CN117940119A - Meflofen for the treatment of multiple myeloma - Google Patents
Meflofen for the treatment of multiple myeloma Download PDFInfo
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- CN117940119A CN117940119A CN202280058782.7A CN202280058782A CN117940119A CN 117940119 A CN117940119 A CN 117940119A CN 202280058782 A CN202280058782 A CN 202280058782A CN 117940119 A CN117940119 A CN 117940119A
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- stem cell
- meflofen
- patient
- received
- multiple myeloma
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Abstract
The present invention relates to a particularly advantageous novel therapeutic use of meflofen (melphalan fluorobenzamide; L-melphalan-4-fluoro-L-phenylalanine ethyl ester) or a salt thereof: multiple myeloma for use in treating or preventing a patient with multiple myeloma, said patient: -no stem cell transplantation has been received; or-has received stem cell transplantation at least 5 years ago; or-75 years old or older; or-not received stem cell transplantation and is 75 years old or older, or received stem cell transplantation at least 5 years ago and is 75 years old or older; or-receiving a stem cell transplant and the disease later progresses at least 36 months after the transplant. The inventors have found that meflofen, and in particular the combination of meflofen and dexamethasone, is unexpectedly effective in treating or preventing multiple myeloma in these patients. More specifically, the inventors have found that meflofen exhibits excellent anti-tumor activity in these patient populations compared to other treatments for multiple myeloma.
Description
Technical Field
The present invention relates to a particularly advantageous novel therapeutic use of meflofen (melphalan fluorobenzamide (MELPHALAN FLUFENAMIDE); L-melphalan-4-fluoro-L-phenylalanine ethyl ester) or a salt thereof for the treatment or prevention of multiple myeloma in patients with multiple myeloma, said patients
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-Not receiving a stem cell transplant and being 75 years old or older, or receiving a stem cell transplant at least 5 years ago and being 75 years old or older; or (b)
-Receiving a stem cell transplant and the disease later progresses at least 36 months after the transplant.
Background
Multiple Myeloma (MM) is a malignant cancer that differentiates plasma cells. Characterized by clonal proliferation of plasma cells in the bone marrow and production of an excess of monoclonal immunoglobulins (usually of the IgG or IgA type or free urinary light chain [ accessory protein, M protein or M component ]). Multiple myeloma refractory to relapse (RRMM) is a specific subtype of multiple myeloma that can be defined as multiple myeloma that initially responds to treatment, but does not respond to treatment after relapse.
MM is the second most common hematological malignancy, and approximately 24000 myeloma patients are diagnosed annually in the united states. The quality of life of MM patients may be severely impaired, including bone pain, bone fracture, fatigue, anemia, infection, hypercalcemia, hyperviscosity, and impairment of renal function (including renal failure). The course of MM varies with the disease stage at diagnosis, cytogenetic characteristics, age and patient complications. The disease is ultimately fatal with median survival of about 3 to 5 years, with 5-year survival estimated to be 44.9％("Surveillance,Epidemiology,and End Results Program Cancer statistics Stat Fact Sheets:Myeloma."National Cancer Institute;http://www.seer.cancer.gov/statfacts/html/mulmy.html)., however, some patients can have lifetimes of over 10 years.
In many countries, the standard of care for patients with multiple myeloma is to receive (after induction treatment is complete) high dose chemotherapy (HDT) and autologous stem cell rescue. Autologous stem cell rescue is commonly referred to as Autologous Stem Cell Transplantation (ASCT). Autologous stem cell transplantation can provide significant relief over long periods and depths, thereby extending survival.
Treatment options for patients who cannot receive autologous stem cell transplantation are limited. Particularly in recurrent/refractory cases, the results of the phase 3 randomized study may not always be applicable to populations unsuitable for transplantation, and thus require extrapolation of data obtained from predominantly young/suitable populations with potentially different disease biology and toxicity profiles. An overview of the treatment regimen for patients with multiple myeloma who were unsuitable for transplantation in 2021 (Elnair and Holstein, oncology, vol 35,Issue 4,Pages:170-182) led to the conclusion that the best answer for these patients was to take part in clinical trials and consult MM specialists and aged oncologists. That is, no approved treatment method is reliably beneficial to the patient population.
The Cochrane review ("Multipledrug combinations of bortezomib,lenalidomide,and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma:a network meta-analysis".Piechotta V et al ,Cochrane Database of Systematic Reviews 2019,Issue11.Art.No.:CD013487.DOI:10.1002/14651858.CD013487.) published in 2019 concludes that VRDc (bortezomib, lenalidomide and dexamethasone continued treatment) showed the highest overall survival benefit compared to MP (melphalan and prednisone). RD (lenalidomide and dexamethasone) and TMP (thalidomide, melphalan, and prednisone) also increased overall survival compared to MP. However, these drug combinations also lead to more adverse events and to more people stopping the treatment than MP. The authors concluded that more experimentation was required to carefully investigate hazards and quality of life.
Meflofen (also known as melphalan fluorobenzamide and L-melphalan-4-fluoro-L-phenylalanine ethyl ester) is an antitumor agent useful for the treatment of multiple myeloma. Meflofen is described in WO 01/96367 and WO 2014/065751. The structure of meflofen hydrochloride is shown in the following formula 1:
Meflofen is an effective, highly lipophilic alkylating agent that can target the alkylating metabolite to tumor cells. Due to its high lipophilicity, meflofen rapidly enters tumor cells and is immediately cleaved by peptidases, resulting in entrapment and enrichment of the alkylation payload (STILLER CA et al Cancer epidemic 2018; 56:146-153). Over-expression of peptidases is common in tumor cells, which may be responsible for the sensitivity to homomeflofen (STILLER CA et al Cancer epidemic 2018; 56:146-153). Esterases may also play a role in this observed effect. Results of the meflofen test in human MM patients have been published and shown to have clinically significant efficacy and controlled safety in RRMM patients (including patients with tertiary refractory and extramedullary disease) who have undergone extensive pretreatment (Richardson, p.g. et al Journal of Clinical Oncology 2021:7, 757-767). The effectiveness of meflofen in patients not suitable for transplantation has not been studied or reported.
Thus, while recent improvements to MM treatment have significantly prolonged the survival of patients suitable for autologous stem cell transplantation, the outcome of the same treatment is highly uncertain for patients who are not receiving autologous stem cell transplantation and is clearly less beneficial, especially for relapsed or refractory patients. Thus, for MM patients who are not receptive to autologous stem cell transplantation, there is still an urgent need for further therapeutic options. For MM patients who have received autologous stem cell transplantation in the past (e.g., at least 5 years in the past) but are not suitable for further autologous stem cell transplantation conditions, especially relapsed or refractory patients, there is still an urgent need for further treatment options.
Disclosure of Invention
The present invention provides meflofen or a salt thereof for use in the treatment or prevention of multiple myeloma in a patient suffering from multiple myeloma, said patient
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-Not received stem cell transplantation and is 75 years old or older, or at least 5 years ago received stem cell transplantation and is 75 years old or older; or (b)
-Receiving a stem cell transplant and the disease later progresses at least 36 months after the transplant.
The present invention also provides a method of treating or preventing multiple myeloma comprising the step of administering meflofen or a salt thereof to a patient suffering from multiple myeloma, said patient
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-Not received stem cell transplantation and is 75 years old or older, or at least 5 years ago received stem cell transplantation and is 75 years old or older; or (b)
-Receiving a stem cell transplant and the disease later progresses at least 36 months after the transplant.
The present invention also provides a pharmaceutical formulation comprising meflofen or a salt thereof for use in the treatment and/or prophylaxis of multiple myeloma in a patient suffering from multiple myeloma, said patient
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-Not received stem cell transplantation and is 75 years old or older, or at least 5 years ago received stem cell transplantation and is 75 years old or older; or (b)
-Receiving a stem cell transplant and the disease later progresses at least 36 months after the transplant.
The invention also provides the use of meflofen or a salt thereof in the manufacture of a medicament for the treatment of multiple myeloma in a patient suffering from multiple myeloma, said patient
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-Not received stem cell transplantation and is 75 years old or older, or at least 5 years ago received stem cell transplantation and is 75 years old or older; or (b)
-Receiving a stem cell transplant and the disease later progresses at least 36 months after the transplant.
The present invention also provides the use of meflofen or a salt thereof in the manufacture of a medicament for the treatment and/or prophylaxis of multiple myeloma in a patient having multiple myeloma who has not received a stem cell transplant or in a patient having multiple myeloma who has received a stem cell transplant at least 5 years ago. The invention also provides the use of meflofen or a salt thereof in the manufacture of a medicament for the treatment and/or prophylaxis of patients suffering from multiple myeloma aged 75 years or older (and optionally, not received a stem cell transplant, or received a stem cell transplant at least 5 years ago).
The invention also provides a kit comprising meflofen and one or more other therapeutic agents, for example selected from dexamethasone, bortezomib and up to Lei Tuoyou mab (daratumumab); preferably dexamethasone), for the treatment and/or prophylaxis of multiple myeloma in a patient suffering from multiple myeloma, said patient
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-Not received stem cell transplantation and is 75 years old or older, or at least 5 years ago received stem cell transplantation and is 75 years old or older; or (b)
-Receiving a stem cell transplant and the disease later progresses at least 36 months after the transplant.
The present invention provides meflofen or a salt thereof and dexamethasone for use in the treatment and/or prevention of multiple myeloma in a patient suffering from multiple myeloma, said patient
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-No stem cell transplantation and 75 years or older, or at least 5 years no stem cell transplantation and 75 years or older; or (b)
-Receiving a stem cell transplant and the disease later progresses at least 36 months after the transplant.
The invention also provides a method of treating or preventing multiple myeloma comprising the step of administering to a patient with multiple myeloma, meflofen or a salt thereof and dexamethasone, said patient having not received a stem cell transplant, or having received a stem cell transplant at least 5 years ago, and/or having been 75 years old or older, and/or having received a stem cell transplant and the disease later progressing at least 36 months after the transplant. The invention also provides a pharmaceutical formulation comprising meflofen or a salt thereof and dexamethasone for use in the treatment and/or prophylaxis of multiple myeloma in a patient suffering from multiple myeloma who has not received a stem cell transplant, or has received a stem cell transplant at least 5 years ago, and/or has been 75 years old or older, and/or has received a stem cell transplant and the disease has progressed at least 36 months after the transplant. The invention also provides the use of meflofen or a salt thereof and dexamethasone in the manufacture of a medicament for the treatment and/or prophylaxis of multiple myeloma in a patient who has not received a stem cell transplant, or has received a stem cell transplant at least 5 years ago, and/or has been 75 years old or older, and/or has received a stem cell transplant and the disease later progressed at least 36 months after the transplant.
The invention is particularly applicable to patients with multiple myeloma, which
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-No stem cell transplantation and 75 years or older, or at least 5 years no stem cell transplantation and 75 years or older.
In one embodiment, the patient is a multiple myeloma patient who has not received a stem cell transplant.
Drawings
Figure 1 shows a forest graph of Progression Free Survival (PFS) non-stratified risk ratios for patients without stem cell transplantation and treated with meflofen + dexamethasone (n=121) or pomalidomide + dexamethasone (n=129) in example 1, divided into demographic subgroups.
Figure 2 shows a forest map of PFS non-stratification risk ratio (BSA median = 1.855m 2) of patients without stem cell transplantation and treated with meflofen + dexamethasone (n = 121) or pomalidomide + dexamethasone (n = 129) in example 1, divided by a subset of disease features. The last row of PFS numbers in fig. 1 is also associated with disease features.
Figure 3 shows a forest graph of total survival (OS) non-stratified risk ratios for patients without stem cell transplantation and treated with meflofen + dexamethasone (n=121) or pomalidomide + dexamethasone (n=129) in example 1, divided into demographic subgroups.
Fig. 4 shows a forest map of OS non-stratified risk ratios (BSA median = 1.855m 2) for patients without stem cell transplantation and treated with meflofen + dexamethasone (n = 121) or pomalidomide + dexamethasone (n = 129) in example 1, divided by a subset of disease features. The last row of OS numbers in fig. 3 is also associated with disease features.
Fig. 5 shows a graph of PFS (%) over time for patients without stem cell transplantation and treated with either meflofen+dexamethasone (n=121) or pomalidomide+dexamethasone (n=129) or patients with stem cell transplantation and treated with either meflofen+dexamethasone (n=125) or pomalidomide+dexamethasone (n=120) in example 1 (a represents non-stratified HR; b represents log rank P values).
Fig. 6 shows a graph of OS (%) versus time for patients without stem cell transplantation and treated with meflofen+dexamethasone (n=121) or pomalidomide+dexamethasone (n=129) in example 1 (a for non-stratified HR; b for log rank P values).
Fig. 7 shows PFS risk ratio and event table for patients without stem cell transplantation and treated with meflofen+dexamethasone (n=121) or pomalidomide+dexamethasone (n=129) in example 1. It also shows PFS risk ratio and event for patients in example 1 who received meflofen+dexamethasone treatment and received stem cell transplantation less than 2.5 years ago (n=43), 2.5 to 5 years ago (n=48) or more than 5 years ago (n=34), or who received pomalidomide+dexamethasone treatment and received stem cell transplantation less than 2.5 years ago (n=35), 2.5 to 5 years ago (n=51) or more than 5 years ago (n=34) (a represents non-stratified HR; b represents log rank P values).
Fig. 8 shows the OS risk ratio and event table for patients without stem cell transplantation and receiving meflofen+dexamethasone (n=121) or pomalidomide+dexamethasone (n=129) treatment in example 1. It also shows the OS risk ratio and events (a represents non-stratified HR; b represents log rank P value) for patients receiving meflofen+dexamethasone treatment and receiving stem cell transplantation less than 2.5 years ago (n=43), 2.5 to 5 years ago (n=48) or more than 5 years ago (n=34) or for patients receiving pomalidomide+dexamethasone treatment and receiving stem cell transplantation less than 2.5 years ago (n=35), 2.5 to 5 years ago (n=51) or more than 5 years ago (n=34) in example 1.
Figure 9 shows a forest graph of Overall Survival (OS) non-stratified risk ratios for demographics and disease characteristics for patients treated with meflofen + dexamethasone (n=145) or pomalidomide + dexamethasone (n=148) with stem cell transplantation except for the occurrence of disease progression within 36 months in example 1.
Fig. 10 shows a graph of OS (%) versus time (HR is a risk ratio; a represents non-stratified HR; b represents log rank P-value) for patients treated with meflofen+dexamethasone (n=145) or pomalidomide+dexamethasone (n=148) in example 1 (except for the presence of stem cell transplantation but with progression within 36 months).
Detailed Description
The inventors have found that meflofen, and in particular the combination of meflofen and dexamethasone, is surprisingly effective for the treatment or prevention of multiple myeloma in patients who have not received stem cell transplantation or who have received stem cell transplantation at least 5 years ago. The inventors have also found that meflofen, in particular a combination of meflofen and dexamethasone, is surprisingly effective for the treatment or prevention of multiple myeloma in patients aged 75 years or older, in particular aged 75 years or older and not receiving a stem cell transplant, or aged 75 years or older and receiving a stem cell transplant at least 5 years ago. The inventors have also found that meflofen, and in particular the combination of meflofen and dexamethasone, is surprisingly effective in treating or preventing multiple myeloma in patients who have received stem cell transplantation and who have developed the disease at least 36 months after transplantation.
