound 1, Compound 2, or Compound 3 twice daily at a dosage of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 -3 28-day cycle. In other embodiments, the treatment cycle includes administration of Compound 1, Compound 2, or Compound 3 twice daily at a dosage of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 3 and 15 to 19 of the 28-day cycle. In other embodiments, the treatment cycle includes administration of Compound 1, Compound 2, or Compound 3 twice daily at a dosage of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 3 and 15 to 17 of the 28-day cycle. In other embodiments, the treatment cycle includes administration of Compound 1, Compound 2, or Compound 3 twice daily at a dosage of about 0.2 mg on days 1 to 3 and 15 to 17 of the 28-day cycle. In one such embodiment, the compound is administered on days 1-3 (morning and evening), day 14 (evening only), days 15 and 16 (morning and evening), and day 17 (morning only) of a 28-day cycle, for example , in cycle 1.

H. Dosage of Second Active Agents.

In one embodiment, the specific amount (dose) of the second active agent provided herein, as used in the methods provided herein, is determined by factors such as the specific agent used, the type of multiple myeloma being treated or controlled, the severity and stage of the disease. , the amount of Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof, and any optional additional active agents simultaneously administered to the patient.

In one embodiment, the dose of the second active agent provided herein, as used in the methods presented herein, is determined based on the

- 34 045949 marketing information for a drug (eg, label) approved by the FDA or equivalent regulatory agency of a country other than the United States for the specified active agent. In one embodiment, the dose of the second active agent provided herein, when used in the methods presented herein, is the dose approved by the FDA or equivalent regulatory authority of a country other than the United States for the specified active agent. In one embodiment, the dose of the second active agent provided herein, as used in the methods provided herein, is the dose used in human clinical trials for the specified active agent. In one embodiment, the dose of the second active agent provided herein used in the methods presented herein is lower than the dose approved by the FDA or similar regulatory authority of a country other than the United States for the specified active agent, or the dose used in clinical trials in humans, for the specified active agent depending, for example, on the synergistic effects between the second active agent and compound 1, compound 2 or compound 3.

In one embodiment, the second active agent used in the methods presented herein is a BTK inhibitor. In one embodiment, a BTK inhibitor (eg, ibrutinib) is administered at a dose ranging from about 140 mg to about 700 mg, from about 280 mg to about 560 mg, or from about 420 mg to about 560 mg once daily. In one embodiment, a BTK inhibitor (eg, ibrutinib) is administered at a dose of no more than about 700 mg, no more than about 560 mg, no more than about 420 mg, no more than about 280 mg, or no more than about 140 mg at a time per day. In one embodiment, a BTK inhibitor (eg, ibrutinib) is administered at a dose of about 560 mg once daily. In one embodiment, a BTK inhibitor (eg, ibrutinib) is administered at a dose of about 420 mg once daily. In one embodiment, a BTK inhibitor (eg, ibrutinib) is administered at a dose of about 280 mg once daily. In one embodiment, a BTK inhibitor (eg, ibrutinib) is administered at a dose of about 140 mg once daily. In one embodiment, a BTK inhibitor (eg, ibrutinib) is administered orally.

In one embodiment, the second active agent used in the methods presented herein is an mTOR inhibitor. In one embodiment, an mTOR inhibitor (eg, everolimus) is administered at a dosage ranging from about 1 mg to about 20 mg, about 2.5 mg to about 15 mg, or about 5 mg to about 10 mg once daily. In one embodiment, an mTOR inhibitor (eg, everolimus) is administered at a dose of no more than about 20 mg, no more than about 15 mg, no more than about 10 mg, no more than about 5 mg, or no more than about 2.5 mg once a day. In one embodiment, an mTOR inhibitor (eg, everolimus) is administered at a dose of about 10 mg once daily. In one embodiment, an mTOR inhibitor (eg, everolimus) is administered at a dose of about 5 mg once daily. In one embodiment, an mTOR inhibitor (eg, everolimus) is administered at a dose of about 2.5 mg once daily. In one embodiment, an mTOR inhibitor (eg, everolimus) is administered orally.

In one embodiment, the second active agent used in the methods presented herein is a PIM inhibitor. In one embodiment, a PIM inhibitor (e.g., LGH-447) is administered at a dose ranging from about 30 mg to about 1000 mg, from about 70 mg to about 700 mg, from about 150 mg to about 500 mg, from about 200 mg to about 350 mg or from about 250 mg to about 300 mg once daily. In one embodiment, a PIM inhibitor (e.g., LGH-447) is administered at a dose of no more than about 700 mg, no more than about 500 mg, no more than about 350 mg, no more than about 300 mg, no more than about 250 mg , no more than about 200 mg, no more than about 150 mg, or no more than about 70 mg once daily. In one embodiment, a PIM inhibitor (eg, LGH-447) is administered at a dose of about 500 mg once daily. In one embodiment, a PIM inhibitor (eg, LGH-447) is administered at a dose of about 350 mg once daily. In one embodiment, a PIM inhibitor (eg, LGH-447) is administered at a dose of about 300 mg once daily. In one embodiment, a PIM inhibitor (eg, LGH-447) is administered at a dose of about 250 mg once daily. In one embodiment, a PIM inhibitor (eg, LGH-447) is administered at a dose of about 200 mg once daily. In one embodiment, a PIM inhibitor (eg, LGH-447) is administered at a dose of about 150 mg once daily. In one embodiment, a PIM inhibitor (eg, LGH-447) is administered orally.

In one embodiment, the second active agent used in the methods presented herein is an IGF-1R inhibitor. In one embodiment, an IGF-1R inhibitor (eg, linsitinib) is administered at a dose ranging from about 100 mg to about 500 mg, from about 150 mg to about 450 mg, from about 200 mg to about 400 mg, or from about 250 mg to about 300 mg once a day. In one embodiment, an IGF-1R inhibitor (eg, linsitinib) is administered at a dose ranging from about 50 mg to about 250 mg, from about 75 mg to about 225 mg, from about 100 mg to about 200 mg, or from about 125 mg to about 150 mg twice daily (BID). In one embodiment, an IGF-1R inhibitor (eg, linsitinib) is administered at a dose of no more than about 450 mg, no more than about 400 mg, no more than about 300 mg, no more than about 250 mg, no more than about 200 mg or no more than about 150 mg once daily. In one embodiment, an IGF-1R inhibitor (eg, linsitinib) is administered to

- 35 045949 dose of no more than about 450 mg, no more than about 400 mg, no more than about 300 mg, no more than about 250 mg, no more than about 200 mg or no more than about 150 mg once a day. In one embodiment, an IGF-1R inhibitor (eg, linsitinib) is administered at a dose of no more than about 225 mg, no more than about 200 mg, no more than about 150 mg, no more than about 125 mg, no more than about 100 mg or no more than about 75 mg twice daily. In one embodiment, an IGF-1R inhibitor (eg, linsitinib) is administered at a dose of about 450 mg, about 400 mg, about 300 mg, about 250 mg, about 200 mg, or about 150 mg once daily. In one embodiment, an IGF-1R inhibitor (eg, linsitinib) is administered at a dose of about 225 mg, about 200 mg, about 150 mg, about 125 mg, about 100 mg, or about 75 mg twice daily. In one embodiment, an IGF-1R inhibitor (eg, linsitinib) is administered on days 1-3 every 7 days. In one embodiment, an IGF-1R inhibitor (eg, linsitinib) is administered orally.

In one embodiment, the second active agent used in the methods presented herein is a MEK inhibitor. In one embodiment, a MEK inhibitor (e.g., trametinib or trametinib dimethyl sulfoxide) is administered at a dose ranging from about 0.25 mg to about 3 mg, from about 0.5 mg to about 2 mg, or from about 1 mg to about 1.5 mg once daily. In one embodiment, a MEK inhibitor (e.g., trametinib or trametinib dimethyl sulfoxide) is administered at a dose of no more than about 2 mg, no more than about 1.5 mg, no more than about 1 mg, or no more than about 0.5 mg at a time per day. In one embodiment, a MEK inhibitor (eg, trametinib or trametinib dimethyl sulfoxide) is administered at a dose of about 2 mg once daily. In one embodiment, a MEK inhibitor (eg, trametinib or trametinib dimethyl sulfoxide) is administered at a dose of about 1.5 mg once daily. In one embodiment, a MEK inhibitor (eg, trametinib or trametinib dimethyl sulfoxide) is administered at a dose of about 1 mg once daily. In one embodiment, a MEK inhibitor (eg, trametinib or trametinib dimethyl sulfoxide) is administered at a dose of about 0.5 mg once daily. In one embodiment, a MEK inhibitor (eg, trametinib or trametinib dimethyl sulfoxide) is administered orally.

In one embodiment, the second active agent used in the methods presented herein is an XPO1 inhibitor. In one embodiment, an XPO1 inhibitor (eg, selinexor) is administered at a dose ranging from about 30 mg to about 200 mg twice weekly, from about 45 mg to about 150 mg twice weekly, or from about 60 mg to about 100 mg two times a week. In one embodiment, an XPO1 inhibitor (eg, selinexor) is administered at a dose of no more than about 100 mg, no more than about 80 mg, no more than about 60 mg, or no more than about 40 mg twice per week. In one embodiment, an XPO1 inhibitor (eg, selinexor) is administered at a dose of about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg twice in Week. In one embodiment, the dose is about 40 mg twice a week. In one embodiment, the dose is about 60 mg twice a week. In one embodiment, the dose is about 80 mg twice a week. In one embodiment, the dose is about 100 mg twice a week. In one embodiment, an XPO1 inhibitor (eg, selinexor) is administered orally.

In one embodiment, the second active agent used in the methods presented herein is a DOT1L inhibitor. In one embodiment, a DOT1L inhibitor (e.g., SGC0946) is administered at a dose ranging from about 10 mg to about 500 mg, from about 25 mg to about 400 mg, from about 50 mg to about 300 mg, from about 75 mg to about 200 mg. mg or from about 100 mg to about 150 mg per day. In one embodiment, a DOT1L inhibitor (e.g., SGC0946) is administered at a dose of no more than about 500 mg, no more than about 400 mg, no more than about 300 mg, no more than about 200 mg, no more than about 150 mg, no more than about 100 mg, no more than about 75 mg, no more than about 50 mg, or no more than about 25 mg per day. In one embodiment, a DOT1L inhibitor (eg, SGC0946) is administered at a dose of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg. In one embodiment, a DOT1L inhibitor (eg, SGC0946) is administered at a dose ranging from about 18 mg/ ^m2 to about 126 mg/ ^m2 , from about 36 mg/ ^m2 to about 108 mg/m2 ^{, or} from about 54 mg / ^m2 to about 90 mg/ ^m2 per day. In one embodiment, a DOT1L inhibitor (eg, SGC0946) is administered at a dose of no more than about 126 mg/m ² , no more than about 108 mg/m ² , no more than about 90 mg/m ² , no more than about 72 mg /m ² , not more than about 54 mg/m ² , not more than about 36 mg/m ² or not more than about 18 mg/m ² per day. In one embodiment, a DOT1L inhibitor (eg, SGC0946) is administered at a dose of about 18 mg/ ^m2 , about 36 mg/ ^m2 , about 54 mg/m2, about 72 mg/ ^m2 , about 90 mg/ ^{m2 ,} about 108 mg/ ^m2 or about 126 mg/ ^m2 per day. In one embodiment, a DOT1L inhibitor (eg, SGC0946) is administered orally. In one embodiment, a DOT1L inhibitor (eg, SGC0946) is administered intravenously.

In one embodiment, a DOT1L inhibitor (eg, pinometostat) is administered at a dose ranging from about 18 mg/ ^m2 to about 108 mg/ ^m2 , from about 36 mg/ ^m2 to about 90 mg/ ^m2 , or from about 54 mg / ^m2 to about 72 mg/ ^m2 per day. In one embodiment, a DOT1L inhibitor (eg, pinometostat) is administered at a dose of no more than about 108 mg/m ² , no more than about 90 mg/m ² , no more than about 72 mg/m ² , no more than about 54 mg /m ² , no more than about 36 mg/m ² or no more than about 18 mg/m ² per day. In one

- 36 045949 embodiment, a DOT1L inhibitor (eg pinometostat) is administered at a dose of about 18 mg/m ² per day. In one embodiment, a DOT1L inhibitor (eg, pinometostat) is administered at a dose of about 36 mg/m ² per day. In one embodiment, a DOT1L inhibitor (eg, pinometostat) is administered at a dose of about 54 mg/m ² per day. In one embodiment, a DOT1L inhibitor (eg, pinometostat) is administered at a dose of about 70 mg/m ² per day. In one embodiment, a DOT1L inhibitor (eg, pinometostat) is administered at a dose of about 72 mg/m ² per day. In one embodiment, a DOT1L inhibitor (eg, pinometostat) is administered at a dose of about 90 mg/m ² per day. In one embodiment, a DOT1L inhibitor (eg, pinometostat) is administered at a dose of about 108 mg/m ² per day. In one embodiment, a DOT1L inhibitor (eg, pinometostat) is administered intravenously.

