TW201823471A - Methods of treating patients with a retinoic acid receptor-[alpha] agonist and an anti-CD38 antibody - Google Patents

Abstract

The invention provides methods that define cellular populations that are sensitive to RARA agonists and identify patient subgroups that will benefit from treatment with RARA agonists in combination with another therapy, more specifically an anti-CD38 therapy. The invention also provides packaged pharmaceutical compositions that comprise a RARA agonist and instructions for determining if such combination therapy is suitable for use in treatment.

Description

Method for treating patients with retinoic acid receptor-α agonist and anti-CD38 antibody

Retinoids are a class of structural compounds related to vitamin A, including natural and synthetic compounds. Several series of retinoids have been found to be clinically suitable for the treatment of skin and carcinogenic diseases. Retinoic acid and its other naturally occurring retinoid analogs (9-cis retinoic acid, all-trans 3,4-didehydroretinoic acid, 4-oxo-retinoic acid and retinol) are mostly A potency-modulating compound that regulates the structure and function of a wide variety of inflammatory cells, immune and structural cells. It is an important regulator of epithelial cell proliferation, differentiation and morphogenesis in the lung. Retinoids exert their biological effects through a series of hormone nuclear receptors, which are ligand-inducible transcription factors belonging to the steroid / thyroid receptor superfamily. Retinoid receptors are divided into two families, retinoic acid receptors (RAR) and retinoid X receptors (RXR), each consisting of three different subtypes (α, β, and γ). Each subtype of the RAR gene family encodes a variable number of isoforms, which results from the differential splicing of two primary RNA transcripts. All-trans retinoic acid is a physiological hormone of the retinoic acid receptor and binds to all three RAR subtypes with approximately equal affinity, but does not bind to the RXR receptor with 9-cis retinoic acid as the natural ligand . Retinoids have anti-inflammatory effects, change the process of epithelial cell differentiation, and inhibit stromal cell matrix production. These properties have led to the progress of local and systemic retinoid treatments for skin disorders such as psoriasis, acne and hypertrophic skin scars. Other applications include the control of acute promyelocytic leukemia, adenocarcinoma and squamous cell carcinoma, and liver fibrosis. Limitations in the therapeutic use of retinoids stem from the relative toxicity observed with naturally occurring retinoids, all-trans retinoic acid, and 9-cis retinoic acid. These natural ligands are non-selective with respect to RAR subtypes, and therefore have a generally toxic pleiotropic effect throughout the body. Various retinoids have been described that interact selectively or exclusively with RAR or RXR receptors or with specific subtypes (α, β, γ) within a class. RARA-specific agonists have broad prospects for cancer treatment, and many have entered human clinical trials. However, only one RARA-specific agonist, tamibarotene, has been approved for the treatment of cancer. In addition, Tamibarotene is only approved in Japan and is only approved for the treatment of acute promyelocytic leukemia, despite trials in the United States and Europe. The disconnect between the theoretical efficacy of RARA agonists in cancer and the lack of regulatory approval for such agents raises the question of why such agonists are ineffective and unsafe in the human body. Therefore, there is a need to better understand why RARA agonists have not yet met their therapeutic potential. Differentiation cluster 38 (CD38) is a protein that appears on the surface, mainly on white blood cells, and is regarded as a cell surface marker that indicates the beginning of differentiation. It acts as a cyclic ADP-ribose hydroxylase that plays a role in cell signaling (Mehta, K. & Cheema, S., Leuk. Lymphoma , 32, 441-449 (1999)). It is usually found to be highly expressed in cells of the B cell and plasma cell lineages. In multiple myeloma, patients with high CD38 expression subset, which has led to the progress of civil engineering, such as monoclonal antibody (daratumumab) of anti-CD38 therapeutic antibody (Lokhorst, HM et al., N. Engl. J. Med ., 373, 1207-1219 (2015) ;. de Weers, M. et al., J Immunol, 186, 1840-1848 ( 2011)).. Therefore, cancer cells expressing CD38 can be selectively targeted for elimination by the immune system using these therapeutic antibodies. In multiple myeloma, datulimumab is most effective in tumor cells with higher CD38 expression (CD38 ^hi ), and the lower level of CD38 expression makes the therapeutic antibody less effective to no effect (Nijhof, IS et al. , Blood , 128, 959-970 (2016)). This is why multiple myeloma cells with normal white blood cells or low initial CD38 performance (or decreased with resistance mechanism) have not been effectively cleared by anti-CD38 treatment. The performance of CD38 in AML was considered generally low (CD38 ^lo ), but the performance in the patient subgroup was considered moderate (CD38 ^dim ). Naturally occurring CD38 ^hi AML cells are atypical, and the percentage of positive AML is generally low. Therefore, it is believed that AML is unlikely to respond to anti-CD38 treatment, which has been proved by the study of dalmatumab monotherapy (Dos Santos, C. et al., Blood , 124, 2312-2312 (2014)). Recent advances in genomic technology and understanding of gene regulatory circuits have led to the discovery of superenhancers. Given that many genes or cancer types in a given tissue can be regulated by the presence of enhancers close to the gene coding region, a few of these genes represent a high degree of asymmetry and a disproportionately large load of transcriptional markers and mechanisms relative to all other active genes . Recent findings indicate that such enhancers bind to genes specifically related to the function and survival of cells containing them. Therefore, the correlation between the superenhancer and the gene indicates the relative importance of the gene for the survival of the cell.

The present invention provides for the administration of retinoids (eg, retinoic acid receptor alpha specific agonists, such as Tamibarotene) and anti-CD38 antibodies (eg, dalteumab) to individuals Combination to treat blood cancers (eg, multiple myeloma (MM), acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), pleomorphic large cell lymphoma (ALCL), B-cell acute lymphoblastoma Cell leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myeloid lymphoma (CML), diffuse large Methods for individuals with B-cell lymphoma (DLBCL), Hodgkin lymphoma or T-cell acute lymphoblastic leukemia (TALL), where blood cancer: a) is not available for CD38 inhibitors as monotherapy reaction; and / or b) is characterized by CD38 ^-, CD38 ^lo or CD38 ^dim. The present invention also provides RARA agonists including, for example, detecting RARA biomarkers or IRF8 biomarkers and administering RARA agonists in combination with CD38-specific antibodies when the RARA biomarkers or IRF8 biomarkers are above a predetermined threshold level to treat A method of acute myeloid leukemia ("non-APL AML"), myelodysplastic syndrome ("MDS"), or multiple myeloma ("MM") of the acute promyelocytic leukemia type. Detecting RARA biomarkers or IRF8 biomarkers includes determining the presence, level, form, and / or activity of one or more RARA or IRF8 gene components or products, including, for example, RARA or IRF8 superenhancer intensity, ordinal or prevalent grading, and RARA Or IRF8 mRNA level or prevalent classification. The present invention shows that cells containing one or more of the super- enhancers associated with the RARA or IRF8 genes (eg, cancer cells or cells from individuals with non-APL AML, MDS, or MM) are more susceptible to RARA agonists (Such as Tamibarotene) The effect of combining with CD38 specific antibody. Various embodiments, aspects and alternatives of the present invention address the definition of which cell populations are sensitive to the combination of retinoic acid receptor alpha ("RARA") agonists and CD38 specific antibodies, and identification will benefit from RARA agonists Treatment and the subgroup of patients treated with CD38-specific antibodies (eg, grading patients for treatment; separating responders from non-responders) and the problem of providing therapeutic treatment for such subgroups of patients. The solution is based at least in part on our findings: the higher performance of the RARA biomarker or IRF8 biomarker in non-APL AML, MDS, or MM indicates that this cell will respond to treatment with RARA agonist and CD38 specific antibody. In a first embodiment, the present invention relates to a method of diagnosing and treating individuals with non-APL AML, MDS, or MM, the method comprising: a) based on the diagnosis of whether the individual has RARA agonist sensitivity (eg , Tamibarotene sensitive) type disease: i) pre-determined retinoic acid receptor alpha mRNA level in a sample of diseased cells from an individual equal to or greater than a predetermined threshold; and / or ii) in advance IRF8 mRNA level in a sample of diseased cells from an individual determined to be equal to or greater than a predetermined threshold; b) administer a certain amount of RARA agonist (eg, Tamibalo) to the individual to effectively treat the disease Ting); and c) Co-administer CD38-specific antibodies to individuals. In some aspects of the first embodiment, the RARA agonist is Tamibarotene. In some aspects of the first embodiment, the CD38 specific antibody is daclizumab. In some aspects of the first embodiment, before the administration of the CD38-specific antibody, the individual is administered Tamibarotene for a period of time; and after starting the administration of Tamibarotene, only CD38 in the individual When the level has been determined to be CD38 ^hi , CD38 specific antibody was co-administered. In some aspects of the first embodiment, the CD38 level in the individual is determined between 6 and 72 hours after the start of administration of Tamibarotene. In a second embodiment, the present invention provides a method for treating a human subject suffering from non-APL AML, MDS or MM, wherein the level of retinoic acid receptor α mRNA and / or IRF8 in the diseased cells of the individual The mRNA level has been determined to have a retinoic acid receptor alpha mRNA level equal to or greater than a predetermined threshold, or an IRF8 mRNA level equal to or greater than a predetermined threshold. The method includes the following steps: administration to the individual is effective A certain amount of RARA agonist (eg, Tamibarotene) to treat the disease; and co-administer CD38 specific antibody to the individual. In some aspects of the second embodiment, the RARA agonist is Tamibarotene. In some aspects of the second embodiment, the CD38 specific antibody is daclizumab. In some aspects of the second embodiment, before administering the CD38-specific antibody, the individual is administered Tamibarotene for a period of time; and after starting the administration of Tamibarotene, only CD38 in the individual When the level has been determined to be CD38 ^hi , CD38 specific antibody was co-administered. In some aspects of the second embodiment, the CD38 level in the individual is determined between 6 and 72 hours after the start of administration of Tamibarotene. In a third embodiment, the present invention provides a method for diagnosing and treating human subjects with non APL AML, MDS or MM, the method comprising: a) level based on retinoic acid receptor alpha mRNA and / or The level of IRF8 mRNA diagnoses whether an individual has a RARA agonist sensitive (eg, Tamibarotene sensitive) type disease, either or both of these levels are pre-determined to be present in the disease from the individual In a sample of cells; and b) administration of the therapy to the individual, where i) if the level indicates that the disease is sensitive to Tamibarotene, then the therapy includes the administration of a certain amount of RARA agonist (eg, he Mibarotene) and co-administration of CD38-specific antibodies; and ii) If the level indicates that the disease is not sensitive to RARA agonists (eg, not sensitive to Tamibarotene), then the therapy includes administration of RARA Agents other than effective agents (eg, other than Tamibarotene). In some aspects of the third embodiment, the level of retinoic acid receptor alpha mRNA and / or IRF8 mRNA indicates that if it is greater than a predetermined threshold, the disease is sensitive to RARA agonists (eg, to Tamiba Rotin is sensitive), and if it is less than a predetermined threshold, the disease is not sensitive to RARA agonists (eg, not sensitive to Tamibarotene). In some aspects of the third embodiment, the RARA agonist is Tamibarotene. In some aspects of the third embodiment, the CD38 specific antibody is daclizumab. In some aspects of the third embodiment, if the level of retinoic acid receptor alpha mRNA or IRF8 mRNA indicates that the disease is sensitive to RARA agonists (eg, sensitive to Tamibarotene), then CD38 is administered Before specific antibodies, the RARA agonist (eg, Tamibarotene) is administered to the individual for a period of time; and after starting the RARA agonist (eg, Tamibarotene), only in the individual When the CD38 level was determined to be CD38 ^hi , CD38 specific antibody was co-administered. In some aspects of the third embodiment, the CD38 level in the individual is determined between 6 and 72 hours after the start of administration of the RARA agonist (eg, Tamibarotene). In a fourth embodiment, the present invention provides a method for treating an individual with a blood cancer who does not respond to treatment with an anti-CD38 antibody in the absence of retinoids, wherein the method includes Administration of retinoids and anti-CD38 antibodies. In some aspects of the fourth embodiment, the individual has a blood cancer selected from the group consisting of multiple myeloma (MM), acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and pleomorphic large cells Lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin's lymphoma (BNHL), Burkitt's lymphoma, chronic myeloid lymphoma (CML), diffuse large B cells Lymphoma (DLBCL), Hodgkin lymphoma, or T-cell acute lymphoblastic leukemia (TALL). In some more specific aspects of the fourth embodiment, the individual has a blood cancer selected from the group consisting of pleomorphic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), and B-cell non-Hodgkin Gold lymphoma (BNHL), Burkitt's lymphoma, chronic myeloid lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin's lymphoma, or T-cell acute lymphoblastic leukemia (TALL) . In some aspects of the fourth embodiment, the retinoid is a RARA-specific agonist. In a more specific aspect of the fourth embodiment, the retinoid is Tamibarotene. In other aspects of the fourth embodiment, the anti-CD38 antibody is daclizumab. In some aspects of the fourth embodiment, prior to the administration of the anti-CD38 antibody (eg, daclizumab), the individual is administered a retinoid (eg, RARA agonist, such as Tamibarotene) For a period of time; and after starting retinoids (eg, Tamibarotene), co-administer only when the CD38 level in the individual (eg, in the individual's blood cancer cells) is determined to be CD38 ^hi With anti-CD38 antibody. In some aspects of the fourth embodiment, the CD38 level in the individual is determined between 6 and 120 hours after the start of administration of retinoid (eg, Tamibarotene). In some aspects of the fourth embodiment, only retinoids (eg, Tamibarotene) and anti-CD38 antibodies (eg, darumumab) are administered to individuals with the following: The retinoic acid receptor α mRNA level in a sample of diseased cells from an individual equal to or greater than a predetermined threshold; and / or ii) diseased cells from an individual previously determined to be equal to or greater than a predetermined threshold IRF8 mRNA level in the sample. In some aspects of the fourth embodiment, a sample of diseased cells of an individual is subjected to a CD38 induction test before any treatment