More specifically, the inventors have found that meflofen exhibits excellent antitumor activity compared to other treatments of multiple myeloma in these patient populations, and in particular compared to treatment of multiple myeloma in these patient populations with pomalidomide. For example, the inventors conducted a randomized, controlled, open-label, stage 3 multicentric study that recruited patients who had relapsed refractory multiple myeloma after 2-4 past treatment lines, and these patients proved refractory to lenalidomide in the last treatment line due to disease progression 60 days or less after completion of the last dose of lenalidomide, in which the patients received meflofen and dexamethasone, or pomalidomide and dexamethasone, as described in example 1 below. In this study, the inventors have surprisingly found that the median progression-free survival (PFS) of patients with multiple myeloma who had not received stem cell transplantation therapy and received meflofen in the trial was 9.3 months, while the median progression-free survival of patients who had not received stem cell transplantation therapy and received pomalidomide therapy in the past was 4.6 months. Furthermore, the inventors found that the median total survival (OS) in patients with multiple myeloma who had not received stem cell transplantation therapy and received meflofen in the test was 21.6 months, whereas the median total survival in patients who had not received stem cell transplantation therapy and received pomalidomide therapy in the past was 16.5 months.
This significant improvement exists in demographics and disease subgroups. For example, in the following subgroups: patients under 65 years old (PFS of Meflofen group: 10.8; PFS of Pomalidomide group: 4.7; OS of Meflofen group: 27.5; OS of Pomalidomide group: NA), patients between 64 and 74 years old (PFS of Meflofen group: 9.3; PFS of Pomalidomide group: 3.9; OS of Meflofen group: 22.2; OS of Pomalidomide group: 15.0), patients under 75 years old (PFS of Meflofen group: 9.4; PFS of Pomalidomide group: 4.3; OS of Meflofen group: 22.2; OS of Pomalidomide group: 18.2); patients 75 years old and older (PFS of the Meflofen group: 9.3; PFS of the Pomalidomide group: 4.9; OS of the Meflofen group: 14.8; OS of the Pomalidomide group: 8.1).
Furthermore, it can be seen in example 1 that for patients who have not received stem cell transplantation therapy in the past or who have received stem cell transplantation therapy in the past and who subsequently developed disease progression only 36 months or more after transplantation, their response rate to meflofen (and dexamethasone) is higher compared to other treatments of multiple myeloma in these patient populations, especially compared to pomalidomide (and dexamethasone) therapy. The inventors found that the median total survival (OS) of patients with multiple myeloma in the trial (excluding those who had received stem cell transplantation therapy in the past and had progressed within 36 months) was 23.6 months when receiving meflofen, while the median OS was 19.8 months in patients who received pomalidomide. The same findings are also shown in fig. 10.
The use of meflofen to treat multiple myeloma in patients with multiple myeloma who have not had stem cell transplantation is particularly surprising because, to the inventors' knowledge, no known treatment for multiple myeloma has shown a particularly beneficial effect in this patient population. Similarly, to the inventors' knowledge, no known treatment for multiple myeloma has shown particularly beneficial effects on patients who have received stem cell transplantation and who subsequently develop the disease at least 36 months after transplantation. As mentioned above, patients with multiple myeloma who cannot undergo stem cell transplantation still have urgent need for further treatment options. The results reported in example 1 of the present application show an extremely significant improvement in median PFS and median OS for a population of patients with multiple myeloma who did not receive stem cell transplantation. As multiple myeloma remains incurable and fatal, these surprising results provide a new treatment for patients in this patient population, which can provide them with valuable months of time compared to other treatment options.
Furthermore, there are a number of reasons for the patient not receiving stem cell transplantation, and more surprisingly, there is a consistent benefit in the patient population and in multiple demographics and disease subgroups in the patient population. As can be seen from figures 1 to 4, which show the PFS and OS non-stratified risk ratios divided by demographics subgroups (figures 1 and 3, respectively) and disease characteristics subgroups (figures 2 and 4, respectively), the current therapeutic efficacy persists in multiple myeloma populations that have not received stem cell transplantation.
In the results of example 1, the risk ratio is a measure of the relative risk of the event at each time point during the follow-up when receiving meflofen versus pomalidomide. A value below 1 indicates a better therapeutic effect of meflofen and a value above 1 indicates a better therapeutic effect of pomalidomide. In the study of example 1, the inventors have also unexpectedly found that patients with multiple myeloma who received stem cell transplantation at least 5 years ago in the trial had a PFS risk ratio of 0.76 for supporting meflofen therapy compared to pomalidomide therapy and an OS risk ratio of 0.87 for supporting meflofen compared to pomalidomide therapy. In addition, patients with multiple myeloma who received stem cell transplantation 2.5 to 5 years ago in the trial had a risk ratio of 0.83 for supporting meflofen therapy compared to pomalidomide therapy. Thus, these results indicate that meflofen is particularly beneficial for treating multiple myeloma patients who have received stem cell transplantation at least 2.5 years ago, and in particular at least 5 years ago. The study also found that meflofen is particularly beneficial for treating multiple myeloma patients who received stem cell transplantation and did not develop disease progression until at least 36 months after transplantation.
The use of meflofen for the treatment of multiple myeloma in patients with multiple myeloma who received stem cell transplantation at least 2.5 years ago, and in particular at least 5 years ago, is particularly surprising, as no known treatment for multiple myeloma has shown particularly beneficial effects on these patient populations to the inventors' knowledge. As noted above, there remains an urgent need for further treatment options for patients with multiple myeloma who have previously received stem cell transplantation but who have failed to undergo further stem cell transplantation, these results providing a new therapy to patients in this patient population, which can provide them with valuable months of time compared to other treatment options. Also, for patients who have received stem cell transplantation and who have progressed at least 36 months after the disease, these results provide a new therapy for patients in this patient population, which can provide them with valuable months of time compared to other treatment options.
Finally, the inventors surprisingly found that meflofen treatment is particularly beneficial in PFS and OS for patients aged 75 years or older.
For example, median PFS in multiple myeloma patients aged 75 years or older and receiving meflofen treatment in the trial was 9.4 months, while median PFS in multiple myeloma patients who had not received stem cell transplantation treatment in the past and received pomalidomide treatment was 4.6 months. In addition, the inventors found that the median total survival (OS) for patients with multiple myeloma 75 years old or older and receiving meflofen treatment in the trial was 21.6 months, whereas the median OS for patients with multiple myeloma who had not received stem cell transplantation treatment and receiving pomalidomide treatment in the past was 8.3 months.
Meflofen and its salts
Meflofen (also known as melphalan fluorobenzamide and L-melphalan-4-fluoro-L-phenylalanine ethyl ester) is an antineoplastic agent useful in the treatment of cancer, particularly in the treatment of multiple myeloma. Meflofen and its salts, in particular its hydrochloride salts, are known, for example from WO 01/96367 and WO 2014/065751 (the contents of which are incorporated herein by reference). The structure of meflofen hydrochloride is as follows:
For the avoidance of doubt, in this document, when the term "meflofen" is used, it includes salts of meflofen as well as isotopic derivatives of meflofen unless otherwise indicated. Isotopic derivatives of meflofen are described in WO 2020/079165, the contents of which are incorporated herein by reference.
Also for the avoidance of doubt, when referred to in this document, the mass of meflofen refers to the mass of the meflofen molecule excluding the mass of any counterion (counterion) unless explicitly stated otherwise.
Salts of meflofen suitable for use in the present invention are salts in which the counter ion is pharmaceutically acceptable. Suitable salts include salts with organic or inorganic acids. In particular, suitable salts with acids according to the invention include salts with inorganic acids, strong organic carboxylic acids such as alkane carboxylic acids of 1 to 4 carbon atoms (e.g. saturated or unsaturated dicarboxylic acids, e.g. hydroxycarboxylic acids, e.g. amino acids) which are unsubstituted or substituted by, e.g. halogen, and with organic sulphonic acids (e.g. unsubstituted or substituted by, e.g. halogen, (C 1-C4) alkyl or aryl sulphonic acids). Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxalic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, 2-naphthalenesulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic and glutamic acids, lysine and arginine.
Preferred salts of meflofen include acid addition salts such as those formed from hydrochloric, hydrobromic, acetic, p-toluenesulfonic, tartaric, sulfuric, succinic, phosphoric, oxalic, nitric, methanesulfonic, malic, maleic and citric acids. More preferably, the salt of meflofen used according to the present invention is the hydrochloride salt (i.e. the addition salt formed by hydrochloric acid).
Those skilled in the art of organic chemistry will appreciate that many organic compounds may form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates". For example, complexes with water are known as "hydrates". The complex may be incorporated into the solvent in stoichiometric or non-stoichiometric amounts. Solvates are described in Water-Insoluble Drug Formulation,2 nd ed R.Lui CRC Press, page 553 and Byrn et al Pharm Res 12 (7), 1995, 945-954. Before being made into a solution, the meflofen or its salts used in the present invention may be in the form of solvates. The solvates of meflofen suitable for use according to the invention are those in which the relevant solvents are pharmaceutically acceptable. For example, a hydrate is a pharmaceutically acceptable solvate.
Formulations
Although meflofen and its salts may be administered alone, it is preferred that they are present in the formulation, in particular in the pharmaceutical formulation. Pharmaceutical formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intraosseous infusion, intramuscular, intravascular (bolus or infusion) and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including skin, oral, sublingual and intraocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the subject being treated.
In one embodiment of the invention, meflofen is administered as a pharmaceutical formulation suitable for oral or parenteral (including subcutaneous, intradermal, intraosseous infusion, intramuscular, intravascular (bolus or infusion) and intramedullary) administration.
Pharmaceutical formulations of meflofen suitable for oral administration may be presented in discrete units, for example as capsules, cachets or tablets, each unit containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. Meflofen may also be provided in the form of pills, granules or pastes. Various pharmaceutically acceptable carriers and formulations thereof are described in standard formulation paper, such as Remington's Pharmaceutical Sciences for e.w. martin. See also Wang, Y.J. and Hanson, M.A., journal of PARENTERAL SCIENCE AND Technology, TECHNICAL REPORT No.10, support.42:2S, 1988.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Preferably, the formulations may be presented in unit-dose or divided-dose containers, for example sealed ampules and vials. The formulations may be stored under freeze-dried (lyophilized) conditions requiring only the addition of a sterile liquid carrier, such as saline, a physiologically acceptable solution or water for injection, immediately prior to use. The formulation may also be stored as a liquid pharmaceutical formulation, requiring only the addition of a sterile liquid carrier, such as saline, a physiologically acceptable solution, or water for injection, immediately prior to use.
Extemporaneous injection and infusion solutions and suspensions may be prepared from sterile powders, granules or other dry compositions. Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1, 3-butanediol, water, ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting agents and suspending agents, including synthetic mono-or diglycerides, and fatty acids, including oleic acid or Cremaphor.
In a preferred embodiment of the present invention, the meflofen used in the present invention comprises a lyophilized pharmaceutical formulation of meflofen or a salt thereof. The term "lyophilized pharmaceutical formulation of meflofen or a salt thereof" is understood to mean that the meflofen or a salt thereof is lyophilized ("lyophilization", "freeze-dried" etc. are used interchangeably herein with "lyophilization", "freeze-drying"). In contrast to non-lyophilized meflofen or a pharmaceutically acceptable salt thereof (which is typically in the form of a dense, yellowish powder), the lyophilized pharmaceutical formulation of meflofen or a pharmaceutically acceptable salt thereof described herein may be a white, fluffy powder.
The lyophilized pharmaceutical formulation of meflofen or a salt thereof for use in the present invention may comprise sucrose. The inclusion of sucrose provides a lyophilized formulation that is stable in itself and soluble in water in the absence of an organic solvent at a rate sufficient to match the degradation rate, and thus is useful for therapy and does not have the toxicity imposed by the organic solvent. Due to the increased solubility and/or dissolution rate of the meflofen or its salts, after lyophilization in the presence of sucrose, a dissolved meflofen or its salt solution, e.g., a pharmaceutical composition comprising meflofen or its salts, can be prepared which has a useful high concentration of meflofen and is substantially free of organic solvents. The preparation of lyophilized pharmaceutical formulations, lyophilized pharmaceutical compositions, and kits for preparing such compositions of meflofen or its salts are described in detail in WO 2012/146625 and WO 2014/065751, the contents of which are incorporated herein by reference.
The pharmaceutical formulation of meflofen or a salt thereof for use in the present invention may comprise a lyophilized pharmaceutical formulation comprising meflofen or a salt thereof. Preferably, the formulation comprises sucrose. More preferably, the formulation comprises sucrose, the weight ratio (w/w) between meflofen and sucrose being about 1:25 to 1:75, for example 1:50.
When the formulation is a pharmaceutical solution, it may be prepared from a lyophilized pharmaceutical formulation comprising meflofen or a salt thereof, and further comprising a physiologically acceptable solvent, such as a dextrose solution and/or saline solution.
In another preferred embodiment of the present invention, the meflofen used in the present invention comprises a liquid pharmaceutical formulation of meflofen or a salt thereof. Preferably, the liquid pharmaceutical formulation consists essentially of: i) Meflofen or a salt thereof; ii) propylene glycol; iii) Optionally one or more physiologically acceptable aqueous solvents; and iv) optionally one or more other therapeutic agents; or the liquid pharmaceutical formulation consists essentially of: i) Meflofen or a salt thereof; ii) polyethylene glycol; iii) Optionally one or more physiologically acceptable aqueous solvents; and iv) optionally one or more other therapeutic agents. The preparation of liquid pharmaceutical formulations, liquid pharmaceutical formulations and kits for preparing such liquid pharmaceutical formulations of meflofen or salts thereof are described in detail in WO 2020/212594, the contents of which are incorporated herein by reference.
It will be appreciated that in addition to the ingredients specifically mentioned above, the formulations used in the present invention may include other agents conventional in the art, in view of the type of formulation in question.
Dosage regimen
Meflofen or a salt thereof and a pharmaceutical formulation comprising meflofen are useful for the treatment and/or prevention of multiple myeloma in patients with multiple myeloma who have not received stem cell transplantation.
Meflofen or a salt thereof and pharmaceutical formulations comprising meflofen may also be used for the treatment and/or prevention of multiple myeloma in patients with multiple myeloma who have received stem cell transplantation at least 5 years ago.
Meflofen or a salt thereof and pharmaceutical formulations comprising meflofen may also be used for the treatment and/or prevention of multiple myeloma in patients aged 75 years or older and optionally multiple myeloma who have not received a stem cell transplant or have received a stem cell transplant at least 5 years ago.
Meflofen or a salt thereof and pharmaceutical formulations comprising meflofen are also useful for the treatment and/or prevention of multiple myeloma in patients with multiple myeloma who have received stem cell transplantation and who have developed the disease at least 36 months after transplantation.
For the avoidance of doubt, when a patient is defined herein as a patient with multiple myeloma who has not received a stem cell transplant, or has received a stem cell transplant at least 5 years ago, and/or is 75 years old or older, or a similar phrase, the patient may: (i) not receiving a stem cell transplant, or (ii) receiving a stem cell transplant at least 5 years ago, or (iii) being 75 years old or older, or (iv) not receiving a stem cell transplant and being 75 years old or older, or (v) receiving a stem cell transplant at least 5 years ago and being 75 years old or older.
For the avoidance of doubt, when a patient is defined herein as a patient with multiple myeloma who has received a stem cell transplant and the disease has progressed at least 36 months after the transplant, or a similar phrase, the patient may also belong to one or more of the following groups: (i) has received a stem cell transplant at least 5 years ago, or (ii) is 75 years old or older, or (iii) has received a stem cell transplant at least 5 years ago and is 75 years old or older.
The amount of meflofen required to achieve a therapeutic effect will vary with the particular route of administration and the characteristics of the subject being treated, such as the species, age, weight, sex, medical condition, the particular disease and its severity, and other relevant medical and physical factors. For patients with multiple myeloma who have not received a stem cell transplant, or who have received a stem cell transplant at least 5 years ago, and/or who are 75 years old or older, the ordinarily skilled physician can readily determine and administer an effective amount of meflofen that is required to treat or prevent multiple myeloma.