In one embodiment, the second active agent used in the methods presented herein is an EZH2 inhibitor. In one embodiment, an EZH2 inhibitor (eg, tazemetostat) is administered at a dose ranging from about 50 mg to about 1600 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 400 mg twice daily (BID). In one embodiment, an EZH2 inhibitor (eg, tazemetostat) is administered at a dose of no more than about 800 mg, no more than about 600 mg, no more than about 400 mg, no more than about 200 mg, or no more than about 100 mg twice daily. day. In one embodiment, an EZH2 inhibitor (eg, tazemetostat) is administered at a dose of about 800 mg twice daily. In one embodiment, an EZH2 inhibitor (eg, tazemetostat) is administered at a dose of about 600 mg twice daily. In one embodiment, an EZH2 inhibitor (eg, tazemetostat) is administered at a dose of about 400 mg twice daily. In one embodiment, an EZH2 inhibitor (eg, tazemetostat) is administered at a dose of about 200 mg twice daily. In one embodiment, an EZH2 inhibitor (eg, tazemetostat) is administered orally.

In one embodiment, an EZH2 inhibitor (eg, CPI-1205) is administered at a dose ranging from about 100 mg to about 3200 mg, from about 200 mg to about 1600 mg, or from about 400 mg to about 800 mg twice daily. In one embodiment, an EZH2 inhibitor (e.g., CPI-1205) is administered at a dose of no more than about 3200 mg, no more than about 1600 mg, no more than about 800 mg, no more than about 400 mg, no more than about 200 mg or no more than about 100 mg twice daily. In one embodiment, an EZH2 inhibitor (eg, CPI-1205) is administered at a dose of about 3200 mg twice daily. In one embodiment, an EZH2 inhibitor (eg, CPI-1205) is administered at a dose of about 1600 mg twice daily. In one embodiment, an EZH2 inhibitor (eg, CPI-1205) is administered at a dose of about 800 mg twice daily. In one embodiment, an EZH2 inhibitor (eg, CPI-1205) is administered at a dose of about 400 mg twice daily. In one embodiment, an EZH2 inhibitor (eg, CPI-1205) is administered at a dose of about 200 mg twice daily. In one embodiment, an EZH2 inhibitor (eg, CPI-1205) is administered at a dose of about 100 mg twice daily. In one embodiment, an EZH2 inhibitor (eg, CPI-1205) is administered over one or more 28-day cycles. In one embodiment, an EZH2 inhibitor (eg, CPI-1205) is administered orally.

In one embodiment, the second active agent used in the methods presented herein is a JAK2 inhibitor. In one embodiment, a JAK2 inhibitor (eg, fedratinib) is administered at a dose ranging from about 120 mg to about 680 mg, from about 240 mg to about 500 mg, or from about 300 mg to about 400 mg once daily. In one embodiment, a JAK2 inhibitor (e.g., fedratinib) is administered at a dose of no more than about 680 mg, no more than about 500 mg, no more than about 400 mg, no more than about 300 mg, or no more than about 240 mg at a time per day. In one embodiment, a JAK2 inhibitor (eg, fedratinib) is administered at a dose of about 500 mg once daily. In one embodiment, a JAK2 inhibitor (eg, fedratinib) is administered at a dose of about 400 mg once daily. In one embodiment, a JAK2 inhibitor (eg, fedratinib) is administered at a dose of about 300 mg once daily.

In one embodiment, the second active agent used in the methods presented herein is a PLK1 inhibitor. In one embodiment, a PLK1 inhibitor (eg, BI2536) is administered at a dose ranging from about 20 mg to about 200 mg, from about 40 mg to about 100 mg, or from about 50 mg to about 60 mg per day. In one embodiment, a PLK1 inhibitor (e.g., BI2536) is administered at a dose of no more than about 200 mg, no more than about 100 mg, no more than about 60 mg, no more than about 50 mg, no more than about 40 mg, or no more than about 20 mg per day. In one embodiment, a PLK1 inhibitor (eg, BI2536) is administered at a dose of about 200 mg, about 100 mg, about 60 mg, about 50 mg, about 40 mg, or about 20 mg per day. In one embodiment, a PLK1 inhibitor (eg, BI2536) is administered at a dose of about 200 mg once every 21-day cycle. In one embodiment, a PLK1 inhibitor (eg, BI2536) is administered at a dose of about 100 mg per day on days 1 and 8 of a 21-day cycle. In one embodiment, a PLK1 inhibitor (eg, BI2536) is administered at a dose of about 50 mg per day on days 1-3 of a 21-day cycle. In one embodiment, a PLK1 inhibitor (eg, BI2536) is administered at a dose of about 60 mg per day on days 1-3 of a 21-day cycle. In one embodiment, a PLK1 inhibitor (eg, BI2536) is administered intravenously.

In one embodiment, the second active agent used in the methods presented herein is an AURKB inhibitor. In one embodiment, an AURKB inhibitor (eg, AZD1152) is administered at a dose ranging from about 50 mg to about 200 mg, ca.

- 37 045949 lo 75 mg to about 150 mg or from about 100 mg to about 110 mg per day. In one embodiment, an AURKB inhibitor (e.g., AZD1152) is administered at a dose of no more than about 200 mg, no more than about 150 mg, no more than about 110 mg, no more than about 100 mg, no more than about 75 mg, or no more than about 50 mg per day. In one embodiment, an AURKB inhibitor (eg, AZD1152) is administered at a dose of about 200 mg, about 150 mg, about 110 mg, about 100 mg, about 75 mg, or about 50 mg per day. In one embodiment, an AURKB inhibitor (eg, AZD1152) is administered at the dose described herein on days 1, 2, 15, and 16 of a 28-day cycle. In one embodiment, an AURKB inhibitor (eg, AZD1152) is administered intravenously. In one embodiment, an AURKB inhibitor (eg, AZD1152) is administered at a dose of about 150 mg as a 48-hour continuous infusion every 14 days of a 28-day cycle. In one embodiment, an AURKB inhibitor (eg, AZD1152) is administered at a dose of about 220 mg as 2x2-hour infusions every 14 days of a 28-day cycle (eg, 110 mg/day on days 1, 2, 15, and 16). In one embodiment, an AURKB inhibitor (eg, AZD1152) is administered at a dose of about 200 mg as a 2-hour infusion every 7 days. In one embodiment, an AURKB inhibitor (eg, AZD1152) is administered at a dose of about 450 mg as a 2-hour infusion every 14 days.

In one embodiment, the second active agent used in the methods presented herein is a BIRC5 inhibitor. In one embodiment, a BIRC5 inhibitor (eg, YM155) is administered at a dose ranging from about 2 mg/m ² to about 15 mg/m ² or from about 4 mg/m ² to about 10 mg/m ² per day. In one embodiment, a BIRC5 inhibitor (eg, YM155) is administered at a dose of no more than about 15 mg/ ^m2 , no more than about 10 mg/ ^m2 , no more than about 4.8 mg/ ^m2 , no more than about 4 mg/ ^m2 or no more than about 2 mg/ ^m2 per day. In one embodiment, a BIRC5 inhibitor (eg, YM155) is administered at a dose of about 15 mg/m ² per day. In one embodiment, a BIRC5 inhibitor (eg, YM155) is administered at a dose of about 10 mg/m ² per day. In one embodiment, a BIRC5 inhibitor (eg, YM155) is administered at a dose of about 4.8 mg/m ² per day. In one embodiment, a BIRC5 inhibitor (eg, YM155) is administered at a dose of about 4 mg/m ² per day. In one embodiment, a BIRC5 inhibitor (eg, YM155) is administered at a dose of about 2 mg/m ² per day. In one embodiment, a BIRC5 inhibitor (eg, YM155) is administered intravenously. In one embodiment, a BIRC5 inhibitor (eg, YM155) is administered at a dose of about 4.8 mg/m ² /day over about 168 hours of continuous intravenous infusion every 3 weeks. In one embodiment, a BIRC5 inhibitor (eg, YM155) is administered at a dose of about 5 mg/m ² /day over about 168 hours of continuous intravenous infusion every 3 weeks. In one embodiment, a BIRC5 inhibitor (eg, YM155) is administered at a dose of about 10 mg/m ² /day over about 72 hours of continuous intravenous infusion every 3 weeks.

In one embodiment, the second active agent used in the methods presented herein is a BET inhibitor. In one embodiment, a BET inhibitor (eg, birabresib) is administered at a dose ranging from about 10 mg to about 160 mg, about 20 mg to about 120 mg, or about 40 mg to about 80 mg once daily. In one embodiment, a BET inhibitor (eg, birabresib) is administered at a dose of no more than about 160 mg, no more than about 120 mg, no more than about 80 mg, no more than about 40 mg, no more than about 20 mg, or no more than about 10 mg once daily. In one embodiment, a BET inhibitor (eg, birabresib) is administered at a dose of about 160 mg once daily. In one embodiment, a BET inhibitor (eg, birabresib) is administered at a dose of about 120 mg once daily. In one embodiment, a BET inhibitor (eg, birabresib) is administered at a dose of about 80 mg once daily. In one embodiment, a BET inhibitor (eg, birabresib) is administered at a dose of about 40 mg once daily. In one embodiment, a BET inhibitor (eg, birabresib) is administered at a dose of about 20 mg once daily. In one embodiment, a BET inhibitor (eg, birabresib) is administered at a dose of about 10 mg once daily. In one embodiment, a BET inhibitor (eg, birabresib) is administered at the dose described herein on days 1-7 of a 21-day cycle. In one embodiment, a BET inhibitor (eg, birabresib) is administered at the dose described herein on days 1-14 of a 21-day cycle. In one embodiment, a BET inhibitor (eg, birabresib) is administered at the dose described herein on days 1-21 of a 21-day cycle. In one embodiment, a BET inhibitor (eg, birabresib) is administered at the dose described herein on days 1-5 of a 7-day cycle. In one embodiment, a BET inhibitor (eg, birabresib) is administered orally.

In one embodiment, the second active agent used in the methods presented herein is a DNA methyltransferase inhibitor. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose ranging from about 25 mg/ ^m2 to about 150 mg/ ^m2 , about 50 mg/ ^m2 to about 125 mg/ ^m2, or about 75 mg/m ² to about 100 mg/m ² times a day. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of no more than about 150 mg/m ² , no more than about 125 mg/m ² , no more than about 100 mg/m ² , no more than about 75 mg/m ² , no more than about 50 mg/m ² or no more than about 25 mg/m ² times a day. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 150 mg/m ² times daily. In one embodiment, a DNA inhibitor

- 38 045949 methyltransferase (for example, azacitidine) is administered at a dose of about 125 mg/m ² times a day. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 100 mg/m ² times daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 75 mg/m ² times daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 50 mg/m ² times daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 25 mg/m ² times daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered subcutaneously. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered intravenously.

In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose ranging from about 100 mg to about 500 mg or from about 200 mg to about 400 mg once daily. In one embodiment, a DNA methyltransferase inhibitor (e.g., azacitidine) is administered at a dose of no more than about 500 mg, no more than about 400 mg, no more than about 300 mg, no more than about 200 mg, or no more than about 100 mg once a day. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 500 mg once daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 400 mg once daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 300 mg once daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 200 mg once daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 100 mg once daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose ranging from about 100 mg to about 300 mg or from about 150 mg to about 250 mg twice daily. In one embodiment, a DNA methyltransferase inhibitor (e.g., azacitidine) is administered at a dose of no more than about 300 mg, no more than about 250 mg, no more than about 200 mg, no more than about 150 mg, or no more than about 100 mg twice a day. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 300 mg twice daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 250 mg twice daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 200 mg twice daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 150 mg twice daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose of about 100 mg twice daily. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at the dose described herein on days 1-14 of a 28-day cycle. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered at a dose described herein on days 1-21 of a 28-day cycle. In one embodiment, a DNA methyltransferase inhibitor (eg, azacitidine) is administered orally.

