Melflufen for use in the treatment of multiple myeloma

Abstract

The present invention relates to a particularly advantageous and novel therapeutic use of melflufen (melphalan flufenamide, L-melphalanyl-4-fluoro-L-phenylalanine ethyl ester) or its salt in the prevention or treatment of multiple myeloma in multiple myeloma patients who have not undergone stem cell transplantation, have undergone stem cell transplantation at least 5 years ago, are 75 years old or older, have not undergone stem cell transplantation, or have undergone stem cell transplantation at least 5 years ago, or have undergone stem cell transplantation and have progressed disease at least 36 months after said transplantation.It has been surprisingly found that melflufen, especially melflufen in combination with dexamethasone, is effective in the prevention or treatment of multiple myeloma in these patients.More specifically, it has been found that in these patient populations, melflufen shows superior antineoplastic activity compared to other treatments for multiple myeloma.

Description

[Technical field]

[0001] The present invention relates to - Not having undergone a stem cell transplant, - Have had a stem cell transplant at least 5 years ago, - Age 75 or older, - Age 75 years or older who have not had a stem cell transplant or who have had a stem cell transplant at least 5 years prior; - Received a stem cell transplant and had disease progression at least 36 months after transplant, A particularly advantageous and novel therapeutic use of melflufen (melphalan flufenamide, L-melphalanyl-4-fluoro-L-phenylalanine ethyl ester) or a salt thereof for use in the prevention or treatment of multiple myeloma in patients with multiple myeloma. [Background technology]

[0002] Multiple myeloma (MM) is a malignant cancer of differentiated plasma cells. It is characterized by clonal proliferation of plasma cells in the bone marrow and production of excessive amounts of monoclonal immunoglobulins, usually of IgG or IgA type or urinary free light chains [paraproteins, M-proteins, or M-components]. Relapsed refractory multiple myeloma (RRMM) is a specific subtype of multiple myeloma that can be defined as multiple myeloma that responds initially to treatment but does not respond to treatment after relapse.

[0003] MM is the second most common hematopoietic malignancy, with approximately 24,000 myeloma patients diagnosed annually in the United States. Patients with MM can experience a significant decrease in quality of life, including bone pain, fractures, fatigue, anemia, infections, hypercalcemia, hyperviscosity, and renal function problems (including renal failure). The disease process of MM varies depending on the stage of disease at diagnosis, the cytogenetic profile, age, and comorbidities of the patient. The disease is ultimately fatal, with a median survival of approximately 3-5 years, and an estimated 5-year survival rate of 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 survive for more than 10 years.

[0004] In many countries, the standard treatment for patients with multiple myeloma is autologous stem cell rescue (after induction therapy) combined with high-dose chemotherapy (HDT). Autologous stem cell rescue is often also called autologous stem cell transplantation (ASCT). Autologous stem cell transplantation can result in deep, long-term, and significant remissions and prolong survival.

[0005] Patients who cannot undergo autologous stem cell transplant have limited options. Phase III randomized trial results, especially in the relapsed / refractory setting, may not necessarily be applicable to the transplant-ineligible population, necessitating extrapolation of data obtained from primarily younger / transplant-eligible populations, where disease biology and toxicity profiles may differ. A 2021 review of treatment options for transplant-ineligible multiple myeloma patients (Elnair and Holstein, Oncology, Vol 35, Issue 4,Pages: 170-182) concludes that the optimal solution for these patients is clinical trial participation and consultation with MM specialists and geriatric oncologists. In other words, there are no approved treatments that are proven to be beneficial for this patient population.

[0006] A Cochrane review published in 2019 ("Multiple drug 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, Issue 11. Art. No.: CD013487. DOI: 10.1002 / 14651858.CD013487.) concluded that VRDc (continuous therapy with bortezomib, lenalidomide, and dexamethasone) provided the longest survival compared with MP (melphalan and prednisone). RD (lenalidomide and dexamethasone) and TMP (thalidomide, melphalan, and prednisone) also improved overall survival compared with MP. However, these drug combinations also resulted in more adverse events than MP, leading many to stop treatment, the authors conclude. More trials that closely monitor both adverse events and quality of life are therefore needed.

[0007] Melflufen (also known as melphalan flufenamide and L-melphalanyl-4-fluoro-L-phenylalanine ethyl ester) is an antitumor agent useful in the treatment of multiple myeloma. Melflufen is described in WO 01 / 96367 and WO 2014 / 065751. The structure of the hydrochloride salt of melflufen is shown below.

[0008] [ka]

[0009] Melflufen is a potent and highly lipophilic alkylating agent that achieves targeted delivery of alkylated metabolites to tumor cells. Due to its high lipophilicity, melflufen rapidly enters tumor cells, where it is immediately cleaved by peptidases, resulting in the containment and concentration of the alkylated payload (Stiller CA, et al. Cancer Epidemiol. 2018;56:146-153). Overexpression of peptidases is often found in tumor cells, which may account for their high sensitivity to melflufen (Stiller CA, et al. Cancer Epidemiol. 2018;56:146-153). Esterases may also play a role in this observed effect. Results from studies of melflufen in human patients with MM have been published, demonstrating clinically meaningful efficacy and a manageable safety profile in heavily pretreated patients with RRMM, including those with triple-refractory and extramedullary disease (Richardson, PG, et al, Journal of Clinical Oncology 2021 39:7, 757-767). The efficacy of melflufen in patients not suitable for transplant has not been studied or reported.

[0010] Thus, although recent improvements in the treatment of MM have significantly extended the survival of patients suitable for autologous stem cell transplantation, the outcomes of the same treatment in patients who cannot receive autologous stem cell transplantation, especially in relapsed or refractory patients, are highly uncertain and significantly less desirable. Thus, there remains a strong need for additional treatment options in MM patients who cannot receive autologous stem cell transplantation. There also remains a strong need for additional treatment options in MM patients who have previously received an autologous stem cell transplantation (e.g., at least in the past 5 years) but are not suitable for another autologous stem cell transplantation, especially in relapsed or refractory patients. Summary of the Invention

[0011] The present invention relates to - Not having had a stem cell transplant, - Have had a stem cell transplant at least 5 years ago, - 75 years of age or older; - Age 75 or older who have not had a stem cell transplant or who have had a stem cell transplant at least 5 years ago; or - Received a stem cell transplant and had disease progression at least 36 months after transplant, The present invention provides melflufen or a salt thereof for use in the prevention or treatment of multiple myeloma in a multiple myeloma patient.

[0012] The present invention provides a method for preventing or treating multiple myeloma, comprising: - Not having had a stem cell transplant, - Have had a stem cell transplant at least 5 years ago, - 75 years of age or older; - Age 75 or older who have not had a stem cell transplant or who have had a stem cell transplant at least 5 years ago; or - Received a stem cell transplant and had disease progression at least 36 months after transplant, Further provided is a method comprising the step of administering melflufen or a salt thereof to a patient with multiple myeloma.

[0013] The present invention relates to - Not having had a stem cell transplant, - Have had a stem cell transplant at least 5 years ago, - 75 years of age or older; - Age 75 or older who have not had a stem cell transplant or who have had a stem cell transplant at least 5 years ago; or - Received a stem cell transplant and had disease progression at least 36 months after transplant, There is further provided a pharmaceutical formulation comprising melflufen or a salt thereof for use in the treatment and / or prevention of multiple myeloma in a multiple myeloma patient.

[0014] The present invention also provides - Not having had a stem cell transplant, - Have had a stem cell transplant at least 5 years ago, - 75 years of age or older; - Age 75 or older who have not had a stem cell transplant or who have had a stem cell transplant at least 5 years ago; or - Received a stem cell transplant and had disease progression at least 36 months after transplant, There is provided the use of melflufen or a salt thereof in the manufacture of a medicament for the treatment of multiple myeloma in a multiple myeloma patient.

[0015] The present invention also provides the use of melflufen or a salt thereof in the manufacture of a medicament for the treatment and / or prevention of multiple myeloma in multiple myeloma patients who have not undergone stem cell transplantation or who have undergone stem cell transplantation at least 5 years prior.The present invention also provides the use of melflufen or a salt thereof in the manufacture of a medicament for the treatment and / or prevention of multiple myeloma in multiple myeloma patients aged 75 years or older (who have not undergone stem cell transplantation or who have undergone stem cell transplantation at least 5 years prior).

[0016] The present invention also provides - Not having had a stem cell transplant, - Have had a stem cell transplant at least 5 years ago, - 75 years of age or older; - Age 75 or older who have not had a stem cell transplant or who have had a stem cell transplant at least 5 years ago; or - Received a stem cell transplant and had disease progression at least 36 months after transplant, A kit is provided comprising melflufen and one or more additional therapeutic agents (e.g., selected from dexamethasone, bortezomib, and daratumumab, preferably dexamethasone) for use in the treatment and / or prevention of multiple myeloma in a multiple myeloma patient.

[0017] The present invention relates to - Not having had a stem cell transplant, - Have had a stem cell transplant at least 5 years ago, - 75 years of age or older; - 75 years of age or older who have not had a stem cell transplant or 75 years of age or older who have had a stem cell transplant at least 5 years prior; - Received a stem cell transplant and had disease progression at least 36 months after transplant, Provided is melflufen or a salt thereof and dexamethasone for use in the treatment and / or prevention of multiple myeloma in a multiple myeloma patient.

[0018] The present invention also provides a method for preventing or treating multiple myeloma, comprising the step of administering melflufen or a salt thereof and dexamethasone to a multiple myeloma patient who has not undergone stem cell transplantation, who has undergone stem cell transplantation at least 5 years ago, and / or who is 75 years old or older, and / or who has undergone stem cell transplantation and the disease has progressed at least 36 months after transplantation. The present invention also provides a pharmaceutical preparation comprising melflufen or a salt thereof and dexamethasone for use in the treatment and / or prevention of multiple myeloma in a multiple myeloma patient who has not undergone stem cell transplantation, who has undergone stem cell transplantation at least 5 years ago, and / or who is 75 years old or older, and / or who has undergone stem cell transplantation and the disease has progressed at least 36 months after transplantation. The present invention also provides the use of melflufen or a salt thereof and dexamethasone in the manufacture of a medicament for the treatment and / or prevention of multiple myeloma in a multiple myeloma patient who has not undergone stem cell transplantation, who has undergone stem cell transplantation at least 5 years ago, and / or who is 75 years old or older, and / or who has undergone stem cell transplantation and the disease has progressed at least 36 months after transplantation.

[0019] The present invention relates to - Not having had a stem cell transplant, - Have had a stem cell transplant at least 5 years ago, - 75 years of age or older; - Age 75 or older who have not had a stem cell transplant or who have had a stem cell transplant at least 5 years prior It is particularly applicable in patients with multiple myeloma.

[0020] In certain embodiments, the patient is a multiple myeloma patient who has not undergone a stem cell transplant. [Brief description of the drawings]

[0021] [Figure 1] FIG. 1 shows a forest plot of unstratified hazard ratios for progression-free survival (PFS) by demographic group of patients in Example 1 who did not undergo stem cell transplantation and were treated with melflufen + dexamethasone (n=121) or pomalidomide + dexamethasone (n=129). [Diagram 2] Figure 2 shows a forest plot of unstratified hazard ratios for PFS by disease characteristic group for patients in Example 1 who were treated with melflufen + dexamethasone (n = 121) or pomalidomide + dexamethasone (n = 129) without stem cell transplantation (median BSA = 1.855 m2). The PFS numbers in the last row in Figure 1 also relate to disease characteristics. [Diagram 3] FIG. 3 shows a forest plot of unstratified hazard ratios for overall survival (OS) by demographic group of patients in Example 1 who did not undergo stem cell transplantation and were treated with melflufen + dexamethasone (n=121) or pomalidomide + dexamethasone (n=129). [Figure 4] Figure 4 shows a forest plot of unstratified hazard ratios for OS by disease characteristic group for patients in Example 1 treated with melflufen + dexamethasone (n = 121) or pomalidomide + dexamethasone (n = 129) who did not undergo stem cell transplantation (median BSA = 1.855 m2). The OS numbers in the last row in Figure 3 also relate to disease characteristics. [Diagram 5] FIG. 5 shows a graph of PFS (%) over time for patients in Example 1 who had not undergone stem cell transplantation and were treated with melflufen + dexamethasone (n=121) or pomalidomide + dexamethasone (n=129), or who had undergone stem cell transplantation and were treated with melflufen + dexamethasone (n=125) or pomalidomide + dexamethasone (n=120) (a shows unstratified HR; b shows log-rank P-value). [Figure 6]FIG. 6 shows a graph of OS (%) over time for patients in Example 1 treated with melflufen + dexamethasone (n=121) or pomalidomide + dexamethasone (n=129) who did not undergo stem cell transplantation (a shows unstratified HR; b shows log-rank P-value). [Figure 7] Figure 7 shows a table of PFS hazard ratios and events for patients in Example 1 who have not undergone stem cell transplantation and have been treated with melflufen + dexamethasone (n=121) or pomalidomide + dexamethasone (n=129). It also shows PFS hazard ratios and events for patients in Example 1 who have undergone stem cell transplantation within 2.5 years (n=43), 2.5-5 years (n=48), or more than 5 years (n=34) and have been treated with pomalidomide + dexamethasone and have undergone stem cell transplantation within 2.5 years (n=35), 2.5-5 years (n=51), or more than 5 years (n=34) (a shows unstratified HR; b shows log-rank P value). [Figure 8] Figure 8 shows a table of OS hazard ratios and events for patients in Example 1 who have not undergone stem cell transplantation and who have been treated with melflufen + dexamethasone (n=121) or pomalidomide + dexamethasone (n=129). It also shows OS hazard ratios and events for patients in Example 1 who have undergone stem cell transplantation within 2.5 years (n=43), 2.5-5 years (n=48), or more than 5 years (n=34) and who have been treated with pomalidomide + dexamethasone within 2.5 years (n=35), 2.5-5 years (n=51), or more than 5 years (n=34) (a shows unstratified HR; b shows log-rank P value). [Figure 9] FIG. 9 shows a forest plot of unstratified hazard ratios for overall survival (OS) by patient demographic and disease characteristics in Example 1 treated with melflufen + dexamethasone (n=145) or pomalidomide + dexamethasone (n=148), excluding patients who had undergone stem cell transplant but progressed within 36 months. [Figure 10]FIG. 10 shows a graph of OS (%) over time for patients in Example 1 treated with melflufen + dexamethasone (n=145) and pomalidomide + dexamethasone (n=148), excluding patients who had undergone stem cell transplant but progressed within 36 months (HR is hazard ratio; a shows unstratified HR; b shows log-rank P value). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Detailed Description The inventors have found that melflufen, particularly melflufen combined with dexamethasone, is surprisingly effective in preventing or treating multiple myeloma in multiple myeloma patients who have not undergone stem cell transplantation or who have undergone stem cell transplantation at least 5 years ago.Furthermore, it has been found that melflufen, particularly melflufen combined with dexamethasone, is surprisingly effective in preventing or treating multiple myeloma in patients aged 75 years or older, particularly patients aged 75 years or older who have not undergone stem cell transplantation and patients aged 75 years or older who have undergone stem cell transplantation at least 5 years ago.It has also been found that melflufen, particularly melflufen combined with dexamethasone, is surprisingly effective in preventing or treating multiple myeloma in patients who have undergone stem cell transplantation and whose disease has progressed at least 36 months after transplantation.