Meflofen may be administered daily, every two or three days, weekly, every two, three or four weeks or even as a high single dose, depending on the subject to be treated and the severity of the multiple myeloma.
In one embodiment of the invention, meflofen or a salt thereof may be administered in an amount of about 1 to 150mg (excluding the mass of any counter ion). For example, 1,5, 10, 15, 20, 25, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150mg (mass excluding any counter ion). Preferably, the dose of meflofen or a salt thereof per administration is 1 to 50mg (excluding the mass of any counter ion), for example 1,5, 10, 15, 20, 25, 30, 35, 40, 45 or 50mg. More preferably, the dose of meflofen or a salt thereof per administration is from 1 to 40mg (excluding the mass of any counter ion), for example 1,5, 10, 15, 20, 25, 30, 35 or 40mg. For example, the dose of meflofen or a salt thereof per administration is 10 to 40mg (excluding the mass of any counter ion), for example 10, 15, 20, 25, 30, 35 or 40mg. In certain embodiments, the dose of meflofen or a salt thereof per administration may be 10 to 20mg, 20 to 30mg, or 30 to 40mg.
In one embodiment of the invention, meflofen or a salt thereof may be present in an amount of about 35.0 to 45.0mg of meflofen, preferably 36.0 to 44.0mg, preferably 37.0 to 43.0mg, preferably 37.5 to 42.5mg (e.g., 37.5, 38.0, 38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5, 42.0 or 42.5 mg), more preferably 38.0 to 42.0mg; most preferably 39.0 to 41.0mg (e.g. 39.0, 39.5, 40.0, 40.5 or 41.0mg, more preferably 39.5, 40.0 or 40.5mg, most preferably 40.0 mg). Meflofen or a salt thereof may be administered, for example, as a parenteral dose within 25-35 minutes.
In embodiments where the meflofen is in its hydrochloride (HCl) salt form, the amount of meflofen hydrochloride (including the mass of the salt components) administered is about 37.6 to 48.3mg, preferably 39.0 to 47.0mg, more preferably 41.0 to 45.0mg, more preferably 42.5 to 43.5mg, and most preferably 42.9 mg. Meflofen hydrochloride may be administered, for example, as a parenteral dose over 25-35 minutes.
Preferably, the meflofen or its salt of the invention is administered within 26 to 34 minutes, more preferably within 27 to 33 minutes, even more preferably within 28 to 32 minutes, even more preferably within 29 to 31 minutes, and most preferably within 30 minutes.
Meflofen or its salts may be administered as a parenteral or oral dose. In a preferred embodiment of the invention, the meflofen or its salts are administered in parenteral doses. Thus, pharmaceutical formulations useful according to the present invention are those suitable for parenteral administration.
Parenteral administration includes intravenous (into a vein, such as a central or peripheral vein) (bolus or infusion), intra-arterial (into an artery, such as a central or peripheral artery), intra-osseous (into bone marrow), intramuscular (into muscle), intradermal (into dermis), and subcutaneous (under skin) administration. Preferably, the doses of the invention are administered intravenously or intra-arterially, more preferably by intravenous infusion (e.g. central or peripheral intravenous infusion). Thus, pharmaceutical formulations particularly suitable for use in the present invention are those suitable for intravenous administration, more particularly intravenous infusion.
In one embodiment of the invention, the dose of meflofen (excluding the mass of any counter ions) is administered as a parenteral dose at an infusion rate of about 0.3 to 1.8mg/min, such as 0.5 to 1.8mg/min, such as 0.8 to 1.8mg/min, such as 1.0 to 1.8mg/min, such as 1.1 to 1.7mg/min, such as 1.1 to 1.6mg/min, such as 1.2 to 1.6mg/min, or such as 1.2 to 1.5mg/min. In one embodiment the dose of meflofen (excluding the mass of any counter ions) is administered as a parenteral dose at an infusion rate of about 1.2 to 1.4mg/min (e.g. 1.2, 1.3 or 1.4 mg/min).
In one embodiment of the invention, a dose of about 1 to 50mg (excluding the mass of the counter ion) (e.g., 1 to 45 mg) of meflofen is administered as a parenteral dose within about 5-35 minutes. For example, the dose of meflofen is 40mg (excluding the mass of the counter ion) and is as a parenteral dose within about 30 minutes, or for example, the dose of meflofen is 20mg (excluding the mass of the counter ion) and is as a parenteral dose within about 15 minutes, or for example, the dose of meflofen is 10mg (excluding the mass of the counter ion) and is as a parenteral dose within about 7.5 minutes.
Regarding the dose of meflofen used in the present invention, when referring to the mass of meflofen or a salt thereof, it is the mass when no counter ion is included in calculating the dose mass of meflofen. The molecular weight of the free counter ion meflofen is 498.42g/mol. For a dose of meflofen salt, the actual dose mass administered to the patient must take into account the mass of the counter ion. This is conventional to those skilled in the art.
For example, when meflofen is in its hydrochloride (HCl) salt form (its molecular weight is 534.88 g/mol), the equivalent dose rate for meflofen hydrochloride (including the mass of the counter ion) is 1.2 to 1.9mg/min, as compared to 1.1 to 1.8 mg/min. For a dose of meflofen of 1 to 50mg, the equivalent dose of meflofen hydrochloride is about 1.1 to 53.8mg. For a dose of meflofen of 10 to 45mg, the equivalent dose of meflofen hydrochloride is about 10.7 to 48.3mg.
When meflofen or a salt thereof is administered as a parenteral dose, the dose of meflofen must be in liquid form, for example a solution or suspension comprising meflofen.
Preferably, the meflofen or its salts of the application are used as part of the treatment cycle. In one cycle, meflofen may be administered on the first day of the cycle, where the cycle lasts for X days and no meflofen is administered for the next X-1 days. X may be, for example, 1 to 42, 5 to 42, 7 to 42, 10 to 42, or 14 to 42. Preferably X may be 14 to 35 days, more preferably 21 to 35 days, and more preferably 21 to 30 days; for example 21 days, 28 days, 29 days, 30 days or 35 days. In certain embodiments, X may be, for example, 21 to 30 days, 21 to 28 days, 28 to 30 days, or 28 to 29 days. For the avoidance of doubt, the dose of meflofen administered during a treatment cycle may be a dose as described elsewhere in the present application, for example a dose of 1 to 50mg of meflofen.
In a preferred embodiment of the invention, meflofen or a salt thereof is administered on the first day of a 21-day cycle followed by a rest period of 20 days during which meflofen is no longer administered; or on day 1 of a 28 day cycle followed by a rest period of 27 days during which no more meflofen is administered; or on day 1 of a 29 day cycle followed by a rest period of 28 days during which meflofen is no longer administered; or on day 1 of a 30 day cycle followed by a rest period of 29 days during which no more meflofen is administered; or on the first day of a 35 day cycle followed by a 34 day rest period during which meflofen is no longer administered. In certain embodiments, the treatment period is 28 days; or on the first day of a 42 day cycle followed by a rest period of 41 days during which no more meflofen is administered. In certain embodiments, the treatment period is 28 days.
This cycle may be repeated one or more times depending on the level (e.g., advanced or low), class (e.g., recurrent, refractory, etc.), or stage of multiple myeloma. For example, the cycle may be repeated 1 to 15 times, such as 2 to 12 times, such as 2 to 7 times, such as 2,3, 4,5,6 times. This cycle may be repeated 3,4 or 5 times.
The number of cycles of meflofen or a salt thereof required to treat, prevent, counter or arrest the progression of multiple myeloma in a patient with multiple myeloma who has not received a stem cell transplant, or has received a stem cell transplant at least 5 years ago, and/or is 75 years old or older, can be readily determined by a physician or clinician of ordinary skill. The number of cycles of meflofen or a salt thereof required to treat, prevent, counter or arrest the progression of multiple myeloma in a patient with multiple myeloma who has received a stem cell transplant and who has later progressed at least 36 months after the transplant can be readily determined by a physician or clinician of ordinary skill.
The dosage regimen of the invention is particularly safe and effective for treating and preventing multiple myeloma in a patient suffering from multiple myeloma or at risk of developing multiple myeloma who has not received stem cell transplantation, or has received stem cell transplantation at least 5 years ago, and/or is 75 years old or older. Similarly, the dosage regimen of the invention is particularly safe and effective for treating and preventing multiple myeloma in patients suffering from multiple myeloma or at risk of developing multiple myeloma who have received stem cell transplantation and who have later progressed at least 36 months after transplantation.
Although meflofen or a salt thereof may be used as the sole active ingredient in the present invention, it may also be used in combination with one or more other therapeutic agents and the use of such a combination provides a preferred embodiment of the present invention.
Such other therapeutic agents may be agents useful in the treatment or prevention of multiple myeloma, or other pharmaceutically active substances. Such agents are known in the art. Examples of other therapeutic agents for use in the present invention include steroids (prednisone and dexamethasone), IMiD (thalidomide, lenalidomide, and pomalidomide), PI (bortezomib, carfilzomib, and ib Sha Zuo meters), histone Deacetylase (HDAC) inhibitors (panobinostat), conventional chemotherapeutics (alkylating agents (e.g., melphalan, cyclophosphamide, bendamustine)), doxorubicin, anti-CD 38 antibodies (up Lei Tuoyou mab), and anti-SLAMF 7 antibodies (erltuzumab (elotuzumab)); such as steroids (prednisone and dexamethasone), IMiD (thalidomide, lenalidomide and pomalidomide), PI (bortezomib and carfilzomib), histone Deacetylase (HDAC) inhibitors (panobinostat) and conventional chemotherapeutics (alkylating agents (e.g. melphalan, cyclophosphamide) and doxorubicin). Examples of other therapeutic agents for use in the present invention also include antibodies to B cell maturation antigens (Bei Lan tamab (belantamab)), nuclear export inhibitors (plug Li Nisuo (selinexor)), and autologous Chimeric Antigen Receptor (CAR) T cell therapies to B cell maturation antigens (ciltacabtagene). Preferred other therapeutic agents for use in the present invention include dexamethasone, pomalidomide, and bortezomib. For example, other therapeutic agents for use in the present invention include dexamethasone; or dexamethasone and pomalidomide; or dexamethasone and bortezomib.
Accordingly, the present invention also provides for the use of meflofen or a salt thereof, together with one or more other therapeutic agents, for the treatment or prophylaxis of multiple myeloma in a patient who has not received a stem cell transplant, or has received a stem cell transplant at least 5 years ago, and/or is 75 years old or older, wherein the dose of meflofen is administered at a rate of 1.0 to 1.8 mg/min. For example, a dose of 35 to 45mg (preferably 37.5 to 42.5mg, more preferably 39 to 41mg, most preferably 40 mg) is administered as a parenteral dose within 25-35 minutes (preferably 30 minutes). Preferably, the other therapeutic agent is dexamethasone. In another embodiment, the one or more additional therapeutic agents are selected from dexamethasone, pomalidomide, and bortezomib. For example, dexamethasone; or dexamethasone and pomalidomide; or dexamethasone and bortezomib.
The invention further provides for the use of meflofen hydrochloride with one or more other therapeutic agents for the treatment or prevention of multiple myeloma in a patient who has not received a stem cell transplant, or has received a stem cell transplant at least 5 years ago, and/or is 75 years old or older, wherein the dose of meflofen hydrochloride (including the mass of the salt) is administered at a rate of 1.1 to 1.9 mg/min. For example, a dose of 37.6 to 48.3mg (preferably 40 to 45mg, more preferably 42.9 mg) of meflofen hydrochloride (including the mass of the salt) is administered as a parenteral dose over 25-35 minutes (preferably 30 minutes). Preferably, the other therapeutic agent is dexamethasone. In another embodiment, the one or more additional therapeutic agents are selected from dexamethasone, pomalidomide, and bortezomib. For example, dexamethasone; or dexamethasone and pomalidomide; or dexamethasone and bortezomib.
In a very preferred embodiment, the present invention provides meflofen or a salt thereof and dexamethasone for use in the treatment or prevention of multiple myeloma in patients who have not received a stem cell transplant, have received a stem cell transplant at least 5 years ago, and/or are multiple myeloma patients aged 75 years or older, wherein the dose of meflofen is administered at a rate of 1.0 to 1.8 mg/min. For example, a dose of 35 to 45mg (preferably 37.5 to 42.5mg, more preferably 39 to 41mg, most preferably 40 mg) is administered as a parenteral dose within 25-35 minutes (preferably 30 minutes). For example, the present invention provides meflofen hydrochloride and dexamethasone for use in treating or preventing multiple myeloma in patients with multiple myeloma who have not received stem cell transplantation, wherein the dose of meflofen hydrochloride (including the mass of the salt) is administered at a rate of 1.1 to 1.9 mg/min. For example, a dose of 37.6 to 48.3mg (preferably 40 to 45mg, more preferably 42.9 mg) of meflofen hydrochloride (including the mass of the salt) is administered as a parenteral dose within 25-35 minutes (preferably 30 minutes).
When used in combination, the precise dosage of the other pharmaceutically active substance(s) will vary with the regimen, the potency of the particular agent selected, the age, size, sex and condition of the subject (typically a mammal, such as a human), the nature and severity of the melanoma, and other relevant medical and physical factors.
When used in combination with meflofen or a salt thereof, the above therapeutic agents may be used, for example, in amounts specified in the physician's desktop reference manual (PDR) or in amounts otherwise determined by one of ordinary skill in the art.
When the other therapeutic agent is dexamethasone, the preferred dosage is 1mg to 200mg, preferably 5mg to 100mg, more preferably 10mg to 80mg, most preferably 20mg to 60mg, for example 40mg or 20mg.
In a preferred embodiment, the multiple myeloma patient has not received a stem cell transplant or has received a stem cell transplant at least 5 years ago, and the other therapeutic agent is dexamethasone and the dosage of dexamethasone is 40mg or 20mg. Optionally, the patient may be 75 years old or over 75 years old.
In a preferred embodiment, the multiple myeloma patient is 75 years old or older, and optionally, has not received a stem cell transplant or has received a stem cell transplant at least 5 years ago, and the other therapeutic agent is dexamethasone at a dosage of 20mg.
One or more other therapeutic agents (e.g., dexamethasone) can be administered concurrently, sequentially or separately with the dosage of meflofen or its salts. The individual components of such a combination may be administered separately at different times during the course of treatment or simultaneously in separate or single combinations.
When the other therapeutic agent is dexamethasone, it is preferred that the administration of dexamethasone and meflofen or a salt thereof be on the same day and administered simultaneously, sequentially or separately. More preferably, it is administered separately from and on the same day as meflofen or a salt thereof.
For example, when the meflofen or a salt thereof used in the present invention is administered as part of a treatment cycle (e.g., meflofen or a salt thereof is administered on the first day of a cycle lasting X days and meflofen is no longer administered on the next X-1 day), dexamethasone may be administered simultaneously, sequentially or separately on the same day as meflofen (i.e., day 1). X may be, for example, 14 to 42 days, preferably 14 to 35 days, more preferably 21 to 28 days; for example 21 days or 28 days.
In a preferred embodiment of the invention, dexamethasone is administered on the first day of the treatment cycle. More preferably, dexamethasone is also administered weekly during such a treatment cycle, e.g., on days 1, 8 and 15 of a 21 day cycle; or on days 1, 8, 15 and 22 of the 28 day cycle.