I. Combination therapy with an additional active agent.

The combined use of a compound provided herein (e.g., compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) and a second active agent provided herein (e.g., one or several of ibrutinib, everolimus, LGH-447, lensitinib, trametinib, trametinib dimethyl sulfoxide, selinexor, SGC0946, pinometostat, tazemetostat, UNC1999, CPI-1205, fedratinib, JQ1, BI2536, JH295, barasertib, AZD1152-HQPA, YM155, connections C or azacitidine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof), may also be further combined or used in combination with (e.g., before, during, or after) conventional therapy, including, but not limited to, surgery, biological therapy (including immunotherapy, such as checkpoint inhibitors), radiation therapy, chemotherapy, stem cell transplantation, cell therapy or other non-drug therapy currently used to treat, prevent or control multiple myeloma. The combined use of a compound provided herein, a second active agent provided herein, and conventional therapy may provide a unique treatment regimen that is unexpectedly effective for certain patients. Without being limited by theory, it is believed that Compound 1, Compound 2, or Compound 3 and the second active agent provided herein may provide additive or synergistic effects when administered concomitantly with conventional therapy.

As discussed elsewhere herein, included within the context of this document is a method of reducing, treating and/or preventing adverse or undesirable effects associated with conventional therapy, including, but not limited to, surgery, chemotherapy, radiation therapy, biological therapy and immunotherapy. A compound provided herein, such as Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, a second active agent provided herein, and an additional active ingredient may be administered

- 39 045949 to the patient before, during or after the occurrence of an adverse event associated with traditional therapy. In one such embodiment, the additional active agent is dexamethasone.

The combined use of a compound provided herein (e.g., compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt) and a second active agent provided herein (e.g., one or several of ibrutinib, everolimus, LGH-447, lensitinib, trametinib, trametinib dimethyl sulfoxide, selinexor, SGC0946, pinometostat, tazemetostat, UNC1999, CPI-1205, fedratinib, JQ1, BI2536, JH295, barasertib, AZD1152-HQPA, YM155, connections C or azacitidine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) may also be further combined or used in combination with other therapeutic agents useful for the treatment and/or prevention of multiple myeloma described herein. In one such embodiment, the additional active agent is dexamethasone.

In one embodiment, provided herein is a method of treating, preventing, or controlling multiple myeloma, comprising administering to a patient Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt in combination with a second active agent represented by herein, additionally in combination with one or more additional active agents, and optionally additionally in combination with radiation therapy, blood transfusion, or surgery.

As used herein, the term combination includes the use of more than one therapy (eg, one or more prophylactic and/or therapeutic agents). However, use of the term in combination does not limit the order in which therapies (eg, prophylactic and/or therapeutic agents) are administered to a patient with a disease or disorder. The first therapy (e.g., a prophylactic or therapeutic agent, such as a compound provided herein, e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) may be administered before ( for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before, at the same time, or after (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) a second therapy (for example, the second active agent presented in this document, for example, one or more of ibrutinib, everolimus, LGH-447, linsitinib, trametinib, trametinib dimethyl sulfoxide, selinexor, SGC0946, pinometostat, tazemetostat, UNC 1999, CPI-1205, fedratinib, JQ1, BI2536, JH295, barasertib, AZD1 152- HQPA, YM155, Compound C or azacitidine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof) to a subject. The first therapy and the second therapy can be carried out independently up to (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours , 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before, at the same time, or after (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours , 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks after) administration to the subject third therapy (eg, additional prophylactic or therapeutic agent). Quadruple therapy is also discussed in this document, as is quintuple therapy. In one embodiment, the third therapeutic agent is dexamethasone.

Administration of Compound 1, Compound 2, or Compound 3, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharmaceutically acceptable salt thereof, a second active agent provided herein, and one or more additional active agents to a patient may occur simultaneously or sequentially. the same or different routes of administration. The suitability of the particular route of administration used for a particular active agent will depend on the active agent itself (eg, whether it can be administered orally without degradation before entering the bloodstream).

The route of administration of Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof, is independent of the route of administration of the second active agent provided herein, as well as additional therapy. In one embodiment, Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administered orally. In another embodiment, Compound 1, Compound 2, or Compound 3 is administered intravenously. In one embodiment, the second active agent provided herein is administered orally. In one embodiment, the second active agent provided herein is administered intravenously. Thus, according to these embodiments, compound 1,

- 40 045949 compound 2 or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt is administered orally or intravenously, the second active agent presented herein is administered orally or intravenously, and additional therapy can be administered orally, parenterally , intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal, inhalation, vaginal, intraocular, local catheter or stent delivery, subcutaneous, intra-adiposal, intra-articular, intrathecal, or sustained-release dosage form. In one embodiment, Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, a second active agent provided herein, and additional therapy are administered by the same route of administration orally or intravenously. In another embodiment, Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is administered by a single route of administration, e.g., intravenously, while a second active agent provided herein or an additional agent (multiple myeloma agent) is administered by another route, such as orally.

In one embodiment, the additional active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 mg to about 200 mg. The specific amount of additional active agent will depend on the particular agent used, the type of multiple myeloma being treated or controlled, the severity and stage of the disease, the amount of compound 1, compound 2 or compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt, the amount of the second active agent provided herein and any optional additional active agents simultaneously administered to the patient.

One or more additional active ingredients or agents may be used in conjunction with Compound 1, Compound 2, or Compound 3 and a second active agent provided herein in the methods and compositions provided herein. Additional active agents may be large molecules (eg, proteins), small molecules (eg, synthetic inorganic, organometallic, or organic molecules), or cellular therapeutics (eg, CAR cells).

Examples of additional active agents that may be used in the methods and compositions described herein include one or more of the following: melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, obinutuzmab, a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or oprosomib marizomib), histone deacetylase inhibitor (eg panobinostat, ACY241), BET inhibitor (eg GSK525762A, OTX015, BMS-986158, TEN-010, CPI-0610, INCB54329, BAY1238097, FT-1101, ABBV-075, BI 894999 , GS-5829, GSK1210151A (I-BET-151), CPI-203, RVX 208, XD46, MS436, PFI-1, RVX2135, ZEN3365, XD14, ARV-771, MZ 1, PLX5117, 4-[2-(cyclopropylmethoxy )-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one, EP11313 and EP11336), BCL2 inhibitor (e.g. venetoclax or navitoclax), MCL-1 inhibitor (e.g. AZD5991, AMG176, MIK665, S64315 or S63845), LSD-1 inhibitor (e.g. ORY-1001, ORY 2001, INCB-59872, IMG-7289, TAK 418, GSK-2879552, 4-[2-(4-aminopiperidin-1-yl)-5- (3-fluoro-4methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluorobenzonitrile or its salt), corticosteroid (eg prednisone), dexamethasone; an antibody (eg, a CS1 antibody such as elotuzumab; an anti-CD38 antibody such as daratumumab or isatuximab; or a BCMA antibody or an antibody conjugate such as GSK2857916 or BI 836909), a checkpoint inhibitor (as described herein), or cells CAR (as described in this document).

In one embodiment, an additional active agent used in conjunction with Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a second active agent provided herein in the methods and compositions described as used herein, is dexamethasone.

In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 4 mg on days 1, 10, 15, and 22 of cycle 1. In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 4 mg on days 1, 3, 14, and 17 of cycle 1.

In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 8, and 15.

- 41 045949 day cycle. In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 8 mg on days 1, 10, 15, and 22 of cycle 1. In some embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 8 mg on days 1, 3, 14, and 17 of cycle 1.

In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 10 mg on days 1, 10, 15, and 22 of cycle 1. In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 10 mg on days 1, 3, 14, and 17 of cycle 1.

In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 10, 15, and 22 of cycle 1. In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 3, 14, and 17 of cycle 1.

In some embodiments, dexamethasone is administered at a dose of 40 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 8, and 15 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 40 mg on days 1, 10, 15, and 22 of cycle 1. In certain other embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. cycle. In other such embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. In other such embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 40 mg on days 1, 3, 14, and 17 of cycle 1.

In another embodiment, an additional active agent used in conjunction with Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a second active agent provided herein in the methods and compositions described as used herein, is bortezomib. In yet another embodiment, an additional active agent used in conjunction with Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a second active agent provided herein in the methods and compositions described herein is daratumumab. In some such embodiments, the methods further comprise administering dexamethasone. In some embodiments, the methods comprise administering Compound 1, Compound 2, or Compound 3, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharmaceutically acceptable salt and a second active agent as provided herein, with a proteasome inhibitor as described herein, an inhibitor CD38, as described herein, and corticosteroid, as described herein.

In certain embodiments, Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a second active agent provided herein are administered in combination with checkpoint inhibitors. In one embodiment, one checkpoint inhibitor is used in combination with Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a second active agent provided herein, together with methods, presented in this document. In another embodiment, two checkpoint inhibitors are used in combination with Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a second active agent provided herein, together with methods, presented in this document. In yet another embodiment, three or more checkpoint inhibitors are used in combination with Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a second active agent provided herein together with the methods presented in this document.

- 42 045949

As used herein, the term immune checkpoint inhibitor or checkpoint inhibitor refers to molecules that completely or partially reduce, inhibit, interfere with, or modulate one or more checkpoint proteins. Without being limited to any particular theory, checkpoint proteins regulate T cell activation or function. Numerous checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 with its ligands PD-L1 and PD-L2 (Pardoll, Nature Reviews Cancer, 2012, 12, 252-264). These proteins appear to be responsible for co-stimulatory or inhibitory interactions of T-cell responses. Immune checkpoint proteins appear to regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies.

In one embodiment, the checkpoint inhibitor is a CTLA4 inhibitor. In one embodiment, the CTLA-4 inhibitor is an anti-CTLA-4 antibody. Examples of anti-CTLA-4 antibodies include, but are not limited to, the antibodies described in US Pat. Nos. 5,811,097; 5811097; 5855887; 6051227; 6207157; 6682736; 6984720; and 7605238, all of which are incorporated herein in their entirety. In one embodiment, the anti-CTLA-4 antibody is tremelimumab (also known as ticilimumab or CP-675,206). In another embodiment, the anti-CTLA-4 antibody is ipilimumab (also known as MDX-010 or MDX-101). Ipilimumab is a fully human IgG monoclonal antibody that binds to CTLA-4. Ipilimumab is sold under the trade name Yervoy™.

In one embodiment, the checkpoint inhibitor is a PD1/PD-L1 inhibitor. Examples of PD-1/PD-L1 inhibitors include, but are not limited to, those described in US Pat. No. 7,488,802; 7,943,743; 8,008,449; 8,168,757; 8,217,149 and publications of PCT patent applications WO2003042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400 and WO2011161699, all of which are fully included in this document.

In one embodiment, the checkpoint inhibitor is a PD-1 inhibitor. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody is BGB-A317, nivolumab (also known as ONO-4538, BMS-936558, or MDX1106), or pembrolizumab (also known as MK-3475, SCH 900475, or lambrolizumab). In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a human IgG4 monoclonal antibody against PD-1 and is marketed under the brand name Opdivo™. In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized IgG4 monoclonal antibody marketed under the brand name Keytruda™. In yet another embodiment, the anti-PD-1 antibody is a humanized antibody CT-011. CT-011, administered alone, showed no response in the treatment of relapsed acute myeloid leukemia (AML). In yet another embodiment, the anti-PD-1 antibody is an AMP-224 fusion protein. In another embodiment, the PD-1 antibody is BGB-A317. BGB-A317 is a monoclonal antibody that is specifically engineered to bind Fc gamma receptor I and has a unique PD-1 binding signature with high affinity and excellent target specificity.

In one embodiment, the checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody. In one embodiment, the anti-PD-L1 antibody is MEDI4736 (durvalumab). In another embodiment, the anti-PD-L1 antibody is BMS-936559 (also known as MDX1105-01). In yet another embodiment, the PD-L1 inhibitor is atezolizumab (also known as MPDL3280A and Tecentriq®).

In one embodiment, the checkpoint inhibitor is a PD-L2 inhibitor. In one embodiment, the PD-L2 inhibitor is an anti-PD-L2 antibody. In one embodiment, the anti-PD-L2 antibody is rHIgM12B7A.

In one embodiment, the checkpoint inhibitor is a lymphocyte activating gene-3 (LAG-3) inhibitor. In one embodiment, the LAG-3 inhibitor is IMP321, a soluble Ig fusion protein (Brignone et al., J. Immunol., 2007, 179, 4202-4211). In another embodiment, the LAG-3 inhibitor is BMS-986016.