is performed. Typically, this will involve obtaining a sample of the individual ’s diseased cells; growing such cells in vitro; measuring the baseline level of CD38 induction in these cells as appropriate; using retinoids (eg, Tamibarotene ) Treatment of ex vivo cells; and determination of the level of CD38 induction after such treatment. If, after treatment with retinoids, the CD38 level in this sample of an individual's diseased cells is determined to be CD38 ^HI , then the individual is determined to be retinoid (eg, Tamibarotene) / anti- Candidate for combination therapy with CD38 antibodies (eg, datulimumab). In some aspects of the fourth embodiment, the anti-CD38 antibody (eg, darumumab) is administered before or after the administration of retinoid (eg, RARA agonist, such as Tamibarotene). In some aspects of the fourth embodiment, when using the ex vivo technique described above to determine the CD38 level in an individual's diseased cells as retinoid-inducible, the treatment regimen does not require administration of retinoid In any specific order. Therefore, it may be advantageous to administer anti-CD38 antibodies before retinoids in order to limit or eliminate any side effects of the antibodies and / or to optimize the pharmacokinetics of each agent. In some aspects of the fourth embodiment, the anti-CD38 antibody (eg, up to 6 hours) is administered between 6 and 120 hours before the administration of retinoid (eg, RARA agonist, eg, Tamibarotene) Civil engineering monoclonal antibody). In a fifth embodiment, the present invention provides a method for treating a subject characterized by CD38 ^-, CD38 ^lo method of individual blood or CD38 ^dim of cancers, wherein the method comprises co-administering to a subject and retinoid anti CD38 antibody. In some aspects of the fifth embodiment, the individual has a blood cancer selected from the group consisting of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), pleomorphic large cell lymphoma (ALCL), and B cells Acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin's lymphoma (BNHL), Burkitt's lymphoma, chronic myeloid lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodge Gold lymphoma or T-cell acute lymphoblastic leukemia (TALL). In some more specific aspects of the fifth embodiment, the individual has a blood cancer selected from the group consisting of pleomorphic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), and B-cell non-Hodgkin Gold lymphoma (BNHL), Burkitt's lymphoma, chronic myeloid lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin's lymphoma, or T-cell acute lymphoblastic leukemia (TALL) . In some aspects of the fifth embodiment, retinoid is a RARA specific agonist. In a more specific aspect of the fifth embodiment, the retinoid is Tamibarotene, ATRA, or a derivative thereof (eg, fenretinide). In other aspects of the fifth embodiment, the anti-CD38 antibody is daclizumab. In still other aspects of the fifth embodiment, the CD38 level in the individual (eg, in the individual's blood cancer cells) is determined before administration of the therapy. In some aspects of the fifth embodiment, a sample of diseased cells of an individual is subjected to a CD38 induction test prior to any treatment as described for the fourth embodiment. If, after treatment with retinoids, the CD38 level in this sample of an individual's diseased cells is determined to be CD38 ^HI , then the individual is determined to be retinoid (eg, Tamibarotene) / anti- Candidate for combination therapy with CD38 antibodies (eg, datulimumab). In some aspects of the fifth embodiment, only individuals with the following are administered retinoids (eg, Tamibarotene) and anti-CD38 antibodies (eg, darumumab): i) pre-determined as The retinoic acid receptor α mRNA level in a sample of diseased cells from an individual equal to or greater than a predetermined threshold; and / or ii) diseased cells from an individual previously determined to be equal to or greater than a predetermined threshold IRF8 mRNA level in the sample. In yet other aspects of the fifth embodiment, prior to the administration of the anti-CD38 antibody (eg, daclizumab), the individual is administered a retinoid (eg, RARA agonist, such as Tamibarotene) ) For a period of time; and after starting retinoids (eg, Tamibarotene), only the CD38 level in the individual (eg, in the individual ’s blood cancer cells) has been determined to be CD38 ^hi Anti-CD38 antibody is administered. In some aspects of the fifth embodiment, the CD38 level in the individual is determined between 6 and 120 hours after the start of administration of retinoid (eg, Tamibarotene). In some aspects of the fifth embodiment, the anti-CD38 antibody (eg, darumumab) is administered before or after administration of retinoid (eg, RARA agonist, such as Tamibarotene). In some aspects of the fifth embodiment, when using the ex vivo technique described above to determine the CD38 level in an individual's diseased cells as retinoid-inducible, the treatment regimen does not require administration of retinoid In any specific order. Therefore, it may be advantageous to administer anti-CD38 antibodies before retinoids in order to limit or eliminate any side effects of the antibodies and / or to optimize the pharmacokinetics of each agent. In some aspects of the fifth embodiment, the anti-CD38 antibody (eg, up to 6 hours) is administered between 6 and 120 hours before the administration of retinoid (eg, RARA agonist, eg, Tamibarotene) Civil engineering monoclonal antibody). In any and all embodiments, in some aspects, the invention provides a method for treating an individual suffering from cancer (eg, non-APL AML, MDS, or MM), wherein the composition comprises an antibody specific for CD38 ( For example, darcimumab) is co-administered with a RARA agonist (eg, Tamibarotene). In some forms, he was given orally by Mibarotene. In some aspects, the Tamibarotene is administered to the individual at a dose between 6 mg / m ² / day and 12 mg / m ² / day, where the dose is divided into two doses. In some aspects, the anti-CD38 antibody is administered at a dose between 10 and 20 mg / kg of the individual's body weight no more than once a week. The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the embodiments, drawings, examples, and examples.

Definitions As used herein, the term "administer / administering / administration" as used herein refers to implantation, absorption, ingestion, infusion, inhalation, or other introduction of the compound of the present invention or its pharmaceutical composition. As used herein, the term "agonist" can be used to refer to its presence, level, level, type, or form related to the increased level or activity of another agent (ie, an agent that is agonized) Medicine, condition or event. In general, an agonist may be or include an agent of any chemical class, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entities that exhibit related activation activities. In some embodiments, the agonist may be direct (in this case, it directly exerts its influence on its target); in some embodiments, the agonist may be indirect (in this case, it borrows In addition to binding to its target, for example, by interacting with the regulator of the target so as to change the level or activity of the target to exert its influence). The term "biological sample" refers to any sample that includes the following: tissue samples (such as tissue sections and tissue biopsies); cell samples (eg, cytological smears (such as Pap smear or blood smears) Or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeast or bacteria); or cell fragments, fragments, or organelles (such as by lysing cells and centrifuging or otherwise separating their groups) Points). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (eg, obtained by surgical biopsy or biopsy), nipples Aspirates, milk, vaginal fluid, saliva, swabs (such as oral swabs), or any substance containing biomolecules derived from the first biological sample. Biological samples also include biological samples of transgenic genes, such as transgenic gene oocytes, sperm cells, blastocysts, embryos, fetuses, donor cells or nuclei. In some aspects, the biological sample from an individual with AML, MDS, or MM is a bone marrow aspirate. As used herein, the term "biomarker" refers to an entity whose existence, level, or form is related to a specific biological event or state of interest, and therefore is considered a "marker" of that event or state. To give only a few examples, in some embodiments, the biomarker may be or include a marker of a specific disease condition or stage or the possibility of suffering from a specific disease, disorder or condition. In some embodiments, the biomarker may be or include a marker for a specific disease or treatment outcome or its likelihood. Therefore, for related biological events or states of interest, in some embodiments, the biomarker is predictive, in some embodiments, the biomarker is prognostic, and in some embodiments, the biomarker is diagnostic . Biomarkers can be entities of any chemical substance category. For example, in some embodiments, the biomarker may be or include a nucleic acid, polypeptide, lipid, carbohydrate, small molecule, inorganic agent (eg, metal or ion), or a combination thereof. In some embodiments, the biomarker is a cell surface marker. In some embodiments, the biomarker is an intracellular biomarker. In some embodiments, biomarkers are found outside the cell (eg, secreted or otherwise produced or present outside the cell, for example, in body fluids such as blood, urine, tears, saliva, cerebrospinal fluid, etc.). In some embodiments, the term refers to a gene expression product characterized by a specific tumor, tumor subclass, tumor stage, and the like. Alternatively or additionally, in some embodiments, the presence or level of a specific marker is related to the activity (or active level) of a specific signaling pathway that may be characteristic of a tumor of a specific class, for example. The statistical significance of the presence or absence of biomarkers can vary depending on the specific biomarkers. In some embodiments, the detection of biomarkers is highly specific because it reflects a high probability that the tumor belongs to a specific sub-category. This specificity may come at the expense of sensitivity (for example, even if the tumor is a tumor that will be expected to exhibit a biomarker, a negative result may still occur). In some embodiments, the biomarkers comprise RARA biomarkers (eg, one or more RARA biomarkers (eg, one or moreRARA The presence, level, form and / or activity of genetic components or products, including for exampleRARA Super enhancer intensity, ordinal grade or prevalent grade and RARA mRNA level or prevalent grade)). In some embodiments, the biomarker comprises an IRF8 biomarker (eg, one or moreIRF8 The presence, level, form and / or activity of genetic components or products, including for exampleIRF8 (Super-enhancer intensity, ordinal grade or prevalent grade and IRF8 mRNA level or prevalent grade). In some embodiments, biomarkers refer to a combination of one or more biomarkers, such as RARA biomarkers or IRF8 biomarkers. As used herein, the term "co-administer (co-administer / co-administering)" in the case of administration therapy (eg, RARA agonist and CD38-specific antibody) indicates that a therapy can cause disease in an individual Use in combination with one or more therapies during the procedure. In some embodiments, the administration of therapy is simultaneous or simultaneous, meaning that the delivery of one treatment is still ongoing at the beginning of the delivery of the second treatment. In other embodiments, the delivery of one treatment ends before the delivery of another treatment begins. In some embodiments of either case, the treatment is more effective due to combined administration. For example, the second treatment is more effective, for example, an equivalent effect is found when the second treatment is performed less frequently, or the second treatment is more effective than the second treatment in the absence of the first treatment Will be found to relieve symptoms to a greater extent, or a similar condition is found in the first treatment. In some embodiments, the delivery reduces symptoms, or other parameters related to the condition are greater than the parameters that would be observed for one treatment delivered in the absence of another treatment. The effects of the two treatments can be partially additive, fully additive or greater than additive. The delivery can make the effect of the delivered first treatment still detectable when delivering the second treatment. Here, the RARA agonist and CD38 specific antibody may be administered simultaneously or sequentially in the same or separate compositions. For sequential administration, the RARA agonist can be administered first and the CD38 specific antibody can be administered second or the order of administration can be reversed. As used herein, the terms "disease", "disease" and "disease" are used interchangeably. The "effective amount" of the compounds described herein (such as RARA agonists and / or CD38 specific antibodies) refers to an amount sufficient to elicit the desired biological response (ie, to treat the condition). As one of ordinary skill will appreciate, the effective amount of compounds described herein (such as RARA agonists and / or CD38-specific antibodies) can depend on the desired biological endpoint, the pharmacokinetics of the compound, the pathological condition being treated, Such factors as the dosage pattern and the individual's age and health status vary. In some embodiments, the effective amount encompasses both therapeutic and prophylactic treatment. In other embodiments, the effective amount covers only therapeutic treatment. For example, in the treatment of cancer, an effective amount of a compound or composition of the invention can reduce tumor burden or stop tumor growth or spread. "Individuals" expected to be administered include, but are not limited to, humans (ie, men or women of any age group, such as pediatric individuals (eg, infants, children, youth) or adult individuals (eg, young, middle-aged, or elderly Human)) and / or other non-human animals, such as mammals (eg, primates (eg, crab-eating macaques, rhesus monkeys); commercially relevant mammals, such as cattle, pigs, horses, sheep, goats, Cats and / or dogs) and birds (eg, commercially relevant birds such as chickens, ducks, geese and / or turkeys). In some embodiments, the animal is a mammal. Animals can be male or female and at any stage of development. The non-human animal may be a transgenic animal. In some embodiments, the individual is a human. The "therapeutically effective amount" of the compounds described herein (such as RARA agonists and / or CD38 specific antibodies) is one that is sufficient to provide a therapeutic benefit in the treatment of the condition or sufficient to delay or minimize the association with the condition Or the amount of multiple symptoms. In some embodiments, the therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in treating the condition or sufficient to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means a therapeutic agent that alone or in combination with other therapies, provides a quantitative amount of therapeutic benefit in treating the condition. The term "therapeutically effective amount" may encompass an amount that improves the entire therapy, reduces or avoids the symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent. As used herein, the term "treatment (treat / treating)" refers to reversing, slowing, or delaying the "pathological conditions" described herein (e.g., a disease, disorder or condition, or one or more symptoms Or symptom), or inhibit the progression of the "pathological condition". In some embodiments, "treatment (treat / treating)" requires that the signs or symptoms of the disease, disorder, or condition have developed or have been observed. In other embodiments, the treatment can be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to susceptible individuals prior to the onset of symptoms (eg, based on the history of symptoms and / or based on genetic factors or other susceptibility factors). It is also possible to