[0023] More specifically, melflufen has been found to exhibit superior antineoplastic activity compared to other treatments for multiple myeloma in these patient populations, and in particular compared to treatment of multiple myeloma with pomalidomide in these patient populations. For example, the inventors conducted a randomized, controlled, open-label, multicenter Phase III study in patients with relapsed multiple myeloma after 2-4 prior lines of therapy who were refractory to lenalidomide in their most recent line of therapy as indicated by disease progression within 60 days of the last dose of lenalidomide, in which patients were administered melflufen and dexamethasone, or pomalidomide and dexamethasone, as described in Example 1. Surprisingly, this study found that the median progression-free survival (PFS) of multiple myeloma patients who had not undergone a prior stem cell transplant and were treated with melflufen was 9.3 months, while the median PFS of multiple myeloma patients who had not undergone a prior stem cell transplant and were treated with pomalidomide was 4.6 months. In addition, this study also found that the median overall survival (OS) of multiple myeloma patients who had not undergone a prior stem cell transplant and were treated with melflufen was 21.6 months, while the median OS of multiple myeloma patients who had not undergone a prior stem cell transplant and were treated with pomalidomide was 16.5 months.

[0024] This significant improvement exists across demographic and disease groups. For example, this is present in patients younger than 65 years (PFS in the melflufen group: 10.8, PFS in the pomalidomide group: 4.7, OS in the melflufen group: 27.5, OS in the pomalidomide group: NA), patients aged 64 to 74 years (PFS in the melflufen group: 9.3, PFS in the pomalidomide group: 3.9, OS in the melflufen group: 22.2, OS in the pomalidomide group: 15.0), patients younger than 75 years (PFS in the melflufen group: 9.4, PFS in the pomalidomide group: 4.3, OS in the melflufen group: 22.2, OS in the pomalidomide group: 18.2), and patients aged 75 years or older (PFS in the melflufen group: 9.3, PFS in the pomalidomide group: 4.9, OS in the melflufen group: 14.8, OS in the pomalidomide group: 8.1).

[0025] Furthermore, Example 1 confirms that patients who have not previously undergone stem cell transplantation, or who have previously undergone stem cell transplantation and subsequently progressed after only 36 months or more after transplantation, had a better response rate to melflufen (and dexamethasone) compared to other treatments for multiple myeloma in these patient populations, particularly compared to treatment with pomalidomide (and dexamethasone). The inventors found that, excluding patients who had previously undergone stem cell transplantation and progressed within 36 months, the median overall survival (OS) of multiple myeloma patients in this study when treated with melflufen was 23.6 months, and the median OS of patients who received pomalidomide was 19.8 months. The same findings are confirmed in Figure 10.

[0026] The use of melflufen to treat multiple myeloma in multiple myeloma patients who have not undergone stem cell transplantation is particularly surprising because, to the inventors' knowledge, there are no known multiple myeloma treatments that show particularly beneficial effects in this patient population.Similarly, to the inventors' knowledge, there are no known multiple myeloma treatments that show particularly beneficial effects in patients who have undergone stem cell transplantation and whose disease has progressed at least 36 months after transplantation.As mentioned above, there remains a strong need for additional treatment options in multiple myeloma patients who cannot undergo stem cell transplantation.The results reported in Example 1 of this application show a highly significant improvement in median PFS and OS for multiple myeloma patient populations who have not undergone stem cell transplantation.Since multiple myeloma remains incurable and fatal, these surprising results provide patients in this patient population with a novel treatment that can provide valuable months of time compared to alternative treatment options.

[0027] Moreover, because there are multiple reasons why patients are not able to undergo stem cell transplantation, the consistent beneficial effect within this patient population and across multiple demographic and disease groups within this patient population is even more surprising. The efficacy of this treatment persists in multiple myeloma populations not undergoing stem cell transplantation, as can be seen in Figures 1-4, which show unstratified hazard ratios for PFS and OS by demographic (Figures 1 and 3, respectively) and disease characteristic (Figures 2 and 4, respectively) groups.

[0028] In the results of Example 1, the hazard ratio is a measure of the relative risk of an event at each time point during follow-up when melflufen is administered compared to pomalidomide. A value below 1 indicates a favorable therapeutic effect for melflufen, and a value above 1 indicates a favorable therapeutic effect for pomalidomide. In the study of Example 1, it was surprisingly found that multiple myeloma patients who had undergone stem cell transplantation at least 5 years ago in this study had a PFS hazard ratio of 0.76 in favor of melflufen compared to pomalidomide treatment, and an OS hazard ratio of 0.87 in favor of melflufen compared to pomalidomide treatment. In addition, multiple myeloma patients who had undergone stem cell transplantation 2.5 years to 5 years ago in this study had a hazard ratio of 0.83 in favor of melflufen compared to pomalidomide treatment. Therefore, these results show that melflufen is particularly useful for treating multiple myeloma patients who have undergone stem cell transplantation at least 2.5 years ago, particularly at least 5 years ago.It is also confirmed that melflufen is particularly useful for treating multiple myeloma patients who have undergone stem cell transplantation and have not progressed to at least 36 months after transplantation.

[0029] The use of melflufen to treat multiple myeloma in multiple myeloma patients who have undergone stem cell transplantation at least 2.5 years ago, particularly at least 5 years ago, is particularly surprising because, to the inventors' knowledge, there are no known multiple myeloma treatments that show particularly beneficial effects in these patient populations.As mentioned above, there remains a strong need for additional treatment options in multiple myeloma patients who have undergone stem cell transplantation before but cannot undergo stem cell transplantation again, and these results provide patients in this patient population with a new treatment that can provide valuable months of time compared to alternative treatment options.Similarly, for patients who have undergone stem cell transplantation and whose disease has progressed at least 36 months after transplantation, these results provide patients in this patient population with a new treatment that can provide valuable months of time compared to alternative treatment options.

[0030] Finally, it was surprisingly found that melflufen treatment had a particularly beneficial effect in patients aged 75 years or older, both in terms of PFS and OS.

[0031] For example, the median PFS for multiple myeloma patients aged 75 years or older who received melflufen in this study was 9.4 months, while the median PFS for multiple myeloma patients who had not previously undergone stem cell transplantation who received pomalidomide was 4.6 months. Additionally, the study found that the median overall survival (OS) for multiple myeloma patients aged 75 years or older who received melflufen was 21.6 months, while the median OS for multiple myeloma patients who had not previously undergone stem cell transplantation who received pomalidomide was 8.3 months.

[0032] Melflufen and its salts Melflufen (also known as melphalan flufenamide and L-melphalanyl-4-fluoro-L-phenylalanine ethyl ester) is an antitumor agent useful in the treatment of cancer, particularly in the treatment of multiple myeloma.Melflufen and its salts, particularly its hydrochloride, are known from WO 01 / 96367 and WO 2014 / 065751, the contents of which are incorporated herein by reference.The structure of melflufen hydrochloride is shown below.

[0033] [ka]

[0034] For the avoidance of doubt, when the term "melflufen" is used in this document, this includes, unless otherwise indicated, salts of melflufen as well as isotopic derivatives of melflufen. Isotopic derivatives of melflufen are described in WO 2020 / 079165, the contents of which are incorporated herein by reference.

[0035] Also for the avoidance of doubt, when referred to in this document, the mass of melflufen is the mass of the melflufen molecule excluding the mass of the counterion, unless expressly indicated otherwise.

[0036] The salts of melflufen suitable for use in the present invention are those whose counter ions are pharma- ceutically acceptable. Suitable salts include those formed with organic or inorganic acids. In particular, suitable salts formed with acids according to the present invention include those formed with mineral acids, strong organic carboxylic acids, such as alkane carboxylic acids of 1-4 carbon atoms, unsubstituted or substituted, for example, with halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or organic sulfonic acids, such as (C1-C4) alkyl or aryl sulfonic acids, unsubstituted or substituted, for example, with halogen. 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, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine, and arginine.

[0037] Preferred salts of melflufen include acid addition salts, such as those formed with hydrochloric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid, tartaric acid, sulfuric acid, succinic acid, phosphoric acid, oxalic acid, nitric acid, methanesulfonic acid, malic acid, maleic acid and citric acid. More preferably, the salt of melflufen for use according to the invention is the hydrochloride salt (i.e., an addition salt formed with hydrochloric acid).

[0038] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents with which the compound reacts or from which the compound precipitates or crystallizes. These complexes are known as "solvates". For example, complexes with water are known as "hydrates". Complexes can incorporate the solvent in stoichiometric or non-stoichiometric amounts. Solvates are described in Water-Insoluble Drug Formulation, 2nd ed R. Lui CRC Press, page 553 and Byrn et al Pharm Res 12(7), 1995, 945-954. Melflufen or a salt thereof for use in the present invention may be in the form of a solvate prior to going into solution. Solvates of melflufen suitable for use in the present invention are those in which the associated solvent is pharma- ceutically acceptable. For example, hydrates are pharma- ceutically acceptable solvates.

[0039] formulation Although it is possible to administer melflufen and its salts alone, it is preferred that it is present in a formulation, particularly a pharmaceutical formulation.The pharmaceutical formulation includes those suitable for oral, parenteral (including subcutaneous, intradermal, intraosseous injection, intramuscular, intravascular (bolus or injection), and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and local (including dermal, buccal, sublingual, and intraocular) administration, and the most suitable route may depend, for example, on the condition and disorder of the subject being treated.

[0040] In one embodiment of the invention, melflufen is administered in a pharmaceutical formulation suitable for oral or parenteral (including subcutaneous, intradermal, intraosseous injection, intramuscular, intravascular (bolus or infusion), and intramedullary) administration.

[0041] The pharmaceutical formulation of melflufen suitable for oral administration may be presented as discrete dosage units, such as capsules, cachets, or tablets, each containing a predetermined amount of active ingredient; as 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.Melflufen may also be presented as a bolus, a drench, or a paste.Various pharmaceutical acceptable carriers and their formulations are described in standard formulation treatises, such as Remington's Pharmaceutical Sciences by EW Martin. See also Wang, YJ and Hanson, MA, Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42:2S, 1988.

[0042] Preparations for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that render the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents.Preferably, the preparations may be presented in unit-dose or divided-dose containers, such as sealed ampoules and vials.The preparations may be stored in a freeze-dried (lyophilized) state, 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 preparations may also be stored as liquid pharmaceutical preparations, requiring only the addition of a sterile liquid carrier, such as saline, a physiologically acceptable solution, or water for injection, immediately prior to use.

[0043] Extemporaneous injection and infusion solutions and suspensions may be prepared from sterile powders, granules, or other dry compositions.Typical compositions for parenteral administration include, for example, injectable solutions or suspensions, which may contain a suitable non-toxic parenterally acceptable diluent or solvent, 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, fatty acids including oleic acid, or Cremaphor.

[0044] In a preferred embodiment of the present invention, the melflufen for use in the present invention comprises a lyophilized pharmaceutical preparation of melflufen or a salt thereof. The term "lyophilized pharmaceutical preparation of melflufen or a salt thereof" is understood to mean that melflufen or a salt thereof is freeze-dried ("lyophilized", "lyophilized" and the like may be used interchangeably with "freeze-dried", "freeze-dried" and the like in this context). The lyophilized pharmaceutical preparation of melflufen or a salt thereof described in this specification may be a white fluffy powder, in contrast to non-lyophilized melflufen or a pharma- ceutical acceptable salt thereof, which is usually a dense, slightly yellowish powder.

[0045] The lyophilized pharmaceutical preparation of melflufen or its salt for use in the present invention may contain sucrose. The inclusion of sucrose results in a lyophilized preparation that is stable by itself and dissolves in water at a sufficient rate compared to the decomposition rate without the presence of organic solvents, thereby being useful in therapy and not having the toxicity caused by organic solvents. Due to the increase in the solubility and / or dissolution rate of melflufen or its salt after lyophilization in the presence of sucrose, it is possible to prepare a solution of dissolved melflufen or its salt, for example a pharmaceutical composition containing melflufen or its salt that has a usefully high concentration of melflufen and is substantially free of organic solvents. The preparation of lyophilized pharmaceutical preparations of melflufen or its salt, lyophilized pharmaceutical compositions, and kits for making such compositions are described in detail in WO 2012 / 146625 and WO 2014 / 065751, the contents of which are incorporated herein by reference.

[0046] The pharmaceutical formulation of melflufen or a salt thereof for use in the present invention may include a lyophilized pharmaceutical preparation containing melflufen or a salt thereof. Preferably, the formulation contains sucrose. More preferably, the formulation contains sucrose at a weight ratio (w / w) between melflufen and sucrose of about 1:25 to 1:75, for example, 1:50.

[0047] When the formulation is a pharmaceutical solution, it may be prepared from a lyophilized pharmaceutical preparation containing melflufen or a salt thereof and may further contain a physiologically acceptable solvent, such as a glucose solution and / or saline.

[0048] In another preferred embodiment of the present invention, the melflufen for use in the present invention comprises a liquid pharmaceutical preparation of melflufen or a salt thereof. Preferably, the liquid pharmaceutical preparation consists essentially of the following components: i) melflufen or a salt thereof; ii) propylene glycol; iii) optionally, one or more physiologically acceptable aqueous solvents; and iv) optionally, one or more additional therapeutic agents; or the liquid pharmaceutical preparation consists essentially of the following components: i) melflufen or a salt thereof; ii) polyethylene glycol; iii) optionally, one or more physiologically acceptable aqueous solvents; and iv) optionally, one or more additional therapeutic agents. The preparation of the liquid pharmaceutical formulation of melflufen or a salt thereof, the liquid pharmaceutical formulation, and the kit for making such a liquid pharmaceutical formulation are described in detail in WO 2020 / 212594, the contents of which are incorporated herein by reference.