In one embodiment, the checkpoint inhibitors are a B7 inhibitor. In one embodiment, the B7 inhibitor is a B7-H3 inhibitor or a B7-H4 inhibitor. In one embodiment, the B7-H3 inhibitor is MGA271, an anti-B7-H3 antibody (Loo et al., Clin. Cancer Res., 2012, 3834).

In one embodiment, the checkpoint inhibitors are a TIM3 (T cell immunoglobulin domain and mucin domain 3) inhibitor (Fourcade et al., J. Exp. Med., 2010, 207, 2175-86; Sakuishi et al., J. Exp Med., 2010, 207, 2187-94).

In one embodiment, the checkpoint inhibitor is an OX40 (CD134) agonist. In one embodiment, the checkpoint inhibitor is a pro antibody.

- 43 045949 tiv OX40. In one embodiment, the anti-OX40 antibody is anti-OX-40. In another embodiment, the anti-OX40 antibody is MEDI6469.

In one embodiment, the checkpoint inhibitor is a GITR agonist. In one embodiment, the checkpoint inhibitor is an anti-GITR antibody. In one embodiment, the anti-GITR antibody is TRX518.

In one embodiment, the checkpoint inhibitor is a CD137 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD137 antibody. In one embodiment, the anti-CD137 antibody is urelumab. In another embodiment, the anti-CD137 antibody is PF-05082566.

In one embodiment, the checkpoint inhibitor is a CD40 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD40 antibody. In one embodiment, the anti-CD40 antibody is CF-870,893.

In one embodiment, the checkpoint inhibitor is recombinant human interleukin-15 (rhIL-15).

In one embodiment, the checkpoint inhibitor is an IDO inhibitor. In one embodiment, the IDO inhibitor is INCB024360. In another embodiment, the IDO inhibitor is indoximod.

In some embodiments, the combination therapies provided herein include two or more checkpoint inhibitors described herein (including checkpoint inhibitors of the same or a different class). Moreover, the combination therapies described herein can be used in combination with one or more second active agents as described herein, where appropriate for the treatment of diseases described herein and understood in the art.

In some embodiments, Compound 1, Compound 2, or Compound 3 and the second active agent provided herein may be used in combination with one or more immune cells expressing on their surface one or more chimeric antigen receptors (CARs) (e.g., a modified immune cell). Typically, CARs include an extracellular domain of a first protein (eg, antigen binding protein), a transmembrane domain, and an intracellular signaling domain. In some embodiments, once the extracellular domain binds to a target protein, such as tumor-associated antigen (TAA) or tumor-specific antigen (TSA), a signal is generated through the intracellular signaling domain that activates the immune cell, for example, to target and kill the cell expressing the target protein.

Extracellular domains. The extracellular domains of the CAR bind to the antigen of interest. In some embodiments, the extracellular domain of the CAR includes a receptor or portion of a receptor that binds to the antigen. In some embodiments, the extracellular domain includes or is an antibody or an antigen-binding portion thereof. In particular embodiments, the extracellular domain comprises or is a single chain Fv (scFv) domain. A single chain Fv domain may include, for example, a _VL linked to a VH by a flexible linker, wherein said VL and VH are derived from an antibody that binds the antigen.

In some embodiments, the antigen recognized by the extracellular domain of a polypeptide described herein is a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA). In various specific embodiments, the tumor associated antigen or tumor specific antigen is, without limitation, Her2, prostate stem cell antigen (PSCA), alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen-125 (CA-125), CA19 -9, calretinin, MUC-1, B cell maturation antigen (BCMA), epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen-24 (MAGE), CD19, CD22, CD27, CD30 , CD34, CD45, CD70, CD99, CD117, EGFRvIII (epidermal growth factor III variant), mesothelin, PAP (prostate acid phosphatase), prostein, TARP (T-cell receptor gamma alternative reading frame protein), Trpp8, STEAPI (six transmembrane epithelial prostate antigen 1), chromogranin, cytokeratin, desmin, glial fibrillary acidic protein (GFAP), liquid macrogenic cystic disease protein (GCDFP-15), HMB-45 antigen, melan-A protein (melanoma antigen is recognized by T lymphocytes; MART-I), myo-DI, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (N SE), placental alkaline phosphatase, synaptophysis, thyroglobulin, thyroid transcription factor-1, dimeric form of pyruvate kinase type M2 isoenzyme (M2 tumor -PK), abnormal ras protein or abnormal p53 protein. In some other embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is ave3 integrin (CD61), galactin, or Ral-B.

In some embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is a cancer/testis (CT) antigen, e.g., BAGE, CAGE, CTAGE, FATE, GAGE, HCA661, HOM-TES-85, MAGEA, MAGEB, MAGEC, NA88 , NY-ES0-1, NY-SAR-35, OY-TES-1, SPANXBI, SPA17,

- 44 045949

SSX, SYCPI or TPTE.

In some other embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is a carbohydrate or ganglioside, for example, fuc-GMI, GM2 (oncofetal antigen-immunogenic-1; OFA-I-1); GD2 (OFA-I-2), GM3, GD3, etc.

In some other embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is alpha-actinin-4, Bage-1, BCR-ABL, Bcr-Abl fusion protein, beta-catenin, CA 125, CA 15-3 (CA 27.29 \BCAA), CA 195, CA 242, CA-50, CAM43, Casp-8, cdc27, cdk4, cdkn2a, CEA, coa-l, dek-can fusion protein, EBNA, EF2, Epstein-Barr virus antigens, ETV6- AML1 fusion protein, HLAA2, HLA-All, hsp70-2, KIAA0205, Mart2, Mum-1, 2 and 3, neo-PAP, class I myosin, OS-9, pml-RARa fusion protein, PTPRK, K-ras, N-ras, triose phosphate isomerase, Gage 3,4,5,6,7, GnTV, Herv-K-mel, Lage-1, NA88, NY-Eso-1/Lage-2, SP17, SSX-2, TRP2 -Int2, gp100 (Pmel17), tyrosinase, TRP-1, TRP-2, MAGE-1, MAGE-3, RAGE, GAGE-1, GAGE-2, p15 (58), RAGE, SCP-1, Hom/Mel -40, PRAME, p53, HRas, HER-2/neu, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, 13 -Catenin, Mum-1, p16, TAGE, P SMA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, 13HCG, BCA225, BTAA, CD68\KP1, C0-029, FGF-5, G250, Ga733 (EpCAM) , HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\70K, NY-C0-1, RCAS1, SDCCAG16, TA-90, TAAL6, TAG72, TLP or TPS.

In various specific embodiments, the tumor antigen or tumor-specific antigen are tumor antigens associated with AML, as described in S. Anguille et al, Leukemia (2012), 26, 2186-2196.

Other tumor-associated and tumor-specific antigens are known to those skilled in the art.

Receptors, antibodies and scFvs that bind to TSA and TAA useful for constructing chimeric antigen receptors are known in the art, as are the nucleotide sequences that encode them.

In some specific embodiments, the antigen recognized by the extracellular domain of the chimeric antigen receptor is an antigen that is not typically considered a TSA or TAA, but that is nonetheless associated with tumor cells or tumor-induced damage. In some embodiments, for example, the antigen is, for example, a growth factor, cytokine, or interleukin, such as a growth factor, cytokine, or interleukin associated with angiogenesis or vasculogenesis. Such growth factors, cytokines or interleukins may include, for example, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), insulin-like growth factor. (IGF) or interleukin-8 (IL-8). Tumors can also create a local hypoxic environment relative to the tumor. Thus, in other specific embodiments, the antigen is a hypoxia-associated factor, such as HIF-1a, HIF-1e, HIF-2a, HIF-2e, HIF-3a, or HIF-3e. Tumors can also cause local damage to normal tissue by causing the release of molecules known as damage-associated molecular pattern molecules (DAMPs; also known as alarmins - damage-associated molecular moieties). Therefore, in some other specific embodiments, the antigen is a DAMP, e.g., heat shock protein, chromatin-associated protein high mobility group block 1 (HMGB 1), S100A8 (MRP8, calgranulin A), S100A9 (MRP14, calgranulin B), serum amyloid A (SAA), or may be deoxyribonucleic acid, adenosine triphosphate, uric acid or heparin sulfate.

Transmembrane domain. In some embodiments, the extracellular domain of the CAR is linked to the transmembrane domain of the polypeptide via a linker, spacer, or hinge polypeptide sequence, such as a CD28 sequence or a CTLA4 sequence. The transmembrane domain may be derived from or derived from the transmembrane domain of any transmembrane protein and may include all or part of such transmembrane domain. In specific embodiments, the transmembrane domain may be derived from, for example, CD8, CD16, cytokine receptor and interleukin receptor, or growth factor receptor or the like.

Intracellular signaling domains. In some embodiments, a CAR intracellular domain is or includes an intracellular domain or protein motif that is expressed on the surface of T cells and triggers the activation and/or proliferation of said T cells. Such a domain or motif is capable of transmitting the primary antigen-binding signal, which is necessary for T-lymphocyte activation in response to antigen binding to the extracellular part of the CAR. Typically this domain or motif includes or is an ITAM (immunoreceptor tyrosine-based activation motif). ITAM-containing polypeptides suitable for CAR include, for example, CD3 zeta chain (CD3Z) or ITAM-containing portions thereof. In a specific embodiment, the intracellular domain is a CD3Z intracellular signaling domain. In other specific embodiments, the intracellular domain is derived from the lymphocyte receptor chain, a complex protein

- 45 045949

TCR/CD3, Fe receptor subunit or IL-2 receptor subunit. In some embodiments, the CAR further comprises one or more co-stimulatory domains or motifs, for example, as part of an intracellular domain of a polypeptide. One or more costimulatory domains or motifs may be or may contain one or more CD27 costimulatory polypeptide sequences, a CD28 costimulatory polypeptide sequence, an OX40 costimulatory polypeptide sequence (CD134), a co-stimulatory polypeptide sequence 4-1BB (CD137), or a costimulatory inducible T cell costimulatory sequence (ICOS) polypeptide sequence, or other co-stimulatory domain or motif, or any combination thereof.

CAR may also contain a T cell survival motif. A T cell survival motif can be any polypeptide sequence or motif that promotes the survival of a T lymphocyte following antigen stimulation. In some embodiments, the T cell survival motif is or is derived from CD3, CD28, IL7 receptor (IL-7R) intracellular signaling domain, IL-12 receptor intracellular signaling domain, IL-15 receptor intracellular signaling domain, IL-15 receptor intracellular signaling domain -21 or the intracellular signaling domain of the transforming growth factor β receptor (TGFe).

Modified immune cells expressing CARs may be, for example, T lymphocytes (T cells, e.g. CD4+ T cells or CD8+ T cells), cytotoxic lymphocytes (CTL) or natural killer (NK) cells. T lymphocytes used in the compositions and methods presented herein can be naïve T lymphocytes or MHC-restricted T lymphocytes. In some embodiments, the T lymphocytes are tumor infiltrating lymphocytes (TILs). In some embodiments, T lymphocytes were isolated from a tumor biopsy or were expanded from T lymphocytes isolated from a tumor biopsy. In some other embodiments, T cells have been isolated or expanded from T lymphocytes isolated from peripheral blood, umbilical cord blood, or lymph. Immune cells to be used to generate modified CAR-expressing immune cells can be isolated using conventional techniques known in the art, such as blood collection followed by apheresis and possibly antibody-mediated cell isolation or sorting.

The modified immune cells are preferably autologous to the individual to whom the modified immune cells are to be administered. In some other embodiments, the modified immune cells are allogeneic to the individual to whom the modified immune cells are to be administered. When allogeneic T lymphocytes or NK cells are used to produce modified T lymphocytes, T lymphocytes or NK cells are preferably selected, which reduces the likelihood of graft-versus-host disease (GVHD) occurring in the individual. For example, in some embodiments, virus-specific T lymphocytes are selected to produce modified T lymphocytes; such lymphocytes are expected to have a significantly reduced native ability to bind to, and thus be activated by, any recipient antigens. In some embodiments, recipient-mediated rejection of allogeneic T lymphocytes can be reduced by coadministration of one or more immunosuppressive drugs, such as cyclosporine, tacrolimus, sirolimus, cyclophosphamide, or the like, to the host.

T lymphocytes, for example, unmodified T lymphocytes or T lymphocytes expressing CD3 and CD28, or containing a polypeptide containing a CD3Z signaling domain and a CD28 co-stimulatory domain, can be expanded using antibodies to CD3 and CD28, for example, antibodies attached to balls; see, for example, US patent No. 5948893; 6534055; 6352694; 6692964; 6887466; and 6905681.