continue treatment after the symptoms have subsided, for example to delay or prevent relapse. the term"RARA "Gene" refers to a gene encoding a functional retinoic acid receptor-α and specifically excludesRARA The genomic DNA sequence of the gene fusion of all or part of the gene. In some embodiments,RARA The gene is located in chr17: 38458152-38516681 in the genome structure hg19. the term"IRF8 "Gene" refers to an interferon-encoding common sequence binding protein or its splice variant and specifically excludes inclusionIRF8 The genomic DNA sequence of the gene fusion of all or part of the gene. In some embodiments,IRF8 The gene is located in chr16: 85862582-85990086 in genome structure hg19. The term "enhancer" refers to the region of genomic DNA used to regulate genes up to 1 Mbp away. The enhancer may overlap with the gene coding region, but usually does not consist of it. Enhancers are usually bound by transcription factors and designated by specific tissue protein markers. The term "superenhancer" refers to a subset of enhancers that contain an asymmetric share of tissue protein markers and / or transcribed proteins relative to other enhancers in a particular cell. Because of this, it is predicted that genes regulated by superenhancers are highly important for the function of the cell. Superenhancers are usually determined by sorting all enhancers in the cell based on intensity and using available software such as ROSE (https://bitbucket.org/young_computation/rose) to determine that the A subset of high-strength enhancers is determined (see, for example, US Patent 9,181,580, which is incorporated herein by reference). The term "strength" as used herein when referring to the part of an enhancer or super-enhancer means the area under the curve of the number of reads of H3K27Ac or other genomic markers plotted against the length of the analyzed genomic DNA fragments. Therefore, "intensity" is the integral of the signal generated by measuring the marker at a given base pair over the span of base pairs defining the area selected for measurement. The term specifies the value (for example, withRARA The "prevalence rating" of the intensity of super-enhancers associated with genes means the percentage of groups that are equal to or greater than a certain value. For example, with the test cellRARA The prevalence of 35% of the intensity of gene-associated superenhancers means that 35% of the population has an intensity equal to or greater than that of the test cellRARA Gene enhancer. The term specifies the value (for example, withRARA The "prevalence cutoff" of the intensity of super-enhancers associated with genes means the prevalence of the dividing line that defines the dividing line between two subsets of a population (eg, responders and non-responders). Thus, a prevalence rating that is equal to or higher than (ie, a lower percentage value) a subset of the prevalence rating group that defines the prevalence cutoff; and a subset of the prevalence rating that is lower than (eg, a higher percentage value) prevalence definition community . The terms "cutoff" and "cutoff value" mean the value of the dividing line measured between two subsets of defined populations (eg, responders and non-responders) measured in the analysis method. Therefore, a value equal to or higher than the cut-off value defines a subset of the population; and a value lower than the cut-off value defines another subset of the population. The terms "threshold value" and "threshold value level" are meant to define the level of the dividing line between two subsets of a population (eg, responders and non-responders). The threshold level may be the prevailing cut-off or cut-off value. The term "population" or "population of samples" means a sufficient number of different samples (eg, at least 30, 40, 50, or more) that reasonably reflect the distribution of measured values in a larger group. Each sample in the sample population may be a cell line, a biological sample obtained from an organism (eg, a biopsy or body fluid sample), or a sample obtained from a xenotransplantation (eg, grown in a mouse by implanting a cell line or a patient sample Tumors), where each sample is from an organism with the same disease, condition or condition or from a cell line or xenograft showing the same disease, condition or condition. The term "ordinal ranking" of a specified value means that the value is ordered compared to the set of other values. For example, in terms of the intensity of the superenhancer associated with the RARA gene in the test cell compared to other superenhancers in the test cell, an ordinal rating of 100 means 99 other superenhancers in the test cell It has a greater intensity than the superenhancer associated with the RARA gene. The term "sorting" means sorting values from highest to lowest or from lowest to highest.RARA and IRF8 The present invention provides methods for treating individuals with cancer (eg, non-APL AML, MDS, or MM) with RARA agonists combined with CD38-specific antibodies, for example, by measuring RARA biomarkers and / or IRF8 The prevalence of biomarkers (for example, to determine one or moreRARA orIRF8 Gene component or product level, strength, ordinal ranking, prevalent ranking, and / or activity, including for exampleRARA orIRF8 Super-enhancer intensity, ordinal or prevalent grade and RARA or IRF8 mRNA level or prevalent grade), and therefore co-administered RARA agonist and CD38 specific antibody. Retinoic acid receptor subtype α (RARA) is a nuclear hormone receptor that acts as a transcription repressor when unbound or bound by an antagonist and as a gene activator in the agonist-bound state. The natural ligand of RARA is retinoic acid produced by vitamin A, also known as all-trans retinoic acid (ATRA). Super-enhancers (SE) are large, highly active chromatin regions that regulate key cell recognition genes (including oncogenes in malignant cells). Using a genetic control platform, SE was identified in 60 primary AML patient samples as a whole genome capable of discovering new tumor weaknesses. One of the SEs showing differences in the patient sample and the code RARARARA Genes are related. Use pre-analysisRARA Different AML cell lines and patient samples from the intensity and ordinal of the enhancer were found to have upregulated the level of interferon response factor 8 (IRF8) mRNA similar to RARA in the patient population. IRF8 is an interferon-reactive transcription factor known to be essential for hematopoiesis and its lack of signal transduction causes abnormal proliferation of immature bone marrow cells. In AML, IRF8 overexpression is observed and it may be correlated with poor clinical outcome. Regardless of this upregulation, IRF8 signaling is actually attenuated by suppressed transcription cofactors and potentially RARA when IRF8 signaling is in the SE-driven inhibition state. In addition, interferon-α itself (the upstream signaling ligand of IRF) exhibits pro-differentiation and cross-talk with the RARA pathway in AML. The present invention describes the latest discovery that RARA agonists (eg, Tamibarotene) can induce CD38 upregulation in non-APL AML, MDS, or MM in a RARA or IRF8 SE dependent manner. In addition, it provides various compositions and methods that are particularly suitable for characterizing, identifying, selecting, or stratifying patients based on a possible response to co-administration of Tamibarotene and CD38-specific antibodies.RARA and IRF8 Super enhancer identification and threshold Level determination Described herein is by determining the presence of RARA biomarkers and / or IRF8 biomarkers (eg, measuring one or moreRARA orIRF8 The prevalence, level, form and / or activity of genetic components or products, including for exampleRARA orIRF8 Super-enhancer intensity, ordinal or prevalent grading, and RARA or IRF8 mRNA level or prevalent grading), a method of treating cancer by administering RARA agonist (eg, Tamibarotene) and CD38 specific antibody. The identification of enhancers or super enhancers can be achieved by various methods known in the art, for example, as described in Cell 2013, 155, 934-947 and PCT / US2013 / 066957, both of which are cited by reference Incorporated in this article. In some embodiments, the identification of superenhancers is achieved by obtaining cellular material and DNA from cancer samples in patients (eg, from biopsies). The important measurement of enhancer measurement is performed in two dimensions: the DNA length of the genomic marker (eg, H3K27Ac) is continuously detected within it, and the genomic marker is located at each base pair along the DNA span that constitutes the measure Compile rate. The measurement of the area under the curve ("AUC") resulting from the integration of length and magnitude analysis determines the strength of the enhancer. systemIRF8 orRARA The intensity of the superenhancer relative to the control group used in one aspect of the invention determines whether the individual will respond to RARA agonists (eg, Tamibarotene) and CD38 specific antibodies. It will be easy for those familiar with this technique to detect the length of DNA within the genome markerRARA orIRF8 The same as the control group, thenRARA orIRF8 The ratio of the amount of superenhancer to the control group will be equivalent to intensity, and can also be used to determine whether an individual will respond to RARA agonists and CD38 specific antibodies. In some embodiments, prior to comparison with other samplesRARA orIRF8 The intensity of the enhancer is normalized. Normalization is achieved by comparison with regions in the same cell that are known to contain ubiquitous superenhancers or enhancers that appear at similar levels in all cells. An example of such a ubiquitous superenhancer region is the MALAT1 superenhancer locus (chr11: 65263724-65266724) (genomic structure hg19). It has been determined by the H3K27Ac ChIP-seq method to exist and be located at chr17: 38458152-38516681 (genomic structure hg19)RARA Gene-linked super-enhancer locus. ChIP sequencing (also called ChIP-seq) is used to analyze the interaction of proteins and DNA. ChIP-seq combines chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing to identify binding sites for DNA-related proteins. It can be used to pinpoint the global binding site of any protein of interest. Previously, ChIP-on-chip (ChIP-on-chip) was the most common technique used to study these protein-DNA relationships. Successful ChIP-seq depends on many factors, including the intensity and method of sonic processing, buffer composition, antibody quality, and cell number; see, for example, T. Furey, Nature Reviews Genetics 13, 840-852 (December 2012); ML Metzker, Nature Reviews Genetics 11, 31-46 (January 2010); and PJ Park, Nature Reviews Genetics 10, 669-680 (October 2009). Genomic markers other than H3K27Ac that can be used to identify super-enhancers using ChIP-seq include components of P300, CBP, BRD2, BRD3, BRD4, and media complex (J Loven et al., Cell, 153 (2): 320-334 , 2013), tissue protein 3 lysine 4 monomethylation (H3K4me1) or other tissue-specific enhancer-linked transcription factors (E Smith and A Shilatifard, Nat Struct Mol Biol, 21 (3): 210-219, 2014 ) (S Pott and Jason Lieb, Nature Genetics, 47 (1): 8-12, 2015). In some embodiments, the H3K27ac or other marker ChIP-seq data super-enhancer localization of the entire genome of the cell line or patient sample already exists. In these examples, we will only determine whether the intensity or ordinal rank of the enhancer or super-enhancer in such a location at the locus of chr17: 38458152-38516681 (genomic structure hg19) is equal to or greater than the predetermined threshold Level. It should be understood thatRARA ,IRF8 andMALAT1 The specific chromosomal location may be different for different genome structures and / or for different cell types. However, in view of this specification, those skilled in the art can locate theRARA And / orMALAT1 Such different positions are determined in such other genome-specific sequences of loci. Other methods for identifying superenhancers include chromatin immunoprecipitation (JE Delmore et al., Cell, 146 (6) 904-917, 2011) and chip array (ChIP-chip), and the use of the same immunoprecipitation genomic markers and chr17: 38458152-38516681 (genomic structure hg19)RARA Locus or chr16: 85862582-85990086 (genomic structure hg19)IRF8 Chromatin immunoprecipitation of oligonucleotide sequences hybridized to loci followed by qPCR (ChIP-qPCR). In the case of ChIP-chip, like other array-based technologies, the fluorescence intensity detection signal is usually generated by the hybridization of the probe and the input analysis sample. For ChIP-qPCR, dyes that emit fluorescence only after the double-stranded DNA generated in the PCR reaction is embedded are used to measure template amplification. In some embodiments, whether the cell has a threshold level greater than necessaryRARA orIRF8 The determination of superenhancers is achieved byRARA orIRF8 The strength of the enhancer corresponds to that of cells that are known not to respond to RARA or IRF8 ("control cells")RARA orIRF8 The intensity is compared to achieve. The control cell is preferably the same cell type as the test cell. In one aspect of these embodiments, the control cells are such cells in HCC1143. In some embodiments, whether the cell has a threshold level greater than necessaryRARA orIRF8 The determination of super-autron intensity is achieved byRARA orIRF8 Enhancer intensity and correspondence in cell sample populationRARA orIRF8 The intensity is compared by comparison, where each of the cell samples is obtained from different sources (ie, different individuals, different cell lines, different xenotransplantations). In some aspects of these embodiments, only the primary tumor cell sample from the individual is used to determine the threshold level. In some aspects of these embodiments, at least some of the samples in the population have been tested for response to specific RARA agonists and CD38 specific antibodies in order to establish: a) for specific RARA agonists and The sample with the lowest CD38 specific antibody responseRARA Enhancer intensity ("lowest responder"); and / or b) the lowest sample in the population that responds to specific RARA agonists and CD38 specific antibodiesIRF8 Enhancer intensity ("lowest responder"); and as appropriate c) the highest sample in the population that does not respond to specific RARA agonists and CD38 specific antibodiesRARA Enhancer intensity ("highest non-responder") and / or d) highest in population samples that do not respond to specific RARA agonists and CD38 specific antibodiesIRF8 Enhance sub-intensity ("the highest non-responder"). In these embodiments,RARA orIRF8 The intensity of the enhancer (the test cell will be regarded as reacting to the specific RARA agonist and CD38 specific antibody) when the intensity is greater than: i) equal to or at most greater than the lowest responder in the populationRARA orIRF8 Enhancer strength 5%; or ii) equal to or at most greater than the highest non-responder in the groupRARA orIRF8 Enhancer strength 5%; or iii) the lowest responder and highest non-responder in the groupRARA orIRF8 Value between enhancer intensities. It should be understood that in the above embodiments, generally not all samples in the population need to be tested for the reaction of RARA agonist and CD38 specific antibody, but all samples are measuredRARA orIRF8 Enhance sub-intensity. In some embodiments, the sample is based onRARA orIRF8 Enhancer intensity ranking. The selection of the three methods used to establish the cutoff described above will depend on the difference between the lowest responder and the highest non-responder in the group.RARA orIRF8 The intensities of the enhancers and the goal are to minimize the number of false positives or to minimize the chance of missing potential reaction samples or individuals. When the difference between the lowest responder and the highest non-responder is large (for example, when many samples are not tested and fallRARA orIRF8 (In the case of the reaction between the lowest responder and the highest non-responder in the order of enhancer intensity), the cutoff is usually set to be equal to or at most greater than the lowest responder in the groupRARA