In another preferred embodiment, according to the invention, meflofen or a salt thereof is administered on day 1 of a 21-day cycle, and dexamethasone is administered simultaneously, sequentially or separately on day 1 of the cycle, followed by a rest period of 20 days during which meflofen is no longer administered; or according to the invention, meflofen or a salt thereof is administered on day 1 of a 28 day cycle and dexamethasone is administered simultaneously, sequentially or separately on day 1 of the cycle, followed by a rest period of 27 days during which meflofen is no longer administered. The preferred period is 28 days. Preferably, dexamethasone is administered on the first day separately from meflofen or a salt thereof. Preferably, dexamethasone is administered orally or intravenously. Preferably, the dosage of dexamethasone is 20mg or 40mg.
In another preferred embodiment, when meflofen or a salt thereof for use in the present invention is administered as part of a cycle (e.g., meflofen is administered on the first day of a cycle lasting X days and meflofen is no longer administered on the next X-1 day), dexamethasone is administered simultaneously, sequentially or separately on the same day as meflofen (i.e., day 1) and weekly during the subsequent cycle. For example, dexamethasone is administered on days 1, 8, 15, 22, 29, etc., depending on the length of the cycle. X may be, for example, 14 to 42 days, preferably 14 to 35 days, more preferably 21 to 28 days; for example 21 days or 28 days.
In such embodiments, according to the invention, meflofen or a salt thereof is administered on the first day of a 21-day cycle followed by a rest period of 20 days during which meflofen is no longer administered and dexamethasone is administered simultaneously, sequentially or separately on day 1 of the cycle and dexamethasone is administered on days 8 and 15 of the 21-day cycle; or according to the invention, meflofen or a salt thereof is administered on the first day of a 28 day cycle followed by a rest for 27 days during which time meflofen is no longer administered and dexamethasone is administered simultaneously, sequentially or separately on day 1 of the cycle and dexamethasone is administered on days 8, 15 and 22 of the 28 day cycle. Preferably, dexamethasone is administered on the first day as an oral dose or intravenous dose (preferably an oral dose) separate from the meflofen or a salt thereof. The subsequent dose of dexamethasone may be an oral dose or an intravenous dose (preferably the subsequent dose is an oral dose).
It is noted that preferred aspects of the invention in terms of the compounds of the invention and their uses are equally applicable to the methods of treatment of the invention and to the methods of manufacture of the invention.
Kit for detecting a substance in a sample
The present invention provides kits comprising meflofen or a salt thereof and one or more other therapeutic agents, which kits are useful for treating or preventing multiple myeloma in patients with multiple myeloma who have not received a stem cell transplant.
The invention also provides a kit comprising meflofen or a salt thereof and one or more other therapeutic agents, which kit is useful for treating or preventing multiple myeloma in a patient who has received a stem cell transplant at least 5 years ago.
The present invention provides kits comprising meflofen or a salt thereof and one or more other therapeutic agents, which kits are useful for treating or preventing multiple myeloma in patients 75 years old or older, and optionally, multiple myeloma who have not received a stem cell transplant or who have received a stem cell transplant at least 5 years ago.
Examples of other therapeutic agents for use in the present invention include steroids (e.g., prednisone and dexamethasone), imids (e.g., thalidomide, lenalidomide, and pomalidomide), PI (e.g., bortezomib, carfilzomib, and ib Sha Zuo meters), histone Deacetylase (HDAC) inhibitors (e.g., panorastat), conventional chemotherapy (e.g., melphalan, cyclophosphamide, doxorubicin, bendamustine), anti-CD 38 antibodies (up Lei Tuoyou mab), and anti-SLAMF 7 antibodies (erltuzumab). Examples of other therapeutic agents for use in the present invention also include antibodies to B cell maturation antigens (Bei Lan tamab), nuclear export inhibitors (plug Li Nisuo), and autologous Chimeric Antigen Receptor (CAR) T cell therapies (ciltacabtagene) to B cell maturation antigens.
In a preferred embodiment of the invention, at least one of the one or more other therapeutic agents comprised in the kit of the invention is a steroid (e.g. prednisone and dexamethasone), PI (bortezomib, carfilzomib and Sha Zuo meters), or an anti-CD 38 antibody (up to Lei Tuoyou mab). In a preferred embodiment of the invention, at least one of the one or more other therapeutic agents comprised in the kit of the invention is dexamethasone, bortezomib, or up to Lei Tuoyou mab.
In one embodiment, the kit may comprise meflofen or a salt thereof, dexamethasone, and optionally further comprising bortezomib and/or up to Lei Tuoyou mab. In one embodiment, the kit may comprise meflofen or a salt thereof, and dexamethasone.
The kits of the invention are useful in the therapeutic and/or prophylactic uses and methods of the invention as described herein.
For the avoidance of doubt, meflofen or a salt thereof is present in a kit according to the invention in a form and amount suitable for use according to the invention. Suitable pharmaceutical formulations are described herein. The amount of meflofen or a salt thereof and one or more other therapeutic agents suitable for use in the present invention can be readily determined by the skilled artisan.
Multiple myeloma
The treatment of the invention is useful for treating multiple myeloma in patients who have not received stem cell transplantation. The treatment of the present invention may also be used to treat multiple myeloma in patients who received stem cell transplants at least 5 years ago. The treatment of the invention may also be used to treat multiple myeloma in patients 75 years old or older, and optionally, who have not received a stem cell transplant or have received a stem cell transplant at least 5 years ago. The treatment of the invention may also be used to treat multiple myeloma in patients who have received stem cell transplantation and who have developed disease later at least 36 months after transplantation.
Multiple myeloma is of various types, including Monoclonal Gammaglobulosis (MGUS), asymptomatic myeloma (further subdivided into slow-progressive myeloma (smoldering myeloma) or indolent myeloma) and symptomatic myeloma. Multiple myeloma can be categorized into primary, refractory, recurrent, and relapsed refractory.
Relapsed multiple myeloma (also known as relapsed myeloma, recurrent myeloma) can be defined as multiple myeloma that recurs within 60 days or less of the last therapeutic administration. Relapsing multiple myeloma is generally considered to be a recurrence of disease after previous responses to treatment.
Refractory multiple myeloma may be defined as multiple myeloma that does not respond to a particular treatment. Refractory myeloma may occur in patients who have never responded to treatment, or may occur in patients who initially respond to treatment but who do not respond to the same treatment after relapse.
Multiple myeloma refractory (RRMM) is a specific subtype of multiple myeloma refractory, and can be defined as multiple myeloma that initially responds to treatment, but does not respond to treatment after relapse. For example RRMM may be defined as multiple myeloma that recurs within 60 days or less of the last treatment administration and initially responds to the treatment, but does not respond to the same treatment after recurrence. Multiple refractory myeloma is sometimes referred to as refractory relapsed multiple myeloma.
Currently approved drugs for the treatment of MM are 7 classes, namely steroids (prednisone and dexamethasone), IMiD (thalidomide, lenalidomide and pomalidomide), PI (bortezomib, carfilzomib and ib Sha Zuo meters), histone Deacetylase (HDAC) inhibitors (panorastat), conventional chemotherapies (e.g. melphalan, cyclophosphamide, doxorubicin, bendamustine), anti-CD 38 antibodies (up Lei Tuoyou mab) and anti-SLAMF 7 antibodies (erltuzumab). Also approved are antibodies to B cell maturation antigens (Bei Lan tamab), nuclear export inhibitors (plug Li Nisuo), and autologous Chimeric Antigen Receptor (CAR) T cell therapies to B cell maturation antigens (ciltacabtagene).
Symptomatic active MM patients received primary induction treatment. Patients under about 65 years old and other well-being conditions may also be considered for consolidation therapy with stem cell transplantation (particularly autologous stem cell transplantation) to extend the duration of remission (Moreau, P. Et al J Clin Oncol (2011), vol 29, pages 1898-1906; rosin, L. Et al Expert Rev Hematol (2014) Vol 7, pages 43-53.). The type of induction therapy will vary greatly depending on age, disease condition and the presence of other complications. NCCN multiple myeloma guidelines (NCCN(2019)"NCCN Guidelines for Patients."National Comprehensive Cancer Network;https://www.nccn.org/patients/guidelines/content/PDF/myeloma-patient.pdf) provide a list of protocols recommended as primary treatment for patients who are suitable for transplantation and unsuitable for transplantation. Treatment regimens including bortezomib and lenalidomide are most commonly used as primary treatments; for non-transplant candidates, these drugs are typically used in combination with alkylating agents. Several treatment regimens were recommended in the international working group for myeloma 2014 for patients who did not qualify for standard stem cell transplantation (Palumbo, a., et al, J Clin Oncol (2014) Vol 32, pages 587-600). After the use of these drugs, recurrence always occurs, and thus a rescue treatment is required.
Refractory multiple myeloma (and/or RRMM) may be refractory to at least one drug selected from the group consisting of Protease Inhibitors (PI), immunomodulatory drugs (IMiD), alkylating agents, or anti-CD 38 antibodies. Some refractory multiple myeloma (and/or RRMM) is refractory to one or more (e.g., 1, 2, 3, 4, or 5 or more) drugs selected from the group consisting of Protease Inhibitors (PI), immunomodulatory drugs (IMiD), alkylating agents, and anti-CD 38 antibodies. Refractory multiple myeloma (and/or RRMM) may even be refractory to two or more drugs selected from the group consisting of Protease Inhibitors (PI), immunomodulatory drugs (imids), alkylating agents, or two or more classes of anti-CD 38 antibodies.
The choice of treatment for any individual with recurrent disease will depend on a number of variables, including the response and duration to initial chemotherapy, complications, bone marrow reserves, and whether the patient is experiencing an inert or aggressive recurrence. RRMM are particularly challenging to choose a treatment. A combination of multiple therapies and some of the approved drugs described above may be used for treatment RRMM. In general, myeloma patients will receive an average of 4 to 8 different treatment regimens throughout their lifetime. However, despite the existence of effective therapies, the optimal combination and ordering of these drugs with other therapies and with each other is still unclear. Eventually, the patient relapses in all currently available treatment regimens.
In many cases, if the disease recurs more than 6 to 12 months after the end of the last treatment, the same drug used for induction treatment can be reapplied for the recurrent disease. However, if the recurrence is after a short duration, the patient is refractory to the initial treatment, or the disease is associated with severe symptoms such as renal failure or hypercalcemia, a treatment regimen with a different mechanism of action (class switching) is typically selected.
The meflofen or a salt thereof used according to the present invention is suitable for use in any of the foregoing classes and classes of multiple myeloma in patients who have not received a stem cell transplant, or have received a stem cell transplant at least 5 years ago, and/or are 75 years old or older, or have received a stem cell transplant and the disease later progresses at least 36 months after the transplant. It is particularly useful for patients who have not received stem cell transplantation.
The meflofen or its salts used according to the present invention are very effective for refractory, relapsed and relapsed refractory multiple myeloma in patients who have not received stem cell transplantation, or have received stem cell transplantation at least 5 years ago, and/or are 75 years old or older (particularly in patients who have not received stem cell transplantation).
For example, the meflofen or a salt thereof used according to the present invention may be used in patients who have not received a stem cell transplant, or have received a stem cell transplant at least 5 years ago, or who have received a stem cell transplant and who have progressed at least 36 months after the transplant and/or are 75 years old or older (particularly, patients who have not received a stem cell transplant), and who have a refractory (e.g., refractory or relapse-refractory) to a Protease Inhibitor (PI), an immunomodulatory drug (IMiD), an alkylating agent, or an anti-CD 38 antibody.
The meflofen or a salt thereof used according to the present invention is particularly useful for patients who have not received a stem cell transplant, or have received a stem cell transplant at least 5 years ago, or who have received a stem cell transplant and who have progressed at least 36 months after the transplant, and/or who are 75 years old or older (particularly, patients who have not received a stem cell transplant), and who have refractory (e.g., refractory or relapse refractory) to alkylating agents such as one or more of low-dose melphalan, high-dose melphalan, and cyclophosphamide. It is particularly useful for patients who have not received a stem cell transplant, or have received a stem cell transplant at least 5 years ago, or who have received a stem cell transplant and who have progressed at least 36 months after the transplant, and/or who are 75 years old or older (particularly, patients who have not received a stem cell transplant), and who have refractory (e.g., refractory or relapsed refractory) to anti-CD 38 antibodies. It is particularly useful for patients who have not received a stem cell transplant, or have received a stem cell transplant at least 5 years ago, or have received a stem cell transplant and who have progressed at least 36 months after the transplant, and/or are 75 years old or older (particularly, patients who have not received a stem cell transplant), and who have a refractory (e.g., refractory or relapsed refractory) to lenalidomide, particularly, lenalidomide that has a refractory (e.g., refractory or relapsed refractory) to the last treatment in which the lenalidomide was the patient received for multiple melanoma. It may also be used in patients who have not received a stem cell transplant, or have received a stem cell transplant at least 5 years ago, or who have received a stem cell transplant and who have progressed at least 36 months after the transplant, and/or who are 75 years old or older (particularly, patients who have not received a stem cell transplant), and who have refractory to one or more (e.g., 1,2, 3, 4, or 5 or more) drugs selected from the group consisting of Protease Inhibitors (PI), immunomodulatory drugs (imids), alkylating agents, and anti-CD 38 antibodies.
It is also particularly useful for patients who have not received a stem cell transplant, or have received a stem cell transplant at least 5 years ago, or who have received a stem cell transplant and who have progressed at least 36 months after the transplant, and/or who are 75 years old or older (more particularly, patients who have not received a stem cell transplant), and who have been refractory to one or more (e.g., 1, 2,3, 4, or 5 or more) drugs selected from the group consisting of Protease Inhibitors (PI), immunomodulatory drugs (IMiD), alkylating agents, and anti-CD 38 antibodies.
The meflofen or a salt thereof used according to the present invention is also particularly useful for patients having a refractory (e.g. refractory or relapsed refractory) to at least one immunomodulatory drug (IMiD), more particularly also for patients having a refractory (e.g. refractory or relapsed refractory) to at least the immunomodulatory drug lenalidomide, more particularly also for patients having a refractory (e.g. refractory or relapsed refractory) to at least lenalidomide and 1,2, 3 or 4 other drugs, e.g. at least one drug selected from the group consisting of Protease Inhibitors (PI), immunomodulatory drugs (IMiD), alkylating agents and anti-CD 38 antibodies. For example, 2, 3 or 4 other drugs, including at least one Protease Inhibitor (PI) and an immunomodulatory drug (IMiD). For example, a patient with multiple myeloma may have received at least three past lines of treatment and suffers from a disease that is refractory to at least one proteasome inhibitor, one immunomodulator, and one anti-CD 38 monoclonal antibody, and the patient has shown disease progression at or after the last treatment. If the patient has received Autologous Stem Cell Transplantation (ASCT), the time from the time after transplantation to the time of disease progression should be at least 3 years.
The metaflumine or a salt thereof used according to the present invention is also particularly useful in patients with a median Body Surface Area (BSA) of 1.855m 2.
In a particularly preferred embodiment, the invention is useful for treating multiple myeloma in patients who have not received stem cell transplantation, have RRMM, are refractory to the immunomodulator lenalidomide, and have received 2, 3, or 4 past lines of treatment (e.g., 3 past lines of treatment).
In another embodiment, the invention is useful for treating multiple myeloma in a patient who has received a stem cell transplant at least 5 years ago, has RRMM, is refractory to the immunomodulator lenalidomide, and has received 2, 3, or 4 prior treatment lines (e.g., 3 prior treatment lines).
In another embodiment, the invention is useful for treating multiple myeloma in patients at least 75 years old or older (and, for example, at least 5 years ago, either received stem cell transplantation or not), had RRMM, had refractory to the immunomodulatory agent lenalidomide, and received 2,3, or 4 past treatment lines (e.g., 3 past treatment lines).