Modified immune cells, such as modified T lymphocytes, may optionally contain a suicide gene or safety switch that allows virtually all modified immune cells to be killed if desired. For example, the modified T lymphocytes, in some embodiments, may contain the HSV thymidine kinase (HSV-TK) gene, which causes the modified T lymphocytes to die upon contact with ganciclovir. In another embodiment, the modified T lymphocytes contain an inducible caspase, for example, inducible caspase 9 (icaspase9), for example, a fusion protein between caspase 9 and the human binding protein FK506, allowing dimerization using a specific small molecule pharmaceutical. See Straathof et al., Blood 1 05 (11): 4247-4254 (2005).

In some embodiments, Compound 1, Compound 2, or Compound 3 and a second active agent provided herein are administered to patients with various types or stages of multiple myeloma in combination with chimeric antigen receptor (CAR) T cells. In some embodiments, the CAR T cell in combination targets B-cell maturation antigen (BCMA), and in more specific embodiments, the CAR T cell is bb2121 or bb21217. In some embodiments, the CAR T cell is JCARH125.

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J. Pharmaceutical compositions.

Pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more compounds provided herein and/or a second active agent provided herein, and optionally a pharmaceutically acceptable carrier, diluent or excipient.

The compounds may be formulated as suitable pharmaceutical formulations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or as sterile solutions or suspensions for ophthalmic or parenteral administration. and transdermal patch and dry powder inhaler formulations. Typically, the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

In the compositions, effective concentrations of one or more compounds or pharmaceutically acceptable salts are admixed with a suitable pharmaceutical carrier or carrier medium. In some embodiments, the concentrations of the compounds in the compositions are effective to deliver an amount when administered that treats, prevents, or alleviates one or more symptoms and/or progression of multiple myeloma.

Typically the compositions are formulated for single dose administration. To formulate the composition, a mass fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the condition being treated is alleviated or improved. Pharmaceutical carriers or carrier media suitable for administration of the compounds presented herein include any such carriers known to those skilled in the art as suitable for the particular route of administration.

In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in a composition or may be combined with other active ingredients. Liposome suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. They can be prepared in accordance with methods known to those skilled in the art. For example, liposomal dosage forms can be prepared as known in the art. Briefly, liposomes such as multilayer vesicles (MLVs) can be formed by drying egg phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio) on the inside of a flask. Add a solution of the compound provided herein in divalent cation-free phosphate buffered saline (PBS) and shake the flask until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation and then resuspended in PBS.

The active compound is included in a pharmaceutically acceptable carrier in an amount sufficient to provide a therapeutically beneficial effect without causing undesirable side effects in the patient being treated. The therapeutically effective concentration can be determined empirically by testing the compounds in the in vitro and in vivo systems described herein and then extrapolated from this for human dosing.

The concentration of the active compound in the pharmaceutical composition will depend on the absorption, tissue distribution, inactivation, metabolism and excretion of the active compound, the physicochemical characteristics of the compound, the dosage regimen and amount administered, as well as other factors known to those skilled in the art. For example, the amount that is delivered is sufficient to improve one or more symptoms of cancer, including solid tumors and hematologic tumors.

Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical use may include any of the following: a sterile diluent such as water for injection, saline, fatty vegetable oil, polyethylene glycol, glycerin, propylene glycol, dimethyl acetamide or other synthetic solvent; antimicrobial agents such as benzyl alcohol and methylparabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates and phosphates; and tone-regulating agents such as sodium chloride or dextrose. Formulations for parenteral administration may be contained in ampoules, pens, disposable syringes, or single-dose or multiple-dose vials made of glass, plastic, or other suitable material.

In cases where compounds exhibit insufficient solubility, methods for solubilizing the compounds can be used. Such methods are known to those skilled in the art and include, but are not limited to, the use of co-solvents such as dimethyl sulfoxide (DMSO), the use of surfactants such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

When mixing or adding compound(s), the resulting mixture may be a solution, suspension

- 47 045949 gap, emulsion, etc. The form of the resulting mixture depends on a number of factors, including the intended route of administration and the solubility of the compound in the selected vehicle or carrier medium. The effective concentration is sufficient to relieve the symptoms of the disease, disorder or condition being treated and can be determined empirically.

The pharmaceutical compositions are intended for administration to humans and animals in unit dosage forms such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, as well as oil-in-water emulsions, containing suitable amounts of the compounds or their pharmaceutically acceptable salts. Pharmaceutically therapeutically active compounds and their salts are formulated and administered in single dosage forms or multiple dosage forms. Unit dose dosage forms as used herein refer to physically discrete units suitable for use in humans and animals and are individually packaged as is known in the art. Each unit dose contains a predetermined amount of a therapeutically active compound sufficient to produce the desired therapeutic effect, in combination with the necessary pharmaceutical carrier, excipient or diluent. Examples of unit dosage forms include ampoules and syringes, as well as individually packaged tablets or capsules. Unit dose forms can be administered in fractional or multiple doses. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container for administration in separate unit dosage forms. Examples of multiple dose forms include vials, tablet or capsule bottles, or bottles of the order of a pint (473 ml) (or several pints) or a gallon (3.8 L) (or several gallons). Therefore, a multiple dose form is a plurality of unit doses that are not separated within the package.

Dosage forms or compositions can be prepared containing the active ingredient in the range of 0.005% to 100%, with the balance being a non-toxic carrier. For oral administration, a pharmaceutically acceptable non-toxic composition is prepared by including any of the commonly used excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, crosscarmellose sodium, glucose, sucrose, magnesium carbonate or sodium saccharin . Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations such as, but not limited to, implants and microencapsulated delivery systems, as well as biodegradable, biocompatible polymers such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparing these compositions are known to those skilled in the art.

The active compounds or pharmaceutically acceptable salts can be formulated with carriers that protect the compound from rapid elimination from the body, such as sustained release formulations or coatings.

The compositions may include other active compounds to provide the desired combinations of properties. The compounds provided herein, or pharmaceutically acceptable salts thereof, as described herein, may also advantageously be administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the art to be valuable in the treatment of one or more diseases or medical conditions. mentioned above, such as diseases associated with oxidative stress. It should be understood that such combination therapy constitutes an additional aspect of the compositions and methods of treatment presented herein.

K. Evaluation of the activity and properties of the combination.

Standard physiological, pharmacological, and biochemical procedures are available to screen compounds to identify those that have desired properties, including activity against multiple myeloma proliferation and an adequate safety profile. Such assays include, for example, biochemical assays such as binding assays, radioactive inclusion assays, and various cell-based assays.

Isoindolinone derivatives and their therapeutic uses are described, for example, in US Pat. No. 8,518,972. Surprisingly, Compound 1, Compound 2, and Compound 3 exhibit unexpected and beneficial properties, as shown in the Examples section. These benefits include significantly increased efficacy against multiple myeloma, increased rates of apoptosis, and a more potent and effective combination response with dexamethasone, as well as an unexpectedly improved safety profile as evidenced by decreased functional activity of α1-adrenergic and D2-dopamine receptors (in vitro as well as in vitro). vivo), improved cell killing selectivity (as evidenced by reduced non-MM cell death) and reduced CYP3A4 inhibition. In addition, Compound 1, Compound 2 and Compound 3 exhibit unexpected synergy when used in combination with second active agents, as shown in the Examples section.

It is understood that the above detailed description and accompanying examples are only

- 48 045949 are illustrative only and should not be construed as limiting the scope of the invention. Various changes and modifications to the described embodiments will be apparent to those skilled in the art. Such changes and modifications, including, but not limited to, those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use presented herein, may be made without departing from their spirit or scope. US patents and publications referenced herein are incorporated herein by reference.

5. Examples

Some embodiments of the invention are illustrated by the following non-limiting examples.

Abbreviations:

AcN/ACN - acetonitrile;

AIBN - azobiisobutyronitrile;

Boc - tert-butyloxycarbonyl;

BOC2O - di-tert-butyl dicarbonate;

tBuOK - potassium tert-butoxide;

DIEA - diisopropylethylamine;

DMF - ^Ni-dimethylformamide;

DMSO - dimethyl sulfoxide;

EtOAc - ethyl acetate;

IPA - isopropanol or 2-propanol;

MeOH - methanol;

MM - multiple myeloma;

NBS - N-bromosuccinimide;

NMR - nuclear magnetic resonance;

PBMC - human peripheral blood mononuclear cells;

i-PrOAc - isopropyl acetate;

TBS - tert-butyldimethylsilyl;

TBSCl - tert-butyldimethylsilyl chloride;

THF - tetrahydrofuran;

TLC - thin layer chromatography;

TMSCl - trimethylsilyl chloride.

Example 1. Synthesis of ^)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine-1- silt)-3-fluorobenzonitrile (compound 2).

tert-Butyl (4S)-5-amino-4-(benzyloxycarbonylamino)-5-oxopentanoate. To a solution of (2S)-2(benzyloxycarbonylamino)-5-tert-butoxy-5-oxopentanoic acid (150 g, 445 mmol) in 1,4-dioxane (1.50 L) was added di-tert-butyl dicarbonate (155 g , 711 mmol), pyridine (70.3 g, 889 mmol) and ammonium bicarbonate (105 g, 1.33 mol). The reaction mixture was stirred at 18°C for 16 hours and then evaporated. The residue was dissolved in ethyl acetate (5.0 L) and water (5.0 L), the organic layer was separated and washed with HCl (3.0 ml, 1N), saturated sodium bicarbonate (3.0 L), brine (3.0 L), 0 L), dried over anhydrous sodium sulfate, filtered and evaporated to give crude tert-butyl (4S)-5amino-4-(benzyloxycarbonylamino)-5-oxopentanoate (450 g, crude) as a white solid, which was used in the following stage without further purification. ¹ H NMR 400 MHz DMSOd6 δ: 7.35-7.30 (m, 5H), 7.02 (s, 1H), 5.01 (d, J=3.2 Hz, 1H), 3.93-3, 90 (m, 1H), 2.20 (t, J=8.0 Hz, 2H), 1.88-1.84 (m, 1H), 1.72-1.69 (m, 1H), 1 .35 (s, 9H).

tert-Butyl (4S)-4,5-diamino-5-oxo-pentanoate. To a solution of tert-butyl ^S^^muho^(benzyloxycarbonylamino)-5-oxopentanoate (112 g, 333 mmol) in methanol (1.0 L) was added 10% palladium on carbon (15 g) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under an atmosphere of hydrogen gas (40 psi) at 30°C for 16 hours. The reaction mixture was filtered and the filtrate was evaporated to give crude tert-butyl (4S)-4,5-diamino-5-oxopentanoate as colorless oil. 1H NMR 400 MHz DMSO^δ: 7.30 (s, 1H), 6.95 (s, 1H), 3.10-3.07 (m, 1H), 2.27-2.23 (m, 2H ), 1.69-1.78 (m, 1H), 1.59-1.55 (m, 1H), 1.38 (s, 9H).

Methyl 3-hydroxy-2-methyl benzoate. Four batches (200 g each) were processed in parallel. To a solution of 3-hydroxy-2-methylbenzoic acid (200 g, 1.31 mol) in methanol (4.0 L) was added concentrated sulfuric acid (47.7 g, 486 mmol). The reaction mixture was stirred at 60°C for

- 49 045949

h. The reaction mixture was concentrated to 800 ml. The resulting mixture was cooled to 20°C and slowly poured into water (400 ml) over 30 min. Water (1200 ml) was added at 20°C over 3 hours and the resulting mixture was stirred at 20°C for 1 hour. The precipitated solid was collected by vacuum filtration (four batches combined) and washed three times with water/methanol (1000 ml, 9: 1) or until the filtrate reaches pH>3. The solid was dried in vacuo at 45°C to obtain methyl 3-hydroxy-2-methyl benzoate (700 g, 80.4% yield) as a gray solid. 1H NMR: 400 MHz DMSO-de δ: 9.70 (s, 1H), 7.18 (t, J=6.8 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H) , 7.00 (t, J=6.8 Hz, 1H), 3.81 (s, 3H), 2.29 (s, 3H).