orIRF8 Strengthen sub-strength 5%. This cutoff maximizes the number of potential responders. When the difference is small (for example, when a few samples or no samples are not tested and fallRARA orIRF8 (In the order of strengthening the intensity of the reaction between the lowest responder and the highest non-responder), the cutoff is usually set to the lowest responder and the highest non-responderRARA orIRF8 Value between enhancer intensities. This cut-off minimizes the number of false positives. When the highest non-responderRARA orIRF8 When the intensifier intensity is higher than the lowest responder, the cutoff is usually set to be equal to or at most greater than the highest non-responderRARA orIRF8 Strengthen the value of 5%. This method also minimizes the number of false positives. In some embodiments, whether the cell has a threshold level greater than necessaryRARA orIRF8 The determination of super-autron intensity is achieved byRARA The number of enhancer intensities and the number of cell sample populationsRARA orIRF8 The ordinal number of enhancer intensity is compared by comparison, where each of the cell samples is obtained from different sources (ie, different individuals, different cell lines, different xenotransplantations). In these embodiments, at least some of the samples in the population have been tested for response to specific RARA agonists in order to establish: a) a population that responds to specific RARA agonists and CD38 specific antibodies The lowest sampleRARA Enhancer strength ("lowest ordinal responder"); b) The lowest sample in the population that responded to specific RARA agonists and CD38 specific antibodiesIRF8 Enhancer intensity ordinal number ("lowest ordinal responder"); and as appropriate c) the highest sample in the group that does not respond to specific RARA agonists and CD38 specific antibodiesRARA Enhancer intensity ordinal number ("the highest ordinal non-responder"); and / or d) the highest sample in the population that does not respond to specific RARA agonists and CD38 specific antibodiesRARA Strengthen the sub-intensity number ("the highest number without responders"). In these embodiments,RARA orIRF8 The intensity of the enhancer (the test cell will be regarded as reacting to the specific RARA agonist and CD38 specific antibody) when the intensity is greater than: i) is equal to or at most greater than the lowest ordinal responderRARA orIRF8 The intensity of the enhancer is 5%; or ii) equal to or at most greater than the highest number of non-responders in the groupRARA orIRF8 Enhancer intensity 5%; or iii) The lowest ordinal responder in the group and the highest ordinal non-responderRARA orIRF8 Value between enhancer intensities. It should be understood that in the above embodiments, not all samples in the population usually need to be tested for the response to RARA agonist and CD38 specific antibody, but all samples are measured.RARA orIRF8 Enhance substrength and establishRARA orIRF8 The number of enhancers compared to other enhancers in the same sample. The ordinal number is usually determined by measuring the strength of all other enhancers in the cell and determiningRARA orIRF8 Compared with other enhancers, what kind of order does the enhancer have in terms of strength (ie, ordinal number). In some embodiments, the sample is based onRARA Sort by the ordinal number of enhancer intensity. In some embodiments, the sample is based onIRF8 Sort by the ordinal number of enhancer intensity. The selection of the sample used to establish the cutoff method described above will depend on the difference between the lowest ordinal responder and the highest ordinal responder in the population.RARA orIRF8 The sequence number difference and cutoff of enhancer intensity are designed to minimize the number of false positives or maximize the number of responders. When this difference is large (for example, when many samples are not tested and fallRARA orIRF8 (Strength of the ordinal substrength ordinal number is the reaction between the lowest ordinal responder and the highest ordinal non-responder).RARA orIRF8 The intensity number of the enhancer is 5%. When this difference is small (for example, when a few samples or no samples are not tested and fallRARA orIRF8 (Strength of substrength ordinal number is the reaction between the lowest ordinal responder and the highest ordinal non-responder), the cutoff is usually set to the lowest ordinal responder and the highest ordinal non-responderRARA orIRF8 Values between ordinal intensity intensities. When the highest number of non-respondersRARA orIRF8 The sequence number of the enhancer intensity is higher than the lowest responderRARA orIRF8 When strengthening the ordinal intensity number, the cutoff is usually set to be equal to or at most greater than the highest number in the group of non-respondersRARA orIRF8 The value of 5% of the ordinal intensity. In some aspects of embodiments in which test cells or samples are compared to a population, one or more cut-off values will be obtained for the population (eg,RARA Enhancer strength orRARA Strengthen sub-sequence and / orIRF8 Enhancer strength orIRF8 The enhanced sub-sequence number) is converted into a prevalence ranking, and the cut-off is expressed as the percentage of the population having a cut-off value or higher (ie, prevalence cut-off). Without being limited by theory, the applicant believes that the prevalence of test samples will be similar, regardless of whether it is used for determinationRARA orIRF8 How to strengthen the sub-intensity. Therefore, for a parameter (for example,RARA Enhancer intensity ordinalIRF8 The prevalence cutoff of the enhancer intensity number) is portable and can be applied to another parameter (eg, RARA mRNA level or IRF8 mRNA level) to determine the cutoff value of the other parameter. This allows the cut-off value of any parameter to be determined without having to experimentally determine the correlation between the level of such parameter and the response to the RARA agonist and CD38 specific antibody.RARA and IRF8 mRNA Level determination The present invention provides methods for treating cancer with RARA agonists (eg, Tamibarotene) and CD38 specific antibodies in the presence of RARA biomarkers and / or IRF8 biomarkers. DeterminedRARA And / orIRF8 The identification of super-enhancer loci allows us to use RNA transcripts to measure sensitivity rather than super-enhancer levels to determine sensitivity to RARA agonists and CD38 specific antibodies. The RNA transcript from the super-enhancer locus itself can be quantified and is extremely well correlated with the super-enhancer level at that locus. It has also been shown that mRNA transcripts encoding RARA are also associated with sensitivity to RARA agonists alone or in combination with CD38-specific antibodies, and therefore mRNA levels can be used to identify cells that will respond to this therapy combination. Therefore, in some embodiments, the RARA or IFR8 mRNA level rather than superenhancer intensity or ordinal ranking can be used to determine sensitivity to RARA agonists and CD38 specific antibodies. In some embodiments, RNA transcription levels from super-enhancer loci are quantified using quantitative techniques, which quantify theRARA orIRF8 Enhancer RNA transcription levels correspond to cells or cell lines known not to respond to RARA agonists and CD38 specific antibodiesRARA orIRF8 Enhancer RNA transcription levels are compared. Such methods include RNA array-based or sequencing-based methods for eRNA (N Hah et al., PNAS, 112 (3): E297-302, 2015) associated with read-through and enhancer read-through, and RNA qPCR. In an alternative embodiment, the RNA-Seq or RNA-qPCR technology is used to place the RARA or IRF8 mRNA levels in the individual (ie, in the tumor sample, cancer cell sample, blood sample, etc.) as if they had the same disease or condition RARA or IRF8 mRNA levels in a population of individuals are compared to identify responders to RARA agonists and CD38 specific antibodies. In these embodiments, at least some of the samples in the population have been tested for response to specific RARA agonists and CD38 specific antibodies in order to establish: a) specific RARA agonists and CD38 specific antibodies The lowest RARA mRNA level of the sample in the responding group ("the lowest mRNA responder"); and / or b) the lowest IRF8 mRNA of the sample in the group responding to the specific RARA agonist and CD38 specific antibody Level ("Minimum mRNA Responder"); and optionally c) The highest RARA mRNA level of samples in a population that does not respond to specific RARA agonists and CD38-specific antibodies ("Highest mRNA Unresponder") ); And / or d) the highest level of IRF8 mRNA in samples from groups that do not respond to specific RARA agonists and CD38 specific antibodies ("the highest mRNA non-responders"). In these embodiments, the RARA or IRF8 mRNA level (a test cell greater than this level will be considered to react to the specific RARA agonist and CD38 specific antibody) is set to: i) equal to or at most The RARA or IRF8 mRNA level of the lowest mRNA responder in the population is 5%; or ii) is equal to or at most greater than the RARA or IRF8 mRNA level of the highest mRNA non-responder in the population 5%; or iii) the lowest mRNA responder in the population is The value between RARA or IRF8 mRNA level of the highest mRNA non-responder. In some embodiments, not all samples in a population need to be tested for response to RARA agonists and CD38 specific antibodies, but all samples are measured for RARA or IRF8 mRNA levels. In some embodiments, the samples are ordered based on RARA mRNA levels. In some embodiments, the samples are ordered based on IRF8 mRNA levels. The selection of samples for the three methods described above to establish the cut-off will depend on the RARA or IRF8 mRNA level difference between the lowest mRNA responder and the highest mRNA non-responder in the population and the cut-off is designed to minimize false positives Or to maximize the number of potential responders. When this difference is large (for example, when many samples are not tested for the reaction between the lowest mRNA responder and the highest mRNA non-responder in the order of RARA or IRF8 mRNA level), the cutoff is usually set to be equal to or at most The RARA or IRF8 mRNA level of the lowest mRNA responder in the population was 5%. When the difference is small (for example, when a small number of samples or no samples are not tested, the reaction falls between the lowest mRNA responder and the highest mRNA non-responder in the ranking of RARA or IRF8 mRNA level), the cutoff is usually set to the lowest The value between the RARA or IRF8 mRNA level of the mRNA responder and the highest mRNA non-responder. When the RARA or IRF8 mRNA level of the highest mRNA non-responder is higher than the lowest mRNA responder, the cutoff is usually set to a value equal to or at most greater than 5% of the RARA or IRF8 mRNA level of the highest mRNA non-responder in the population. In some embodiments, the population is ranked based on RARA mRNA levels. In some embodiments, the population is ranked based on IRF8 mRNA levels. In these embodiments, the RARA or IRF8 mRNA levels in each sample are measured and compared to the mRNA levels of all other mRNAs in the cell to obtain the ordinal ranking of the RARA or IRF8 mRNA levels. Subsequently, the cut-off based on RARA or IRF8 mRNA ordinal ranking is determined based on the samples in the population toRARA orIFR8 The response of the samples to the RARA agonist was tested in the same manner as described in the Super Enhancer Intensity Number Cutoff. Subsequently, the measured RARA or IRF8 mRNA number cutoff is used directly or used to determine the prevalence cutoff, and then either of them is used to stratify additional samples that potentially respond to RARA agonists and CD38 specific antibodies. In some embodiments, the use is based onRARA Enhancer strength orRARA Enhancer intensity number, orIRF8 Enhancer strength orIRF8 The prevalent cut-off established by the intensity number of the enhancer was used to determine the cut-off of the RARA or IRF8 mRNA level. In some aspects of these embodiments, the mRNA level of the population is measured, and the pre-determined prevalence cutoff is applied to the population to determine the mRNA cutoff level. In some aspects of these embodiments, a ranking standard curve for the RARA or IRF8 mRNA level of the population is established, and a predetermined prevalent cutoff is applied to the standard curve to determine the RARA or IRF8 mRNA cutoff level. In some aspects of the embodiment where the test cell or sample is compared with the population, the cut-off mRNA level value of the obtained population is converted into a prevalent grade, and the mRNA level cut-off is expressed as having a cut-off value or higher ( That is, the percentage of groups that are prevalently cut off. Without being limited by theory, the applicant believes that the prevalence of test samples and the prevalence of population will be similar, regardless of the method used to determine IRF8 or RARA mRNA levels. In some aspects of these embodiments, if the individual's RARA or IRF8 mRNA level corresponds to 79%, 78%, 77%, 76%, 75 as determined by the RARA or IRF8 mRNA level in the population %, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42% , 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25 %, 24%, 23%, 22%, 21%, or 20% of the prevalent groups, the individual is identified as a RARA agonist responder. In one aspect of these embodiments, based onRARA orIRF8 The prevalence of strengthening substrength is established and the cutoff value is established. In one alternative form of these embodiments, based onRARA orIRF8 The prevalence of the establishment of the substrength ordinal number cutoff establishes the cutoff value. In another alternative aspect of these embodiments, a cut-off value is established based on the RARA or IRF8 mRNA level. In other more specific aspects of these embodiments, based onRARA orIRF8 The prevalence value of the enhancer intensity ordinal number determination establishes the cut-off value of AML patients, and the prevalence value is used to determine the cut-off value of RARA or IRF8 mRNA level. In even more specific aspects of these embodiments, use is between 25 to 45% (eg, between 25 to 30%, 25 to 35%, 25 to 40%, 30 to 35%, 30 to 40%, 35 to 45%, 35 to 40%, 31 to 35%, 32 to 35%, 33 to 35%, 34 to 35%, 31 to 36%, 32 to 36%, 33 to 36%, 34 to 36% or Between 35 and 36%) to determine the cut-off value of AML patients. In other even more specific aspects of these embodiments, a prevalence value of 36% is used to determine the cutoff value for AML patients. In yet other even more specific aspects of these embodiments, a prevalence value of 25% is used to determine the cutoff value for AML patients. In still other embodiments, the group may be divided into three groups-responders, partial responders, and non-responders, and two cut-off values or prevalent cut-off values are set. Part of the responder group may include responders and non-responders, as well as members of other groups whose response to RARA agonists and CD38 specific antibodies is not as high as the responder group. In these embodiments, two cutoff values or prevailing cutoff values are determined. This type of stratification may be particularly applicable when the RARA or IRF8 mRNA level of the highest RARA or IRF8 mRNA non-responder in the population is higher than the lowest RARA mRNA responder. In this situation, the cutoff level or prevalence cutoff between the responders and some of the responders is set to be equal to or at most greater than 5% of the RARA or IRF8 mRNA level of the highest RARA or IRF8 mRNA non-responders; The cutoff level or prevalence cutoff between responders is set to be equal to or at most greater than 5% of the RARA or IRF8 mRNA level of the lowest RARA or IRF8 mRNA responder. The decision whether to administer RARA agonists and CD38 specific antibodies to some responders will depend on the judgment of the treating physician and / or the approval of the regulatory agency. Methods for quantifying specific RNA sequences in cells or biological samples are known in the art, and