In another embodiment, the invention is useful for treating multiple myeloma in patients who have received stem cell transplantation and the disease has progressed at least 36 months after transplantation, had RRMM, had refractory to the immunomodulator lenalidomide, and received 2,3, or 4 past treatment lines (e.g., 3 past treatment lines).
The 3 previous lines of treatment may be, for example, a proteasome inhibitor (e.g., bortezomib, carfilzomib, or ib Sha Zuo meters), an immunomodulator (lenalidomide, pomalidomide, or thalidomide), and an anti-CD 38 monoclonal antibody (e.g., up to Lei Tuoyou mab).
The meflofen or a salt thereof used according to the present invention may also be used in patients having a refractory (e.g. refractory or relapsed refractory) to at least pomalidomide and/or up to Lei Tuoyou mab.
The present invention is particularly beneficial for patients with multiple myeloma who have not received a stem cell transplant, or have received a stem cell transplant at least 5 years ago, or who have received a stem cell transplant and who have progressed at least 36 months after the transplant (particularly, patients who have not received a stem cell transplant), and who have:
receiving at least 2 prior lines of multiple myeloma treatment, for example at least 2 prior lines of treatment comprising lenalidomide and a protease inhibitor, either sequentially or as part of a combination treatment regimen; and/or
Refractory (e.g., recurrent and refractory, or refractory) to the last line of treatment and/or lenalidomide administered within 18 months prior to the present treatment; and/or
Refractory (e.g., recurrent and refractory, or refractory) to at least one alkylating agent; and/or
Refractory (e.g., recurrent and refractory, or refractory) to at least one anti-CD 38 antibody; and/or
Refractory (e.g., recurrent and refractory, or refractory) to at least one immunomodulatory drug (IMiD); and/or
Lenalidomide is refractory (e.g., refractory or relapsed refractory), particularly refractory to lenalidomide (e.g., refractory or relapsed refractory) and wherein lenalidomide is the last treatment a patient receives for multiple myeloma; and/or
For one or more of two or more classes of drugs selected from the group consisting of Protease Inhibitors (PI), immunomodulatory drugs (IMiD), alkylating agents and anti-CD 38 antibodies (e.g., 1, 2,3,
4 Or 5 or more) drugs have intractability; and/or
Refractory (e.g., refractory or relapsed refractory) to at least lenalidomide and 1,2,3, or 4 other drugs (e.g., at least one drug selected from the group consisting of Protease Inhibitors (PI), immunomodulatory drugs (imids), alkylating agents, and anti-CD 38 antibodies) (or, e.g., 2,3, or 4 other drugs, including at least one Protease Inhibitor (PI) and immunomodulatory drug (IMiD)).
In such embodiments, the patient may have RRMM and/or the patient may be 75 years old or older.
The invention is also particularly beneficial for patients with multiple myeloma who have not received a stem cell transplant, or have received a stem cell transplant at least 5 years ago, or have received a stem cell transplant and the disease has progressed at least 36 months after the transplant, and/or 75 years old or older (especially patients who have not received a stem cell transplant), and who:
2 past treatment lines were received; and/or
Has refractory property (refractory property or relapse refractory property) to alkylating agents; and/or refractory to anti-CD 38 antibodies (refractory or relapsed refractory); and/or
The last treatment for multiple myeloma that patients received was an immunomodulatory drug (IMiD), particularly lenalidomide; and/or
Refractory (recurrent and refractory, or refractory) to both the last line and lenalidomide administered within 18 months prior to treatment (10 mg or more).
In such embodiments, the patient may have RRMM and/or the patient may be 75 years old or older.
The combination of meflofen or a salt thereof and dexamethasone for use according to the present invention is very useful in the treatment of refractory, relapsed and relapsed-refractory multiple myeloma, and more particularly in the treatment of relapsed-refractory multiple myeloma. For example, the methods and uses of the invention comprising administering meflofen and dexamethasone can be used in patients refractory (e.g., refractory or relapsed refractory) to Protease Inhibitors (PI), immunomodulatory drugs (imids), alkylating agents, or anti-CD 38 antibodies. It is particularly useful for patients having a refractory (e.g., refractory or relapsed refractory) to alkylating agents, such as one or more of low-dose melphalan, high-dose melphalan, and cyclophosphamide. It may also be used in patients refractory to one or more (e.g., 1,2, 3, 4 or 5 or more) of two or more classes of drugs selected from Protease Inhibitors (PI), immunomodulatory drugs (IMiD), alkylating agents and anti-CD 38 antibodies. The methods and uses of the invention comprising administration of meflofen and dexamethasone are also extremely suitable for patients having a refractory (e.g. refractory or relapsed refractory) to at least one immunomodulatory drug (IMiD), more particularly for patients having a refractory (e.g. refractory or relapsed refractory) to at least the immunomodulatory drug lenalidomide; more particularly for patients refractory to at least lenalidomide and 1,2, 3 or 4 other drugs, such as at least one drug selected from the group consisting of Protease Inhibitors (PI), immunomodulatory drugs (IMiD), alkylating agents and anti-CD 38 antibodies. For example, 2,3 or 4 other drugs, including at least one Protease Inhibitor (PI) and an immunomodulatory drug (IMiD). The methods and uses of the invention comprising administering meflofen and dexamethasone are also useful for patients having a refractory (e.g., refractory or relapsed refractory) to at least pomalidomide and/or up to Lei Tuoyou mab.
As described above, the present invention provides treatment of a subpopulation of patients with multiple myeloma. One subpopulation is of patients with multiple myeloma who have not received stem cell transplantation. For the avoidance of doubt, a "patient who has not received a stem cell transplant" refers to a patient who has never received a stem cell transplant for the lifetime. Thus, the patient has never received a stem cell transplant prior to (or during) the treatment of the present invention. Examples of stem cell transplantation include autologous stem cell transplantation, tandem stem cell transplantation, allogeneic stem cell transplantation, donor lymphocyte infusion or minitransplantation. In an exemplary embodiment of the invention, the patient who has not received a stem cell transplant is a patient who has not received an autologous stem cell transplant.
Patients who have not received a stem cell transplant may choose not to receive the treatment, or may be advised by a medical professional that they are not suitable for such treatment after personal assessment of their health. For example, patients aged 65 or over 70 are not generally recommended for stem cell transplantation unless their physical health is very good. Stem cell transplantation is also generally not recommended for patients with underlying diseases such as heart and/or lung diseases. Stem cell transplantation may not be suggested depending on other factors, such as the type and stage of multiple myeloma, its aggressiveness and responsiveness to treatment. The reason why multiple myeloma patients have not received stem cell transplantation may be numerous due to the choice or disease characteristics, and thus surprisingly, is a patient population that may benefit from a particular treatment. As shown in fig. 1-4, individual patient subgroups in the patient population that did not receive stem cell transplantation benefited.
In certain preferred embodiments of the invention, a patient with multiple myeloma has not received a stem cell transplant, and the patient:
At least 65, 70, 75 or 80 years old (preferably at least 75 or 80 years old); and/or
Suffering from cardiovascular disease; and/or
Has lung disease.
The inventors have also found that the treatment of patients with multiple myeloma who have not received a stem cell transplant according to the present invention is also particularly beneficial for patients who have not received a stem cell transplant and who meet the following criteria:
The surface area (BSA) of the middle position is less than or equal to 1.855m 2; and/or
ISS groups with multiple myeloma, revised multiple myeloma International System for staging (R-ISS), are I or II; and/or
In view of the cytogenetics of the patient, the patient is a high risk patient; and/or
Renal function is impaired (e.g., creatine clearance is less than 60 milliliters per minute (mL/min), or 60 to 90mL/min; and in particular creatine clearance is less than 60 mL/min).
The inventors have also found that the treatment of patients with multiple myeloma who have not received a stem cell transplant according to the present invention is extremely beneficial for patients who have not received a stem cell transplant and who meet the following:
RRMM; and/or
Refractory to lenalidomide (e.g., refractory to lenalidomide administered within 18 months prior to treatment (e.g.,. Gtoreq.10 mg); and/or
At least 2 past treatment lines (e.g., 2,3, or 4 past treatment lines) have been accepted.
The inventors have also found that the treatment of patients with multiple myeloma who have not received a stem cell transplant according to the present invention is extremely beneficial for patients who have not received a stem cell transplant and who meet the following:
RRMM; and is also provided with
Refractory to lenalidomide (e.g., refractory to lenalidomide administered within 18 months prior to treatment (e.g.,. Gtoreq.10 mg); and is also provided with
At least 2 past treatment lines (e.g., 2, 3, or 4 past treatment lines) are received.
Since the treatment of the present invention is for patients who have not received stem cell transplantation, the methods and uses of the present invention may further comprise the steps of: determining whether the patient has received a stem cell transplant, and if the patient has not received a stem cell transplant, administering meflofen or a salt thereof to the patient with the multiple myeloma who has not received a stem cell transplant.
A physician of ordinary skill can readily determine whether a patient with multiple myeloma has received a stem cell transplant, for example, by querying the patient and/or examining their medical records.
For example, the invention provides a method for treating or preventing multiple myeloma in a patient with multiple myeloma comprising: determining whether the patient has received a stem cell transplant, and if the patient has not received a stem cell transplant, administering meflofen or a salt thereof to the patient with the multiple myeloma who has not received a stem cell transplant.
The invention also provides a method for treating or preventing multiple myeloma in a patient suffering from multiple myeloma comprising: determining whether the patient has received a stem cell transplant, and if the patient has not received a stem cell transplant, administering meflofen or a salt thereof, and dexamethasone to the patient having multiple myeloma who has not received a stem cell transplant. The inventors of the present invention have also found that the treatment of patients with multiple myeloma who have not received a stem cell transplant, is also particularly beneficial for patients who have not received a stem cell transplant and who do not meet (also referred to herein as "not fit") stem cell transplant conditions.
After an individual assessment of the health status of a multiple myeloma patient, a physician of ordinary skill can readily determine whether the multiple myeloma patient is suitable for stem cell transplantation, e.g., taking into account age, physical health, underlying medical conditions (e.g., heart and/or lung disease), and other factors such as the type and stage of multiple myeloma, its aggressiveness, and responsiveness to treatment.
Accordingly, the present invention may further comprise the steps of: determining whether the patient is suitable for stem cell transplantation and if the patient is not suitable for stem cell transplantation, administering meflofen or a salt thereof to the patient with multiple myeloma who has not received stem cell transplantation.
For example, the invention provides methods for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining whether the patient is suitable for stem cell transplantation and administering meflofen or a salt thereof to a patient with multiple myeloma who has not received stem cell transplantation if the patient is not suitable for stem cell transplantation.
The invention also provides a method for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining whether the patient is suitable for stem cell transplantation and if the patient is not suitable for stem cell transplantation, administering meflofen or a salt thereof and dexamethasone to the patient with multiple myeloma who has not received stem cell transplantation.
The present invention also provides a method for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining whether the patient has received a stem cell transplant, and determining whether the patient is suitable for a stem cell transplant, and if the patient has not received a stem cell transplant and is not suitable for a stem cell transplant, administering meflofen or a salt thereof to the patient with multiple myeloma who has not received a stem cell transplant.
In certain embodiments, the invention provides methods for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining whether the patient has received a stem cell transplant and whether the patient is suitable for a stem cell transplant, and if the patient has not received a stem cell transplant and is not suitable for a stem cell transplant, administering meflofen or a salt thereof and dexamethasone to the multiple myeloma patient who has not received a stem cell transplant.
The present invention also provides meflofen or a salt thereof for use in the treatment or prevention of multiple myeloma in a patient who has not received stem cell transplantation and who is not suitable for stem cell transplantation. The present invention also provides meflofen or a salt thereof and dexamethasone for treating or preventing multiple myeloma in a patient who has not received stem cell transplantation and who is not suitable for stem cell transplantation.
The invention also provides treatment of a subpopulation of patients with multiple myeloma who have received stem cell transplantation at least 2.5 years ago, preferably at least 5 years ago. For the avoidance of doubt, "a patient who received a stem cell transplant at least X years ago" refers to a patient who received a stem cell transplant in the past but did not receive a stem cell transplant at least X years before receiving the treatment according to the present invention. (e.g., "a patient who received stem cell transplantation at least 5 years ago" refers to a patient who received stem cell therapy in the past but did not receive stem cell transplantation at least 5 years prior to receiving therapy according to the present invention.) thus, at least X years (e.g., 5 years) prior to the treatment of the present invention, the patient did not receive stem cell transplantation, but they did receive stem cell transplantation more than X years (e.g., 5 years) prior to the past. Thus, such patients may also be described as "patients who have not received stem cell transplantation for at least X years". For example, a patient who received a stem cell transplant at least 5 years ago may also be described as a patient who did not receive a stem cell transplant at least 5 years ago. Examples of stem cell transplantation include autologous stem cell transplantation, tandem stem cell transplantation, allogeneic stem cell transplantation, donor lymphocyte infusion or minitransplantation. In exemplary embodiments of the invention, the patient who received a stem cell transplant at least X years ago (e.g., at least 5 years ago) is a patient who received an autologous stem cell transplant at least X years ago (e.g., at least 5 years ago).
In certain embodiments, the invention provides treatment of a subpopulation of patients having multiple myeloma that have received stem cell transplantation at least 2.5 years ago, at least 5 years ago, at least 6 years ago, at least 7 years ago, at least 8 years ago, at least 9 years ago, at least 10 years ago, at least 12 years ago, or at least 15 years ago. In a preferred embodiment, the invention provides treatment of a subpopulation of patients having multiple myeloma that received stem cell transplantation at least 5 years ago, at least 6 years ago, at least 7 years ago, at least 8 years ago, at least 9 years ago, at least 10 years ago, at least 12 years ago, or at least 15 years ago.
Patients who received stem cell transplantation at least 5 years ago may choose not to receive further stem cell transplantation therapy at the time, or may be informed that they are not suitable candidates for such therapy after having been personally assessed for their health by a medical professional. For example, due to their age, underlying medical condition (e.g., heart disease and/or lung disease), or other factors such as the type and stage of multiple myeloma, its aggressiveness, and responsiveness to treatment. As shown in fig. 7 and 8, individual patient subgroups benefit from a population of patients who received stem cell transplantation at least 2.5 years ago, and in particular at least 5 years ago, particularly as compared to patients who received stem cell transplantation over the past 2.5 years.
In certain embodiments of the invention, a patient with multiple myeloma has received a stem cell transplant at least 5 years ago, and the patient:
At least 65, 70, 75 or 80 years old (preferably at least 75 or 80 years old); and/or
Suffering from cardiovascular disease; and/or
Has lung disease.
In certain embodiments of the invention, a patient with multiple myeloma has received a stem cell transplant at least 5 years ago, and the patient:
The surface area (BSA) of the middle position is less than or equal to 1.855m 2; and/or
The modified multiple myeloma International staging System (R-ISS) for multiple myeloma with ISS groups I or II; and/or
In view of the cytogenetics of patients, are high risk patients; and/or
Renal function is impaired (e.g., creatine clearance is less than 60 milliliters per minute (mL/min), or 60 to 90mL/min; and in particular creatine clearance is less than 60 mL/min).
In certain embodiments of the invention, a patient with multiple myeloma has received a stem cell transplant at least 5 years ago, and the patient:
RRMM; and/or (preferably and)
Refractory to lenalidomide (e.g., refractory to lenalidomide administered within 18 months prior to treatment (e.g.,. Gtoreq.10 mg); and/or (preferably and)
At least 2 past treatment lines (e.g., 2,3, or 4 past treatment lines) have been accepted.