[0049] It will be understood that in addition to the ingredients particularly mentioned above, formulations for use in the present invention may include other agents conventional in the art having relevance to the formulation type in question.

[0050] Medication Regimen Melflufen or its salts, and pharmaceutical formulations containing melflufen, find use in the treatment and / or prevention of multiple myeloma in multiple myeloma patients who have not undergone stem cell transplantation.

[0051] Melflufen or its salts, and pharmaceutical formulations containing melflufen, also find use in the treatment and / or prevention of multiple myeloma in multiple myeloma patients who have undergone a stem cell transplant at least 5 years prior.

[0052] Melflufen or its salts, and pharmaceutical formulations containing melflufen also find use in the treatment and / or prevention of multiple myeloma in multiple myeloma patients aged 75 years or older who have not undergone a stem cell transplant or who have undergone a stem cell transplant at least 5 years prior.

[0053] Melflufen or its salts, and pharmaceutical formulations containing melflufen also find use in the treatment and / or prevention of multiple myeloma in multiple myeloma patients who have undergone stem cell transplantation and have experienced disease progression at least 36 months after transplantation.

[0054] For the avoidance of doubt, when a patient is defined herein as a multiple myeloma patient who "has not had a stem cell transplant or has had a stem cell transplant at least 5 years ago and / or is 75 years of age or older," or similar language, the patient may be: (i) who has not had a stem cell transplant; (ii) who has had a stem cell transplant at least 5 years ago; (iii) who is 75 years of age or older; (iv) who is 75 years of age or older and has not had a stem cell transplant; or (v) who is 75 years of age or older and has had a stem cell transplant at least 5 years ago.

[0055] For the avoidance of doubt, when a patient is defined herein as a multiple myeloma patient who "underwent a stem cell transplant and experienced disease progression at least 36 months after transplant," or similar language, the patient may also be included in one or more of the following groups: (i) underwent a stem cell transplant at least 5 years ago; (ii) is 75 years of age or older; or (iii) is 75 years of age or older who underwent a stem cell transplant at least 5 years ago.

[0056] The amount of melflufen required to achieve a therapeutic effect varies depending on the particular route of administration and the characteristics of the subject under treatment, such as species, age, weight, sex, medical condition, the particular disease and its severity, and other relevant medical and physical factors. A skilled physician can easily determine and administer the effective amount of melflufen required to prevent or treat multiple myeloma in multiple myeloma patients who have not undergone stem cell transplantation, have undergone stem cell transplantation at least 5 years prior, and / or are 75 years of age or older.

[0057] Melflufen may be administered daily, every 2 or 3 days, every week, every 2 weeks, every 3 or 4 weeks, or even as a single high dose, depending on the subject being treated and the severity of the multiple myeloma.

[0058] In one embodiment of the present invention, melflufen or a salt thereof may be administered in an amount of about 1 to 150 mg (excluding the mass of counterions). For example, 1, 5, 10, 15, 20, 25, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 or 150 mg (excluding the mass of counterions). Preferably, the amount of melflufen or a salt thereof per administration is 1 to 50 mg (excluding the mass of counterions), for example, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 mg. More preferably, the amount of melflufen or a salt thereof per administration is 1 to 40 mg (excluding the mass of counterions), for example, 1, 5, 10, 15, 20, 25, 30, 35 or 40 mg. For example, the amount of melflufen or a salt thereof per administration is 10 to 40 mg (excluding the mass of the counter ion), for example, 10, 15, 20, 25, 30, 35, or 40 mg. In a specific embodiment, the amount of melflufen or a salt thereof per administration may be 10 to 20 mg, 20 to 30 mg, or 30 to 40 mg.

[0059] In one embodiment of the present invention, melflufen or a salt thereof may be administered in an amount of about 35.0 to 45.0 mg, preferably 36.0 to 44.0 mg, preferably 37.0 to 43.0 mg, preferably 37.5 to 42.5 mg (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 42.0 mg, most preferably 39.0 to 41.0 mg (e.g., 39.0, 39.5, 40.0, 40.5 or 41.0 mg, more preferably 39.5, 40.0 or 40.5 mg, most preferably 40.0 mg). Melflufen or a salt thereof may be administered, for example, over 25 to 35 minutes as a parenteral dose.

[0060] In embodiments where melflufen is in the form of its hydrochloride (HCl) salt, about 37.6 to 48.3 mg, preferably 39.0 to 47.0 mg, more preferably 41.0 to 45.0 mg, more preferably 42.5 to 43.5 mg, and most preferably 42.9 mg of melflufen hydrochloride (including the mass of the salt component) is administered. Melflufen hydrochloride may be administered, for example, as a parenteral dose over 25 to 35 minutes.

[0061] Preferably, the melflufen or a salt thereof of the present invention is administered over a period of 26 to 34 minutes, more preferably 27 to 33 minutes, even more preferably 28 to 32 minutes, even more preferably 29 to 31 minutes, and most preferably 30 minutes.

[0062] Melflufen or its salt may be administered parenterally or orally. In a preferred embodiment of the present invention, Melflufen or its salt is administered parenterally. Therefore, the pharmaceutical preparation useful according to the present invention is suitable for parenteral administration.

[0063] Parenteral administration includes intravenous (into a vein, e.g., a central or peripheral vein) (bolus or infusion), intra-arterial (into an artery, e.g., a central or peripheral artery), intraosseous injection (into bone marrow), intramuscular (into a muscle), intradermal (into the dermis), and subcutaneous (under the 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 useful in the present invention are those suitable for intravenous administration, more particularly intravenous infusion.

[0064] In one embodiment of the invention, the dosage of melflufen (excluding the mass of the counterion) is administered parenterally at a rate of about 0.3 to 1.8 mg / min, such as 0.5 to 1.8 mg / min, for example 0.8 to 1.8 mg / min, for example 1.0 to 1.8 mg / min, for example 1.1 to 1.8 mg / min, for example 1.1 to 1.7 mg / min, for example 1.1 to 1.6 mg / min, for example 1.2 to 1.6 mg / min, or for example at an infusion rate of 1.2 to 1.5 mg / min. In one embodiment, the dosage of melflufen (excluding the mass of the counterion) is administered parenterally at a rate of about 1.2 to 1.4 mg / min (for example 1.2, 1.3 or 1.4 mg / min).

[0065] In certain embodiments of the invention, approximately 1-50 mg (excluding the mass of the counterion) of melflufen (e.g., 1-45 mg) is administered as a parenteral dose over approximately 5-35 minutes, e.g., 40 mg (excluding the mass of the counterion) of melflufen as a parenteral dose over approximately 30 minutes, 20 mg (excluding the mass of the counterion) of melflufen as a parenteral dose over approximately 15 minutes, or 10 mg (excluding the mass of the counterion) of melflufen as a parenteral dose over approximately 7.5 minutes.

[0066] When referring to the mass of melflufen or its salts with respect to the dosage of melflufen for use in the present invention, it is the mass when the counterion is not included in the calculation of the dosage mass of melflufen. The molecular weight of melflufen without the counterion is 498.42 g / mol. For the dosage of a salt of melflufen, the actual dosage mass administered to a patient must take into account the mass of the counterion. This is conventional for those skilled in the art.

[0067] For example, when melflufen is in the form of its hydrochloride (HCl) salt (molecular weight 534.88 g / mol), the equivalent dosage rate of 1.1-1.8 mg / min for melflufen hydrochloride (including the mass of the counterion) is 1.2-1.9 mg / min. For a dosage of 1-50 mg melflufen, the equivalent dosage of melflufen hydrochloride is approximately 1.1-53.8 mg. For a dosage of 10-45 mg melflufen, the equivalent dosage of melflufen hydrochloride is approximately 10.7-48.3 mg.

[0068] When melflufen or a salt thereof is administered as a parenteral dosage, the melflufen dosage should be in the form of a liquid, such as a solution or suspension, that contains melflufen.

[0069] Preferably, the melflufen or salt thereof of the present invention is administered as part of a treatment cycle. In the cycle, melflufen may be administered on day 1 of the cycle on X days, followed by no further administration of melflufen 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, more preferably 21 to 35, more preferably 21 to 30; for example, 21, 28, 29, 30 or 35. In certain embodiments, X may be, for example, 21 to 30, 21 to 28, 28 to 30 or 28 to 29. For the avoidance of doubt, the dose of melflufen administered in the treatment cycle may be a dose as described elsewhere in this application, for example, a dose of 1 to 50 mg of melflufen.

[0070] In a preferred embodiment of the present invention, melflufen or a salt thereof is administered on the first day of a 21-day cycle, followed by a 20-day rest period during which melflufen is not administered further; on the first day of a 28-day cycle, followed by a 27-day rest period during which melflufen is not administered further; on the first day of a 29-day cycle, followed by a 28-day rest period during which melflufen is not administered further; on the first day of a 30-day cycle, followed by a 29-day rest period during which melflufen is not administered further; or on the first day of a 35-day cycle, followed by a 34-day rest period during which melflufen is not administered further. In certain embodiments, the treatment cycle is 28 days; or on the first day of a 42-day cycle, followed by a 41-day rest period during which melflufen is not administered further. In certain embodiments, the treatment cycle is 28 days.

[0071] The cycle may be repeated one or more times depending on the category (e.g., high-grade or low-grade), class (e.g., relapsed, 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 or more times. The cycle may be repeated 3, 4 or 5 times.

[0072] A skilled physician or clinician can readily determine the number of cycles of melflufen or a salt thereof that are required to treat, prevent, combat, or halt the progression of multiple myeloma in multiple myeloma patients who have not undergone a stem cell transplant, who have undergone a stem cell transplant at least 5 years ago, and / or who are over the age of 75. A skilled physician or clinician can readily determine the number of cycles of melflufen or a salt thereof that are required to treat, prevent, combat, or halt the progression of multiple myeloma in multiple myeloma patients who have undergone a stem cell transplant and have experienced disease progression at least 36 months after transplant.

[0073] The dosing regimens of the invention are particularly safe and effective for the treatment and prevention of multiple myeloma in patients with or at risk of developing multiple myeloma who have not undergone a stem cell transplant, who have undergone a stem cell transplant at least 5 years ago, and / or who are over the age of 75. Similarly, the dosing regimens of the invention are particularly safe and effective for the treatment and prevention of multiple myeloma in patients with or at risk of developing multiple myeloma who have undergone a stem cell transplant and have progressed in disease at least 36 months after transplant.

[0074] While melflufen or a salt thereof may be used as the sole active ingredient in the present invention, it is also possible to use it in combination with one or more additional therapeutic agents, the use of such a combination providing one preferred embodiment of the present invention.

[0075] Such additional therapeutic agents may be agents useful in the treatment or prevention of multiple myeloma, or other pharma- ceutically active materials. Such agents are known in the art. Examples of additional therapeutic agents for use in the present invention include steroids (prednisone and dexamethasone), IMiDs (thalidomide, lenalidomide and pomalidomide), PIs (bortezomib, carfilzomib and ixazomib), histone deacetylase (HDAC) inhibitors (panobinostat), conventional chemotherapeutic agents (alkylating agents (e.g., melphalan, cyclophosphamide, bendamustine), doxorubicin), anti-CD38 antibodies, and the like. (daratumumab), and anti-SLAMF7 antibodies (elotuzumab); for example, steroids (prednisone and dexamethasone), IMiDs (thalidomide, lenalidomide, and pomalidomide), PIs (bortezomib and carfilzomib), histone deacetylase (HDAC) inhibitors (panobinostat), and traditional chemotherapy drugs (alkylating agents (e.g., melphalan, cyclophosphamide), and doxorubicin). Examples of alternative therapeutic agents for use in the present invention also include antibodies against B cell maturation antigens (belantamab), inhibitors of nuclear export (selinexol), and autologous chimeric antigen receptor (CAR) T cell therapy against B cell maturation antigens (siltacabtagene). Preferred alternative therapeutic agents for use in the present invention include dexamethasone, pomalidomide, and bortezomib. For example, alternative therapeutic agents for use in the present invention include dexamethasone; or dexamethasone and pomalidomide or dexamethasone and bortezomib.

[0076] Thus, the present invention also provides melflufen or a salt thereof together with one or more further therapeutic agents for use in the prevention or treatment of multiple myeloma in multiple myeloma patients who have not undergone stem cell transplantation, have undergone stem cell transplantation at least 5 years ago, and / or are 75 years of age or older, wherein melflufen is administered at a rate of 1.0-1.8 mg / min. For example, a dose of 35-45 mg (preferably 37.5-42.5 mg, more preferably 39-41 mg, most preferably 40 mg) is administered over 25-35 minutes (preferably over 30 minutes) as a parenteral dose. Preferably, the further therapeutic agent is dexamethasone. In another embodiment, the one or more further therapeutic agents are selected from the group consisting of dexamethasone, pomalidomide, and bortezomib. For example, dexamethasone; or dexamethasone and pomalidomide or dexamethasone and bortezomib.

[0077] The present invention further provides melflufen hydrochloride together with one or more other therapeutic agents for use in the prevention or treatment of multiple myeloma in multiple myeloma patients who have not undergone stem cell transplantation or have undergone stem cell transplantation at least 5 years ago and / or are 75 years of age or older, wherein melflufen hydrochloride (including the mass of the salt) is administered at a rate of 1.1-1.9 mg / min. For example, a dosage of 37.6-48.3 mg (preferably 40-45 mg, more preferably 42.9 mg) of melflufen hydrochloride (including the mass of the salt) is administered as a parenteral dose over 25-35 minutes (preferably over 30 minutes). Preferably, the other therapeutic agent is dexamethasone. In another embodiment, the one or more other therapeutic agents are selected from the group consisting of dexamethasone, pomalidomide, and bortezomib. For example, dexamethasone; or dexamethasone and pomalidomide; or dexamethasone and bortezomib.