include, but are not limited to, such as fluorescent hybridization for services and products provided by NanoString Technologies, array-based technology (Affymetrix), Reverse transcriptase qPCR using SYBR® Green (Life Technologies) or TaqMan® technology (Life Technologies), RNA sequencing (e.g., RNA-seq), RNA hybridization and signals as used with RNAscope® (Advanced Cell Diagnostics) Zoom in, or northern blot. In some aspects of these embodiments, the RNA transcript (mRNA or anotherRARA orIRF8 Transcripts) are normalized. Normalization involves the use of another RNA transcript (eg, GADPH mRNA, 18S RNA) that is native to its parents at the equivalent level in both cells, or prior to the determination of superaugrator intensity. "Apply" to the fixed level in the sample of each of the cells to adjust for comparisonRARA orIRF8 The measured levels of RNA transcripts (J Lovén et al., Cell, 151 (3): 476-82 (2012); J Kanno et al., BMC Genomics 7:64 (2006); J Van de Peppel et al., EMBO Rep 4: 387-93 (2003)).RARA Agonists and targeting CD38 Of Antibodies The present invention provides methods for treating individuals with cancer (eg, non-APL AML, MDS, or MM) with RARA agonists in combination with CD38-specific antibodies when, for example, RARA or IRF8 biomarkers are identified. RARA Agonist Used for treatment identification as havingRARA The selection of RARA agonists for patients with gene-associated superenhancers can be made from any RARA agonist known in the art. Preferably, the RARA agonist pair used in the method of the inventionRARA Other forms specific for RaR (eg, RaR-ß and RaR-γ) are significantly lower (at least 10 ×, at least 100 ×, at least 1,000 ×, at least 10,000 ×, at least 100,000 ×) Promoting activity. In some embodiments, the RARA agonist is selected from any compound disclosed in any of the following U.S. patents or within the class set forth in any of these patents: US 4,703,110, US 5,081,271, US 5,089,509, US 5,455,265, US 5,759,785, US 5,856,490, US 5,965,606, US 6,063,797, US 6,071,924, US 6,075,032, US 6,187,950, US 6,355,669, US 6,358,995 and US 6,387,950, each of which is incorporated herein by reference. In some embodiments, the RARA agonist is selected from any one of the known RARA agonists described in Table 1 below, or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the foregoing Materials: Table 1. Exemplary RARA agonists suitable for the present invention. In some embodiments, the RARA agonist is Tamibarotene. In some embodiments, the RARA agonist is(AGN-195183). CD38 Specific antibody CD38 is a transmembrane glycoprotein involved in many metabolic functions (including catabolism of extracellular nucleotides, receptor-mediated adhesion, migration regulation, and various signaling events). Antibodies targeting CD38 can modulate any of these functions, thereby promoting the efficacy of RARA agonists in cancer treatment. In some embodiments, the CD38 specific antibody can recognize and / or bind to any part of the CD38 fragment. CD38-specific antibodies may comprise monoclonal antibodies, humanized antibodies, or human antibodies. Exemplary antibodies specific for CD38 include isatuximab, daratumumab, MOR202, Ab79, Ab19 and EPR4106. In some embodiments, the CD38 specific antibody is daclizumab.treatment solutions The method of the present invention is theoretically applicable to treatments characterized by biomarkers with RARA or IRF8 (eg, one or moreRARA orIRF8 The presence, level, form and / or activity of genetic components or products, including for exampleRARA orIRF8 Super enhancer intensity, ordinal classification or prevalent classification andRARA Or IRF8 mRNA level or prevalence grade) associated with cancer. SuperenhancerRARA orIRF8 Genes can be more common in certain types of cancer than others. The present invention is specifically related to AML (for example, not characterized as involvingRARA Gene chromosomal translocation (non-APL AML and other forms of AML) and the treatment of MDS and MM. In some embodiments, the disease to be treated is not characterized as involvingRARA Non-APL AML, MDS or MM of chromosomal translocation of genes. In some embodiments, the disease to be treated is not characterized as involvingIRF8 Non-APL AML, MDS or MM of chromosomal translocation of genes. In some embodiments, individuals to be treated with RARA agonists (eg, Tamibarotene) and CD38-specific antibodies have relapsed or refractory non-APL AML. If the individual: a) does not show a partial response after the first cycle of induction chemotherapy; or b) does not show a complete response after the second cycle of induction chemotherapy; or c) relapses after conventional chemotherapy; or d) Relapse after a single stem cell transplantation is classified as having relapsed or refractory non-APL AML. In some embodiments, individuals to be treated with RARA agonists (eg, Tamibarotene) and CD38 specific antibodies have refractory MM. In other embodiments, the individual to be treated with a RARA agonist (eg, Tamibarotene) is an inappropriate elderly individual. The term "inappropriate elderly person" as used herein means a person who is at least 60 years old and is determined by a physician as a candidate for non-standard induction therapy. In some embodiments, the individual is co-administered with an RARA agonist (eg, Tamibarotene) and a CD38-specific antibody (eg, darumumab). In some embodiments, the RARA agonist (eg, Tamibarotene) and CD38-specific antibody (eg, darumumab) are administered simultaneously. In some embodiments, the RARA agonist (eg, Tamibarotene) and the CD38-specific antibody (eg, darumumab) are administered to each other within about 1 hour to about 48 hours. In some embodiments, the RARA agonist (eg, Tamibarotene) and the CD38-specific antibody (eg, darumumab) are administered to each other within the following time: about 1 minute, about 2 minutes, about 5 Minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, About 8 hours, about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 36 hours, or about 48 hours. In some embodiments, the patient population includes one or more individuals (e.g., comprising or consisting of multiple individuals) undergoing previous therapy for cancer (eg, non-APL AML, MDS, or MM). In some embodiments, the patient population includes one or more individuals (eg, comprising or consisting of multiple individuals) who have not received previous therapy for cancer (eg, non-APL AML, MDS, or MM). In some embodiments, the patient population includes or consists of patients who have not received prior therapy with non-APL AML, MDS, or MM. In some embodiments, the patient receiving the previous therapy may have received a previous therapy selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, palliative care, surgery, and combinations thereof. In some embodiments, the patient has undergone transplantation. In some embodiments, the patient has received standard cytotoxic chemotherapy. In some embodiments, standard cytotoxic chemotherapy includes cytarabine and / or anthracycline. In some embodiments, standard cytotoxic chemotherapy may include additional chemotherapy and / or hematopoietic stem cell transplantation (HSCT). In some embodiments, the patient has received a hypomethylated agent. In some embodiments, the patient has received lenalidomide. In some embodiments, the patient population includes those who have received and / or are receiving other therapies such as to allow administration of RARA agonist therapy (e.g., tamil) in combination with other therapies (eg, chemotherapy agents) in addition to CD38 specific antibodies (Barorotene) One or more individuals of the composition (e.g., comprising or consisting of multiple individuals). In some embodiments, such other therapies may include cancer (eg, as described herein), therapy for pain, nausea, constipation, etc., one or more side effects associated with cancer therapy (eg, pruritus, off Hair, insomnia, etc.) or any combination thereof, or consist of it. The present invention provides a method for treating non-APL AML, MDS, or MM, which includes therapy with a therapeutically effective amount of RARA agonist (eg, Tamibarotene) or a pharmaceutically acceptable salt thereof and a CD38-specific antibody Treatment is identified as patients with non-APL AML, MDS, or MM. In some embodiments, the present invention provides a method of treating non-APL AML, MDS, or MM of a patient previously treated with a treatment regimen including chemotherapy by administering a therapeutically effective amount of RARA to such patient Agonists (eg, Tamibarotene) and CD38 specific antibodies are performed. In some embodiments, the present invention provides a method for treating non-APL AML, MDS, or MM of patients without the presence of standard therapies. In some embodiments, the present invention provides a method for treating patients who are not suitable for standard therapy. In some embodiments, the patient or patient group may not be (eg, may not include) a patient with a previous history of allergy to the ingredients of Tamibarotene. In some embodiments, the patient or group of patients may not be (eg, may not include) patients who are receiving vitamin A formulations. In some embodiments, the patient or group of patients may not be (eg, may not include) patients suffering from hypervitaminosis A. In some embodiments, the patient or group of patients may not be (eg, may not include) elderly patients. In some embodiments, the patient or group of patients may be or include one or more elderly patients. In some embodiments, when compared to one or more younger patients, older patients may be monitored more frequently to detect possible adverse events (including, for example, low levels of serum albumin and / or plasma Higher concentration of free drugs, etc.). In some embodiments, administration of RARA agonists and / or CD38 specific antibodies may be reduced, suspended, and / or terminated in elderly patients determined to exhibit one or more symptoms of such adverse events.Dosage form and dosing regimen In general, each therapeutic agent used in accordance with the present invention is formulated, administered, and administered in a therapeutically effective amount in accordance with good medical practice and in a pharmaceutical composition and administration regimen suitable for the relevant agent and individual (e.g. Agents or CD38 specific antibodies). In principle, the therapeutic composition can be administered by any suitable method known in the art, including but not limited to oral, transmucosal, inhalation, topical, buccal, nasal, transrectal or parenteral Administration (eg, intravenous, infusion, intratumor, intranodular, subcutaneous, intraperitoneal, intramuscular, intradermal, transdermal, or other types of administration). In some embodiments, the RARA agonist (eg, Tamibarotene) will be administered orally. In some embodiments, the CD38 specific antibody will be administered intravenously. In some embodiments, the dosing regimen of a specific active agent may involve intermittent or continuous administration, for example, to achieve a specific desired pharmacokinetic profile or other exposure in one or more tissues or body fluids of interest in the individual receiving therapy mode. In some embodiments, different agents administered in combination may be administered via different delivery routes and / or according to different time courses. Alternatively or additionally, in some embodiments, one or more doses of the first active agent are administered substantially simultaneously with one or more other active agents, and in some embodiments, the one or more doses of the first active agent It is administered with one or more other active agents via common routes and / or as part of a single composition. Factors considered in optimizing the route and / or dosing schedule of a given treatment regimen may include, for example: the specific indication being treated, the individual ’s clinical condition (eg, age, overall health status, previous received Therapy and / or its response, etc.), the site of delivery of the agent, the nature of the agent, the mode and / or route of administration of the agent, the presence or absence of combination therapy and other factors known to medical practitioners. For example, in the treatment of cancer, the relevant characteristics of the indication being treated may include, among other things, one or more of the type, stage, location, etc. of the cancer. In some embodiments, one or more characteristics of a particular pharmaceutical composition and / or dosing regimen used can be adjusted over time (eg, increase or decrease the effective amount in any individual dose, increase or decrease administration Time interval, etc.), for example, in order to optimize the desired therapeutic effect or response. In general, the type, amount, and frequency of administration of the active agent according to the present invention are controlled by the safety and efficacy requirements for the application of one or more related agents to mammals (preferably humans). In general, such administration characteristics are selected to provide specific and usually detectable treatment responses compared to unobserved therapies. In the context of the present invention, exemplary desired therapeutic responses may include, but are not limited to, inhibition and / or reduction of one or more of tumor growth, tumor size, metastasis, symptoms and side effects associated with the tumor, and tumor Increased apoptosis, treatment-related decrease or increase in one or more cell markers or circulating markers, and the like. Such criteria can be easily assessed by any of various immunology, cytology, and other methods disclosed in the literature. In some embodiments, based on the timing and / or threshold performance of inducible markers, it may be necessary to adapt the dosing regimen, and in particular, a continuous dosing regimen needs to be designed, Patient groups (eg, patient groups carrying genetic markers) and / or specific patients. In some such embodiments, the therapeutic dosing regimen can be combined with or adjusted according to a detection method that evaluates the performance of one or more inducible markers before and / or during therapy. In some embodiments, the RARA agonist (eg, Tamibarotene) therapy regimen contains about 1 mg / m² , 2 mg / m² , 3 mg / m² , 4 mg / m² , 5 mg / m² , 6 mg / m² , 7 mg / m² , 8 mg / m² , 9 mg / m² , 10 mg / m² , 11 mg / m² , 12 mg / m² , 13 mg / m² , 14 mg / m² , 15 mg / m² , 16 mg / m² At least one (or include one or consist of exactly one) dose, or a dose between any of these equivalents of a RARA agonist (eg, Tamibarotene). In some embodiments, the RARA agonist (eg, Tamibarotene) therapy regimen is included at 1 mg / m² With 50 mg / m² Between doses. In some embodiments, the RARA agonist (eg, Tamibarotene) therapy regimen is contained at 5 mg / m² With 25 mg / m² Between doses. In some embodiments, the RARA agonist (eg, Tamibarotene) therapy regimen is contained at 5 mg / m² With 15 mg / m² Between doses. In some embodiments, the RARA agonist (eg, Tamibarotene) therapy regimen comprises 12 mg / m² Of dosage. In some embodiments, the RARA agonist (eg, Tamibarotene) therapy regimen contains 6 mg / m² Of dosage. In some embodiments, the RARA agonist (eg, Tamibarotene) therapy regimen includes multiple doses of the Tamibarotene composition. In some such embodiments, the Tamibarotene therapy regimen includes, for example, 2, 5, 10, 20, 30, 60, 90, 180, 365 doses or one of these values Multiple doses between any two, and / or include repeated dose patterns (eg, at least one cycle of two daily doses, which can be repeated, with alternate administration as appropriate or without administration for a period of time Open different cycles). In some embodiments, the Tamibarotene therapy regimen is administered twice a day. In some embodiments, the Tamibarotene therapy regimen is administered once a day. In some embodiments, the Tamibarotene therapy regimen contains 6 mg / m² Up to 12 mg / m² The total dose is divided into oral administration twice a day. In some embodiments, the CD38 specific antibody (eg, daclizumab) therapy regimen comprises about 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / At least one (or include one or consist of