Methyl 3-[tert-butyl(dimethyl)silyl]oxy-2-methylbenzoate. Two batches (240 g each) were processed in parallel. To a solution of methyl 3-hydroxy-2-methylbenzoate (240 g, 1.44 mol) in N.N-dimethylformamide (1.40 L) was added imidazole (246 g, 3.61 mol) and tert-butyldimethylsilyl chloride (238 g, 1.58 mol) at 5°C. After addition, the mixture was heated to 20°C and stirred for 6 hours. Isopropyl acetate (1700 ml) was added and then water (2000 ml) was added slowly, maintaining the temperature below 30°C. The resulting mixture was stirred, followed by separation of the organic phase. The combined organic layers (two batches combined) were washed with water (1700 ml x 3) and evaporated to ~1500 ml (KF <0.05%). The product was stored as an isopropyl acetate solution, which was used in the next step without further purification.

Methyl 2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxybenzoate. Two batches (~375 g each) were processed in parallel. N-bromosuccinimide (274 g, 1.54 mol) and azobisisobutyronitrile (4.40 g, 26 .8 mmol). The reaction mixture was heated to 70°C for at least 1 hour and stirred at 70°C for 4 hours. The reaction mixture was cooled to 20°C and kept at 20°C for at least 1 hour. Two batches of the solid (succinimide) were removed filtration and washed with isopropyl acetate (700 ml). The filtrate was washed with a solution of sodium sulfite (700 g) in water (6000 ml) and then with water (1500 ml). The organic layer was distilled in vacuo at 45°C to dryness to obtain methyl 2-(bromomethyl)-3[tert-butyl(dimethyl)silyl]oxybenzoate (920 g, 95.5% yield) as a dark orange oil. 1H NMR: 400 MHz DMSOD ₆ δ: 7.45 (d, J=6.8 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.13 (t, J=7 .2 Hz, 1H), 4.95 (s, 2H), 1.02 (s, 9H), 0.29 (s, 6H).

tert-Butyl (4S)-5-amino-4-[4-[tert-butyl(dimethyl)silyl]oxy-1-oxoisoindolin-2-yl]-5oxopentanoate. To a solution of tert-butyl (4S)-4,5-diamino-5-oxopentanoate (130 g, 643 mmol) in acetonitrile (4.0 L) was added methyl 2-(bromomethyl) 3-[tert-butyl(dimethyl)silyl ]hydroxybenzoate (210 g, 584 mmol) and diisopropylethylamine (113 g, 877 mmol). The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was evaporated to remove most of the acetonitrile, the residue was dissolved in methyl tert-butyl ether (2.0 L) and water (1.5 L), the organic layer was washed with saturated potassium monophosphate ( 1.0 l x 2), saline solution. (1.0 L), dried over anhydrous sodium sulfate, filtered and evaporated to give crude tert-butyl (4S)-5-amino-4-[4-[tert-butyl(dimethyl)silyl]oxy-1oxoisoindoline-2- yl]-5-oxopentanoate (524 g), which was used in the next step without further purification.

tert-Butyl (4S)-5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate. To a solution of tert-butyl (4S)-5-amino-4-[4-[tert-butyl(dimethyl)silyl]oxy-1-oxoisoindolin-2-yl]-5-oxopentanoate (275 g, 613 mmol) in methanol (2 .0 L) tetrabutylammonium fluoride trihydrate (38.7 g, 123 mmol) was added. The mixture was stirred at 18°C for 16 hours. The reaction mixture was evaporated to remove most of the methanol, and the residue was dissolved in dichloromethane/water (3 L/2 L). The organic layer was separated and washed with brine (1.0 L), dried over anhydrous sodium sulfate, filtered and evaporated to give a crude product, which was purified by a silica gel column to give the product (260 g). The product was added to acetonitrile (750 ml) and the mixture was stirred at 60°C for 2 hours, cooled to 18°C and stirred for a further 2 hours. The solid was filtered and the precipitate was dried to give tert-butyl (4S)-5-amino-4 -(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (248 g, 60.5% yield) as a gray solid. 1H NMR 400 MHz DMSOD6 δ: 10.00 (s, 1H), 7.54 (s, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.14 (d, J=4 .8 Hz, 2H), 4.72-4.68 (m, 1H), 4.49-4.28 (m, 2H), 2.17-1.97 (m, 4H), 1.31 ( s, 9H).

4-(4-(4-(Chloromethyl)benzyl)piperazin-1-yl)3-fluorobenzonitrile. 1,4-bis(chloromethyl)benzene (51.2 g, 292 mmol) was placed in a flask with acetonitrile (195 ml) and N,N-dimethylformamide (195 ml). The reaction mixture was stirred at ambient temperature until all solids dissolved. Diisopropylamine (51.1 mL, 292 mmol) was then added along with 3-fluoro-4-(piperazin-1yl)benzonitrile (20 g, 97 mmol). The reaction mixture was heated to 60°C for 1 hour. Acetonitrile was removed under reduced pressure. The remaining mixture was partitioned between ethyl acetate (1.0 L), water (700 ml) and saline (300 ml). The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. Volatile organic compounds were combined and removed under reduced pressure. The solid was dissolved in a minimal amount of dichloromethane and purified on a silica gel column (0-100% ethyl acetate in hexanes, >3 L). Fractions containing the desired product were combined and volatile organic compounds were removed under reduced pressure. The residue was dissolved in minimal

- 50 045949 a certain amount of dichloromethane and purified a second time on a silica gel column (10% isocratic ethyl acetate in hexanes over 800 ml, then 20-80% ethyl acetate in hexanes over 4 l). Fractions containing the desired product were combined and VOCs were removed under reduced pressure to give 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (22.7 g, 66.0 mmol , yield 67.7%) as an off-white solid. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.33-7.39 (m, 5H) 7.29 (d, J=1.96 Hz, 1H) 7.25 (d, J=1 .96 Hz, 1H) 6.91 (t, J=8.56 Hz, 1H) 4.60 (s, 2H) 3.58 (s, 2H) 3.19-3.27 (m, 4H) 2 .58-2.66 (m, 4H). MS (ESI) m/z 344.2 [M+1]+.

(b)-tert-Butyl 5-amino-4-(4-((4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1oxoisoindoline-2- yl)-5-oxopentanoate. (b)-tert-butyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)5-oxopentanoate (22.05 g, 65.9 mmol) was placed in a flask with 4-(4-( 4-(chloromethyl)benzyl)piperazin-1-yl)-3fluorobenzonitrile (22.67 g, 65.9 mmol), potassium carbonate (18.23 g, 132 mmol) and N,Ndimethylformamide (330 ml). The reaction mixture was heated to 45°C for 16 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and filtered. The filtrate was partitioned between ethyl acetate (900 ml), water (600 ml) and saline (200 ml). The organic layer was separated and washed with water (600 ml). The organic layer was dried over sodium sulfate and volatiles were removed under reduced pressure. The residue was treated with 20% ethyl acetate in hexanes and the volatiles were removed under reduced pressure to give (b)-tert-butyl 5-amino-4-(4-((4-((4-(4-cyano-2-fluorophenyl)piperazine -1yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (44.02 g, 68.6 mmol, 104% yield) as an off-white solid. The yield was slightly higher than quantitative, since some DMF remained. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.43-7.49 (m, 2H) 7.40 (s, 4H) 7.36 (dd, J=8.38, 1.28 Hz, 1H) 7.29 (d, J=1.96 Hz, 1H) 7.26 (d, J=1.83 Hz, 1H) 7.11 (dd, J=7.64, 1.16 Hz, 1H) 6.92 (t, J= 8.50 Hz , 1H) 6.23 (lat s, 1H) 5.24-5.32 (m, 1H) 5.15 (s, 2H) 4.86-4.94 (m, 1H) 4.38-4 .55 (m, 2H) 3.61 (s, 2H) 3.18-3.32 (m, 4H) 2.58-2.70 (m, 4H) 2.09-2.47 (m, 4H ) 1.43 (s, 8H). MS (IER) m/z 642.4 [M+1]+.

^)-4-(4-(4-(((2-(2,6-Dioxopiperpdin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin1-yl)-3-fluorobenzonitrile (connection 2). ^)-tert-butyl 5-amino-4-(4-((4-((4-(4-cyano-2fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl )-5-oxopentanoate (12.1 g, 18.86 mmol) was placed in a vial with acetonitrile (189 ml) and benzenesulfonic acid (3.96 g, 24.51 mmol). The reaction mixture was placed under vacuum and purged with nitrogen. This was repeated once more and then the mixture was heated to 85°C overnight under a nitrogen atmosphere. The warm reaction mixture was poured directly into 2 separatory funnels containing dichloromethane (1000 ml) and ethyl acetate (300 ml). To this mixture were added saturated sodium bicarbonate solution (900 ml), water (100 ml) and saline solution (450 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (800 ml) and ethyl acetate (200 ml). The combined organic layers were dried over anhydrous magnesium sulfate and evaporated. Purification by standard methods yielded the title compound. 1H NMR (400 MHz, DMSOO δ ppm 10.96 (s, 1H) 7.68 (dd, J=13.45, 1.83 Hz, 1H) 7.56 (dd, J=8.44 , 1.83 Hz, 1H) 7.43-7.52 (m, 3H) 7.29-7.39 (m, 4H) 7.11 (t, J=8.80 Hz, 1H) 5.24 (s, 2H) 5.11 (dd, J=13.20, 5.14 Hz, 1H) 4.22-4.46 (m, 2H) 3.54 (s, 2H) 3.12-3 .22 (m, 4H) 2.85-2.97 (m, 1H) 2.53-2.62 (m, 2H) 2.38-2.48 (m, 2H) 1.93-2.03 (m, 1H) MS (ESI) m/z 568.2 [M+1]+.

Example 2: Antiproliferative effects on multiple myeloma cells.

Cell Culture Materials: Human multiple myeloma cell lines were purchased from suppliers and cultured at 37°C with 5% CO2 in media as listed in Table 1. 1. Cell lines resistant to lenalidomide and pomalidomide were generated by methods generally described previously (Lopez-Girona et al Leukemia 2012; 26 (11): 2335). All cell lines were maintained in log phase, and cell density and viability were monitored by trypan blue exclusion using a Vicell XR Cell Viability Analyzer (Beckman Coulter, Brea, CA).

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Table 1

Multiple Myeloma Cell Lines Tested

Cell line MM Supplier/Source Catalog number Cultivation conditions Research Institute NCI-H929 ATCC (Manassas, Virginia) CRL-9068 RPMI-1640, 10% FBS NCI-H929-1O51 own development, resistant to lenalidomide No data RPMI-1640, 10%FBS ORM2 DSMZ (Brunschweig, Germany) ACC-50 RPMI-1640, 10% FBS ORM2-R10 own development, resistant to 10 µM pomalidomide No data RPMI-1640, 10% FBS

Preparation of Study Solutions: Compounds were plated in black 384-well plates (Corning Inc.) to a final volume of 0.1% DMSO, assuming a maximum volume of 50 μL. A 10-point dose-response starting at 10 μM with a 1:3 dilution was printed in duplicate by acoustic dispensing using the EDC ATS-100 platform. Alternatively, a 10-point dose response was used, starting at 10 μM at a 1:10 dilution or starting at 100 nM at a 1:3 dilution.

Cell Proliferation Assays: The effect of compounds on the proliferation/viability of hematological cell lines (Table 1) was assessed after 120 hours of incubation using CTG (Promega) according to the manufacturer's instructions. Hematology cell lines were dispensed into compound plates using a Multidrop Combi Reagent Dispenser (Thermo Scientific, Waltham, MA) at a concentration of 0.1 x 10 ⁶ cells per ml in a total volume of 50 μl. After 120 h, 25 μl of CTG per well was dispensed using a Multidrop Combi Reagent Dispenser, and adenosine triphosphate (ATP) release from viable cells was measured as relative luminescence units after 30 min using the Envision platform.

Results. Compound 1 and Compound 2 demonstrate antiproliferative activity against MM cell lines. The MM cell lines selected for this study were those sensitive and resistant to lenalidomide and/or pomalidomide (Table 1), two agents used clinically to treat myeloma patients. Proliferation was assessed using the CellTitre-Glo® test. Results for cultures incubated with compounds were normalized to results for control cultures for each cell line. IC50 for cell growth inhibition by compounds was determined for each cell line using ActivityBase software. Compound 1 and Compound 2 effectively inhibited cell proliferation in four cell lines, as determined by quantifying the levels of ATP present in the medium after 120 hours. The antiproliferative IC50 values of compound 1 and compound 2 ranged from 0.07 nM to 19 nM (Table 2). Compound 1 and Compound 2 showed very effective proliferative activity against multiple myeloma, even against cell lines resistant to lenalidomide and/or pomalidomide.

table 2

Inhibition of Cell Growth by Compound 1 and Compound 2 in MM Cell Lines in Liquid Culture Medium

Conn. No. NCI-H929 120h IC.o NCI-H929.1051 120h 1С.о ORM-2 120h Kao ORM-2.RYU 120h IC.0 1 <0.5 nM 2.5 nM <0.5 nM 19nM 2 0.07 nM 1.0 nM 0.07 nM 4.3 nM

Example 3 Compound 1/Compound 2 Off-Target Effects and Consequences.