[0078] In one highly preferred embodiment, the present invention provides melflufen or a salt thereof and dexamethasone for use in the prevention or treatment of multiple myeloma in multiple myeloma patients who have not undergone stem cell transplantation, have undergone stem cell transplantation at least 5 years ago, and / or are 75 years of age or older, wherein melflufen is administered at a rate of 1.0-1.8 mg / min. For example, a dose of 35-45 mg (preferably 37.5-42.5 mg, more preferably 39-41 mg, most preferably 40 mg) is administered as a parenteral dose over 25-35 minutes (preferably over 30 minutes). For example, the present invention provides melflufen hydrochloride and dexamethasone for use in the prevention or treatment of multiple myeloma in multiple myeloma patients who have not undergone stem cell transplantation, wherein melflufen hydrochloride (including the mass of the salt) is administered at a rate of 1.1-1.9 mg / min. For example, a dose of 37.6 to 48.3 mg (preferably 40 to 45 mg, more preferably 42.9 mg) of melflufen hydrochloride (including the mass of the salt) is administered parenterally over 25 to 35 minutes (preferably over 30 minutes).

[0079] When used in combination, the exact dosage of the other pharma- ceutical active material may vary depending on the dosing schedule, the potency of the particular agent selected, the age, size, sex, and condition of the subject (usually a mammal, e.g., a human), the nature and severity of the melanoma, and other relevant medical and physical factors.

[0080] The above therapeutic agents, when utilized in combination with melflufen or a salt thereof, may be used, for example, in amounts as set forth in the Physicians' Desk Reference (PDR) or as otherwise determined by one of skill in the art.

[0081] When the additional therapeutic agent is dexamethasone, the dosage is preferably from 1 mg to 200 mg, preferably from 5 mg to 100 mg, more preferably from 10 mg to 80 mg, most preferably from 20 mg to 60 mg, for example, 40 mg or 20 mg.

[0082] In one preferred embodiment, the multiple myeloma patient has not undergone a stem cell transplant, has undergone a stem cell transplant at least 5 years ago, and the other therapeutic agent is dexamethasone at a dose of 40 mg or 20 mg. Optionally, the patient may be 75 years of age or older.

[0083] In one preferred embodiment, the multiple myeloma patient is 75 years of age or older, optionally has not undergone a stem cell transplant, or has undergone a stem cell transplant at least 5 years prior, and the other therapeutic agent is dexamethasone, the dosage of which is 20 mg.

[0084] One or more additional therapeutic agents (e.g., dexamethasone) may be used simultaneously, sequentially, or separately with the administration of a dosage of melflufen or a salt thereof. The individual components of such combinations may be administered separately at different times during the course of therapy or may be administered concurrently in divided or single combination forms.

[0085] When the other therapeutic agent is dexamethasone, preferably, the dexamethasone is administered simultaneously, sequentially, or separately from the administration of melflufen or a salt thereof on the same day. More preferably, it is administered separately from melflufen or a salt thereof on the same day.

[0086] For example, melflufen or a salt thereof for use in the present invention may be administered as part of a treatment cycle (e.g., melflufen or a salt thereof is administered on day 1 of an X-day cycle followed by X-1 days of no melflufen administration), and dexamethasone may be administered simultaneously, sequentially, or separately on the same day that melflufen is administered (i.e., day 1). X may be, for example, 14 to 42, preferably 14 to 35, more preferably 21 to 28; for example, 21 or 28.

[0087] In one preferred embodiment of the invention, dexamethasone is administered on day 1 of a treatment cycle. More preferably, dexamethasone is also administered every week during such treatment cycle, e.g., on days 1, 8, and 15 of a 21-day cycle; or on days 1, 8, 15, and 22 of a 28-day cycle.

[0088] In another preferred embodiment, melflufen or a salt thereof is administered according to the present invention 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 20-day rest period during which melflufen is not further administered; or, according to the present invention, 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 27-day rest period during which melflufen is not further administered. Preferably, the cycle is 28 days. Preferably, dexamethasone is administered separately from melflufen or a salt thereof on day 1. Preferably, dexamethasone is administered orally or intravenously. Preferably, the dose of dexamethasone is 20 mg or 40 mg.

[0089] In another preferred embodiment, when melflufen or a salt thereof for use in the present invention is administered as part of a cycle (e.g., melflufen is administered on day 1 of a cycle of X days followed by no administration of melflufen for the next X-1 days), dexamethasone is administered simultaneously, sequentially or separately on the same day that melflufen is administered (i.e., day 1) and weekly thereafter for the duration of the 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, preferably 14 to 35, more preferably 21 to 28; for example, 21 or 28.

[0090] In such an embodiment, melflufen or a salt thereof is administered in accordance with the present invention on day 1 of a 21-day cycle, followed by a 20-day rest period during which melflufen is not further administered, and dexamethasone is administered simultaneously, sequentially, or separately on day 1 of the cycle and on days 8 and 15 of the 21-day cycle; or melflufen or a salt thereof is administered in accordance with the present invention on day 1 of a 28-day cycle, followed by a 27-day rest period during which melflufen is not further administered, and dexamethasone is administered simultaneously, sequentially, or separately on day 1 of the cycle and on days 8, 15, and 22 of the 28-day cycle. Preferably, dexamethasone is administered separately from melflufen or a salt thereof on day 1, as an oral or intravenous dose (preferably an oral dose). Subsequent doses of dexamethasone may be oral or intravenous (preferably, the subsequent doses are oral).

[0091] It should be noted that the preferred aspects of the invention mentioned with respect to the compounds of the invention and their uses are equally applicable to the methods of treatment of the invention and the methods of manufacture of the invention.

[0092] kit The present invention provides a kit comprising melflufen or a salt thereof and one or more additional therapeutic agents useful for the prevention or treatment of multiple myeloma in multiple myeloma patients who have not undergone stem cell transplantation.

[0093] The present invention also provides a kit comprising melflufen or a salt thereof and one or more additional therapeutic agents useful for the prevention or treatment of multiple myeloma in multiple myeloma patients who have undergone stem cell transplantation at least five years prior.

[0094] The present invention provides a kit comprising melflufen or a salt thereof and one or more additional therapeutic agents useful for the prevention or treatment of multiple myeloma in multiple myeloma patients who are 75 years of age or older and, optionally, have not undergone a stem cell transplant or have undergone a stem cell transplant at least 5 years prior.

[0095] 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), PIs (e.g., bortezomib, carfilzomib and ixazomib), histone deacetylase (HDAC) inhibitors (e.g., panobinostat), conventional chemotherapy drugs (e.g., melphalan, cyclophosphamide, doxorubicin, bendamustine), anti-CD38 antibodies (daratumumab), and anti-SLAMF7 antibodies (elotuzumab). Examples of other therapeutic agents for use in the present invention also include antibodies against B-cell maturation antigens (belantamab), inhibitors of nuclear export (selinexol), and autologous chimeric antigen receptor (CAR) T-cell therapy against B-cell maturation antigens (siltacabtagene).

[0096] In a preferred embodiment of the present invention, at least one of the one or more additional therapeutic agents included in the kit of the present invention is a steroid (e.g., prednisone and dexamethasone), a PI (e.g., bortezomib, carfilzomib and ixazomib), or an anti-CD38 antibody (daratumumab). In a preferred embodiment of the present invention, at least one of the one or more additional therapeutic agents included in the kit of the present invention is dexamethasone, bortezomib or daratumumab.

[0097] In one embodiment, the kit may include melflufen or a salt thereof, dexamethasone, and may optionally further include bortezomib and / or daratumumab. In one embodiment, the kit may include melflufen or a salt thereof and dexamethasone.

[0098] Kits of the invention find use in the therapeutic and / or prophylactic uses and methods of the invention, as described herein.

[0099] For the avoidance of doubt, melflufen or its salt is present in the kit according to the present invention in a form and amount suitable for use according to the present invention.Suitable pharmaceutical formulations are described herein.Those skilled in the art can easily determine the amount of melflufen or its salt and one or more additional therapeutic agents suitable for use according to the present invention.

[0100] Multiple myeloma The treatment of the present invention is useful for treating multiple myeloma in patients who have not undergone stem cell transplantation. The treatment of the present invention is also useful for treating multiple myeloma in patients who have undergone stem cell transplantation at least 5 years ago. The treatment of the present invention is also useful for treating multiple myeloma in patients who are 75 years of age or older and who have undergone stem cell transplantation at least 5 years ago, and who have not undergone stem cell transplantation. The treatment of the present invention is also useful for treating multiple myeloma in patients who have undergone stem cell transplantation and have progressed disease at least 36 months after transplantation.

[0101] There are several categories of multiple myeloma, including monoclonal gammopathy of undetermined significance (MGUS), asymptomatic myeloma (which is further divided into smoldering or indolent myeloma), and symptomatic myeloma. Multiple myeloma may be classified as primary, refractory, relapsed, and relapsed refractory.

[0102] Relapsed multiple myeloma (also known as recurrent myeloma) can be defined as multiple myeloma that recurs within 60 days after the last dose of treatment. Relapsed MM is generally considered a return of disease after a previous response to treatment.

[0103] Refractory multiple myeloma can be defined as multiple myeloma that does not respond to a particular treatment. Refractory myeloma can occur in patients who never see a response from treatment or in patients who do respond to treatment initially but do not respond to the same treatment after relapse.

[0104] Relapsed refractory multiple myeloma (RRMM) is a specific subtype of refractory multiple myeloma and can be defined as multiple myeloma that responds to treatment initially but does not respond to treatment after relapse. For example, RRMM can be defined as multiple myeloma that relapses within 60 days of the last dose and responds to treatment initially but does not respond to the same treatment after relapse. Relapsed refractory multiple myeloma is sometimes referred to as refractory relapsed multiple myeloma.

[0105] Currently, there are seven classes of approved drugs available for the treatment of MM: steroids (e.g., prednisone and dexamethasone), IMiDs (e.g., thalidomide, lenalidomide, and pomalidomide), PIs (e.g., bortezomib, carfilzomib, and ixazomib), histone deacetylase (HDAC) inhibitors (e.g., panobinostat), conventional chemotherapy drugs (e.g., melphalan, cyclophosphamide, doxorubicin, bendamustine), anti-CD38 antibodies (daratumumab), and anti-SLAMF7 antibodies (elotuzumab). Also approved are antibodies against B-cell maturation antigens (belantamab), inhibitors of nuclear export (selinexor), and an autologous chimeric antigen receptor (CAR) T-cell therapy against a B-cell maturation antigen (siltacabtagene).

[0106] Patients with symptomatic active MM receive first-line induction therapy. Patients younger than approximately 65 years of age and otherwise in good health may be considered for consolidation therapy with stem cell transplantation, particularly autologous stem cell transplantation, to enhance the duration of remission (Moreau, P., et al, J Clin Oncol (2011), Vol 29, pages 1898-1906;Rosinol, L., et al, Expert Rev Hematol (2014) Vol 7, pages 43-53). The type of induction therapy varies widely depending on age, disease status, and the presence of other comorbidities. The NCCN Guidelines for Multiple Myeloma (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 regimens recommended as first-line therapy for transplant-eligible and non-transplant-eligible patients. Bortezomib and lenalidomide-containing regimens are most commonly used as first-line therapy; these agents are often combined with alkylating agents for non-transplant candidates. In a consensus statement by the International Myeloma Working Group 2014 (Palumbo, A., et al, J Clin Oncol (2014) Vol 32, pages 587-600), there are multiple regimens recommended for patients who are ineligible for standard stem cell transplantation. Without exception, relapse occurs after each of these agents, necessitating salvage therapy.

[0107] Refractory multiple myeloma (and / or RRMM) may be refractory to at least one drug from a class of drugs selected from protease inhibitors (PIs), immunomodulatory agents (IMiDs), alkylating agents, or anti-CD38 antibodies. Some refractory multiple myeloma (and / or RRMM) are refractory to one or more drugs (e.g., 1, 2, 3, 4, or 5 or more) from two or more classes of drugs selected from protease inhibitors (PIs), immunomodulatory agents (IMiDs), alkylating agents, or anti-CD38 antibodies. Refractory multiple myeloma (and / or RRMM) may further be refractory to two or more drugs from two or more classes of drugs selected from protease inhibitors (PIs), immunomodulatory agents (IMiDs), alkylating agents, or anti-CD38 antibodies.

[0108] Treatment options for individuals whose disease has relapsed depend on several variables, including response and duration to initial chemotherapy, comorbidities, bone marrow reserve, and whether the patient experiences an indolent or aggressive relapse. Treatment choices in RRMM are particularly challenging. Multiple therapies, and several combinations of the approved drugs mentioned above, are available for the treatment of RRMM. In general, myeloma patients undergo an average of 4-8 different regimens during their lifetime. However, despite the availability of effective therapies, the optimal combination and sequence of these agents with other therapies and with each other remains unclear. Ultimately, patients relapse from all currently available options.

[0109] In many cases, if disease recurs more than 6-12 months after completion of the last treatment, the recurrent disease may be restarted with the same agent used as induction therapy, but if recurrence occurs more quickly, if the patient is refractory to initial therapy, or if the disease is associated with severe symptoms, such as renal failure or hypercalcemia, a regimen with a different mechanism of action (class switch) is often chosen.

[0110] Melflufen or its salt for use according to the present invention is applicable to the aforementioned categories or classes of multiple myeloma in patients who have not undergone stem cell transplantation, have undergone stem cell transplantation at least 5 years ago, and / or are 75 years of age or older, or have undergone stem cell transplantation and have progressed disease at least 36 months after transplantation. It is particularly useful for patients who have not undergone stem cell transplantation.

[0111] Melflufen or a salt thereof for use according to the present invention is highly effective in the treatment of refractory, relapsed, and relapsed refractory multiple myeloma in patients who have not undergone a stem cell transplant, who have undergone a stem cell transplant at least 5 years ago, and / or who are 75 years of age or older (particularly patients who have not undergone a stem cell transplant).

[0112] For example, melflufen or a salt thereof for use according to the present invention is useful in patients who have not undergone a stem cell transplant, who have undergone a stem cell transplant at least 5 years ago, who have undergone a stem cell transplant and have disease progression at least 36 months after transplant, and / or who are 75 years of age or older (particularly patients who have not undergone a stem cell transplant) and who are refractory (e.g., refractory or relapsed refractory) to a protease inhibitor (PI), an immunomodulatory drug (IMiD), an alkylating agent, or an anti-CD38 antibody.