exactly one) dose of kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, or CD38 specific The dose between any two of these equivalent values of antibody (eg, daclizumab). In some embodiments, the CD38 specific antibody (eg, daclizumab) therapy regimen contains a dose between 1 mg / kg and 100 mg / kg. In some embodiments, a CD38 specific antibody (eg, daclizumab) therapy regimen contains a dose between 5 mg / kg and 50 mg / kg. In some embodiments, the CD38 specific antibody (eg, daclizumab) therapy regimen contains a dose between 10 mg / kg and 20 mg / kg. In some embodiments, the CD38 specific antibody (eg, daclizumab) therapy regimen comprises multiple doses of the daclizumab composition. In some such embodiments, the daclizumab therapy regimen includes, for example, 2, 5, 10, 20, 30, 60, 90, 180, 365 doses, or any of these values Multiple doses between the two, and / or include a repeated dose pattern (eg, at least one cycle of two daily doses, which can be repeated, separated by alternative or non-administrative periods as appropriate Different cycles). In some embodiments, the daclizumab therapy regimen is administered once a week. In some embodiments, daclizumab therapy regimen is administered at most once a week. In some embodiments, the daclizumab therapy regimen is administered every two weeks. In some embodiments, the daclizumab therapy regimen contains a total dose of 10 mg / kg to 20 mg / kg, at most once a week.Formulation As used herein, a pharmaceutical composition refers to a compound (such as a Tamibarotene or CD38 specific antibody) and other chemical components (such as a carrier, stabilizer, diluent, dispersant, suspending agent, thickener) And / or excipients). The pharmaceutical composition helps to administer the compound to the organism. The pharmaceutical composition containing the compound can be administered in a therapeutically effective amount by any known form and route known in the art including but not limited to the following: intravenous, oral, rectal, aerosol, parenteral , Eye, lung, skin, vagina, ear, nose and local administration. For oral administration, the compound can be easily formulated by combining the active compound with pharmaceutically acceptable carriers or excipients well known in the art. Such carriers allow the compounds described herein to be formulated into tablets, powders, pills, sugar-coated pills, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and Its analogs. In general, excipients (such as fillers, disintegrants, slip agents, surfactants, recrystallization inhibitors, lubricants, pigments, binders, flavoring agents, etc.) can be used for routine purposes and without affecting the combination Typical amounts of physical properties are used. In some embodiments, the excipient is one or more of lactose hydrate, corn starch, hydroxypropyl cellulose, and / or magnesium stearate. In some embodiments, Tamibarotene can be formulated with one or more of lactose hydrate, corn starch, hydroxypropyl cellulose, and / or magnesium stearate. The identification of acceptable formulations of Tamibarotene can be achieved by various methods known in the art, for example, as described in US 20100048708, which is incorporated herein by reference.Packaged pharmaceutical composition The packaged pharmaceutical composition of the present invention comprises a written insert or marker, which is included in cancer and has been determined to have an intensity or ordinal grade equal to or greater than the threshold level, or the RARA mRNA level is equal to or greater than the Limit levelRARA Instructions for the use of RARA agonists and CD38-targeting antibodies in individuals with gene-associated superenhancers. As described in detail above, the threshold is determined in a sample population from a cell line or xenograft model from an individual diagnosed with the same disease or the same disease as the disease in which the pharmaceutical composition is indicated to treat the disease Level. Description Can be adhered or otherwise attached to a container containing RARA agonist and CD38-targeting antibody. Alternatively, the instructions and the containers containing the RARA agonist will be separate from each other, but together exist in a single package, box, or other type of container. Instructions for packaged pharmaceutical compositions will usually be authorized or recommended by government agencies that approve the therapeutic use of RARA agonists and antibodies targeting CD38. The description may include determining whether the superenhancer is compatible withRARA orIRF8 Specific methods associated with genes, and determination andRARA orIRF8 Quantitative method to determine whether the gene-related enhancer is a super-enhancer, and the quantitative method to determine the RARA or IRF8 mRNA level; and / or the threshold level of the super-enhancer or RARA or IRF8 mRNA, at the threshold level Treatment with packaged RARA agonists and antibodies targeting CD38 is recommended and / or presumed to be effective. In some aspects, the instructions instruct to administer the composition to an individual whose RARA or IRF8 mRNA level falls in at least the 30th percentile of a population whose RARA or IRF8 mRNA level has been measured. In some aspects, if the individual ’s RARA or IRF8 mRNA level is prevalently classified as 79%, 78%, 77%, 76%, 75%, 74%, 73% of the group whose RARA or IRF8 mRNA level has been measured , 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56 %, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23% , 22%, 21%, or 20%, the individual is identified as a RARA agonist responder. In some aspects, instructions are given to administer the composition to individuals whose RARA or IRF8 mRNA levels have been measured by specific tests. Instructions may include information on administration, the type of cancer approved for treatment with RARA agonists and / or CD38-targeting antibodies, physicochemical information on RARA agonists and / or CD38-targeting antibodies; about RARA agonists Information on the pharmacokinetics of the agent and / or antibody targeting CD38; or information on drug-drug interactions. In some aspects, the instructions direct administration of the composition to individuals diagnosed with non-APL AML. In some aspects, the instructions direct administration of the composition to individuals diagnosed with non-APL MM. In some aspects, the pharmaceutical composition comprises Tamibarotene. In some aspects, the pharmaceutical composition comprises AGN-195183. In some aspects, the pharmaceutical composition comprises daclizumab. In some embodiments, the pharmaceutical composition includes both Tamibarotene and Daclizumab. Examples For a more complete understanding of the invention described herein, the following examples are illustrated. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein, and should not be construed as limiting its scope in any way.Examples 1 . RARA RNA And measurement of protein expression Use performance measurement to determine the markedRARA Gene mRNA level. The mRNA level is well correlated with the enhancer level and therefore also has predictive sensitivity to RARA agonists. We use various methods for measuring RNA as described below.I . Array-based technology. Use 1x10 in three equal batches⁶ Cells to evaluate the performance in HCC1143 and AU565. Follow manufacturer's protocol, use Trizol® to extract RNA from cells and use mirVana^TM RNA purification kits purify RNA (both from Life Technologies). Affymetrix PrimeView at Dana Farber Cancer Institute Microarray Core (http://mbcf.dfci.harvard.edu/)^TM Read the RNA level on the array. Figure 1 shows the mRNA expression levels of various RAR subtypes measured in the Tamibarotene reactive (Au565) and non-reactive (HCC1143) cell lines using the above protocol. The expression of RARA mRNA in reactive cell lines was 8 times higher than that of non-reactive cell lines, and the performance of RaR-ß and RaR-γ did not differ significantly between these cell lines. This confirms RARA mRNA performance analysis andRARA Superenhancer strength is related to sensitivity to RARA agonists, and indicates that RARA mRNA levels can be used to predict sensitivity to such agonists.II . RNA - Seq . RARA performance was quantified by RNA-Seq. Run Poly-A RNA-Seq and use rsem v1.2.21 software (rsem-calculate-expression; parameter = -p 4 --samtools-sort-mem 3G --ci-memory 3072 --bowtie-chunkmbs 1024 --quiet- -output-genome-bam --bowtie2 --bowtie2-path /data/devtools/bowtie2-2.0.5 --strand-specific) compare reads to HG19 transcriptome, and then use the same rsem program set (rsem -parse-alignments, rsem-build-read-index, rsem-run-em) and report mRNA quantification per million transcripts (TPM), which represents the specified gene for each million transcripts detected Estimate of the number of transcripts. Subsequently, all protein-coding genes were extracted for each sample and scored together for quantile normalization. We process all AML patient samples, primary AML patient samples and AML cell lines from the PDX model and normalize them together to generate universal mRNA scores. Plotted values show the log2 (TPM + 1) level (y-axis) of RARA for 48 primary AML patientsRARA / MALAT1) (Figure 1).Examples 2 . AML Nakano RARA Super enhancer intensity ordinal number cutoff H3K27Ac and ChIP-Seq were used to analyze the overall enhancer / super enhancer maps of 95 AML samples (both patient samples and AML cell lines (including SigM5, MV411, HEL, and Kasumi1)). In each of the samples, determineRARA The relative enhancers are ranked in terms of strength (as measured by H3K27Ac) compared to other enhancers and superenhancers in the same cell, and the measured ordinal ranks are plotted on the sorting bar graph (Figure 2 ). In MV411, determineRARA The related enhancer is the 133rd strongest enhancer. MV411 is the Tamibarotene-reactive cell line confirmed to have the lowest superenhancer intensity number. In HEL, determineRARA The related enhancer is the 155th strongest enhancer. HEL is a non-reactive cell line of Tamibarotene that has been confirmed to have the highest superenhancer intensity number. Based on these values, we setRARA The cut-off of the intensifier ordinal number is 150 (value between HEL ordinal number and MV411 ordinal number). As determined by the analysis of 70 primary AML cell samples from human individuals, 36% of their samples had the strongest 150th among them.RARA Super enhancer (Figure 3). Therefore, the prevailing cut-off is set at 36%. When identifying potential AML responders to Tamibarotene based on RARA or IRF8 mRNA measurements, the same prevalence cutoff is also used as the RARA mRNA prevalence cutoff. I also useRARA The ratio of enhancer to MALAT1 enhancer ("normalized enhancer intensity") is used to quantitatively expand the enhancer of the AML cell group. Plotting the sensitivity of this normalized enhancer intensity value to Tamibarotene, I confirmRARA Five of the 6 cell lines with an enhancer intensity ratio greater than 1 were reactive, while only 4 of the 7 cell lines with an enhancer less than this level were reactive (Figure 5). When the cutoff moves to a normalized enhancer intensity of 1.4 or higher, all cell lines (4 out of 4) are reactive.Examples 3 . AML Nakano RARA Super-enhancer intensity ordinal grade cutoff and RARA mRNA Level related Will be used to determine 36%RARA Samples of AML patients with cut-off pre-emphasis of super-enhanced intensity are divided into two groups-their prevalence is 36% or higher (i.e., lower% value) and their prevalence is less than 36% (i.e., Higher% values) of their samples-and use RNA-seq as described in Example 1 to analyze the RARA mRNA levels of these samples. The results are shown in Figure 5A. inRARA The 36% of the super-enhancer intensity sequence with a prevalence rating or higher has a statistically significantly higher level of RARA mRNA than the group with a lower prevalence rating (p <0.001). This again confirms that the prevalence cutoff measured in terms of super-enhanced sublevels can also be used as the prevalence cutoff for mRNA levels. We also used RNA-seq to determine the RARA mRNA level in 11 different AML cell lines and compared the mRNA level with the sensitivity to Tamibarotene. The AML cell lines tested were divided into two different groups based on their sensitivity or insensitivity to Tamibarotene. All cell lines sensitive to Tamibarotene had RARA mRNA> 10 TPM measured by RNAseq, while three insensitive cell lines had levels below this cut-off level (Figure 5B).Examples 4 : non- APL AML Of the cell lines IRF8 mRNA Level and Right RARA Agonist response I use Affymetrix GeneChip^® PrimeView^™ Human Gene Expression Array to examine seven of these AML cell lines (four are sensitive to Tamibarotene-NOMO-1, AML3, MV-4-11 and Sig-M5; and three are Tamiba Rotin is insensitive-other mRNAs of KG1a, OCI-M1 and Kasumi-1), which may be particularly high in Tamibarotene sensitive cell lines, and IRF8 mRNA is identified as a potential candidate. We then quantified the IRF8 mRNA levels of each of these seven AML cell lines and each of several other AML cell lines that were tested for sensitivity to Tamibarotene by performing RNA-seq analysis as described below . The results of the first seven cell lines are shown in Figure 6. Interestingly, NOMO-1 does not have a high RARA mRNA level, but responds to Tamibarotene. The fact that NOMO-1 has a higher IRF8 mRNA level helps to explain this apparent inconsistency and further validates the use of IRF8 mRNA level to predict the response to Tamibarotene. RNA isolation, preparation, and RNA-seq data processing were performed in a manner similar to that described in Example 1. We will then compare the sensitivity of Tamibarotene to the IRF8 mRNA level, as shown in Figure 6 and Table 2. Table 2: IRF8 mRNA level of AML cell line and anti-proliferative efficacy of Tamibarotene * HL60 is an APL cell line. As can be seen from the table above, all Tamibarotene-reactive cell lines except HL60 have a higher than 190 TPM (log₂ (7.57)) IRF8 mRNA level, and all non-reactive cell lines have less than 16.5 TPM (log₂ (4.03)) IRF8 mRNA level. In the absence of the corresponding high level of IRF8 mRNA (6.73 TPM), the response of HL60 to Tamibarotene indicates that the correlation between IRF8 mRNA level and Tamibarotene sensitivity may not be effective for APL, and Therefore, it can be better suited for stratifying individuals with non-APL AML. Figure 7 removes the data points of HL60. Table 3 shows the division log₂ The values are similar to Table 2 except for the IRF8 mRNA values described in the values, and show additional data for Sig-M5 and THP-1 cell lines. Table 3. Expressed as log₂ Value of AML cell line mRNA level and anti-proliferative efficacy of Tamibarotene * HL60 is an APL cell line.Examples 5 : RARA Agonist treatment IRF8 mRNA Determination of threshold AML cell line results indicate that the cut-off value in RNA-Seq analysis is between 15.5 and 190 TPM (ie, in the log₂ (4.03) and log₂ (Between 7.57)). We selected a population of AML patient samples (gift from Stanford University) to check the distribution of IRF mRNA levels and determine the prevailing cut-off value based on this cut-off value. We added this population of AML cell lines and then generated a sorted map. Figure 8 shows the sequence distribution of IRF8 mRNA levels in the combined patient sample / AML cell line population. We have determined that the prevailing cut-off of 25% corresponds to approximate log₂ (7) IRF8 mRNA value.Examples 6 : IRF8 mRNA versus RARA mRNA Level correlation We then compared IRF8 and RARA mRNA levels in AML cell lines and patient populations to determine the correlation. Figure 9 shows that some cell lines that respond to Tamibarotene have relatively low RARA mRNA, but have high level IRF8 mRNA. Figure 10 shows that the patient subgroup also exhibits high IRF8 mRNA levels, but exhibits relatively low RARA mRNA levels, and vice versa. If any mRNA level is greater than the threshold, measuring both IRF8 and RARA mRNA in the patient and selecting the patient for treatment with RARA agonists (such as Tamibarotene) may be optimal The idea of treating a patient group.Examples 7 : By him Mibarotene AML Cell line RARA mRNA Dependence CD38 Induce We monitored the induction of CD38 