α1-Adrenergic receptors and dopamine D2 receptors. Methods: Binding and functional assays for α1-adrenergic and dopamine D2 receptors were performed by Eurofins Cerep according to their methods.

α1 Adrenergic receptor. pBinding at 10pM. The binding assay assessed the affinity of the test drug for the non-selective α1-adrenergic receptor in the rat cerebral cortex.

- 52 045949 sy. pMembrane homogenates of the cerebral cortex were incubated in duplicate for 60 minutes at room temperature with 0.25 nM [ ³ H]prazosin in the absence or presence of test samples at 10 μM. After the incubation period, the samples were filtered through glass fiber filters, the filters were dried and then the radioactivity was counted using a scintillation counter. Results are expressed as the average percentage inhibition of control radioligand binding.

IC50 binding. To determine the IC ₅₀ of non-selective α1-adrenergic receptor binding, various concentrations of the test substance were incubated in duplicate with 0.25 nM [ ³ H]prazosin. The previously described compound 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1oxoisoindolyl-2-yl)piperidin-2,6-dione ( example 5.285 in US patent No. 8518972) (Compound A) was tested at 0.01-30 μΐ-M. Compound B, the S-enantiomer of Compound A, was tested at 0.0003-10 μΙΗ. Compound 1 and Compound 2, the S-enantiomer of Compound 1 was assayed at 0.03-100 pM. Radioactivity was measured as described above. IC ₅₀ was defined as the concentration causing half the inhibition of specific binding of the control.

Antagonistic activity. The antagonistic effects of test compounds on the α _1A and α _1B adrenergic receptors were measured using human receptor-transfected Chinese hamster ovary (CHO) cells. Antagonist activity was determined by measuring the effect of the compound on agonist (epinephrine)-induced calcium mobilization in the α _1A receptor assay or cAMP levels in the α _1B receptor assay. In these experiments, CHO cells were incubated in duplicate at room temperature with the test substance and epinephrine at 3 nM in the α _1A receptor assays or at 3000 nM in the α _1B receptor assay. Compound A was tested in the a _1A receptor assay at 0.01-30 μΙΗ. Compound B was tested in the a _1A and a _1B receptor assays at 0.0003-30 μΙΗ. Compound 1 and Compound 2 were assayed at 0.03-30 piM in the a _1A receptor assay and 0.03-100 piM in the a _1B receptor assay. In the a _1A receptor assay, cytosolic calcium levels were measured fluorometrically using the Fluo4 Direct fluorescent probe. Intracellular cAMP levels in the adrenergic receptor a _1B assay were measured using homogeneous time-resolved fluorescence (HTRF). The IC ₅₀ of antagonism was defined as the concentration that caused half the response of the control agonist.

Dopamine D2 receptor. μBinding at 10 pM. The binding assay assessed the affinity of test samples for the dopamine D2 receptor in transfected human embryonic kidney (HEK)-293 cells. To determine binding in the D _2S receptor assay, the test article was incubated with 0.3 nM [ ³ H]methylspiperone or 1 nM [ ³ H]7-hydroxy-2-N,Ni-dipropylaminotetraline (7-OHDPAT). [ ³ H]Methylspiperone at a concentration of 0.3 nM was also used as a control ligand in the D2L binding assay. Cell membrane homogenates were incubated in duplicate at room temperature for 60 minutes with ligand in the absence or presence of test samples at 10 μΙΗ. After the incubation period, the samples were filtered through glass fiber filters, the filters were dried and then the radioactivity was counted using a scintillation counter. Results are expressed as the average percentage inhibition of control radioligand binding.

IC ₅₀ binding. To determine IC ₅₀ binding in D2 receptor assays, HEK-293 was tested as described above, but with different concentrations of test substance. μCompound A was tested at 0.01-30 pM in a D _2S radioligand binding assay. μCompound B was tested at 0.0003-10 μM in D _2S and D2L binding assays. Compound 1 was tested at 0.03-100 pM in both the D _2S and D2L assays, while compound 2 was tested at 0.03-100 piM in the D _2S assay and 0.01-100 piM in the D2L assays. IC ₅₀ was defined as the concentration causing half the inhibition of specific binding of the control.

Agonistic activity. The agonism of test compounds at the dopamine D _2S receptor was assessed using HEK-293 cells transfected with the human receptor. Agonistic activity was determined by measuring the effect of the compound on impedance modulation. In these experiments, HEK-293 cells were incubated in duplicate at 28°C with the test article. Compound A was tested at 0.01-30 μM. Compound B was tested at 0.0003-10 pM, while Compound 1 and Compound 2 were tested at 0.01-10 pM. Dopamine (3 pM) was used as an agonist control. Impedance measurements were monitored for 10 min after ligand addition using cellular dielectric spectroscopy. EC ₅₀ was defined as the concentration that produced half the maximum response compared to the response to the control agonist (dopamine).

Results. Binding at 10 μM at α1 adrenergic and dopamine D2 receptors was assessed for Compound 1, Compound 2, Compound A, Compound B, and a number of compounds exemplified in US Pat. No. 8,518,972 (as indicated by their example number Ex) (Table 3) While the previously disclosed compounds completely inhibited ligand binding at both receptors, surprisingly, compound 1 and compound 2 showed a significantly reduced ability to inhibit ligand binding, showing only 67/ 62% (α1-adrenergic receptor) and 55/52% (dopamine _D2S ) inhibition of ligand binding, respectively.

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Table 3

Effect of compound A, compound B, compound 1, compound 2 and previously described compounds on the α1 adrenergic and dopamine D2 receptor o πόθο Τ'* .,-. .N. JJ) ⁰ ί 1 R ¹ ' ^V ^'R ²

Conn. No. R ¹ R ² X Stereo Adrenergic al Dopamine D _2s % Inhibition (@10 µM) % Inhibition (@ 10 µM) 1 CN F dn ₂ rac 67 55 2 CN F dn ₂ S 62 52 A F F dn ₂ rac 102 99 IN F F dn ₂ S 98 99 Etc. 5.229 AND N dn ₂ rac 98.3 98.7 Etc. 5.273 F N dn ₂ rac 100.3 94.7 Etc. 5,289 F N with rac 97.9 92.4

Example 4. Effect of compound 2 in combination with small molecular inhibitors.

The effect of combining treatment with compound 2 and small molecule inhibitors with different mechanisms was assessed in a panel of MM cell lines. Nine small molecule inhibitors were selected for combination studies with compound 2 based on their preclinical and/or anti-MM activity. Cell lines H929-1051, KMS11, KMS12PE, L363, OPM-P10, and RPMI8226 were selected for this study to represent distinct genetic cluster groups in MM cell lines. Compound concentrations for combination treatments were selected to be 1 log above and 2 log below the IC ₅₀ for a single agent. The combination agents were administered on a 6-point dose-response curve (DRC) at a 1:3 dilution, compound 2 was administered on a 10-point DRC, also at a 1:3 dilution. Combined experiments were performed twice, each time repeating the data on separate plates. Compounds were pre-applied into the appropriate wells of 384-well plates using an acoustic pipette. All MM cell lines were cultured in a 37°C 5% CO incubator using the indicated cell culture media containing 1x penicillin-streptomycin. Cells were added to compound containing 384 well plates using a Multidrop reagent dispenser and allowed to incubate for 3 days at 37°C with 5% CO2. After 3 days, cells were assessed for ATP levels using Cell Titer-Glo measured on a luminescence detector (PerkinElmer Envision).

The highest single agent (HAS) method was used to detect synergy in the dose-response curve data. The combinations were analyzed in terms of response surface. A statistical framework (Van Der Borght, K., et al., BIGL: A biochemically intuitive generalized null Leve model for predicting the expected combined effect consistent with partial agonism and antagonism; Scientific Reports, 7 (1), 17935-1-17935- 9 (2017)) was included in the analysis on top of the HAS null model with two statistical tests.

1) The full response surface differs from the null model.

2) An individual hole is different from the zero model.

Results: The effect of treatment with compound 2 in combination with small molecule inhibitors was assessed in a panel of multiple myeloma cell lines. Compound 2 was screened in

- 54 045949 combinations with 9 compounds, and synergy was calculated for all wells for 6 cell lines, and the results are summarized in FIG. 1. Examples of data plots from selected studies are shown in FIG. 2Afig. 2I, respectively. The PIM inhibitor, LGH-447, showed synergy in combination with compound 2 in all six cell lines tested. The mTOR inhibitor everolimus showed synergy in combination with compound 2 in five of the six cell lines tested. The IGF-1R inhibitor, linsitinib, demonstrated synergy in combination with compound 2 in four of the six cell lines tested. Combining the compound with the BTK inhibitor, ibrutinib, the MEK inhibitor, trametinib, the XPO1 inhibitor, selinexor, the DOT1L inhibitor, SGC0946, the EZH2 inhibitor, EPZ-6438, and the JAK2 inhibitor, fedratinib, demonstrated synergy in one, two, or three of the six cell lines tested. These data suggest that combination treatment with compound 2 with tested small molecule inhibitors represents a potential paradigm for the treatment of MM, including some with synergistic activity.

Example 5. Effect of compound 2 in combination with a BRD4 inhibitor.

K12PE (parental) and K12PE-PR (pomalidomide-resistant) cell lines were treated with varying doses of Compound 2 in combination with increasing doses of the BRD4 inhibitor JQ1 for 3 days. Cell proliferation was analyzed using thymidine incorporation assays. Additivity index values were calculated by Calcusyn, and values below 10 ⁰ represented synergy between combination treatments. The results are shown in Fig. 3A (K12PE), fig. 3B (K12PE additivity index), FIG. 3C (K12PE-PR) and FIG. 3D (K12PE-PR additivity index), respectively. The BRD4 inhibitor (JQ1) showed synergistic activity with compound 2.

Example 6 Effect of compound 2 in combination with a MEK inhibitor.

AMO1 (parental) and AMO1-PR (pomalidomide-resistant) cell lines were treated with varying doses of Compound 2 in combination with increasing doses of MEK inhibitor for 3 days. Cell proliferation was analyzed using thymidine incorporation assays. Additivity index values were calculated by Calcusyn, and values below 10 ⁰ represented synergy between combination treatments. The results are shown in Fig. 4A (AMO1), FIG. 4B (AMO1 additivity index), FIG. 4C (AMO1-PR) and FIG. 4D (AMO1-PR additivity index), respectively. The MEK inhibitor (trametinib) demonstrated synergistic activity with compound 2.

Example 7. Effect of compound 2 in combination with an EZH2 inhibitor.

The H929 cell line was treated with varying doses of Compound 2 in combination with increasing doses of the EZH2 inhibitor UNC1999 for 3 days. Cell proliferation was analyzed using thymidine incorporation assays. Additivity index values were calculated by Calcusyn, and values below 10 ⁰ represented synergy between combination treatments. The results are shown in Fig. 5A (H929) and FIG. 5B (H929 additivity index). The EZH2 inhibitor (UNC1999) showed synergistic activity with compound 2.

Example 8 Effect of compound 2 in combination with a PLK1 inhibitor.

AMO1 and AMO1-PR (pomalidomide-resistant) cell lines were treated with increasing doses of Compound 2 in combination with a PLK1 inhibitor (BI2536). Changes in cell proliferation were studied in response to monotherapy and combinations on day 3 after treatment. The additivity index was calculated using the Calcusyn-based method. Additivity index values were calculated by Calcusyn, and values below 10 ⁰ represented synergy between combination treatments. PLK1 is one of the key target genes of MDMS8 (molecularly defined myeloma segment 8), a high-risk cluster identified in the Myeloma Genome Project. The results are shown in Fig. 6A (AMO1), FIG. 6B (AMO1 additivity index), FIG. 6C (AMO1-PR) and FIG. 6D (AMO1-PR additivity index), respectively. Inhibition of the PLK1 target gene MDMS8 by compound 2 is synergistic in AMO1 and AMO1-PR cells.

Example 9 Effect of Compound 2 in Combination with NEK2 Inhibitor.

