Use of isatuximab for treatment of relapsed and / or refractory multiple myeloma

Abstract

To provide a method for treating a patient who has received one to three prior lines of therapy for multiple myeloma.SOLUTION: The present disclosure provides methods for treating multiple myeloma (such as refractory multiple myeloma or relapsed and refractory multiple myeloma) in an individual who has received one to three prior therapies (or prior lines of therapy) for multiple myeloma. The methods comprise administering to the individual an anti-CD38 antibody, carfilzomib, and dexamethasone.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 944,809, filed December 6, 2019; European Patent Application No. 20315186.5, filed April 17, 2020; U.S. Provisional Application No. 63 / 023,198, filed May 11, 2020; U.S. Provisional Application No. 63 / 037,353, filed June 10, 2020; and U.S. Provisional Application No. 63 / 094,833, filed October 21, 2020, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Submission of sequence listing as an ASCII text file The contents of the following submission regarding ASCII text files are incorporated herein by reference in their entirety: Computer Readable Format (CRF) of Sequence Listing (Filename: 183952033040SEQLIST.txt, Recording Date: December 4, 2020, Size: 10kb).

[0003] Field The present disclosure relates to methods of treating multiple myeloma by administering an anti-CD38 antibody in combination with carfilzomib and dexamethasone. [Background technology]

[0004] Multiple myeloma (MM) is a malignant plasma cell disorder characterized by clonal proliferation of plasma cells in the bone marrow (BM) and the production of excessive amounts of monoclonal immunoglobulins (usually IgG or IgA types or free urinary light chains, i.e., paraproteins, M proteins, or M components). Patients with MM may experience bone pain, fractures, fatigue, anemia, infections, hypercalcemia, and kidney problems (Non-Patent Document 1). CD38 expression is particularly prominent in MM, as over 98% of patients are positive for this protein (Non-Patent Document 2; Non-Patent Document 3). The strong and uniform expression of CD38 on malignant clonal MM cells, in contrast to the restricted expression pattern on normal cells, suggests that this antigen may be useful for specific targeting of tumor cells.

[0005] The current goal of MM therapy is to control the disease as effectively as possible, maximize quality of life, and prolong survival. While the trajectory of the disease varies from patient to patient, relapse is inevitable, and the intensity and duration of response to each treatment after relapse generally diminishes. Generally, MM patients receive lifelong treatment regimens including drugs such as proteasome inhibitors (e.g., bortezomib, ixazomib, and carfilzomib) and immunomodulatory agents or "IMiDs®" (e.g., lenalidomide, pomalidomide, and thalidomide), monoclonal antibodies (e.g., elotuzumab), and histone deacetylase (HDAC) inhibitors (e.g., panobinostat), alone or in combination. However, when patients become refractory to these drugs, survival is limited, and new treatment options are needed to treat patients after failure of stem cell transplantation (SCT), chemotherapy, proteasome inhibitors, and immunomodulatory agents (IMiDs®). Despite dramatic improvements in patient outcomes with new therapies, MM remains an incurable disease. Therefore, treatment of patients who have received one to three prior lines of therapy for multiple myeloma remains an unmet medical need.

[0006] Patent applications, patent publications, and UniProtKB / Swiss-Prot accessions All references cited herein, including reference numbers, are incorporated by reference in their entirety as if each individual reference was specifically and individually indicated to be incorporated by reference. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Rolling et al. (2015) Lancet. Volume 385 (No. 9983): pp. 2197-208 [Non-patent document 2] Goldmacher et al. (1994) Blood. Volume 84 (No. 9): pp. 3017-25 [Non-patent document 3] Lin et al. (2004) Am J Clin Pathol. Volume 121 (No. 4): pp. 482-8 Summary of the Invention [Means for solving the problem]

[0008] A method of treating a human individual with multiple myeloma is provided, the method comprising: (a) administering to a human individual a heavy chain variable domain (V) comprising a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3). H ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). L ), carfilzomib, and dexamethasone to the individual, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg and the carfilzomib is administered at a dose of 20 mg / m 2 or 56 mg / m 2and dexamethasone is administered at a dose of 20 mg, the individual has received at least one prior therapy (e.g., 1 to 3 prior therapies) for multiple myeloma, and the treatment prolongs the individual's progression-free survival (PFS). In some embodiments, the treatment prolongs the individual's overall survival (OS). Methods of treating a human individual with multiple myeloma are provided, comprising: (a) a heavy chain variable domain (V) comprising a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3). H ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). L ), carfilzomib, and dexamethasone to the individual, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg and the carfilzomib is administered at a dose of 20 mg / m 2 or 56 mg / m 2 and dexamethasone is administered at a dose of 20 mg, and the individual has received more than three prior therapies for multiple myeloma, and the treatment prolongs the individual's progression-free survival (PFS). In some embodiments, the treatment prolongs the individual's overall survival (OS).