expression on the cell surface after treatment with Tamibarotene by measuring the mean fluorescence intensity (MFI) of the cell surface stained with the CD38-FITC antibody. FIG. 11A shows that treatment with Tamibarotene at a concentration of 50 nmol / L for 72 h does not induce CD38 expression in the RARA mRNA low cell line Kasumi (CD38^- ). Figure 11B shows that after Tamibarotene treatment of the RARA mRNA high cell line MV411 for 72 h, the entire cell population showed a high level of CD38 (CD38^HI ). In addition, in Figure 11C, OCI-AML3 (RARA mRNA high) has a low CD38 MFI (CD38^DIM ). After Tamibarotene treatment, CD38 performance was further induced and the cell population became CD38^HI . Figure 11D shows that 72h Tamibarotene treatment did not induce CD38 expression in another RARA mRNA low cell line OCI-M1 (CD38^- ). This information indicates CD38 performed by Tamibarotene^HI Induction can be predicted by RARA mRNA level. These results are depicted in FIG. 11E as a bar graph showing the level of CD38 mRNA expression detected in each cell line before and after treatment. Figure 11F shows the FACS-based CD38 before and after treatment with Tamibarotene^HI The percentage of cells. In FIGS. 11E and 11F, the APL cell line NB4 is also shown.Examples 8 : RARA mRNA Predicted after the combination therapy of Tamibarotene and Dacirumab AML Cell line MV411 Of NK cell Cytotoxicity In order to functionally evaluate the efficacy of the combination of Tamibarotene and dalmatumab, AML cell lines with different RARA mRNA levels were treated with Tamibarotene for 72 hours, followed by human NK cells and dalmatumab or Control antibody co-culture. Then during the 38-hour co-culture time course, NK cell proliferation and tumor cell death were imaged with a phase difference. Figures 12A-12D are representative images of phase-contrast images of RARA mRNA high MV411 cell lines in the co-culture analysis under the following treatment conditions: Figure 12A) 72 h DMSO MV411 cell line before treatment and 38 h co-culture control antibody treatment. Figure 12B) 72 h SY1425 (50nM) MV411 cell line before treatment and 38 h co-culture control antibody treatment. Figure 12C) 72 hours of DMSO MV411 cell line before treatment and 38 hours of co-cultivation of damuci monoclonal antibody treatment. Figure 12D) 72 hours of SY1425 (50nM) MV411 cell line before treatment and 38 hours of co-cultivation of damuci monoclonal antibody treatment.Examples 9 : RARA mRNA The level is predicted to be after the combination therapy of tamibarrotin and daclitumab AML Cell line NK cell Cytotoxicity The NK cell-mediated kinetic measurement of tumor cell death by phospholipid binding protein V staining of tumor cells supports the following findings: the combination of Tamibarotene and dalmatumab treatment compared to single agent treatment Tumor cell death increased in some AML cell lines (Figures 13A to 13C). Combination with increased induction of CD38 expression in RARA mRNA high AML cell lines (ie, OCI-AML3 and MV411) but not RARA mRNA low AML cell lines (ie, OCI-M1) (Figures 11B to 11D) These data support the conclusion that Tamibarotene induces CD38 in a RARA mRNA-dependent manner^HI Phenotype, which is required for effective NK cell-mediated tumor cell death after dalmatumab treatment.Examples 10 : Co-cultivation analysis NK cell Activation only occurs after combination therapy with Tamibarotene and dalmatumab , By NK cell IFN γ Determined by secretion. Interferon gamma (IFNγ) secretion is an indicator of NK cell activation. After co-culture of AML cell lines and NK cells for 38 h, IFNγ secretion was quantified following the indicated treatment conditions (Figure 14). Compared to single agent treatment conditions, IFNγ levels were only observed in RARA mRNA high AML cell lines (MV411 and OCI-AML3) and NK cell co-culture analysis after combination treatment with Tamibarotene and dalmatumab Significant increase. In addition, this is shown as CD38 after Tamibarotene treatment^HI Phenotype is the only cell line. These data further support the indication that effective NK cell activation of phospholipid binding protein V quantification (Figures 12A-12D and 13) requires combination therapy.Examples 11 : Tamibarotene increases the number of multiple myeloma cells CD38 The intensity of performance. Datulimumab is clinically approved for the treatment of multiple myeloma (MM). However, due to the low level of CD38 performance, only some of these patients responded. I hereby prove that his Mibarotene increase has been CD38^HI CD38 in multiple myeloma cell line (MM1S)^HI Phenotype (Figure 15A) and can increase CD38^- Multiple myeloma cell line to medium state (HUNS1) (Figure 15B). Based on previous AML experiments, we predict that this may increase CD38^HI High individual response to CD38 therapeutic antibody against immune-mediated death.Examples 12 : CD38 ^HI The increase in the phenotype of Tamibarotene further makes MM Darmuzumab-dependent NK cell Mediated cytotoxicity is sensitive. To investigate whether treatment of MM cell lines with Tamibarotene would increase the sensitivity to CD38 antibody treatment, we repeated the previously described NK cell co-culture analysis with HUNS1 and MM1S MM cell lines. Figure 16 shows that after combination therapy with Tamibarotene and daltelimumab, MM1S tumor cell death was increased compared to single agent anti-CD38 antibody treatment, as quantified by phospholipid binding protein V staining. We further confirmed this by directly monitoring the activation of NK cells secreted by IFNγ after 38 h of treatment in this analysis (Figure 17). Multiple myeloma cell lines MM1S that achieved high CD38 intensity exhibited potent cell killing in response to combination therapy.Examples 13 : Tamibarotene induces primary non- APL AML and MDS Among the patient samples CD38 ^HI Phenotype. To confirm CD38 in AML cell lines^HI Levels of Tamibarotene induction can approach AML and MDS patient samples. We will obtain PBMC from 15 different AML or MDS patients with 50 nM Tamibarotene or with DMSO as a negative control to cultivate. We tested the viability and CD38 induction after 24 and 48 hours of treatment, as measured by flow cytometry. Analyze the CD38 level of samples with at least 10% viability. The results are shown in Figure 18A. Most patient samples (11/15) showed CD38 after 24 hours of treatment^HI The increase in cells. One patient sample showed no response (patient 4) and three patient samples did not meet the vitality criteria (patients 2, 6, and 10) after 24 h. After 48 h, four additional patient samples that had been shown to induce CD38 after 48 h no longer met the viability criteria and were excluded (patients 3, 7, 9 and 14). All remaining patient samples except non-responder patient 4 showed further induction of CD38 level after 48 h. We then measured both the RARA and IRF8 mRNA levels in these subgroups of patients (Patients 1, 5, 11, 12, and 13). The subgroup of patients indicated that patients who showed some responses at 48 h After that, he is still alive and indicates both AML and MDS. As shown in FIG. 18B, the patient samples showing higher levels of RARA mRNA and / or IRF8 mRNA as measured by RNA qPCR (the lower the dCq value, the higher the mRNA level) were compared to those with Samples with lower RARA mRNA and / or IRF8 mRNA showed a greater percentage of CD38 after Tamibarotene treatment^HI . The observed CD38 induction level for AML patient samples correlates well with the results obtained from high RARA RNA AML cell lines (eg, comparing the patient samples AML_1 in Figures 19C to 19D with the Tamiba in AML cell line MV411 Rotin-induced CD38 MFI). For both, Tamibarotene caused a similarity to that observed in multiple myeloma cell lines and multiple myeloma patients with daclizumab sensitivity, phenotype CD38^HI Increased phenotype (for example, comparing the patient sample MM_1 in FIG. 19A to FIG. 19B with the multiple myeloma cell line MM1S). Based on this correlation, the present inventors believe that patients with high RARA mRNA AML will benefit from the combined treatment of RARA-specific agonists (such as Tamibarotene) and anti-CD38 antibodies (such as daratumumab).Examples 15 : Tamibarotene caused higher than RARA or IRF8 Of the level AML Cell line xenotransplantation ATRA bigger CD38 Induced increase. ATRA has been reported to cause greater induction of the CD38 level than tamibarotene in HL-60 cells (usually characterized as AML cell lines of APL) (A Uruno et al., 2011, J Leuk Biol, 90, 235 To page 247). We intend to compare the CD38-inducing effects of ATRA and Tamibarotene in non-APL AML cell lines with different levels of RARA or IRF8 mRNA. In this experiment, we used MV411, THP-1 or Kasumi-1 mouse xenotransplantation. MV411 has high-level RARA mRNA and IRF8 mRNA (ie, greater than the threshold), while THP-1 has high-level IRF-8 mRNA. It is believed that Kasumi-1 cells have IRF8 and RARA levels below the threshold. Each of the cell lines is 5% CO at 37 ° C in vitro₂ Maintain the appropriate medium in the air atmosphere (THP-1 cells: supplemented with 10% heating-inactivated fetal bovine serum and 0.05 mM β-mercaptoethanol in RPMI1640 medium; MV4-11 cells: supplemented with 10% heating inactivated fetal bovine serum IMDM medium; Kasumi-1 cells: suspension culture in RPMI1640 medium supplemented with 20% heat-inactivated fetal bovine serum). Cells grown in the exponential growth phase were collected for tumor inoculation and counted. All mice were irradiated with gamma (200 rad) for 24 h before tumor cell inoculation. Use appropriate tumor cell lines (THP-1 cells: containing 1 × 10 in the right ventral area of each mouse)⁷ 0.1 ml PBS (1: 1 Matrigel) per cell; MV4-11 cells: containing 5 × 10⁶ 0.1 ml PBS (1: 1 Matrigel) per cell; Kasumi-1 cells: containing 1 × 10⁷ Each cell of 0.1 ml PBS (1: 1 Matrigel) was inoculated subcutaneously for tumor development. When the average tumor size reaches approximately 100 to 200 mm³ At the time, began treatment with Tamibarotene, ATRA or vehicle. The mice were divided into 3 groups, nine in each group, and each group was orally administered a drug (ATRA 4 mg / kg; Tamibarotene 3 mg / kg) or vehicle BID lasted up to 28 day. The date of tumor cell inoculation is indicated as day 0. Use a caliper gauge to measure the tumor volume in two dimensions twice a week, and use the following formula in mm³ Express volume as a unit: V = 0.5a ×b ² ,among thema andb Respectively, the length and width of the tumor. After grouping, three mice were killed per group on days 7, 14, and 21 (a total of 4 weeks of study). One half of the tumor was collected for embedding into the FFPE block for immunohistochemistry (IHC) staining, and the other half of the tumor was collected for CD38 FACS analysis of tumor cells. IHC staining was performed using a BOND RX automatic staining instrument using anti-CD38 antibodies against the C-terminus of CD38 (clone SP149; Abcam; Cat. No. ab183326). The antibody was diluted 1: 100 in EDTA buffer at pH 9.0 and then incubated with tumor sections for 20 minutes. Use DAB and manufacturer's combined polymer fine detection kit to generate signals. As seen in Figure 20A, after 7 days, MV4-11 xenograft mice treated with Tamibarotene exhibited an average fluorescence intensity (MFI) greater than 200, where more than 80% of tumor cells were CD38 by FACS analysis^HI . ATRA-treated MV4-11 xenograft mice display a MFI slightly greater than 100, of which approximately 70% of tumor cells are CD38^HI . Immunohistochemical staining of tumor sections with anti-CD38 antibody confirmed the unexpected and unexpected superiority of Tamibarotene over ATRA in this xenograft model (Figure 20B). This trend became even more pronounced at 3 weeks. As shown in Figure 20C, at three weeks, more than 60% of tumor cells maintained CD38 in MV4-11 xenografts treated with Tamibarotene^HI , Of which MFI is about 110, and less than 20% of tumor cells maintain CD38 in ATRA-treated xenografts^HI , Where MFI is about 50. Figure 20D shows immunohistochemical staining of tumor cells after three weeks, which confirms the superiority of Tamibarotene over ATRA. As shown in Figure 21, the superiority of Tamibarotene in inducing CD38 was also observed in THP-1 cells after 7 days. Although xenotransplants treated with ATRA showed similar CD38 compared to Tamibarotene^HI Cell percentage, but Tamibarotene treatment produced a higher MFI (greater than 200) compared to ATRA (~ 175). In contrast, Kasumi-1 cells demonstrated minimal CD38 induction with either treatment (Figure 22). One week later, the immunohistochemical comparison of various types of xenotransplantation and various types of treatment is shown in FIG. 23.Equivalents and categories In embodiments, articles such as "a / an" and "the" can mean one or greater than one unless indicated to the contrary or otherwise obvious from the context. Unless indicated to the contrary or otherwise obvious from the context, an embodiment or description including "or" between one or more members of a group is deemed to satisfy one, more than one, or all group members present in, for a given A condition in a product or method or otherwise related to a given product or method. The invention includes embodiments where exactly one member of the group is present in, used in, or otherwise related to a given product or method. The invention includes embodiments where more than one or all group members are present in, used in, or otherwise related to a given product or method. Furthermore, the present invention covers all variations, combinations, and arrangements in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed embodiments are introduced into another embodiment. For example, any embodiment depending on another embodiment may be modified to include one or more limitations found in any other embodiment depending on the same base embodiment. In the case where the elements are listed, for example, in the Markush group format, each sub-group of the elements is also revealed, and any elements can be removed from the group. It should be understood that, generally speaking, when the invention or aspects of the invention are referred to as including specific elements and / or features, certain embodiments of the invention or aspects of the invention are composed of such elements and / or features or mainly Consist of such elements and / or features. For simplicity, their embodiments have not been specifically described in words herein. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow additional elements or steps to be included. When a range is given, the endpoint is included. In addition, unless otherwise indicated or otherwise obvious from the context and understanding of one of ordinary skill, values expressed as ranges may employ any particular value or subrange within the stated range in different embodiments of the invention, unless the context clearly dictates otherwise , Otherwise it reaches + 1 / unit of the lower limit of the range. This application is about various granted patents, published patent applications, journal articles and other publications, and the above owners are incorporated by reference. If there is a conflict between any incorporated reference and this specification, this specification shall prevail. In addition, any specific embodiment of the present invention belonging to the prior art may be explicitly excluded from any one or more of the embodiments. Because such embodiments are considered to be known to those of ordinary skill, they can be excluded even if the exclusion is not explicitly set forth herein. Any particular embodiment of the present invention may be excluded from any embodiment for any reason, whether related to the existence of the prior art or not. Those skilled in the art using only routine experimentation will recognize or be able to determine many equivalents of the specific embodiments described herein. The scope of the embodiments of the present invention described herein is not intended to be limited to the above description, but is actually as set forth in the accompanying embodiments. A person of ordinary skill will understand that various changes and modifications can be made to this specification without departing from the spirit or scope of the invention as defined in the following embodiments.