Since the treatment of the present invention is for patients who received stem cell transplantation at least 5 years ago, the methods and uses of the present invention may further comprise the steps of: determining whether the patient received a stem cell transplant at least 5 years ago, and administering meflofen or a salt thereof to the patient if the patient received a stem cell transplant at least 5 years ago.
A physician of ordinary skill can readily determine whether a patient with multiple myeloma has received a stem cell transplant at least 5 years ago, for example by asking the patient whether they have received a stem cell transplant and/or checking their medical record, and if so, whether they have received a stem cell transplant less than 5 years ago.
For example, the invention provides a method for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining whether the patient has received a stem cell transplant at least 5 years ago, and if the patient has received a stem cell transplant at least 5 years ago, administering meflofen or a salt thereof to the patient with multiple myeloma who received a stem cell transplant at least 5 years ago.
The invention also provides a method for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining whether the patient has received a stem cell transplant at least 5 years ago, and if the patient has received a stem cell transplant at least 5 years ago, administering meflofen or a salt thereof and dexamethasone to the patient with multiple myeloma who has received a stem cell transplant at least 5 years ago.
The inventors of the present invention have also found that the treatment of patients with multiple myeloma who have not received a stem cell transplant, according to the present invention, is also particularly beneficial for patients who received a stem cell transplant at least 5 years ago and who did not meet (also referred to herein as being "unsuitable") (further) stem cell transplant conditions.
Since the treatment of the present invention is for patients who received stem cell transplantation at least 5 years ago, the methods and uses of the present invention may further comprise the steps of: determining whether the patient is suitable for stem cell transplantation and if the patient is not suitable for stem cell transplantation, administering meflofen or a salt thereof to a patient with multiple myeloma who has received stem cell transplantation at least 5 years ago.
For example, the invention provides a method for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining whether the patient is suitable for stem cell transplantation and, if the patient is not suitable for stem cell transplantation, administering meflofen or a salt thereof to the patient with multiple myeloma who received stem cell transplantation at least 5 years ago.
The invention also provides a method for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining whether the patient is suitable for stem cell transplantation and if the patient is not suitable for stem cell transplantation, administering meflofen or a salt thereof and dexamethasone to the patient with multiple myeloma who received stem cell transplantation at least 5 years ago.
The invention also provides a method for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining whether the patient received a stem cell transplant at least 5 years ago, and determining whether the patient was eligible for a stem cell transplant, and if the patient received a stem cell transplant at least 5 years ago and was not eligible for a stem cell transplant, administering meflofen or a salt thereof to the patient with multiple myeloma who received a stem cell transplant at least 5 years ago.
In certain embodiments, the invention provides methods for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining whether the patient received a stem cell transplant at least 5 years ago, and determining whether the patient was eligible for a stem cell transplant, and if the patient received a stem cell transplant at least 5 years ago and was not eligible for a stem cell transplant, administering meflofen or a salt thereof and dexamethasone to the patient with multiple myeloma who received a stem cell transplant at least 5 years ago.
The invention also provides meflofen or a salt thereof for use in the treatment or prevention of multiple myeloma in a patient who has received stem cell transplantation at least 5 years ago and who is not suitable for stem cell transplantation. The invention also provides for the use of meflofen or a salt thereof and dexamethasone for the treatment or prevention of multiple myeloma in a patient suffering from multiple myeloma who has received stem cell transplantation at least 5 years ago and is not suitable for stem cell transplantation.
The invention also provides treatment of a subpopulation of patients with multiple myeloma age 75 or older. Such patients may also not have received stem cell therapy, or have received stem cell transplantation at least 5 years ago. As discussed in the results section of example 1 and shown in fig. 1 and 3, the treatment of the present invention has benefits for each patient subgroup within a patient population aged 75 years or older.
In certain embodiments, the invention provides treatment of a subpopulation of patients with multiple myeloma that is 78 years old or older, 80 years old or older, or 85 years old or older.
In certain embodiments of the invention, the patient with multiple myeloma is 75 years old or older and the patient:
No stem cell transplantation was received, or at least 5 years ago (e.g., at least 6 years ago, at least 7 years ago, at least 8 years ago, at least 9 years ago, at least 10 years ago, at least 12 years ago, or at least 15 years ago); and/or
Suffering from cardiovascular disease; and/or
Has lung disease.
In certain embodiments of the invention, the patient with multiple myeloma is 75 years old or older and the patient:
No stem cell transplantation was received, or at least 5 years ago (e.g., at least 6 years ago, at least 7 years ago, at least 8 years ago, at least 9 years ago, at least 10 years ago, at least 12 years ago, or at least 15 years ago); and/or
The surface area (BSA) of the middle position is less than or equal to 1.855m 2; and/or
The modified multiple myeloma International staging System (R-ISS) for multiple myeloma has an ISS group of I or II; and/or
In view of the cytogenetics of the patient, the patient is a high risk patient; and/or
Renal function is impaired (e.g., creatine clearance is less than 60 milliliters per minute (mL/min), or 60 to 90mL/min; and in particular creatine clearance is less than 60 mL/min).
In certain embodiments of the invention, the patient with multiple myeloma is 75 years old or older and the patient:
RRMM; and/or (preferably and)
Refractory to lenalidomide (e.g., refractory to lenalidomide administered within 18 months prior to treatment (e.g.,. Gtoreq.10 mg); and/or (preferably and)
At least 2 past treatment lines (e.g., 2, 3, or 4 past treatment lines) are received.
In such embodiments, the patient may optionally have not received stem cell transplantation, or has received stem cell transplantation at least 5 years ago (e.g., at least 6 years ago, at least 7 years ago, at least 8 years ago, at least 9 years ago, at least 10 years ago, at least 12 years ago, or at least 15 years ago).
Since the treatment of the present invention is for patients 75 years old or older, the methods and uses of the present invention may further comprise determining whether the patient is 75 years old or older, and if the patient is 75 years old or older, administering meflofen or a salt thereof to patients with multiple myeloma that are 75 years old or older.
A physician of ordinary skill can readily determine whether a patient with multiple myeloma is 75 years old or older, for example, by querying the patient and/or examining their medical records.
For example, the invention provides a method for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining if the patient is 75 years old or older, and if the patient is 75 years old or older, administering meflofen or a salt thereof to the patient with multiple myeloma 75 years old or older.
The invention also provides a method for treating or preventing multiple myeloma in a patient suffering from multiple myeloma comprising determining if the patient is 75 years old or older, and if the patient is 75 years old or older, administering meflofen or a salt thereof and dexamethasone to the patient suffering from multiple myeloma 75 years old or older.
The inventors of the present invention have also found that the treatment of patients with multiple myeloma aged 75 years or older, according to the present invention, is also particularly beneficial for patients aged 75 years or older and not meeting (also referred to herein as "unsuitable") stem cell transplantation conditions (even more particularly for patients who have not received a stem cell transplant or have received a stem cell transplant at least 5 years ago).
Since the treatment of the present invention is for patients 75 years old or older, the method and use of the present invention may further comprise the steps of: determining whether the patient is suitable for stem cell transplantation and if the patient is not suitable for stem cell transplantation, administering meflofen or a salt thereof to a patient with multiple myeloma aged 75 years or older. For example, the invention provides methods for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining whether the patient is suitable for stem cell transplantation and administering meflofen or a salt thereof to a patient with multiple myeloma 75 years old or older if the patient is not suitable for stem cell transplantation. The invention also provides a method for treating or preventing multiple myeloma in a patient suffering from multiple myeloma comprising determining whether the patient is suitable for stem cell transplantation and if the patient is not suitable for stem cell transplantation, administering to the patient suffering from multiple myeloma 75 years old or older meflofen or a salt thereof and dexamethasone.
The invention also provides a method for treating or preventing multiple myeloma in a patient suffering from multiple myeloma comprising determining if the patient is 75 years old or older, and determining if the patient is suitable for stem cell transplantation, and if the patient is 75 years old or older and unsuitable for stem cell transplantation, administering meflofen or a salt thereof to a patient suffering from multiple myeloma 75 years old or older.
In certain embodiments, the invention provides methods for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining if the patient is 75 years old or older, and determining if the patient is suitable for stem cell transplantation, and if the patient is 75 years old or older and unsuitable for stem cell transplantation, administering meflofen or a salt thereof and dexamethasone to the patient with multiple myeloma that is 75 years old or older.
The present invention also provides meflofen or a salt thereof for use in the treatment or prevention of multiple myeloma in patients aged 75 years or older who are not suitable for stem cell transplantation. The invention also provides for the use of meflofen or a salt thereof and dexamethasone for the treatment or prevention of multiple myeloma in patients 75 years old or older who have multiple myeloma and who are unsuitable for stem cell transplantation.
The invention further provides a method for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining whether the patient has received a stem cell transplant and whether the disease has progressed at least 36 months after the transplant, and administering meflofen or a salt thereof to the patient if the patient has received a stem cell transplant and the disease has progressed at least 36 months after the transplant.
The invention further provides a method for treating or preventing multiple myeloma in a patient with multiple myeloma comprising determining whether the patient has received a stem cell transplant and whether the disease has progressed at least 36 months after the transplant, and administering to the patient meflofen or a salt thereof and dexamethasone if the patient has received a stem cell transplant and the disease has progressed at least 36 months after the transplant.
In such uses and methods of treating a patient with multiple myeloma 75 years old or older, the patient may also be a patient with multiple myeloma who did not receive stem cell transplantation, or a patient with multiple myeloma who received stem cell transplantation at least 5 years ago. Thus, in the use and method of treating a patient with multiple myeloma aged 75 years or older and not receiving a stem cell transplant, the methods and uses of the invention may further comprise the steps of: determining whether the patient has received a stem cell transplant and if the patient has not received a stem cell transplant, administering meflofen or a salt thereof (and optionally dexamethasone) to a patient with multiple myeloma aged 75 years or older and not receiving a stem cell transplant. In the use and method of treating a patient with multiple myeloma aged 75 years or older and having received a stem cell transplant at least 5 years ago, the method and use of the present invention may further comprise the steps of: determining whether the patient received a stem cell transplant at least 5 years ago, and if the patient received a stem cell transplant at least 5 years ago, administering meflofen or a salt thereof (and optionally dexamethasone) to a patient with multiple myeloma 75 years old or older and who received a stem cell transplant at least 5 years ago.
The following further define embodiments of the invention:
2.. Meflofen or a salt thereof and dexamethasone for use in the treatment or prophylaxis of multiple myeloma in a patient suffering from multiple myeloma, said patient
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-Not received stem cell transplantation and is 75 years old or older, or at least 5 years ago received stem cell transplantation and is 75 years old or older; or (b)
-Receiving a stem cell transplant and the disease later progresses at least 36 months after the transplant.
In one embodiment, the present invention provides a method of treating a cancer comprising administering a dose of meflofen or a salt thereof and dexamethasone for use as defined in item 1, wherein meflofen is administered at a dose of about 1 to 150mg (excluding the mass of any counter ion), e.g. a dose of 1 to 50mg (excluding the mass of any counter ion) (e.g. 1, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 mg).
In addition, the present invention provides a pharmaceutical composition comprising ≡3 ≡meflofen or its salt and dexamethasone for use as defined in claim 1 or 2, wherein dexamethasone is administered at a dose of about 5mg to 100mg, more preferably 10mg to 80mg, most preferably 20mg to 60mg (e.g. 40mg or 20 mg).
A dose of meflofen or a salt thereof for use as defined in any one of claims 1 to 3, wherein the dose of meflofen is administered on the first day of a cycle of 1 to 42 days (e.g. 21 to 35 days, in particular 21, 28, 29, 30 or 35 days).
A dose of meflofen or a salt thereof and dexamethasone for use as defined in any one of claims 1 to 4, wherein the meflofen dose (excluding the mass of any salt) is administered as a parenteral dose at an infusion rate of 0.3mg/min to 1.8mg/min (e.g. as a parenteral dose at an infusion rate of 1.1mg/min to 1.8 mg/min).
In combination with dexamethasone, meflofen or a salt thereof for use as defined in any one of claims 1 to 5, wherein the meflofen or salt thereof is administered simultaneously, sequentially or separately with dexamethasone (e.g. at a dose of 20mg or 40mg dexamethasone).
A meflofen or a salt thereof and dexamethasone for use as defined in any one of claims 1 to 5, wherein the meflofen or a salt thereof is administered simultaneously, sequentially or separately with one or more other therapeutic agents, e.g. wherein the one or more other therapeutic agents are selected from the group consisting of steroids (e.g. prednisone), imids (e.g. thalidomide, lenalidomide and pomalidomide), PI (e.g. bortezomib, carfilzomib and Sha Zuo meters), histone Deacetylase (HDAC) inhibitors (e.g. panobinostat), conventional chemotherapy (e.g. melphalan, cyclophosphamide, doxorubicin, bendamustine), anti-CD 38 antibodies (up Lei Tuoyou mab) and anti-SLAMF 7 antibodies (erltuzumab); preferably, the one or more other therapeutic agents are selected from the group consisting of up to Lei Tuoyou mab and bortezomib.
A pharmaceutical formulation comprising meflofen or a salt thereof and a pharmaceutical formulation comprising dexamethasone for use as defined in any one of claims 1 to 7.
A method of treating or preventing multiple myeloma comprising the step of administering to a patient with multiple myeloma meflofen or a salt thereof and dexamethasone, said patient
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-Not received stem cell transplantation and is 75 years old or older, or at least 5 years ago received stem cell transplantation and is 75 years old or older.
The method of claim 9, wherein one or more additional therapeutic agents selected from the group consisting of steroids (e.g., prednisone and dexamethasone), imids (e.g., thalidomide, lenalidomide, and pomalidomide), PI (e.g., bortezomib, carfilzomib, and i Sha Zuo m), histone Deacetylase (HDAC) inhibitors (e.g., panobinostat), conventional chemotherapy (e.g., melphalan, cyclophosphamide, doxorubicin, bendamustine), anti-CD 38 antibodies (up Lei Tuoyou mab), and anti-SLAMF 7 antibodies (erltuzumab), are additionally administered to the patient simultaneously, sequentially or separately with meflofen or a salt thereof; or selected from an antibody to B cell maturation antigen (Bei Lan tamab), a nuclear export inhibitor (plug Li Nisuo), and an autologous Chimeric Antigen Receptor (CAR) T cell therapy (ciltacabtagene) to B cell maturation antigen, and preferably the one or more other therapeutic agents are selected from the group consisting of up Lei Tuoyou monoclonal antibody and bortezomib.
The method of claim 9 or 10, wherein the method comprises determining whether the patient has received a stem cell transplant, and if the patient has not received a stem cell transplant, administering meflofen or a salt thereof to the patient; or (b)
Determining whether the patient received a stem cell transplant at least 5 years ago, and administering meflofen or a salt thereof to the patient if the patient received a stem cell transplant at least 5 years ago; and/or
Determining whether the patient is 75 years old or older, and if the patient is 75 years old or older, administering meflofen or a salt thereof to the patient.
The method of claim 9, 10 or 11, wherein the method comprises determining whether the patient is suitable for stem cell transplantation and administering meflofen or a salt thereof to the patient if the patient is not suitable for stem cell transplantation.
Use of ≡13 ≡meflofen or a salt thereof and dexamethasone in the manufacture of a medicament for the treatment of multiple myeloma in a patient suffering from multiple myeloma, said patient
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-Not received stem cell transplantation and is 75 years old or older, or at least 5 years ago received stem cell transplantation and is 75 years old or older; or (b)
-Receiving a stem cell transplant and the disease later progresses at least 36 months after the transplant.