[0113] Melflufen or a salt thereof for use according to the invention is particularly useful for patients who have not undergone a stem cell transplant, who have undergone a stem cell transplant at least 5 years ago, who have undergone a stem cell transplant and have progressed disease at least 36 months after transplant, and / or who are 75 years of age or older (particularly patients who have not undergone a stem cell transplant) and who are refractory (e.g., refractory or relapsed refractory) to one or more of alkylating agents, such as low-dose melphalan, high-dose melphalan, and cyclophosphamide. It is particularly useful for patients who have not undergone a stem cell transplant, who have undergone a stem cell transplant at least 5 years ago, who have undergone a stem cell transplant and have progressed disease at least 36 months after transplant, and / or who are 75 years of age or older (particularly patients who have not undergone a stem cell transplant) and who are refractory (e.g., refractory or relapsed refractory) to an anti-CD38 antibody. It is very particularly useful for patients who have not undergone a stem cell transplant, who have undergone a stem cell transplant at least 5 years ago, who have undergone a stem cell transplant and have progressed disease at least 36 months after transplant, and / or who are 75 years or older (particularly patients who have not undergone a stem cell transplant) and who are refractory (e.g., refractory or relapsed refractory) to lenalidomide, particularly refractory (e.g., refractory or relapsed refractory) to the last treatment the patient received for multiple myeloma. It is also useful for patients who have not undergone a stem cell transplant, who have undergone a stem cell transplant at least 5 years ago, who have undergone a stem cell transplant and have progressed disease at least 36 months after transplant, and / or who are 75 years or older (particularly patients who have not undergone a stem cell transplant) and who are refractory to one or more (e.g., 1, 2, 3, 4, or 5 or more) drugs from two or more classes of drugs selected from protease inhibitors (PIs), immunomodulatory agents (IMiDs), alkylating agents, or anti-CD38 antibodies.

[0114] It is also particularly useful in patients who have not undergone a stem cell transplant, who have undergone a stem cell transplant at least 5 years ago, who have undergone a stem cell transplant and have disease progression at least 36 months after transplant, and / or who are 75 years of age or older (more particularly patients who have not undergone a stem cell transplant) and who are refractory to one or more (e.g., 1, 2, 3, 4 or 5 or more) drugs from two or more classes of drugs selected from protease inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents, or anti-CD38 antibodies.

[0115] Melflufen or a salt thereof for use according to the invention is also particularly useful in patients who are refractory (e.g. refractory or relapsed refractory) to at least one immunomodulator (IMiD), more particularly in patients who are refractory (e.g. refractory or relapsed refractory) to at least one immunomodulator (IMiD), more particularly in patients who are refractory (e.g. refractory or relapsed refractory) to at least one immunomodulator (IMiD), more particularly in patients who are refractory (e.g. refractory or relapsed refractory) to at least one other drug selected from a protease inhibitor (PI), an immunomodulator (IMiD), an alkylating agent and an anti-CD38 antibody. For example, two, three or four other drugs, including at least one protease inhibitor (PI) and an immunomodulator (IMiD). For example, a multiple myeloma patient may have received at least three prior lines of treatment, has disease that is refractory to at least one proteasome inhibitor, one immunomodulator, and one anti-CD38 monoclonal antibody, and shows disease progression after the last treatment. If the patient has previously undergone autologous stem cell transplantation (ASCT), time to progression should be at least 3 years from transplant.

[0116] Melflufen or a salt thereof for use according to the invention may also be administered to patients with a median body surface area (BSA) of 1.855 m 2 It is particularly useful in the following patients:

[0117] In one particularly preferred embodiment, the present invention is useful for treating multiple myeloma in patients who have not undergone stem cell transplantation, who have RRMM, who are refractory to the immunomodulatory agent lenalidomide, and who have received two, three, or four previous lines of therapy (e.g., three previous lines of therapy).

[0118] In another aspect, the invention is useful for treating multiple myeloma in patients who have undergone a stem cell transplant at least 5 years ago, who have RRMM, who are refractory to the immunomodulatory agent lenalidomide, and who have previously received 2, 3, or 4 lines of therapy (e.g., 3 prior lines of therapy).

[0119] In another aspect, the invention is useful for treating multiple myeloma in patients who are at least 75 years old or older (e.g., have undergone a stem cell transplant at least 5 years prior or have not undergone a stem cell transplant), have RRMM, are refractory to the immunomodulatory agent lenalidomide, and have received 2, 3, or 4 prior lines of therapy (e.g., 3 prior lines of therapy).

[0120] In another aspect, the invention is useful for treating multiple myeloma in patients who have undergone stem cell transplantation and have disease progression at least 36 months after transplantation, who have RRMM, are refractory to the immunomodulatory agent lenalidomide, and have received two, three, or four prior lines of therapy (e.g., three prior lines of therapy).

[0121] The three prior lines of therapy may be, for example, one proteasome inhibitor (e.g., bortezomib, carfilzomib, or ixazomib), one immunomodulatory agent (lenalidomide, pomalidomide, or thalidomide), and one anti-CD38 monoclonal antibody (e.g., daratumumab).

[0122] Melflufen or a salt thereof for use according to the invention is also useful in patients who are refractory (e.g. refractory or relapsed refractory) to at least pomalidomide and / or daratumumab.

[0123] The present invention relates to a method for treating rheumatoid arthritis in patients who have not undergone a stem cell transplant, who have undergone a stem cell transplant at least 5 years ago, or who have undergone a stem cell transplant and have progressed at least 36 months after transplant (particularly patients who have not undergone a stem cell transplant), and have received at least two prior lines of therapy for multiple myeloma, e.g., at least two prior lines of therapy including lenalidomide and a protease inhibitor, either sequentially or as part of a combination regimen; Refractory (e.g., relapsed and refractory or refractory) to the most recent line of therapy and / or lenalidomide administered within 18 months prior to treatment; refractory (e.g., relapsed and refractory, or refractory) to at least one alkylating agent; is refractory (e.g., relapsed and refractory, or refractory) to at least an anti-CD38 antibody; refractory (e.g., relapsed and refractory, or refractory) to at least an immunomodulatory drug (IMiD); is refractory (e.g., refractory or relapsed refractory) to lenalidomide, particularly is refractory (e.g., refractory or relapsed refractory) to lenalidomide in the last treatment the patient received for multiple myeloma; is refractory to one or more (e.g., 1, 2, 3, 4, or 5 or more) drugs from two or more classes of drugs selected from protease inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents, and anti-CD38 antibodies; and / or is refractory (e.g., refractory or relapsed refractory) to at least lenalidomide and one, two, three, or four other drugs, e.g., at least one drug selected from a protease inhibitor (PI), an immunomodulatory drug (IMiD), an alkylating agent, and an anti-CD38 antibody (e.g., at least one protease inhibitor (PI) and an immunomodulatory drug (IMiD)); It is particularly beneficial for patients with multiple myeloma.

[0124] In such embodiments, the patient may have RRMM and / or the patient may be 75 years of age or older.

[0125] The present invention also relates to a method for treating rheumatoid arthritis in patients who have not undergone a stem cell transplant, who have undergone a stem cell transplant at least 5 years ago, or who have undergone a stem cell transplant and have progressed at least 36 months after transplant, and / or who are 75 years of age or older (particularly patients who have not undergone a stem cell transplant) and had received two prior lines of therapy; Alkylating agent refractory (refractory or relapsed refractory); Anti-CD38 antibody refractory (refractory or relapsed refractory); The patient's last treatment for multiple myeloma was an immunomodulatory drug (IMiD), in particular lenalidomide; and / or Patients are refractory (relapsed and refractory or refractory) to both the most recent line of therapy and lenalidomide (≥10 mg) administered within 18 months prior to treatment. It is particularly useful for patients with multiple myeloma.

[0126] In such embodiments, the patient may have RRMM and / or the patient may be 75 years of age or older.

[0127] The combination of melflufen or its salt and dexamethasone for use according to the present invention is very useful in the treatment of refractory, relapsed, and relapsed refractory multiple myeloma, especially in the treatment of relapsed refractory multiple myeloma. For example, the method and use of the present invention comprising administering melflufen and dexamethasone is useful for patients who are refractory (e.g., refractory or relapsed refractory) to protease inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents, or anti-CD38 antibodies. It is particularly useful for patients who are refractory (e.g., refractory or relapsed refractory) to one or more of alkylating agents, such as low-dose melphalan, high-dose melphalan, and cyclophosphamide. It is also useful for patients who are refractory to one or more (e.g., 1, 2, 3, 4 or 5 or more) drugs from two or more classes of drugs selected from protease inhibitors (PIs), immunomodulators (IMiDs), alkylating agents, and anti-CD38 antibodies. The methods and uses of the present invention comprising administering melflufen and dexamethasone are also very particularly useful in patients who are refractory (e.g., refractory or relapsed refractory) to at least one immunomodulator (IMiD), more particularly in patients who are refractory (e.g., refractory or relapsed refractory) to at least one immunomodulator (IMiD), more particularly to at least lenalidomide, and 1, 2, 3 or 4 other drugs, such as protease inhibitors (PIs), immunomodulators (IMiDs), alkylating agents, and anti-CD38 antibodies. For example, two, three or four other drugs including at least one protease inhibitor (PI) and an immunomodulatory drug (IMiD). The methods and uses of the invention comprising administering melflufen and dexamethasone are also particularly useful in patients who are refractory (e.g., refractory or relapsed refractory) to at least pomalidomide and / or daratumumab.

[0128] As mentioned above, the present invention provides treatment of a subpopulation of multiple myeloma patients. One subpopulation is multiple myeloma patients who have not undergone stem cell transplantation. For the avoidance of doubt, a "stem cell transplant-naive patient" is a patient who has never undergone stem cell transplantation in his / her lifetime. Thus, prior to (or during) the treatment of the present invention, the patient has never undergone stem cell transplantation. Examples of stem cell transplantation include autologous stem cell transplantation, tandem stem cell transplantation, allogeneic stem cell transplantation, donor lymphocyte infusion or mini-transplantation. In a representative embodiment of the present invention, the stem cell transplant-naive patient is a patient who has not undergone autologous stem cell transplantation.

[0129] Patients who have not undergone stem cell transplantation may have chosen not to undergo the treatment or may have been advised by a medical professional that they were not suitable candidates for this type of treatment after an individualized assessment of their health status. For example, stem cell transplantation is not usually recommended for patients over 65 or 70 years old unless they are in excellent physical health. Stem cell transplantation is also not usually recommended for patients with underlying diseases, such as cardiac and / or pulmonary disease. Stem cell transplantation may also not be recommended depending on other factors, such as the type and stage of multiple myeloma, its aggressiveness, and response to treatment. There are many reasons why multiple myeloma patients may not have undergone stem cell transplantation based on their selection or disease characteristics, so it is quite surprising that this is a patient population that can benefit from certain treatments. As shown in Figures 1-4, there is a benefit to the patient population that has not undergone stem cell transplantation.

[0130] In certain preferred embodiments of the invention, the multiple myeloma patient has not undergone a stem cell transplant; and is at least 65, 70, 75 or 80 years old (preferably at least 75 or 80 years old); suffer from cardiovascular disease; and / or I suffer from lung disease.

[0131] The inventors have demonstrated that the treatment of the present invention for multiple myeloma patients who have not undergone stem cell transplantation also works well for patients who have not undergone stem cell transplantation and: The median body surface area (BSA) was 1.855 m 2 below; Revised Multiple Myeloma International Staging System (R-ISS) stage I or II; The patient is at high risk based on his / her cytogenetics; and / or Having impaired renal function (e.g., creatine clearance less than 60 mL / min or 60-90 mL / min); in particular, creatine clearance less than 60 mL / min; It has also been found to be particularly beneficial in patients.

[0132] The inventors have demonstrated that the treatment of the present invention for multiple myeloma patients who have not undergone stem cell transplantation is effective in patients who have not undergone stem cell transplantation and: is RRMM; and / or Refractory to lenalidomide (e.g., refractory to lenalidomide administered (e.g., ≥10 mg) within 18 months prior to treatment); and / or have received at least two prior lines of therapy (e.g., 2, 3, or 4 prior lines of therapy); It has also been found to be particularly beneficial in patients.

[0133] The inventors have demonstrated that the treatment of the present invention for multiple myeloma patients who have not undergone stem cell transplantation is effective in patients who have not undergone stem cell transplantation and: RRMM; refractory to lenalidomide (e.g., refractory to lenalidomide administered (e.g., ≥10 mg) within 18 months prior to treatment); have received at least two prior lines of therapy (e.g., 2, 3, or 4 prior lines of therapy); It has also been found to be particularly beneficial in patients.

[0134] Since the treatment of the present invention is for patients who have not undergone stem cell transplantation, the method and use of the present invention may further include the step of determining whether the patient has undergone a stem cell transplantation, and, if the patient has not undergone a stem cell transplantation, administering melflufen or a salt thereof to a multiple myeloma patient who has not undergone a stem cell transplantation.

[0135] A skilled physician can readily determine whether a multiple myeloma patient has undergone a stem cell transplant, for example, by questioning the patient and / or reviewing medical records.

[0136] For example, the present invention provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient has undergone a stem cell transplant, and, if the patient has not undergone a stem cell transplant, administering melflufen or a salt thereof to the multiple myeloma patient who has not undergone a stem cell transplant.

[0137] The present invention further provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient has undergone stem cell transplantation, and administering melflufen or a salt thereof and dexamethasone to the multiple myeloma patient who has not undergone stem cell transplantation if the patient has not undergone stem cell transplantation. The inventors have also found that the present invention's treatment of multiple myeloma patients who have not undergone stem cell transplantation is particularly beneficial in patients who have not undergone stem cell transplantation and are not eligible for stem cell transplantation.

[0138] A skilled physician, after individual assessment of the health status of a multiple myeloma patient, can readily determine whether the patient is suitable for stem cell transplantation, taking into account, for example, age, physical fitness, underlying diseases (e.g., cardiac and / or pulmonary disease), and other factors, such as the type and stage of multiple myeloma, its aggressiveness, and responsiveness to treatment.

[0139] Therefore, the present invention may further include determining whether a patient is suitable for stem cell transplantation, and administering melflufen or a salt thereof to a multiple myeloma patient who has not undergone stem cell transplantation if the patient is not suitable for stem cell transplantation.

[0140] For example, the present invention provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient is suitable for stem cell transplantation, and, if the patient is not suitable for stem cell transplantation, administering melflufen or a salt thereof to a multiple myeloma patient who has not undergone stem cell transplantation.

[0141] The present invention further provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient is suitable for stem cell transplantation, and, if the patient is not suitable for stem cell transplantation, administering melflufen or a salt thereof and dexamethasone to a multiple myeloma patient who has not undergone stem cell transplantation.

[0142] The present invention further provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient has undergone a stem cell transplant, determining whether the patient is suitable for stem cell transplantation, and if the patient has not undergone a stem cell transplant and is not suitable for stem cell transplantation, administering melflufen or a salt thereof to the multiple myeloma patient who has not undergone a stem cell transplant.