AMO1 and AMO1-PR (pomalidomide-resistant) cell lines were treated with increasing doses of Compound 2 in combination with a NEK2 inhibitor (JH295). Changes in cell proliferation were studied in response to monotherapy and combinations on day 3 after treatment. Additivity index values were calculated by Calcusyn, and values below 10 ⁰ represented synergy between combination treatments. NEK2 is one of the key target genes of MDMS8 (molecularly defined myeloma segment 8), a high-risk cluster identified in the Myeloma Genome Project. The results are shown in Fig. 7A (AMO1 additivity index) and FIG. 7B (AMO1-PR additivity index), respectively. Inhibition of the NEK2 target gene MDMS8 by compound 2 is synergistic in AMO1 and AMO1-PR cells.

Example 10. Effect of compound 2 in combination with an AURKB inhibitor.

Cell lines AMO1, AMO1-PR (pomalidomide-resistant), K12PE and K12PE-PR (pomalidomide-resistant) were treated with increasing doses of compound 2 in combination with an AURKB inhibitor (AZD1152). Changes in cell proliferation were studied in response to monotherapy and combinations on day 3 after treatment. Additivity index values were calculated by Calcusyn, and values below 10 ⁰ represented synergy between combination treatments. AUKKB is one of the key

- 55 045949 target genes of MDMS8 (molecularly defined myeloma segment 8), a high-risk cluster identified in the Myeloma Genome Project. The results are shown in Fig. 8A (AMO1 additivity index), FIG. 8B (K12PE additivity index), FIG. 8C (AMO1-PR additivity score) and FIG. 8D (K12PE-PR additivity index), respectively. Inhibition of the AURKB target gene MDMS8 by compound 2 is synergistic in AMO1, AMO1-PR, K12PE and K12PE-PR cells.

Example 11. Effect of compound 2 in combination with a BIRC5 inhibitor.

AMO1, AMO1-PR (pomalidomide-resistant) cell lines were treated with increasing doses of compound 2 in combination with a BIRC5 inhibitor (YM155). Changes in cell proliferation were studied in response to monotherapy and combinations on day 3 after treatment. Additivity index values were calculated by Calcusyn, and values below 10 ⁰ represented synergy between combination treatments. BIRC5 is one of the key target genes of MDMS8 (molecularly defined myeloma segment 8), a high-risk cluster identified in the Myeloma Genome Project. The results are shown in Fig. 9A (AMO1), FIG. 9B (AMO1 additivity index), FIG. 9C (AMO1-PR) and FIG. 9D (AMO1-PR additivity index), respectively. Inhibition of the BIRC5 target gene MDMS8 by compound 2 is synergistic in AMO1 and AMO1-PR cells.

Example 12: Combination studies with additional second agents.

Additional second agents, including DNA methyltransferase inhibitors, EZH2 inhibitors, DOT1L inhibitors, and BET inhibitors, were selected for combination studies with Compound 2 in relapsed refractory multiple myeloma. Five MM cell lines with acquired or innate resistance to lenalidomide or pomalidomide (OPM.2-P10, H929-1051, KMS12BM PR, L363, and JJN3) were included in the studies. The effect of compound 2 in combination with these second agents on MM cells was assessed in a 7-day in vitro assay. MM cells were seeded at a density corresponding to the growth rate of each cell line, aiming to achieve 50D100K cells by day 7. The assay was performed in a 96-well plate. All MM cell lines were cultured in a 37°C 5% CO2 incubator using the indicated cell culture media containing 1x penicillin-streptomycin. MM cells were primed with these second agents for 3 days at an IC ₅₀ value for one agent. For compounds that did not reach the IC ₅₀ value, 3 μM (the highest concentration tested) was used. Compound 2 was added to cells at a dose range of 30 μM to 0.00018 μM, depending on the cell line, to generate an 8-point dose-response curve. Cells were incubated at 37°C for an additional 4 days. At the end of the 7-day treatment, MM cells were stained with Annexin V and 7-AAD and analyzed on a flow cytometer. Live MM cells were identified as double negative for annexin V and 7-AAD. In these experiments, synergy calculations were performed using the fractional product method (Webb, 1963). The combination was considered synergistic if synergy was present at one or more doses of Compound 2 with these second agents.

Results. The effect of combining compound 2 with these second agents was assessed in a panel of MM cell lines in a 7-day assay. Compound 2 was tested in combination with azacitidine (DNA methyltransferase inhibitor), tazemetostat and CPI-1205 (EZH2 inhibitors), Compound C (BET inhibitors) and pinometostat (DOT1L inhibitor). Compound 2 in combination with BET inhibitors (Compound C) showed significant synergy in OPM-2.P10 and H929-1051 cells (Fig. 10A and Fig. 10B). Compound 2 in combination with azacitidine showed synergy in 4 of the cell lines tested (Figure 11A-D). The combination with EZH2 inhibitors was synergistic in all 5 cell lines tested (Fig. 12A-D, Fig. 13A-D, Fig. 14A and B) with a dose-dependent effect shown in Fig. 14A and B with KMS12BM PR cells. Synergism is also evident with compound 2 in combination with pinometostat (Fig. 15A-D).

Conclusions: Compound 2 in combination with 6 co-agents tested demonstrated synergy in at least 2 or more cell lines tested. These data suggest that the combination of compound 2 with these agents may be a potential paradigm for the treatment of relapsed refractory MM.

The embodiments described above are intended as examples only and those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, numerous equivalents of specific compounds, materials and techniques. All such equivalents are considered to be within the scope of the invention and are included in the appended claims.

Claims (54)

1. A method of treating multiple myeloma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound in combination with a second active agent, wherein the compound is Compound 1 of Formula - 56 045949 ABOUT or an enantiomer, mixture of enantiomers, tautomer, isotopologue or a pharmaceutically acceptable salt thereof; and wherein the second active agent is one or more of a BTK inhibitor, an mTOR inhibitor, a PIM inhibitor, an IGF-1R inhibitor, a MEK inhibitor, a XPO1 inhibitor, a DOT1L inhibitor, an EZH2 inhibitor, a JAK2 inhibitor, a BRD4 inhibitor, a PLK1 inhibitor, a NEK2 inhibitor, an AURKB inhibitor, a BIRC5 inhibitor, or a DNA methyltransferase inhibitor. 2. A method of treating multiple myeloma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound in combination with a second active agent, wherein the compound is compound 2 of formula or a tautomer, isotopologue or a pharmaceutically acceptable salt thereof; and wherein the second active agent is one or more of a BTK inhibitor, an mTOR inhibitor, a PIM inhibitor, an IGF-1R inhibitor, a MEK inhibitor, a XPO1 inhibitor, a DOT1L inhibitor, an EZH2 inhibitor, a JAK2 inhibitor, a BRD4 inhibitor, a PLK1 inhibitor, a NEK2 inhibitor, an AURKB inhibitor, a BIRC5 inhibitor, or a DNA methyltransferase inhibitor. 3. The method according to claim 2, wherein the compound is compound 2. 4. Method according to any one of claims 1 to 3, wherein the second active agent is a BTK inhibitor. 5. The method of claim 4, wherein the BTK inhibitor is ibrutinib, or acalabrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or a pharmaceutically acceptable salt thereof. 6. The method of claim 5, wherein the BTK inhibitor is ibrutinib. 7. The method according to any one of claims 1 to 3, wherein the second active agent is an mTOR inhibitor. 8. The method of claim 7, wherein the mTOR inhibitor is rapamycin or an analogue thereof. 9. The method of claim 8, wherein the mTOR inhibitor is everolimus. 10. Method according to any one of claims 1 to 3, wherein the second active agent is a PIM inhibitor. 11. The method of claim 10, wherein the PIM inhibitor is LGH-447, AZD1208, SGI-1776, or TP-3654, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. 12. The method of claim 11, wherein the PIM inhibitor is LGH-447 or a hydrochloride salt of LGH-447. 13. The method according to any one of claims 1 to 3, wherein the second active agent is an IGF-1R inhibitor. 14. The method of claim 13, wherein the IGF-1R inhibitor is linsitinib. 15. Method according to any one of claims 1 to 3, wherein the second active agent is a MEK inhibitor. 16. The method of claim 15, wherein the MEK inhibitor is trametinib, trametinib dimethyl sulfoxide, cobimetinib, binimetinib, or selumetinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or a pharmaceutically acceptable salt thereof. 17. The method of claim 16, wherein the MEK inhibitor is trametinib or trametinib dimethyl sulfoxide. 18. The method of claim 17, wherein trametinib or trametinib dimethyl sulfoxide is administered at a dose of about 1 mg, about 1.5 mg, or about 2 mg once daily. 19. The method according to any one of claims 1 to 3, wherein the second active agent is an XPO1 inhibitor. 20. The method of claim 19, wherein the XPO1 inhibitor is selinexor. 21. The method according to any one of claims 1 to 3, wherein the second active agent is a DOT1L inhibitor. 22. The method of claim 21, wherein the DOT1L inhibitor is SGC0946, or pinometostat, - 57 045949 or their stereoisomer, mixture of stereoisomers, tautomer, isotopologue or pharmaceutically acceptable salt. 23. The method of claim 22, wherein the DOT1L inhibitor is SGC0946. 24. The method of claim 22, wherein the DOT1L inhibitor is pinometostat. 25. Method according to any one of claims 1 to 3, wherein the second active agent is an EZH2 inhibitor. 26. The method of claim 25, wherein the EZH2 inhibitor is tazemetostat, 3deazaneplanocin A (DZNep), EPZ005687, EI1, GSK126, UNC1999, CPI-1205, or sinefungin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable thereof salt. 27. The method of claim 26, wherein the EZH2 inhibitor is tazemetostat. 28. The method according to claim 27, in which tazemetostat is administered at a dose of about 800 mg twice! per day. 29. The method of claim 26, wherein the EZH2 inhibitor is UNC1999. 30. The method of claim 26, wherein the EZH2 inhibitor is CPI-1205. 31. The method according to any one of claims 1 to 3, wherein the second active agent is a JAK2 inhibitor. 32. The method of claim 31, wherein the JAK2 inhibitor is fedratinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, momelotinib, or pacritinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. 33. The method of claim 32, wherein the JAK2 inhibitor is fedratinib. 34. The method according to any one of claims 1 to 3, wherein the second active agent is a BRD4 inhibitor. 35. The method of claim 34, wherein the BRD4 inhibitor is JQ1. 36. The method according to any one of claims 1 to 3, wherein the second active agent is a PLK1 inhibitor. 37. The method of claim 36, wherein the PLK1 inhibitor is BI2536. 38. The method according to any one of claims 1 to 3, wherein the second active agent is an NEK2 inhibitor. 39. The method of claim 38, wherein the NEK2 inhibitor is JH295. 40. The method according to any one of claims 1 to 3, wherein the second active agent is an AURKB inhibitor. 41. The method of claim 40, wherein the AURKB inhibitor is barasertib or AZD1152-HQPA. 42. The method according to any one of claims 1 to 3, wherein the second active agent is a BIRC5 inhibitor. 43. The method of claim 42, wherein the BIRC5 inhibitor is YM155. 44. The method according to any one of claims 1 to 3, wherein the second active agent is a DNA methyltransferase inhibitor. 45. The method of claim 44, wherein the DNA methyltransferase inhibitor is azacitidine. 46. The method according to any one of claims 1 to 45, wherein the multiple myeloma is relapsed, refractory or resistant. 47. The method of claim 46, wherein the multiple myeloma is refractory or resistant to lenalidomide. 48. The method of claim 46, wherein the multiple myeloma is refractory or resistant to pomalidomide. 49. The method according to any one of claims 1 to 45, wherein the multiple myeloma is newly diagnosed multiple myeloma. 50. The method according to any one of claims 1 to 49, further comprising administering to the patient an additional active agent. 51. The method of claim 50, wherein the additional active agent is dexamethasone. 52. The method of claim 50, wherein the additional active agent is bortezomib. 53. A method of treating relapsed or refractory multiple myeloma, comprising administering to a patient in need thereof a compound in combination with (i) trametinib or trametinib dimethyl sulfoxide and (ii) dexamethasone, wherein the compound is compound 2 of formula - 58 045949 or a pharmaceutically acceptable salt thereof. 54. A method of treating relapsed or refractory multiple myeloma, comprising administering to a patient in need thereof a compound in combination with (i) tazemetostat and (ii) dexamethasone, wherein the compound is compound 2 of formula or a pharmaceutically acceptable salt thereof.