A kit comprising meflofen, dexamethasone and one or more other therapeutic agents, for treating or preventing multiple myeloma in a patient as defined in any one of claims 1 to 7,
The one or more other therapeutic agents are selected from the group consisting of steroids (e.g., prednisone), imids (e.g., thalidomide, lenalidomide, and pomalidomide), PI (e.g., bortezomib, carfilzomib, and ib Sha Zuo meters), histone Deacetylase (HDAC) inhibitors (e.g., panobinostat), conventional chemotherapy (e.g., melphalan, cyclophosphamide, doxorubicin, bendamustine), anti-CD 38 antibodies (up Lei Tuoyou mab), and anti-SLAMF 7 antibodies (erltuzumab); or selected from the group consisting of an antibody to B cell maturation antigen (Bei Lan tamab), a nuclear export inhibitor (plug Li Nisuo), and an autologous Chimeric Antigen Receptor (CAR) T cell therapy to B cell maturation antigen (ciltacabtagene); preferably the one or more other therapeutic agents are selected from the group consisting of up to Lei Tuoyou mab and bortezomib.
A pharmaceutical formulation as defined in claim 8, a method as defined in claim 9 to 12, a use as defined in claim 13, or a kit as defined in claim 14, wherein the patient is suffering from multiple myeloma:
receiving at least 2 prior multiple myeloma treatment lines, e.g., at least 2 prior treatment lines comprising lenalidomide and a protease inhibitor, either sequentially or as part of a combination treatment regimen; and/or
Refractory (e.g., recurrent and refractory, or refractory) to the last line of treatment and/or lenalidomide administered within 18 months prior to treatment; and/or
Refractory (e.g., recurrent and refractory, or refractory) to at least one alkylating agent; and/or
Refractory (e.g., recurrent and refractory, or refractory) to at least one anti-CD 38 antibody; and/or
Refractory (e.g., recurrent and refractory, or refractory) to at least one immunomodulatory drug (IMiD); and/or
Lenalidomide is refractory (e.g., refractory or relapsed refractory), and in particular, is refractory (e.g., refractory or relapsed refractory) to lenalidomide in which lenalidomide is the last multiple myeloma treatment that the patient receives; and/or
For one or more of two or more classes of drugs selected from the group consisting of Protease Inhibitors (PI), immunomodulatory drugs (IMiD), alkylating agents and anti-CD 38 antibodies (e.g., 1, 2,3,
4 Or 5 or more) drugs have intractability; and/or
Refractory (e.g., refractory or relapsed refractory) to at least lenalidomide and 1,2, 3, or 4 other drugs (e.g., at least one drug selected from the group consisting of Protease Inhibitors (PI), immunomodulatory drugs (imids), alkylating agents, and anti-CD 38 antibodies) (or, e.g., 2, 3, or 4 other drugs, including at least one Protease Inhibitor (PI) and immunomodulatory drug (IMiD)); and/or
Refractory (e.g., refractory or relapsed refractory) to at least pomalidomide and/or up to Lei Tuoyou mab; and/or
With RRMM.
A pharmaceutical formulation as defined in any one of claims 8 to 12 or 15, a method as defined in claim 9 to 12 or 15, a use as defined in claim 13 or 15, or a kit as defined in claim 14 or 15, wherein the patient is suffering from multiple myeloma:
At least 65, 70, 75, or 80 years old; and/or
Suffering from cardiovascular disease; and/or
Has lung disease.
In a preferred embodiment, the method of treating a patient suffering from multiple myeloma comprises administering to the patient a pharmaceutical formulation as defined in any one of claims 1 to 7 or 15 to 16, a pharmaceutical formulation as defined in claim 8 or 15 to 16, a method as defined in claim 9 to 12 or 15 to 16, a use as defined in claim 13 or 15 to 16, or a kit as defined in claim 14 to 16.
A pharmaceutical formulation as defined in any one of claims 1 to 7 or 15 to 17, a method as defined in any one of claims 9 to 12 or 15 to 17, a use as defined in any one of claims 13 or 15 to 17, or a kit as defined in any one of claims 14 to 17, wherein the patient is suffering from multiple myeloma:
The surface area (BSA) of the middle position is less than or equal to 1.855m 2; and/or
ISS groups with multiple myeloma, revised multiple myeloma International System for staging (R-ISS), are I or II; and/or
In view of the cytogenetics of patients, are high risk patients; and/or
Renal function is impaired (e.g., creatine clearance is less than 60 milliliters per minute (mL/min), or 60 to 90mL/min; and in particular creatine clearance is less than 60 mL/min).
A pharmaceutical formulation as defined in any one of claims 1 to 7 or 15 to 18, a method as defined in any one of claims 9 to 12 or 15 to 18, a use as defined in any one of claims 13 or 15 to 18, or a kit as defined in any one of claims 14 to 18, wherein the patient is suffering from multiple myeloma:
RRMM; and/or (preferably and)
Refractory to lenalidomide (e.g., refractory to lenalidomide administered within 18 months prior to treatment (e.g.,. Gtoreq.10 mg); and/or (preferably and)
At least 2 past treatment lines (e.g., 2, 3, or 4 past treatment lines) are received.
A pharmaceutical formulation as defined in any one of claims 1 to 7 or 15 to 19, a method as defined in any one of claims 9 to 12 or 15 to 19, a use as defined in any one of claims 13 or 15 to 19, or a kit as defined in any one of claims 14 to 19, wherein the multiple myeloma patient has not received a stem cell transplant.
The following examples illustrate the invention.
Example 1
Description of the study
Brief summary: a randomized, controlled, open-label, phase 3 multicentric study included RRMM patients who received 2-4 past treatment lines, who had refractory to lenalidomide (. Gtoreq.10 mg) administered both in the last treatment line and 18 months prior to randomized group, as indicated by disease progression within 60 days or 60 days of completion of the last lenalidomide administration. The patient receives either meflofen + dexamethasone or pomalidomide + dexamethasone.
Detailed description:
a randomized, controlled, open-label, phase 3 multicentric study included RRMM patients who received 2-4 past treatment lines, and who had refractory to both the last treatment line and lenalidomide, as indicated by disease progression within 60 days or 60 days of completion of the last lenalidomide administration. Patients were randomized into either of two groups (see table 1 below):
group A: on day 1 of each 28 day cycle, melphalan fluorobenzamide (meflofen) 40mg, dexamethasone 40mg on days 1, 8, 15 and 22.
Group B: on days 1 to 21 of each 28 day cycle, pomalidomide was 4mg daily, dexamethasone was 40mg on days 1, 8, 15 and 22.
Patients aged 75 years or older reduced the dosage of dexamethasone to 20mg on days 1, 8, 15 and 22 of groups A and B. The patient receives treatment until there is a recorded disease progression, unacceptable toxicity, or the patient/therapist determines that continuing treatment does not meet the patient's best interests. Dose adjustments and delay treatments are made according to patient tolerance as specified in the protocol. If a cycle delay occurs that is independent of dexamethasone toxicity, it is recommended that dexamethasone be continued weekly.
Study design
Study type: intervention (Interventional) (clinical trial)
Actual registered number of people: 495 participants
And (3) distribution: random arrangement
Intervention model: parallel distribution
Blind (Masking): single (result evaluator)
The main purpose is as follows: treatment of
Formal title: phase 3 study comparing the random, control, open label of meflofen/dexamethasone with pomalidomide/dexamethasone for the treatment of relapsed refractory multiple myeloma patients refractory to lenalidomide
Grouping and intervention
TABLE 1
Major outcome measure:
1. Progression Free Survival (PFS) [ time frame: from random grouping to time of progression, or if no progression, 24 months after treatment end ]: PFS comparing meflofen plus dexamethasone (group A) to pomalidomide plus dexamethasone (group B) was evaluated by the Independent Review Committee (IRC) according to the International myeloma working group unified response standard (IMWG-URC)
Secondary outcome measure:
1. Overall Remission Rate (ORR) [ time frame: optimal relief is achieved from random grouping until confirmation of progression, or if no progression, 24 months after treatment is completed ]: evaluation and comparison of ORR for group a and group B
2. Duration of remission (DOR) [ time range: from the first appearance of evidence of remission to confirmation of progression, or if no progression, 24 months after treatment is completed ]: evaluation and comparison of DOR for group A and group B
3. Total lifetime (OS) [ time frame: from random grouping to study end (2 years after confirmation of progression) ]: evaluation and comparison of OS of group A and group B
4. Safety and tolerability: the number of patients with treatment-induced adverse events (including clinical laboratory and vital sign abnormalities) as assessed by CTCAE v4.0 [ time frame: 30 days after the start of the administration to the last administration ]: safety and tolerability of groups a and B were assessed and compared. The number of patients who will present with adverse events (including clinical laboratory and vital sign abnormalities) caused by the emerging treatment as assessed by CTCAE v 4.0. No formal statistical analysis of the safety endpoint is performed.
Qualification criteria
Age appropriate for study: age 18 and above (adult and old people)
Gender suitable for learning: all of which
Healthy volunteers were received: whether or not
Inclusion criteria:
1. Is not limited by men and women, and is 18 years old or older
2. Previously diagnosed as multiple myeloma and with recorded disease progression, further treatment is needed at the time of screening
3. Measurable disease is defined as any one of the following:
The serum monoclonal protein detected by protein electrophoresis is more than or equal to 0.5g/dL.
Monoclonal protein in urine in 24-hour electrophoresis is more than or equal to 200mg/24 hours
O serum free light chain ≡10mg/dL and abnormal serum kappa to lambda free light chain ratio
4. From 2 to 4 past treatment lines, including lenalidomide and PI, were received, either sequentially or in the same treatment line, and were refractory (recurrent and refractory, or refractory) to both the last treatment line and the lenalidomide administered within 18 months prior to the randomized group (.gtoreq.10 mg). Lenalidomide refractory is defined as progression after at least 2 lenalidomide cycles (at least 14 doses of lenalidomide per cycle) during lenalidomide treatment or within 60 days of the last administration
5. The expected life is more than or equal to 6 months
6. The physical state of the eastern tumor cooperative group (ECOG) is less than or equal to 2
7. Women with fertility potential (FCBP) must be negative for serum or urine pregnancy tests before treatment can begin. The participants must agree to an ongoing pregnancy test. All patients must be willing to comply with all requirements of the U.S. pomalidomide risk assessment and mitigation strategy (REMS) program or pomalidomide Pregnancy Prevention Program (PPP)
8. Can learn about the purpose and risk of the study and provide signed and dated informed consent
9.12 Lead Electrocardiogram (ECG) with QT interval calculated from the Fridericia equation (QTcF) interval of 470 ms or less
10. The following laboratory results must be met during screening and prior to study drug administration on day 1 of cycle 1:
Absolute Neutrophil Count (ANC) at least 1000 cells/mm 3(1.0x 109/L
Platelet count ≡75000 cells/mm 3(75x 109/L)
O-hemoglobin of 8.0g/dl or more
Total bilirubin is less than or equal to 1.5x Upper Limit of Normal (ULN), or is diagnosed as Gilbert syndrome (Gilberts syndrome) and is reviewed and approved by a medical monitor
Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT)
≤3.0x ULN
Kidney function: creatinine clearance rate estimated according to Cockcroft-Gault formula is more than or equal to 45mL/min
11. Must be able to take antithrombotic precautions
12. Must or is willing to possess an acceptable central catheter. (catheterization, peripheral catheterization central catheter [ PICC line ] or central venous catheter) (only need to be inserted when randomly assigned to group A)
Exclusion criteria:
1. primary refractory disease (i.e. never responding to any past treatment (. Gtoreq.MR)
2. Evidence of intractable mucosal or internal hemorrhage or platelet infusion
3. Researchers believe that any medical condition may present excessive risk to a patient or adversely affect his participation in the study
4. Past exposure to pomalidomide
5. Are known to be intolerant to IMiD
6. Active infections requiring parenteral or oral anti-infective therapy within 14 days after random grouping are known
7. Other malignancies diagnosed or in need of treatment in the past 3 years, except for fully treated basal cell carcinoma, squamous cell skin carcinoma, cervical or breast carcinoma in situ or very low and low risk prostate cancer in active monitoring
8. Female in pregnancy or lactation period
9. Serious mental illness, alcoholism or drug addiction that may hamper or confound compliance or subsequent assessment
10. Human immunodeficiency virus or active hepatitis C virus infection is known
11. Active hepatitis B virus infection (defined as HBsAg+)
Patients who had been allowed to have been vaccinated against hepatitis B (defined as HBsAg-, anti-HBs+, anti-HBc-)
Inactive hepatitis B (HBsAg-, anti-HBs+, anti-HBc+) may be included by the investigator as appropriate after considering the risk of reactivation
12. Symptomatic amyloidosis or plasma cell leukemia
POEMS syndrome
14. Cytotoxic treatments, including cytotoxic study drugs, have been previously administered within 3 weeks prior to randomization (nitrosoureas 6 weeks) for multiple myeloma. The IMiD, PI and/or corticosteroid were used within 2 weeks prior to random grouping. Other investigational therapies and monoclonal antibodies within 4 weeks after randomization. Prednisone oral doses up to but not exceeding 10mg, once daily, or its equivalent for symptomatic management of complications, are permissible, but the doses should remain stable at least 7 days prior to randomization
15. The residual side effects of the prior treatment for the random grouping > grade 1 (allowing any grade of alopecia and/or grade 2 pain-free neuropathy)
16. Peripheral stem cell transplantation was previously accepted within 12 weeks after random grouping
17. Allogeneic stem cell transplantation with active graft versus host disease has been used in the past.
18. Significant surgery or radiation therapy was previously received within 4 weeks after the random grouping
19. Intolerance to steroid therapy is known
Results
Table 2 below summarizes some of the characteristics of the patients included in the study of example 1.
TABLE 2
ASCT, autologous stem cell transplantation; dex, dexamethasone; ECOG, eastern tumor cooperative group; EMD, extramedullary disease; IQR, quartile range; ISS, international staging system; meflofen, melphalan flufenamide; pom, pomalidomide; PS, performance state.
a Defined by fluorescence in situ hybridization as t (4; 14), t (14; 16), t (14; 20), del (17 p), gain (1 q 21) or gain 1q (+1q). b Has refractory property to more than or equal to 1 immunomodulatory drugs, more than or equal to 1 proteasome inhibitor and more than or equal to 1 anti-CD 38 monoclonal antibody. c At least minimal therapeutic response was not achieved or progression was within 60 days after the last treatment.
PFS and OS forest plots showing the risk ratio of the patient group not receiving stem cell transplantation (meflofen + beset Mi Songya group n=121; pomalidomide + beset Mi Songya group n=129) are shown in fig. 1 to 4. The risk ratio is a measure of the relative risk of event occurrence at each time point during the reception of the meflofen therapy and pomalidomide therapy. A value below 1 indicates a better therapeutic effect of meflofen and a value above 1 indicates a better therapeutic effect of pomalidomide.
Fig. 5 shows a graph of PFS (%) over time for patients not receiving stem cell transplantation (meflofen + beset Mi Songya group n=121; pomalidomide + beset Mi Songya group n=129) and patients receiving stem cell transplantation in the past (meflofen + beset Mi Songya group n=125; pomalidomide + beset Mi Songya group n=120). The data in the figures are also presented in simple numerical form below the figures. The top line in the figure shows the results of the meflofen + beset Mi Songya group that did not receive stem cell transplantation. Fig. 6 shows a graph of OS (%) versus time for patients not receiving stem cell transplantation (meflofen + beset Mi Songya group n=121; pomalidomide + beset Mi Songya group n=129). Likewise, the data in the figures are presented below the chart in a simple numerical form. The top line in the figure shows the results of the meflofen + beset Mi Songya group that did not receive stem cell transplantation.