[0143] In certain aspects, the present invention provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient has undergone a stem cell transplant and whether the patient is suitable for stem cell transplant, and if the patient has not undergone a stem cell transplant and is not suitable for stem cell transplant, administering melflufen or a salt thereof and dexamethasone to a multiple myeloma patient who has not undergone a stem cell transplant.

[0144] The present invention further provides melflufen or a salt thereof for use in the prevention or treatment of multiple myeloma in a multiple myeloma patient who has not undergone a stem cell transplant and is not suitable for stem cell transplantation.The present invention further provides melflufen or a salt thereof and dexamethasone for use in the prevention or treatment of multiple myeloma in a multiple myeloma patient who has not undergone a stem cell transplant and is not suitable for stem cell transplantation.

[0145] The present invention further provides a treatment for a subpopulation of multiple myeloma patients who have undergone stem cell transplantation at least 2.5 years ago, preferably at least 5 years ago. For the avoidance of doubt, a "patient who has undergone stem cell transplantation at least X years ago" is a patient who has undergone stem cell transplantation in the past, but has not undergone stem cell transplantation for at least X years before undergoing treatment according to the present invention. (For example, a "patient who has undergone stem cell transplantation at least 5 years ago" is a patient who has undergone stem cell therapy in the past, but has not undergone stem cell transplantation for at least 5 years before undergoing treatment according to the present invention). Thus, a patient has not undergone stem cell transplantation for at least X years (e.g., 5 years) before the treatment according to the present invention, but has certainly undergone stem cell transplantation more than the past X years (e.g., 5 years). Thus, such a patient can also be described as a patient who has "not undergone stem cell transplantation for at least X years". For example, a patient who has undergone stem cell transplantation at least 5 years ago can also be described as a patient who has not undergone stem cell transplantation for at least 5 years. Examples of stem cell transplantation include autologous stem cell transplantation, tandem stem cell transplantation, allogeneic stem cell transplantation, donor lymphocyte infusion, or mini-transplantation. In an exemplary embodiment of the present invention, a patient who has undergone a stem cell transplant at least X years ago (e.g., at least 5 years ago) is a patient who has undergone an autologous stem cell transplant at least X years ago (e.g., at least 5 years ago).

[0146] In certain embodiments, the invention provides treatment for a subpopulation of multiple myeloma patients who have undergone a stem cell transplant 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 preferred embodiments, the invention provides treatment for a subpopulation of multiple myeloma patients who have undergone a stem cell transplant 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.

[0147] Patients who have undergone stem cell transplantation at least 5 years ago may choose not to undergo stem cell transplantation treatment again during that period, or may be recommended by medical professionals that they were not suitable candidates for this type of treatment after individualized evaluation of their health condition.For example, due to age, underlying disease (e.g., cardiac disease and / or pulmonary disease), or other factors, such as the type and stage of multiple myeloma, its aggressiveness, and responsiveness to treatment.As shown in Figures 7 and 8, there is a benefit in the patient group who have undergone stem cell transplantation at least 2.5 years ago, especially at least 5 years ago, especially compared with patients who have undergone stem cell transplantation in the past 2.5 years.

[0148] In certain embodiments of the present invention, the multiple myeloma patient has undergone a stem cell transplant at least 5 years ago, and is at least 65, 70, 75 or 80 years old (preferably at least 75 or 80 years old); suffer from cardiovascular disease; and / or I suffer from lung disease.

[0149] In certain embodiments of the present invention, the multiple myeloma patient has undergone a stem cell transplant at least 5 years ago, and The median body surface area (BSA) was 1.855 m 2 Below is; Revised International Staging System (R-ISS) classification for multiple myeloma I or II; The patient is at high risk based on his / her cytogenetics; and / or Having impaired renal function (eg, creatine clearance less than 60 mL / min or between 60 and 90 mL / min); in particular, creatine clearance less than 60 mL / min.

[0150] In certain embodiments of the present invention, the multiple myeloma patient has undergone a stem cell transplant at least 5 years ago, and is RRMM; refractory to lenalidomide (e.g., refractory to lenalidomide administered (e.g., 10 mg or more) within 18 months prior to treatment); and / or (preferably and) Having received at least two prior lines of therapy (eg, 2, 3, or 4 prior lines of therapy).

[0151] Since the treatment of the present invention is for patients who underwent a stem cell transplant at least 5 years ago, the method and use of the present invention may further include a step of determining whether the patient underwent a stem cell transplant at least 5 years ago, and administering melflufen or a salt thereof to the patient if the patient underwent a stem cell transplant at least 5 years ago.

[0152] A skilled physician can readily determine whether a multiple myeloma patient has had a stem cell transplant at least five years ago, for example, by asking the patient and / or reviewing medical records as to whether the patient has had a stem cell transplant and, if so, whether it was within the past five years.

[0153] For example, the present invention provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient underwent a stem cell transplant at least 5 years ago, and, if the patient underwent a stem cell transplant at least 5 years ago, administering melflufen or a salt thereof to a multiple myeloma patient who underwent a stem cell transplant at least 5 years ago.

[0154] The present invention further provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient underwent a stem cell transplant at least 5 years ago, and, if the patient underwent a stem cell transplant at least 5 years ago, administering melflufen or a salt thereof and dexamethasone to a multiple myeloma patient who underwent a stem cell transplant at least 5 years ago.

[0155] The inventors have found that the treatment of the present invention for multiple myeloma patients who have not undergone a stem cell transplant is also particularly beneficial in patients who have undergone a stem cell transplant at least 5 years ago and who are not suitable to undergo a (repeated) stem cell transplant.

[0156] Since the treatment of the present invention is for patients who underwent stem cell transplantation at least 5 years ago, the method and use of the present invention may further include a step of determining whether the patient is suitable for stem cell transplantation, and, if the patient is not suitable for stem cell transplantation, administering melflufen or a salt thereof to a multiple myeloma patient who underwent stem cell transplantation at least 5 years ago.

[0157] For example, the present invention provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient is suitable for stem cell transplantation, and, if the patient is not suitable for stem cell transplantation, administering melflufen or a salt thereof to a multiple myeloma patient who underwent stem cell transplantation at least 5 years ago.

[0158] The present invention further provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient is suitable for stem cell transplantation, and, if the patient is not suitable for stem cell transplantation, administering melflufen or a salt thereof and dexamethasone to a multiple myeloma patient who underwent a stem cell transplant at least 5 years ago.

[0159] The present invention further provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient has undergone a stem cell transplant at least 5 years ago, determining whether the patient is suitable for stem cell transplant, and if the patient has undergone a stem cell transplant and it was at least 5 years ago and is not suitable for stem cell transplant, administering melflufen or a salt thereof to the multiple myeloma patient who has undergone a stem cell transplant at least 5 years ago.

[0160] In certain aspects, the present invention provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient has undergone a stem cell transplant at least 5 years ago and whether the patient is suitable for stem cell transplant, and if the patient has undergone a stem cell transplant and it was at least 5 years ago and is not suitable for stem cell transplant, administering melflufen or a salt thereof and dexamethasone to a multiple myeloma patient who has undergone a stem cell transplant at least 5 years ago.

[0161] The present invention further provides melflufen or a salt thereof for use in the prevention or treatment of multiple myeloma in a multiple myeloma patient who has undergone a stem cell transplant at least 5 years ago and who is not suitable for stem cell transplant.The present invention further provides melflufen or a salt thereof and dexamethasone for use in the prevention or treatment of multiple myeloma in a multiple myeloma patient who has undergone a stem cell transplant at least 5 years ago and who is not suitable for stem cell transplant.

[0162] The present invention also provides treatments for the subpopulation of multiple myeloma patients aged 75 years or older. Such patients may also not have undergone stem cell therapy or may have undergone a stem cell transplant at least 5 years prior. As discussed in the Results section of Example 1, and as also shown in Figures 1 and 3, there is benefit to the treatments of the present invention in the patient population aged 75 years or older.

[0163] In certain embodiments, the present invention provides treatment for the subpopulations of multiple myeloma patients who are 78 years of age or older, 80 years of age or older, or 85 years of age or older.

[0164] In certain embodiments of the present invention, the multiple myeloma patient is 75 years of age or older, and have not had a stem cell transplant or have had a stem cell transplant 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); suffer from cardiovascular disease; and / or I suffer from lung disease.

[0165] In certain embodiments of the present invention, the multiple myeloma patient is 75 years of age or older, and have not had a stem cell transplant or have had a stem cell transplant 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); The median body surface area (BSA) was 1.855 m 2 below; Revised International Staging System (R-ISS) classification for multiple myeloma I or II; The patient is at high risk based on his / her cytogenetics; and / or Having impaired renal function (eg, creatine clearance less than 60 mL / min or between 60 and 90 mL / min); in particular, creatine clearance less than 60 mL / min.

[0166] In certain embodiments of the present invention, the multiple myeloma patient is 75 years of age or older, and is RRMM; refractory to lenalidomide (e.g., refractory to lenalidomide administered (e.g., 10 mg or more) within 18 months prior to treatment); and / or (preferably and) Having received at least two prior lines of therapy (eg, 2, 3, or 4 prior lines of therapy).

[0167] In such embodiments, the patient may optionally not have undergone a stem cell transplant or may have undergone a stem cell transplant 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).

[0168] Since the treatment of the present invention is for patients aged 75 years or older, the method and use of the present invention may further include a step of determining whether the patient is aged 75 years or older, and, if the patient is aged 75 years or older, administering melflufen or a salt thereof to the multiple myeloma patient aged 75 years or older.

[0169] A skilled physician can readily determine whether a multiple myeloma patient is over 75 years of age, for example, by questioning the patient and / or reviewing their medical records.

[0170] For example, the present invention provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, which comprises determining whether the patient is 75 years of age or older, and, if the patient is 75 years of age or older, administering melflufen or a salt thereof to the multiple myeloma patient 75 years of age or older.

[0171] The present invention further provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient is 75 years of age or older, and, if the patient is 75 years of age or older, administering melflufen or a salt thereof and dexamethasone to the multiple myeloma patient 75 years of age or older.

[0172] The inventors have found that the treatment of the present invention for multiple myeloma patients aged 75 years or older is also particularly useful in patients aged 75 years or older who are not suitable for stem cell transplant (even more particularly, those who have not undergone a stem cell transplant, and who have undergone a stem cell transplant at least 5 years prior).

[0173] Since the treatment of the present invention is for patients aged 75 years or older, the method and use of the present invention may further comprise the step of determining whether the patient is suitable for stem cell transplantation, and administering melflufen or a salt thereof to the multiple myeloma patient aged 75 years or older if the patient is not suitable for stem cell transplantation.For example, the present invention provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient is suitable for stem cell transplantation, and administering melflufen or a salt thereof to the multiple myeloma patient aged 75 years or older if the patient is not suitable for stem cell transplantation.The present invention further provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient is suitable for stem cell transplantation, and administering melflufen or a salt thereof and dexamethasone to the multiple myeloma patient aged 75 years or older if the patient is not suitable for stem cell transplantation.

[0174] The present invention further provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient is 75 years of age or older, determining whether the patient is suitable for stem cell transplantation, and if the patient is 75 years of age or older and is not suitable for stem cell transplantation, administering melflufen or a salt thereof to the multiple myeloma patient 75 years of age or older.

[0175] In certain aspects, the present invention provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising determining whether the patient is 75 years of age or older and whether the patient is suitable for stem cell transplantation, and if the patient is 75 years of age or older and is not suitable for stem cell transplantation, administering melflufen or a salt thereof and dexamethasone to the multiple myeloma patient 75 years of age or older.

[0176] The present invention further provides melflufen or a salt thereof for use in the prevention or treatment of multiple myeloma in a multiple myeloma patient aged 75 years or older and unsuitable for stem cell transplantation.The present invention further provides melflufen or a salt thereof and dexamethasone for use in the prevention or treatment of multiple myeloma in a multiple myeloma patient aged 75 years or older and unsuitable for stem cell transplantation.

[0177] The present invention further provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising: the patient undergoing stem cell transplantation; determining whether the disease has progressed at least 36 months after transplantation; and if the patient undergoes stem cell transplantation and the disease has progressed at least 36 months after transplantation, administering melflufen or a salt thereof to the patient.

[0178] The present invention further provides a method for preventing or treating multiple myeloma in a multiple myeloma patient, comprising: the patient undergoing a stem cell transplant; determining whether the disease has progressed at least 36 months after transplantation; and if the patient undergoes a stem cell transplant and the disease has progressed at least 36 months after transplantation, administering to the patient melflufen or a salt thereof and dexamethasone.

[0179] In such uses and methods of treatment for multiple myeloma patients aged 75 years or older, the patient may also be a multiple myeloma patient who has not undergone stem cell transplantation, or a multiple myeloma patient who has undergone stem cell transplantation at least 5 years ago. Therefore, in the uses and methods of treatment for multiple myeloma patients aged 75 years or older who have not undergone stem cell transplantation, the methods and uses of the present invention may further comprise a step of determining whether the patient has undergone stem cell transplantation, and administering melflufen or a salt thereof (and optionally dexamethasone) to the multiple myeloma patient aged 75 years or older who has not undergone stem cell transplantation if the patient has not undergone stem cell transplantation. In the uses and methods of treatment for multiple myeloma patients aged 75 years or older who have undergone stem cell transplantation at least 5 years ago, the methods and uses of the present invention may further comprise a step of determining whether the patient has undergone stem cell transplantation at least 5 years ago, and administering melflufen or a salt thereof (and optionally dexamethasone) to the multiple myeloma patient aged 75 years or older who has undergone stem cell transplantation at least 5 years ago if the patient has undergone stem cell transplantation at least 5 years ago.