Figure 1 shows the correlation between RARA mRNA expression (log ₂ (1 + TPM)) and RARA SE intensity ( RARA / MALAT 1-fold enrichment) for 48 different AML patient samples using RNA-Seq. Figure 2 depicts a log ₁₀ ranking chart of the RARA superenhancer intensity numbers in 94 AML samples, which include four AML cell lines-Sig-M5, MV411, HEL, and Kasumi. Figure 3 depicts a log ₁₀ ranking chart of RARA superenhancer intensity numbers in 70 AML patient samples. Lighter bars indicate samples whose RARA superenhancer intensity number is equal to or greater than the prevalent cutoff. The darker bar indicates that the RARA super-enhancer intensity number is less than the prevalent cut-off sample. Figure 4 depicts the correlation between RARA enhancer intensity and tamibarotene sensitivity in 11 different AML cell lines. Figure 5A depicts samples from 70 AML patients and according to whether their RARA superenhancer intensity number is greater than (or equal to) the prevalence cutoff ("High RARA") or less than the prevalence cutoff ("Low RARA") as described in Example The RARA mRNA level of the group. Figure 5B depicts the correlation between RARA mRNA levels and the sensitivity of Tamibarotene in 11 different AML cell lines. Figure 6 depicts IRF8 mRNA levels in seven different AML cell lines. The four cell lines shown on the left side of the graph indicate a substantial response to Tamibarotene treatment. The three cell lines shown on the right side of the graph indicate minimal or no response to Tamibarotene treatment. Figure 7 shows the correlation between the antiproliferative efficacy (EC ₅₀ value, nM) of Tamibarotene and the IRF8 mRNA level, as measured by RNA-Seq. It should be noted that the IRF8 mRNA level = 1 (log10) and the Tamibarotene EC ₅₀ value is estimated to be 50 μM (non-reactive). The point in the upper left corner is from a low IRF8 mRNA level and has no effect on Tamibarotene Data of 2 AML cell lines with anti-proliferative response. The correlation between Tamibarotene sensitivity and IRF8 mRNA level is highly significant (p = 0.0001, Spearman's correlation, two-tailed). FIG. 8 depicts a ranking chart of IRF8 mRNA levels in AML samples and AML cell lines of individual patients, as measured by RNA-Seq. The following AML cell lines are indicated: PL21, which is the cell line with the lowest IRF8 mRNA level that responds to Tamibarotene; and Kasumi, which is the one with the highest IRF8 mRNA level that does not respond to Tamibarotene Cell line. In this group, the 25% prevalence cutoff is equal to the RNA-Seq TPM value of approximately log ₂ (7). Figure 9 depicts the correlation between IRF8 mRNA level and RARA mRNA level in non-APL AML cell lines tested to respond to Tamibarotene. Figure 10 depicts the correlation between IRF8 mRNA level and RARA mRNA level in a population of AML patient samples. The dotted line indicates the prevalence of 25% of each mRNA. Figures 11A-11F depict the effect of Tamibarotene ("SY1425") on the CD38 level in different AML cell lines. 11A to 11D show the effect of Tamibarotene on different cell lines, as measured by FITC cell classification. Figure 11E is a graphical representation of CD38 mRNA levels in different cell lines before and after treatment with Tamibarotene. Figure 11F is a graphical representation of% CD38 positive cells as determined by FITC cell classification. Figures 12A to 12D depict the effects of tamibarotene and darumumab ("Dara") alone or in combination on NK cell proliferation and tumor cell death in different NK cell / AML cell line co-culture media, such as Observed by phase contrast microscope. 13A to 13C depict the effect of control antibody or Dara alone or in combination with Tamibarotene on the number of apoptotic cells in NK cell / AML co-cultures of different AML cell lines. Figure 14 depicts the effect of control antibody or Dara alone or in combination with Tamibarotene on IFN-γ secretion in NK cell / AML co-cultures of different AML cell lines depicted in Figures 13A to 13C. 15A to 15B depict the effect of control antibody or Dara alone or in combination with Tamibarotene on the CD38 level in two different multiple myeloma cell lines (MM1S; FIG. 15A) (HUNS1; FIG. 15B), such as Measured by FITC cell classification. Figure 16 depicts the effect of control antibody or Dara alone or in combination with Tamibarotene on the number of apoptotic cells in two different multiple myeloma cell lines co-cultured with NK cells. Figure 17 depicts interferon in a NK cell / multiple myeloma co-culture of control antibody or Dara alone or in combination with Tamibarotene on multiple different cell lines depicted in Figures 15A to 15B and 16 The role of γ secretion. Figure 18A depicts the effect of Tamibarotene treatment on CD38 performance in different AML and MDS patient samples after 24 or 48 hours. Figure 18B depicts the effect of Tamibarotene treatment on CD38 performance as measured by FACS and RARA and IRF8 mRNA performance as measured by qPCR in different AML and MDS patient samples after 24 or 48 hours . Figures 19A to 19D compare the effect of Tamibarotene treatment on the CD38 level in AML cell lines, AML patient samples and multiple myeloma cell lines, and the baseline CD38 in CD38 ^HI multiple myeloma patient samples The role of level. Figures 20A to 20D compare one of the mice MV4-11 xenograft model with Tamibarotene and all-trans retinoic acid (ATRA) after one week (Figures 20A and 20B) and three weeks (Figures 20C and 20D). The role of CD38 level. The presence of CD38 in tumor cells was tested by both FACS (Figures 20A and 20C) and immunohistochemistry (IHC) staining (Figures 20B and 20D). FIG. 21 compares the effects of Tamibarotene and ATRA on CD38 level in a mouse THP-1 xenograft model one week later, as measured by FACS. Figure 22 compares the effects of tamibarrotin and all-trans retinoic acid (ATRA) on the CD38 level in the mouse Kasumi-1 xenograft model one week later, as measured by FACS. Figure 23 compares the effect of tamibarrotin and all-trans retinoic acid (ATRA) on the CD38 level in mouse THP-1, Kasumi-1 and MV4-11 xenograft models after one week, as measured by IHC Measurement.

Claims (16)

A method for diagnosing whether a human individual has a tamibarotene sensitive disease selected from non-APL AML, multiple myeloma, and MDS, which includes diagnosing whether the individual has: i. Pre-determined as equal to or greater than The retinoic acid receptor α mRNA level in a sample of diseased cells from the individual with a predetermined threshold; and / or ii. Of the diseased cells from the individual previously determined to be equal to or greater than the predetermined threshold IRF8 mRNA level in the sample. A use of Tamibarotene in the manufacture of a medicament for treating a human subject suffering from a disease selected from non-APL AML, multiple myeloma or MDS, wherein the retinoic acid receptor alpha mRNA position in the diseased cells And / or IRF8 mRNA level has been determined to have a retinoic acid receptor alpha mRNA level equal to or greater than a predetermined threshold, or an IRF8 mRNA level equal to or greater than a predetermined threshold, wherein the agent further contains CD38 specificity Sex antibodies may be used in combination with CD38 specific antibodies. The use according to claim 2, wherein the CD38 specific antibody is daratumumab. The use according to claim 3, wherein the agent is used to administer Tamibarotene for a period of time before administering the CD38-specific antibody; and after starting Tamibarotene, only CD38 in the individual The CD38 specific antibody was co-administered when the level was determined to be CD38 ^hi . The use as in claim 4, wherein the CD38 level in the individual is determined between 6 and 72 hours after the start of administration of Tamibarotene. The use as claimed in any one of claims 2 to 5, wherein Tamibarotene is used for oral administration. The use according to any one of claims 2 to 5, wherein the medicament is for administration of Tamibarotene at a dose between 6 mg / m ² / day and 12 mg / m ² / day, wherein the dose is divided For two doses. The use according to any one of claims 2 to 5, wherein the anti-CD38 antibody is used for administration not more than once a week at a dose between 10 and 20 mg / kg of the body weight of the individual. A method of determining a suitable therapy for a human individual with non-APL AML, multiple myeloma, or MDS, which includes diagnosing whether the individual is based on the retinoic acid receptor alpha mRNA level and / or IRF8 mRNA level Suffering from Tamibarotene sensitive disease, either or both of these levels are pre-determined to be present in a sample of diseased cells from the individual; and wherein: i. The individual is suitable to include the following Therapy: If the level indicates that the disease is sensitive to Tamibarotene, then administer a quantitative amount of Tamibarotene effective to treat the disease and co-administer CD38-specific antibodies; The following therapy: If the level indicates that the disease is not sensitive to Tamibarotene, then administer drugs other than Tamibarotene. The method of claim 9, wherein the retinoic acid receptor alpha mRNA and / or the IRF8 mRNA level indicates that if the level is greater than a predetermined threshold, the disease is sensitive to Tamibarotene, and if the bit If it is less than the predetermined threshold, the disease is not sensitive to Tamibarotene. The method of claim 9, wherein the CD38-specific antibody is daclizumab. The method of claim 9, wherein if the retinoic acid receptor alpha mRNA or the IRF8 mRNA level indicates that the disease is sensitive to Tamibarotene, then the therapy comprises administering to the individual before administering the CD38-specific antibody Tamibarotene was administered for a period of time; and after starting Tamibarotene, the CD38 specific antibody was co-administered to the individual only when the CD38 level in the individual was determined to be CD38 ^hi . The method of claim 12, wherein the CD38 level in the individual is determined between 6 and 72 hours after the start of administration of Tamibarotene. The method of any one of claims 9 to 13, wherein Tamibarotene is administered orally. The method according to any one of claims 9 to 13, wherein the subject is administered Tamibarotene at a dose between 6 mg / m ² / day and 12 mg / m ² / day, wherein the dose is Two doses. The method of any one of claims 9 to 13, wherein the anti-CD38 antibody is administered at a dose between 10 and 20 mg / kg of the body weight of the individual no more than once a week.