As can be seen from fig. 1 to 6, for patients who have not previously received stem cell transplantation, meflofen + dexamethasone provided significantly better therapeutic effects in PFS and OS than pomalidomide + dexamethasone. Median PFS in the multiple myeloma patients (n=121) that had not received stem cell transplantation therapy and had now received meflofen therapy in the trial was 9.3 months, while median PFS in the multiple myeloma patients (n=129) that had not received stem cell transplantation therapy and had now received pomalidomide therapy was 4.6 months. In addition, the median OS of the patients with multiple myeloma who had not received stem cell transplantation therapy in the past and had now received meflofen therapy (n=121) in the test was 21.6 months, while the median OS of the patients with multiple myeloma who had not received stem cell transplantation therapy in the past and had now received pomalidomide therapy (n=129) was 16.5 months. As shown in fig. 1-4, the better therapeutic effect of meflofen + dexamethasone compared to pomalidomide + dexamethasone was consistently present in the demographic and disease trait subgroups in the subgroup of patients that had not received stem cell transplantation therapy in the past.
Figures 7 and 8 show PFS risk ratio and event table (fig. 7) and OS risk ratio and event table (fig. 8) for patients in example 1 who did not have stem cell transplantation and received either meflofen+dexamethasone (n=121) or pomalidomide+dexamethasone (n=129), or who received meflofen+dexamethasone treatment and received stem cell transplantation less than 2.5 years ago (n=43), 2.5 to 5 years ago (n=48) or more than 5 years ago (n=34), or patients who received pomalidomide+dexamethasone treatment and received stem cell transplantation less than 2.5 years ago (n=35), 2.5 to 5 years ago (n=51) or more than 5 years ago (n=34).
As can be seen from fig. 7 and 8, for patients not receiving stem cell transplantation (PFS risk ratio=0.59; OS risk ratio=0.78) or patients receiving stem cell transplantation at least 5 years ago (PFS risk ratio=0.73; OS risk ratio=0.87), meflofen+dexamethasone provided significantly better therapeutic effects in PFS and OS compared to pomalidomide+dexamethasone. For patients who received stem cell transplantation 2.5 to 5 years ago, meflofen+dexamethasone also provided better therapeutic effect in PFS compared to pomalidomide+dexamethasone (risk ratio=0.83).
In the data shown in fig. 9 and 10, patients who received past stem cell transplantation and then progressed within 36 months were excluded from analysis. That is, these figures represent patients who have not had past stem cell transplantation, or who have had past stem cell transplantation and then developed disease progression after more than 36 months. As can be seen from fig. 9 and 10, for patients not belonging to the group of patients receiving stem cell transplantation and progressing within 36 months, meflofen+dexamethasone provided significantly better therapeutic effect in terms of OS (23.6 months) than pomalidomide+dexamethasone (19.8 months) (risk ratio=0.83).
Finally, the inventors have unexpectedly found that in the test, median PFS in patients with multiple myeloma 75 years old or older and receiving meflofen treatment was 9.4 months, while median PFS in patients with multiple myeloma who did not receive stem cell transplantation as a prior treatment and receiving pomalidomide treatment was 4.6 months. Furthermore, the inventors found that in the experiments, the median total survival (OS) of patients with multiple myeloma 75 years old or older and receiving meflofen treatment was 21.6 months, whereas the median OS of patients with multiple myeloma who did not receive stem cell transplantation as a previous treatment and receiving pomalidomide treatment was 8.3 months. Many patients within this age range who were part of the study of example 1 have not previously received stem cell transplantation. Similarly, many patients within this age range who were part of the study of example 1 received stem cell transplantation before and then developed disease progression beyond 36 months. In both subsets, the improvement effect is very pronounced. Thus, the results of the examples show that meflofen treatment is particularly beneficial for patients 75 years old or older, particularly those of that age group who have not previously received a stem cell transplant, and those of that age group who have previously received a stem cell transplant and who have later developed disease progression for more than 36 months.
Claims (20)
1. Meflofen or a salt thereof for use in the treatment or prevention of multiple myeloma in a patient suffering from multiple myeloma, said patient
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-Not received stem cell transplantation and is 75 years old or older, or at least 5 years ago received stem cell transplantation and is 75 years old or older; or (b)
-Receiving a stem cell transplant and the disease later progresses at least 36 months after the transplant.
2. Meflofen or a salt thereof for use according to claim 1, wherein meflofen is administered in a dose of about 1mg to 150mg (mass excluding any counter ion).
3. Meflofen or a salt thereof for use according to claim 2, wherein meflofen is administered in a dose of 1 to 50mg (mass excluding any counter ions) (e.g. 1, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 mg).
4. A meflofen or a salt thereof for use according to any one of claims 1 to 3, wherein the dose of meflofen is administered on the first day of a cycle of 1 to 42 days (for example 21 to 35 days, in particular 21, 28, 29, 30 or 35 days).
5. Meflofen or a salt thereof for use according to any one of claims 1 to 4, wherein the dose of meflofen (excluding the mass of any salt) is administered as a parenteral dose at an infusion rate of 0.3mg/min to 1.8mg/min (e.g. as a parenteral dose at an infusion rate of 1.1mg/min to 1.8 mg/min).
6. Meflofen or a salt thereof for use according to any one of claims 1 to 5, wherein meflofen or a salt thereof is administered simultaneously, sequentially or separately with one or more other therapeutic agents.
7. Meflofen or a salt thereof for use according to claim 6, wherein the one or more other therapeutic agents are selected from steroids (e.g. prednisone and dexamethasone), imids (e.g. thalidomide, lenalidomide and pomalidomide), PIs (e.g. bortezomib, carfilzomib and Sha Zuo meters), histone Deacetylase (HDAC) inhibitors (e.g. panobinostat), conventional chemotherapy (e.g. melphalan, cyclophosphamide, doxorubicin, bendamustine), anti-CD 38 antibodies (up Lei Tuoyou mab) and anti-SLAMF 7 antibodies (erltuzumab); preferably, the one or more additional therapeutic agents are selected from dexamethasone, up to Lei Tuoyou mab, and bortezomib; or selected from antibodies against B cell maturation antigens (e.g., bei Lan tamab), nuclear export inhibitors (e.g., plug Li Nisuo), and autologous Chimeric Antigen Receptor (CAR) T cell therapies against B cell maturation antigens (e.g., ciltacabtagene), more preferably the other therapeutic agent is dexamethasone.
8. A pharmaceutical formulation comprising meflofen or a salt thereof for use as defined in any one of claims 1 to 7.
9. A method of treating or preventing multiple myeloma comprising the step of administering meflofen or a salt thereof to a patient suffering from multiple myeloma, said patient
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-Not received stem cell transplantation and is 75 years old or older, or at least 5 years ago received stem cell transplantation and is 75 years old or older; or (b)
-Receiving a stem cell transplant and the disease later progresses at least 36 months after the transplant.
10. The method of claim 9, wherein the patient is additionally administered, concurrently, sequentially or separately with meflofen or a salt thereof, one or more other therapeutic agents selected from the group consisting of steroids (e.g., prednisone and dexamethasone), imids (e.g., thalidomide, lenalidomide, and pomalidomide), PI (e.g., bortezomib, carfilzomib, and Sha Zuo meters), histone Deacetylase (HDAC) inhibitors (e.g., panobinostat), conventional chemotherapy (e.g., melphalan, cyclophosphamide, doxorubicin, bendamustine), anti-CD 38 antibodies (up Lei Tuoyou mab), and anti-SLAMF 7 antibodies (erltuzumab); preferably, the one or more additional therapeutic agents are selected from dexamethasone, up to Lei Tuoyou mab, and bortezomib; or selected from antibodies against B cell maturation antigens (e.g., bei Lan tamab), nuclear export inhibitors (e.g., plug Li Nisuo), and autologous Chimeric Antigen Receptor (CAR) T cell therapies against B cell maturation antigens (e.g., ciltacabtagene), more preferably the other therapeutic agent is dexamethasone.
11. The method of claim 9 or 10, wherein the method comprises determining whether the patient received a stem cell transplant and administering meflofen or a salt thereof to the patient if the patient did not receive a stem cell transplant; or (b)
Determining whether the patient received a stem cell transplant at least 5 years ago, and administering meflofen or a salt thereof to the patient if the patient received a stem cell transplant at least 5 years ago; and/or
Determining whether the patient is 75 years old or older, and if the patient is 75 years old or older, administering meflofen or a salt thereof to the patient; and/or
Determining whether the patient received a stem cell transplant and the disease progressed at least 36 months after the transplant, and administering to the patient meflofen or a salt thereof if the patient received a stem cell transplant and the disease progressed at least 36 months after the transplant.
12. The method of claim 9, 10 or 11, wherein the method comprises determining whether the patient is suitable for stem cell transplantation and administering meflofen or a salt thereof to the patient if the patient is not suitable for stem cell transplantation.
13. Use of meflofen or a salt thereof in the manufacture of a medicament for the treatment of multiple myeloma in a patient suffering from multiple myeloma, said patient
-No stem cell transplantation has been received; or (b)
-Receiving stem cell transplantation at least 5 years ago; or (b)
-75 Years old or older; or (b)
-Not received stem cell transplantation and is 75 years old or older, or at least 5 years ago received stem cell transplantation and is 75 years old or older; or (b)
-Receiving a stem cell transplant and the disease later progresses at least 36 months after the transplant.
14. A kit comprising meflofen and one or more other therapeutic agents selected from the group consisting of steroids (e.g. prednisone and dexamethasone), imids (e.g. thalidomide, lenalidomide and pomalidomide), PI (e.g. bortezomib, carfilzomib and Sha Zuo meters), histone Deacetylase (HDAC) inhibitors (e.g. panobinostat), conventional chemotherapy (e.g. melphalan, cyclophosphamide, doxorubicin, bendamustine), anti-CD 38 antibodies (dar Lei Tuoyou mab) and anti-SLAMF 7 antibodies (erltuzumab), as defined in claim 1 for treating or preventing multiple myeloma in a patient; or selected from the group consisting of an antibody to B cell maturation antigen (Bei Lan tamab), a nuclear export inhibitor (plug Li Nisuo), and an autologous Chimeric Antigen Receptor (CAR) T cell therapy to B cell maturation antigen (ciltacabtagene); preferably, the one or more additional therapeutic agents are selected from dexamethasone, up to Lei Tuoyou mab, and bortezomib; more preferably, the additional therapeutic agent is dexamethasone.
15. Meflofen or a salt thereof for use according to any one of claims 1 to 7, the pharmaceutical formulation of claim 8, the method of claims 9 to 12, the use of claim 13, or the kit of claim 14, wherein the patient with multiple myeloma:
receiving at least 2 prior multiple myeloma treatment lines, e.g., at least 2 prior treatment lines comprising lenalidomide and a protease inhibitor, either sequentially or as part of a combination treatment regimen; and/or
Refractory (e.g., recurrent and refractory, or refractory) to the last line of treatment and/or lenalidomide administered within 18 months prior to treatment; and/or
Refractory (e.g., recurrent and refractory, or refractory) to at least one alkylating agent; and/or
Refractory (e.g., recurrent and refractory, or refractory) to at least one anti-CD 38 antibody; and/or
Refractory (e.g., recurrent and refractory, or refractory) to at least one immunomodulatory drug (IMiD); and/or
Lenalidomide is refractory (e.g., refractory or relapsed refractory), and in particular, is refractory (e.g., refractory or relapsed refractory) to lenalidomide in which lenalidomide is the last multiple myeloma treatment that the patient receives; and/or
Refractory to one or more (e.g., 1,2, 3, 4, or 5 or more) drugs selected from two or more classes of Protease Inhibitors (PI), immunomodulatory drugs (IMiD), alkylating agents, and anti-CD 38 antibodies; and/or
Refractory (e.g., refractory or relapsed refractory) to at least lenalidomide and 1,2,3, or 4 other drugs (e.g., at least one drug selected from the group consisting of Protease Inhibitors (PI), immunomodulatory drugs (imids), alkylating agents, and anti-CD 38 antibodies) (or e.g., 2,3, or 4 other drugs, including at least one Protease Inhibitor (PI) and immunomodulatory drugs (imids)); and/or
At least refractory (e.g., refractory or relapsed refractory) to pomalidomide and/or up to Lei Tuoyou mab; and/or
With RRMM.
16. The meflofen or a salt thereof for use according to any one of claims 1 to 7 or 15, the pharmaceutical formulation of claim 8 or 15, the method of claim 9 to 12 or 15, the use of claim 13 or 15, or the kit of claim 14 or 15, wherein the patient with multiple myeloma:
at least 65, 70, 75, or 80 years old; and/or
Suffering from cardiovascular disease; and/or
Has lung disease.
17. The meflofen or a salt thereof for use according to any one of claims 1 to 7 or 15 to 16, the pharmaceutical formulation of claims 8 or 15 to 16, the method of claims 9 to 12 or 15 to 16, the use of claims 13 or 15 to 16, or the kit of claims 14 to 16, wherein the multiple myeloma patient is not suitable for stem cell transplantation.
18. The meflofen or a salt thereof for use according to any one of claims 1 to 7 or 15 to 17, the pharmaceutical formulation of claim 8 or 15 to 17, the method of claim 9 to 12 or 15 to 17, the use of claim 13 or 15 to 17, or the kit of claim 14 to 17, wherein the patient with multiple myeloma:
The surface area (BSA) of the middle position is less than or equal to 1.855m 2; and/or
ISS groups with multiple myeloma, revised multiple myeloma International System for staging (R-ISS), are I or II; and/or
In view of the cytogenetics of patients, are high risk patients; and/or
Renal function is impaired (e.g., creatine clearance is less than 60 milliliters per minute (mL/min), or 60 to 90mL/min; and in particular creatine clearance is less than 60 mL/min).
19. The meflofen or a salt thereof for use according to any one of claims 1 to 7 or 15 to 18, the pharmaceutical formulation of claim 8 or 15 to 18, the method of claim 9 to 12 or 15 to 18, the use of claim 13 or 15 to 18, or the kit of claim 14 to 18, wherein the patient with multiple myeloma:
RRMM; and/or (preferably and)
Refractory to lenalidomide (e.g., refractory to lenalidomide administered within 18 months prior to treatment (e.g.,. Gtoreq.10 mg); and/or (preferably and)
At least 2 past treatment lines (e.g., 2, 3, or 4 past treatment lines) are received.
20. The meflofen or a salt thereof for use according to any one of claims 1 to 7 or 15 to 19, the pharmaceutical formulation of claims 8 or 15 to 19, the method of claims 9 to 12 or 15 to 19, the use of claims 13 or 15 to 19, or the kit of claims 14 to 19, wherein the multiple myeloma patient has not received a stem cell transplant.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2109894.2 | 2021-07-08 | ||
| GBGB2112976.2A GB202112976D0 (en) | 2021-09-10 | 2021-09-10 | Novel treatments |
| GB2112976.2 | 2021-09-10 | ||
| PCT/EP2022/068974 WO2023281007A1 (en) | 2021-07-08 | 2022-07-07 | Melflufen for use in the treatment of multiple myeloma |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117940119A true CN117940119A (en) | 2024-04-26 |
Family
ID=78149217
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202280058782.7A Pending CN117940119A (en) | 2021-07-08 | 2022-07-07 | Meflofen for the treatment of multiple myeloma |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN117940119A (en) |
| GB (1) | GB202112976D0 (en) |
-
2021
- 2021-09-10 GB GBGB2112976.2A patent/GB202112976D0/en not_active Ceased
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2022
- 2022-07-07 CN CN202280058782.7A patent/CN117940119A/en active Pending
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| GB202112976D0 (en) | 2021-10-27 |
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