[0180] The following remarks further define aspects of the invention. Mode 1 – have not undergone a stem cell transplant; - Have had a stem cell transplant at least 5 years ago, - 75 years of age or older; - Age 75 or older who have not had a stem cell transplant or who have had a stem cell transplant at least 5 years ago; or - has undergone a stem cell transplant and has progressed with disease at least 36 months after said transplant; Melflufen or a salt thereof and dexamethasone for use in the prevention or treatment of multiple myeloma in a multiple myeloma patient. Aspect 2. The melflufen or a salt thereof and dexamethasone for use according to aspect 12, wherein the melflufen is administered at a dose of about 1 to 150 mg (excluding the mass of the counterion), for example, at a dose of 1 to 50 mg (excluding the mass of the counterion) (for example, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 mg). Aspect 3. Melflufen or a salt thereof and dexamethasone for use according to Aspect 1 or 2, wherein the dexamethasone is administered at a dose of about 5 mg to 100 mg, more preferably 10 mg to 80 mg, and most preferably 20 mg to 60 mg (e.g., 40 mg or 20 mg). Aspect 4 Melflufen or a salt thereof for use according to any of aspects 1 to 3, wherein the dose of melflufen is administered on day 1 of a cycle of 1 to 42 days (e.g. 21 to 35 days, in particular 21, 28, 29, 30 or 35 days). Aspect 5: The dose of melflufen (excluding the mass of the salt) is administered parenterally at an infusion rate of 0.3 to 1.8 mg / min (e.g., parenterally at an infusion rate of 1.1 to 1.8 mg / min). Aspect 6. Melflufen or a salt thereof and dexamethasone for use according to any one of Aspects 1 to 4, wherein the melflufen or a salt thereof is administered simultaneously, sequentially or separately with the dexamethasone (e.g., a dose of 20 mg or 40 mg of dexamethasone). Aspect 7 Melflufen or a salt thereof and dexamethasone for use according to any one of Aspects 1 to 5, wherein the melflufen or a salt thereof is administered simultaneously, sequentially or separately with the one or more additional therapeutic agents, for example, the one or more additional therapeutic agents are selected from steroids (e.g., prednisone and dexamethasone), IMiDs (e.g., thalidomide, lenalidomide and pomalidomide), PIs (e.g., bortezomib, carfilzomib and ixazomib), histone deacetylase (HDAC) inhibitors (e.g., panobinostat), conventional chemotherapy drugs (e.g., melphalan, cyclophosphamide, doxorubicin, bendamustine), anti-CD38 antibodies (daratumumab), and anti-SLAMF7 antibodies (elotuzumab), preferably, the one or more additional therapeutic agents are selected from daratumumab and bortezomib. Aspect 8 A pharmaceutical formulation comprising melflufen or a salt thereof, and a pharmaceutical formulation comprising dexamethasone, for use according to any one of aspects 1 to 7. A method for preventing or treating multiple myeloma, comprising: - Not having had a stem cell transplant, - Have had a stem cell transplant at least 5 years ago, - 75 years of age or older, or - Age 75 or older who have not had a stem cell transplant or who have had a stem cell transplant at least 5 years ago A method comprising the step of administering melflufen or a salt thereof and dexamethasone to a patient with multiple myeloma. Aspect 10: The patient is administered melflufen or a salt thereof, either simultaneously, sequentially, or separately, with one or more additional therapeutic agents, the one or more additional therapeutic agents being selected from the group consisting of steroids (e.g., prednisone and dexamethasone), IMiDs (e.g., thalidomide, lenalidomide, and pomalidomide), PIs (e.g., bortezomib, carfilzomib, and ixazomib), histone deacetylase (HDAC) inhibitors (e.g., panobinostat), conventional chemotherapy drugs (e.g., melphalan, cyclophosphamide, cyclosporine, cyclosporine), and the like. 10. The method of embodiment 9, wherein the one or more further therapeutic agents are selected from anti-B cell maturation antigens (belantamab), inhibitors of nuclear export (selinexor), and autologous chimeric antigen receptor (CAR) T cell therapy against a B cell maturation antigen (siltacabtagene), preferably wherein the one or more further therapeutic agents are selected from daratumumab and bortezomib. Aspect 11: The method includes determining whether the patient has undergone a stem cell transplant, and administering melflufen or a salt thereof to the patient if the patient has not undergone a stem cell transplant; or determining whether the patient underwent a stem cell transplant at least 5 years ago, and administering melflufen or a salt thereof to the patient if the patient underwent a stem cell transplant at least 5 years ago; and / or The method according to aspect 9 or 10, comprising determining whether the patient is 75 years of age or older, and administering melflufen or a salt thereof to the patient if the patient is 75 years of age or older. Aspect 12. The method according to any of aspects 9 to 11, wherein the method comprises determining whether the patient is suitable for stem cell transplantation, and if the patient is not suitable for stem cell transplantation, administering melflufen or a salt thereof to the patient. Aspect 13 - not having undergone a stem cell transplant; - Have had a stem cell transplant at least 5 years ago, - 75 years of age or older; - Age 75 or older who have not had a stem cell transplant or who have had a stem cell transplant at least 5 years ago; or - has undergone a stem cell transplant and has progressed with disease at least 36 months after said transplant; 1. Use of melflufen or a salt thereof and dexamethasone in the manufacture of a medicament for the treatment of multiple myeloma in a multiple myeloma patient. Aspect 14. A kit comprising melflufen, dexamethasone and one or more further therapeutic agents for use in the prevention or treatment of multiple myeloma in a patient according to any of aspects 1 to 7, wherein the one or more further therapeutic agents are selected from the group consisting of steroids (e.g. prednisone), IMiDs (e.g. thalidomide, lenalidomide and pomalidomide), PIs (e.g. bortezomib, carfilzomib and ixazomib), histone deacetylase (HDAC) inhibitors (e.g. panobinostat), conventional chemotherapeutic agents (e.g. mesylate), cyclosporine (CSF ... a kit comprising one or more additional therapeutic agents selected from anti-B cell maturation antigens (belantamab), inhibitors of nuclear export (selinexor), and autologous chimeric antigen receptor (CAR) T cell therapy against a B cell maturation antigen (siltacabtagene), preferably selected from daratumumab and bortezomib. Aspect 15: The multiple myeloma patient: have received at least two prior lines of therapy for multiple myeloma, e.g., at least two prior lines of therapy including lenalidomide and a protease inhibitor, either sequentially or as part of a combination regimen; refractory (e.g., relapsed and refractory, or refractory) to the most recent line of therapy and / or lenalidomide administered within 18 months prior to treatment; refractory (e.g., relapsed and refractory, or refractory) to at least an alkylating agent; is refractory (e.g., relapsed and refractory, or refractory) to at least an anti-CD38 antibody; refractory (e.g., relapsing and refractory, or refractory) to at least an immunomodulatory drug (IMiD); refractory to lenalidomide (e.g., refractory or relapsed refractory), particularly refractory to lenalidomide (e.g., refractory or relapsed refractory) to the last treatment the patient received for multiple myeloma; is refractory to one or more (e.g., 1, 2, 3, 4, or 5 or more) drugs from two or more classes of drugs selected from protease inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents, and anti-CD38 antibodies; is refractory (e.g., refractory or relapsed refractory) to at least lenalidomide and one, two, three, or four other drugs, e.g., at least one drug selected from a protease inhibitor (PI), an immunomodulatory drug (IMiD), an alkylating agent, and an anti-CD38 antibody (e.g., two, three, or four other drugs including at least one protease inhibitor (PI) and an immunomodulatory drug (IMiD)); is refractory (e.g., refractory or relapsed refractory) to at least pomalidomide and / or daratumumab, and / or RRMM, Melflufen or a salt thereof for the use according to any one of aspects 1 to 7, the pharmaceutical formulation according to aspect 8, the method according to any one of aspects 9 to 12, the use according to aspect 13, or the kit according to aspect 14. Aspect 16: The multiple myeloma patient, are at least 65, 70, 75 or 80 years old; suffer from cardiovascular disease, and / or Have a lung disease, Melflufen or a salt thereof for use according to any one of aspects 1 to 7 or 15, the pharmaceutical formulation according to aspect 8 or 15, the method according to any one of aspects 9 to 12 or 15, the use according to aspect 13 or 15, or the kit according to aspect 14 or 15. Aspect 17. Melflufen or a salt thereof for use according to any one of aspects 1 to 7 or 15 to 16, the pharmaceutical preparation according to any one of aspects 8 or 15 to 16, the method according to any one of aspects 9 to 12 or 15 to 16, the use according to any one of aspects 13 or 15 to 16, or the kit according to any one of aspects 14 to 16, wherein the multiple myeloma patient is not suitable for stem cell transplantation. Aspect 18, wherein the multiple myeloma patient is Median body surface area (BSA) ≤ 1.855 m2; Revised International Staging Classification (R-ISS) for multiple myeloma, I or II; The patient is at high risk based on their cytogenetics, and / or Renal dysfunction (e.g., creatine clearance is less than 60 mL / min or 60 to 90 mL / min), particularly creatine clearance is less than 60 mL / min; Melflufen or a salt thereof for the use according to any one of aspects 1 to 7 or 15 to 17, the pharmaceutical preparation according to any one of aspects 8 or 15 to 17, the method according to any one of aspects 9 to 12 or 15 to 17, the use according to any one of aspects 13 or 15 to 17, or the kit according to any one of aspects 14 to 17. Aspect 19: wherein the multiple myeloma patient is RRMM, refractory to lenalidomide (e.g., refractory to lenalidomide administered (e.g., 10 mg or more) within 18 months prior to treatment), and / or (preferably and) have received at least two prior lines of therapy (e.g., 2, 3, or 4 prior lines of therapy); Melflufen or a salt thereof for the use according to any one of aspects 1 to 7 or 15 to 18, the pharmaceutical preparation according to any one of aspects 8 or 15 to 18, the method according to any one of aspects 9 to 12 or 15 to 18, the use according to any one of aspects 13 or 15 to 18, or the kit according to any one of aspects 14 to 18. Aspect 20. Melflufen or a salt thereof for use according to any one of aspects 1 to 7 or 15 to 19, the pharmaceutical preparation according to any one of aspects 8 or 15 to 19, the method according to any one of aspects 9 to 12 or 15 to 19, the use according to any one of aspects 13 or 15 to 19, or the kit according to any one of aspects 14 to 19, wherein the multiple myeloma patient has not undergone stem cell transplantation. EXAMPLES

[0181] The following examples illustrate the invention. Example 1 Exam description Overview: A randomized, controlled, open-label, multicenter, phase III study in patients with RRMM after 2-4 prior lines of therapy who were refractory to both the most recent line of therapy and to lenalidomide (≥10 mg) within 18 months prior to randomization as evidenced by disease progression within 60 days of the last dose of lenalidomide. Patients received melflufen plus dexamethasone or pomalidomide plus dexamethasone.

[0182] Detailed Description: A randomized, controlled, open-label, multicenter phase III study in patients with RRMM after 2-4 prior lines of therapy who were refractory to both the most recent line of therapy and to lenalidomide as evidenced by disease progression within 60 days of completing the last dose of lenalidomide. Patients were randomized into one of two arms (see Table 1): Arm A: Melphalan flufenamide (melflufen) 40 mg on day 1 and dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. Arm B: Pomalidomide 4 mg daily on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle.

[0183] Patients 75 years or older had their dexamethasone dose reduced to 20 mg on days 1, 8, 15, and 22 in both arms A and B. Patients received treatment until documented disease progression, unacceptable toxicity, or until the patient / treating physician determined that continuation was not in the patient's best interest. Dose modifications and delays in treatment were based on patient tolerability, as detailed in the protocol. Regardless of dexamethasone toxicity, it was recommended to continue weekly dexamethasone if cycle delays occurred.

[0184] Study design Type of study: Interventional (clinical trial) Actual participants: 495 Allocation: Randomized Intervention model: Parallel group comparison Blinding: Single blind (by assessor) Primary purpose: treatment Official Title: A randomized, controlled, open-label, phase III study comparing melflufen / dexamethasone to pomalidomide / dexamethasone in patients with relapsed refractory multiple myeloma refractory to lenalidomide

[0185] Arms and Interventions [Table 1]

[0186] Primary outcome measures: 1. Progression-free survival (PFS) [time frame: time from randomization to progression or to 24 months after the end of treatment if no progression]: to compare PFS in melflufen plus dexamethasone (Arm A) and pomalidomide plus dexamethasone (Arm B) as assessed by an Independent Review Committee (IRC) according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC)

[0187] Secondary efficacy measures: 1. Overall Response Rate (ORR) [Time frame: from randomization to best response achieved before progression or, if no progression, to 24 months after the end of treatment]: To assess ORR and compare it between Arm A and Arm B. 2. Duration of Response (DOR) [Time frame: from first evidence of response until confirmed progression or, in the absence of progression, until 24 months after the end of treatment]: To assess DOR and compare it between Arm A and Arm B. 3. Overall Survival (OS) [Time frame: from randomization to end of study (2 years after progression)]: To assess OS and compare it between Arm A and Arm B 4. Safety and Tolerability: Number of patients with treatment-emergent adverse events, including laboratory and vital sign abnormalities, as assessed by CTCAE v4.0 [Time frame: from start of dosing to 30 days after last dose]: To assess safety and tolerability and compare it between Arm A and Arm B. Number of patients with treatment-emergent adverse events, including laboratory and vital sign abnormalities, as assessed by CTCAE v4.0, will be presented. No formal statistical analysis will be performed for safety endpoints.

[0188] Eligibility Criteria Eligible age for the test: 18 years and older (adults, seniors) Eligible genders: All Participation of healthy volunteers: None Inclusion criteria: 1. Male or female aged 18 or over 2. Previously diagnosed with multiple myeloma with documented disease progression requiring further treatment at the time of screening 3. Measurable disease defined as any of the following: · Serum monoclonal protein ≥ 0.5 g / dL by protein electrophoresis. - 24-hour urinary monoclonal protein electrophoresis > 200 mg / 24 hours Serum free light chains ≥ 10 mg / dL and abnormal serum kappa to lambda free light chain ratio 4.Has received 2-4 prior lines of therapy, either sequentially or in the same line, including lenalidomide and a PI, and is refractory (relapsed and refractory or unresponsive) to both the most recent line of therapy and to lenalidomide (≥10 mg) within 18 months prior to randomization. Refractory to lenalidomide is defined as progression on lenalidomide therapy or within 60 days of the most recent dose after at least 2 cycles of lenalidomide at least 14 doses per cycle. 5. Life expectancy is 6 months or more 6.Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 7. Females of child bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to initiation of treatment. Participants must consent to ongoing pregnancy testing. All patients must be willing to comply with all requirements of the US Pomalidomide Risk Evaluation and Mitigation Strategy (REMS) program or Pomalidomide Pregnancy Prevention Plan (PPP). 8. Understand the purpose and risks of the study and are competent to provide signed and dated informed consent. 9. In a 12-lead electrocardiogram (ECG), the QT interval calculated by the Fridericia formula (QTcF) is a Fridericia interval of 470 milliseconds or less. 10. The following laboratory test results must be met during screening and immediately prior to study drug administration on Day 1 of Cycle 1: ·1,000 cells / mm 3 (1.0×10 9 Absolute neutrophil count (ANC) of ≥ 100 / L ·75,000 cells / mm 3 (75×10 9 / L) or higher Hemoglobin level above 8.0g / dl Patients with total bilirubin levels less than 1.5 times the upper limit of normal (ULN) or diagnosed with Gilbert syndrome must be confirmed and approved by a medical monitor. Aspartate transaminase (AST / SGOT) and alanine transaminase (ALT / SGPT) levels must be less than 3.0 times the ULN. Renal function: Creatinine clearance estimated by the Cockcroft-Gault formula must be 45 mL / min or greater 11. Must be able to take antithrombotic prophylaxis 12. Have or willing to have an acceptable central venous catheter (Port a cath, peripherally inserted central catheter [PICC-line], or central venous catheter) (insertion required only if randomized to Arm A)

[0189] Exclusion criteria: 1. Primary refractory disease (i.e., no response (MR or better) to any prior therapy) 2. Evidence of mucosal or internal bleeding or unresponsiveness to platelet transfusion 3. Has a medical condition that, in the opinion of the investigator, poses undue risk to the patient or adversely affects the patient's participation in this study 4. Previous exposure to pomalidomide 5. Known intolerance to IMiDs 6. Known active infection requiring parenteral or oral anti-infective therapy within 14 days prior to randomization 7. Other malignancies diagnosed or requiring treatment within the past 3 years, except adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in situ of the cervix or breast, or very low-risk and low-risk prostate cancer under active surveillance 8. Pregnant or breastfeeding women 9. Serious psychiatric illness, active alcoholism, or drug intoxication that may interfere with or confound compliance or follow-up evaluations. 10. Known human immunodeficiency virus or active hepatitis C virus infection 11. Active hepatitis B virus infection (defined as HBsAg+) Patients who have previously received the Hepatitis B vaccine are allowed (defined as HBsAg-, anti-HBs+, or anti-HBc-) Inactive hepatitis B (HBsAg-, anti-HBs+, anti-HBc+) may be included at the investigator's discretion after considering the risk of reactivation 12. Symptomatic amyloidosis or plasma cell leukemia 13. POEMS syndrome 14. Prior cytotoxic therapy for multiple myeloma, including cytotoxic investigational agents, within 3 weeks prior to randomization (within 6 weeks for nitrosoureas). IMiDs, PIs, and / or corticosteroids within 2 weeks prior to randomization. Other investigational therapies and monoclonal antibodies within 4 weeks prior to randomization. Oral prednisone or equivalent up to a maximum of 10 mg once daily for symptomatic management of coexisting conditions is permitted, but the dose must have been stable for at least 7 days prior to randomization. 15. Residual adverse events from prior therapy greater than grade 1 prior to randomization (any grade of alopecia and / or non-painful grade 2 neuropathy is permitted) 16. Peripheral stem cell transplantation within 12 weeks of randomization 17. Allogeneic stem cell transplant with active graft-versus-host disease 18. Major surgery or radiation therapy within 4 weeks of randomization 19. Known intolerance to steroid treatment

[0190] result Table 2 summarizes some of the characteristics of the patients included in the study of Example 1. [Table 2]

[0191] Forest plots of PFS and OS showing hazard ratios for patients not undergoing stem cell transplant (n=121 for melflufen + dexamethasone group; n=129 for pomalidomide + dexamethasone group) are shown in Figures 1-4. Hazard ratios are a measure of the relative risk of an event at each time point during follow-up when melflufen is administered versus pomalidomide. Values ​​below 1 indicate a favorable treatment effect for melflufen and values ​​above 1 indicate a favorable treatment effect for pomalidomide.

[0192] FIG. 5 is a graph of PFS (%) over time for patients who have not undergone stem cell transplantation (n=121 for the melflufen + dexamethasone group; n=129 for the pomalidomide + dexamethasone group) and for patients who have undergone stem cell transplantation (n=125 for the melflufen + dexamethasone group; n=120 for the pomalidomide + dexamethasone group). The data from the graph are also shown as numbers below the graph. The line on the graph shows the results for the melflufen + dexamethasone group who have not undergone stem cell transplantation. FIG. 6 is a graph of OS (%) over time for patients who have not undergone stem cell transplantation (n=121 for the melflufen + dexamethasone group; n=129 for the pomalidomide + dexamethasone group). Again, the data from the graph are also shown as numbers below the graph. The line on the graph shows the results for the melflufen + dexamethasone group who have not undergone stem cell transplantation.

[0193] As can be seen from Figures 1-6, melflufen plus dexamethasone provided significantly better therapeutic effects in terms of PFS and OS compared to pomalidomide plus dexamethasone for patients without prior stem cell transplantation. In this study, the median PFS of melflufen-treated multiple myeloma patients (n=121) without prior stem cell transplantation was 9.3 months, whereas the median PFS of pomalidomide-treated multiple myeloma patients (n=129) without prior stem cell transplantation was 4.6 months. In addition, the median OS of melflufen-treated multiple myeloma patients (n=121) without prior stem cell transplantation was 21.6 months, whereas the median OS of pomalidomide-treated multiple myeloma patients (n=129) without prior stem cell transplantation was 16.5 months. As shown in Figures 1-4, these improved treatment effects of melflufen plus dexamethasone compared to pomalidomide plus dexamethasone were consistent across demographic and disease characteristics in patients who had not previously undergone stem cell transplantation.

[0194] Figures 7 and 8 show a table of hazard ratios and events for PFS (Figure 7) and a table of hazard ratios and events for OS (Figure 8) for patients in Example 1 who were treated with melflufen + dexamethasone (n=121) or pomalidomide + dexamethasone (n=129) without stem cell transplantation, who were treated with melflufen + dexamethasone and had a stem cell transplant that lasted 2.5 years or less (n=43), 2.5 to 5 years (n=48), or more than 5 years (n=34), or who were treated with pomalidomide + dexamethasone and had a stem cell transplant that lasted 2.5 years or less (n=35), 2.5 to 5 years (n=51), or more than 5 years (n=34).

[0195] As can be seen from Figures 7 and 8, melflufen plus dexamethasone provided significantly better therapeutic effects in terms of PFS and OS than pomalidomide plus dexamethasone for patients who had not undergone stem cell transplantation (hazard ratio for PFS = 0.59; hazard ratio for OS = 0.78) or had undergone stem cell transplantation at least 5 years previously (hazard ratio for PFS = 0.73; hazard ratio for OS = 0.87). Melflufen plus dexamethasone also provided better therapeutic effects in terms of PFS compared to pomalidomide plus dexamethasone for patients who had undergone stem cell transplantation 2.5 to 5 years previously (hazard ratio = 0.83).

[0196] In the data shown in Figures 9 and 10, patients who had previously undergone stem cell transplantation and progressed within 36 months thereafter are excluded from the analysis. That is, the figures represent patients who had not previously undergone stem cell transplantation or who had previously undergone stem cell transplantation and progressed disease more than 36 months thereafter. As can be seen from Figures 9 and 10, melflufen + dexamethasone provided a significantly better treatment effect in terms of OS (23.6 months) compared with pomalidomide + dexamethasone (19.8 months) for patients who had not been included in the group of patients who had undergone stem cell transplantation and progressed within 36 months (hazard ratio = 0.83).

[0197] Finally, surprisingly, this study found that the median PFS of multiple myeloma patients aged 75 years or older who received melflufen was 9.4 months, while the median PFS of multiple myeloma patients who received pomalidomide and had not received a previous stem cell transplant was 4.6 months.In addition, this study found that the median overall survival (OS) of multiple myeloma patients aged 75 years or older who received melflufen was 21.6 months, while the median OS of multiple myeloma patients who received pomalidomide and had not received a previous stem cell transplant was 8.3 months.Some of the patients in the age range that was part of the study in Example 1 had not received a previous stem cell transplant.Some of the patients in the age range that was part of the study in Example 1 had received a previous stem cell transplant and had disease progression more than 36 months after that.In both of these subsets, the improvement effect was very significant. Thus, the results of the examples show that melflufen treatment was particularly beneficial in patients aged 75 years and older, particularly in patients of that age who had not previously undergone stem cell transplantation, and also in patients of that age who had previously undergone stem cell transplantation and whose disease progressed more than 36 months thereafter.

Claims

A pharmaceutical preparation for use in the prevention or treatment of multiple myeloma in patients with multiple myeloma, comprising melphufen or a salt thereof, - who have not received a stem cell transplant, - who received a stem cell transplant at least 5 years ago, - who are 75 years of age or older, - who are 75 years of age or older and have not received a stem cell transplant, or who are 75 years of age or older and received a stem cell transplant at least 5 years ago, or - who received a stem cell transplant and whose disease progressed at least 36 months after the transplant,

2. The pharmaceutical preparation according to claim 1, wherein the melphufen is administered at a dose of about 1 to 150 mg (excluding the mass of the counter ion).

3. The pharmaceutical preparation according to claim 2, wherein the melphufen is administered at a dose of 1 to 50 mg (excluding the mass of the counter ion).

4. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the dose of melphufen is administered on the first day of a 1 to 42-day cycle.

5. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the dose of melphufen (excluding the mass of the salt) is administered as parenteral medication at an infusion rate of 0.3 to 1.8 mg / min.

6. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the melphufen or a salt thereof is administered simultaneously, sequentially, or separately with one or more other therapeutic agents.

7. The pharmaceutical preparation 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 ixazomib), histone deacetylase (HDAC) inhibitors (e.g., panobinostat), conventional chemotherapeutic agents (e.g., melphalan, cyclophosphamide, doxorubicin, bendamustine), anti-CD38 antibodies (daratumumab), and anti-SLAMF7 antibodies (elotuzumab).

8. The pharmaceutical preparation according to claim 6, wherein the one or more other therapeutic agents are selected from antibodies against B cell maturation antigen (e.g., belantamab), inhibitors of nuclear export (e.g., selinexor), and autologous chimeric antigen receptor (CAR) T cell therapeutic agents against B cell maturation antigen (e.g., silotuzumab).

9. The pharmaceutical preparation according to claim 7, wherein the other therapeutic agent is dexamethasone.

10. - who have not received a stem cell transplant, - who received a stem cell transplant at least 5 years ago, - who are 75 years of age or older, ​ - For patients aged 75 or older who have not received a stem cell transplant, or who received a stem cell transplant at least 5 years ago, or - For patients who have received a stem cell transplant and in whom the disease has progressed at least 36 months after the transplant, Use of melphufen or a salt thereof in the manufacture of a medicament for the treatment of multiple myeloma in patients with multiple myeloma.

11. A kit comprising melphufen and one or more other therapeutic agents for use in the prevention or treatment of multiple myeloma in a patient according to claim 1, 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 ixazomib), histone deacetylase (HDAC) inhibitors (e.g., panobinostat), conventional chemotherapeutic agents (e.g., melphalan, cyclophosphamide, doxorubicin, bendamustine), anti-CD38 antibodies (daratumumab), and anti-SLAMF7 antibodies (elotuzumab), or an antibody against B cell maturation antigen (belantamab), an inhibitor of nuclear export (selinexor), and an autologous chimeric antigen receptor (CAR) T cell therapeutic agent against B cell maturation antigen (cilta-cel), preferably, the one or more other therapeutic agents are selected from dexamethasone, daratumumab and bortezomib, more preferably, the other therapeutic agent is dexamethasone, the kit.

12. The patient with multiple myeloma has received at least two previous treatment lines for multiple myeloma, for example, at least two previous treatment lines including lenalidomide and a protease inhibitor, sequentially, or as part of a combination regimen, is refractory (e.g., relapsed and refractory, or refractory) to the most recent treatment line and / or lenalidomide administered within 18 months before treatment, is refractory (e.g., relapsed and refractory, or refractory) to at least an alkylating agent, is refractory (e.g., relapsed and refractory, or refractory) to at least an anti-CD38 antibody, and is refractory (e.g., relapsed and refractory, or refractory) to at least an immunomodulatory drug (IMiD), is refractory to lenalidomide (e.g., refractory or relapsed refractory), particularly refractory to the lenalidomide of the last treatment received by the patient with respect to multiple myeloma (e.g., refractory or relapsed refractory), Refractory to one or more (e.g., 1, 2, 3, 4, or more) drugs of two or more classes of drugs selected from protease inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents, and anti-CD38 antibodies Refractory (e.g., refractory or relapsed refractory) to at least lenalidomide and one, two, three, or four other drugs, e.g., at least one drug selected from protease inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents, and anti-CD38 antibodies (e.g., two, three, or four other drugs including at least one protease inhibitor (PI) and immunomodulatory drug (IMiD)) Refractory (e.g., refractory or relapsed refractory) to at least pomalidomide and / or daratumumab, and / or Is RRMM The pharmaceutical preparation according to claim 1, the use according to claim 10, or the kit according to claim 11.

13. Wherein the multiple myeloma patient Is at least 65, 70, 75, or 80 years old Suffers from cardiovascular disease, and / or Suffers from lung disease The pharmaceutical preparation according to claim 1, the use according to claim 10, or the kit according to claim 11.

14. The pharmaceutical preparation according to claim 1, the use according to claim 10, or the kit according to claim 11, wherein the multiple myeloma patient is not suitable for stem cell transplantation.

15. Wherein the multiple myeloma patient The median body surface area (BSA) is 1.855 m ２ Hereinafter, Has an ISS classification of I or II in the Revised International Staging System (R-ISS) for multiple myeloma Is a high-risk patient from the perspective of the patient's cytogenetics, and / or Has renal dysfunction (e.g., creatinine clearance is less than 60 mL / min or 60 - 90 mL / min), in particular, creatinine clearance is less than 60 mL / min The pharmaceutical preparation according to claim 1, the use according to claim 10, or the kit according to claim 11.

16. Wherein the multiple myeloma patient Is RRMM Is refractory to lenalidomide (e.g., refractory to lenalidomide administered within 18 months before treatment (e.g., at 10 mg or more)), and / or (preferably and) Has previously received at least two treatment lines (e.g., 2, 3, or 4 previous treatment lines) The pharmaceutical preparation according to claim 1, the use according to claim 10, or the kit according to claim 11.

17. The pharmaceutical preparation according to claim 1, the use according to claim 10, or the kit according to claim 11, wherein the multiple myeloma patient has not received stem cell transplantation.

Images