[0009] Also provided is a method of treating a human individual with multiple myeloma, the method comprising: (a) administering to a human a subject a heavy chain variable domain (V) comprising a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3). H), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). L administering to the individual an anti-CD38 antibody comprising carfilzomib, and dexamethasone. wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg and the carfilzomib is administered at a dose of 20 mg / m 2 or 56 mg / m 2 and dexamethasone is administered at a dose of 20 mg, wherein the individual has received at least one prior treatment (e.g., 1 to 3 prior treatments) for multiple myeloma, and the treatment prolongs the overall survival (OS) of the individual.

[0010] Also provided is a method of treating a human individual with multiple myeloma, the method comprising: (a) administering to a human a subject a heavy chain variable domain (V) comprising a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3). H ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). L ), carfilzomib, and dexamethasone to the individual, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg and the carfilzomib is administered at a dose of 20 mg / m 2 or 56 mg / m 2 and dexamethasone is administered at a dose of 20 mg, where the individual has received more than three prior therapies for multiple myeloma, and the treatment extends the overall survival (OS) of the individual.

[0011] In some embodiments, a method of treating a human individual with multiple myeloma is provided, the method comprising: (a) administering to a human a subject a heavy chain variable domain (V) comprising a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3). H ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). L ), carfilzomib, and dexamethasone to the individual, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg and the carfilzomib is administered at a dose of 20 mg / m 2 or 56 mg / m 2 and dexamethasone is administered at a dose of 20 mg, wherein the individual has received at least one prior treatment (e.g., 1-3 prior treatments) for multiple myeloma, and wherein the individual has received at least 10 mg of steroid hormone-lowering hormone (HSH) therapy after treatment. -5 The following thresholds are negative for minimal residual disease:

[0012] In some embodiments, a method of treating a human individual with multiple myeloma is provided, the method comprising: (a) administering to a human a subject a heavy chain variable domain (V) comprising a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3). H ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). L), carfilzomib, and dexamethasone to the individual, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg and the carfilzomib is administered at a dose of 20 mg / m 2 or 56 mg / m 2 and dexamethasone is administered at a dose of 20 mg, wherein the individual has received at least one prior treatment (e.g., 1 to 3 prior treatments) for multiple myeloma, and wherein the individual has impaired renal function at the start of treatment.

[0013] In some embodiments, the individual has received one prior treatment for multiple myeloma. In some embodiments, the individual has received two or more prior treatments for multiple myeloma (e.g., two prior treatments or three prior treatments, etc.). In some embodiments, the individual has received one or more prior treatments for multiple myeloma (e.g., two prior treatments or three prior treatments, etc.). The individual has received more than three prior therapies for multiple myeloma. In some embodiments, the individual has received prior treatment with a proteasome inhibitor. In some embodiments, the individual has received prior treatment with an immunomodulatory agent (e.g., thalidomide, lenalidomide, and / or pomalidomide). In some embodiments, the individual has received prior treatment with a proteasome inhibitor and an immunomodulatory agent. In some embodiments, the individual is classified as stage I or stage II according to the Revised International Staging System for multiple myeloma (R-ISS) at the start of treatment. In some embodiments, the individual is classified as stage III according to the R-ISS at the start of treatment. In some embodiments, the individual is not classified according to the R-ISS at the start of treatment. In some embodiments, the individual has one or more cytogenetic abnormalities selected from the group consisting of del(17p), t(4;14), and t(14;16). In some embodiments, the individual has renal impairment at the start of treatment. In some embodiments, the individual is 65 to under 75 years of age at the start of treatment. In some embodiments, the individual is 75 years of age or older at the start of treatment.

[0014] In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region (V) comprising the amino acid sequence of SEQ ID NO:7. H ) and a light chain variable region (V) comprising the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 9 L In some embodiments, the anti-CD38 antibody is isatuximab.

[0015] In some embodiments, the anti-CD38 antibody, carfilzomib, and dexamethasone are administered in a first 28-day cycle, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle, and the carfilzomib is administered at a dose of 20 mg / kg on days 1 and 2 of the first 28-day cycle. 2 at a dose of 56 mg / m on days 8, 9, 15, and 16. 2 and dexamethasone is administered at a dose of 20 mg / m on days 1, 2, 8, 9, 15, 16, 22, and 23 of the first 28-day cycle. In some embodiments, the anti-CD38 antibody, carfilzomib, and dexamethasone are further administered in one or more 28-day cycles following the first 28-day cycle, wherein the anti-CD38 antibody is administered at a dose of 20 mg / m on days 1 and 15 of the one or more 28-day cycles following the first 28-day cycle. 2 and carfilzomib is administered at a dose of 56 mg / m on each of days 1, 2, 8, 9, 15, and 16 of one or more 28-day cycles following the first 28-day cycle. 2and dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of one or more 28-day cycles following the first 28-day cycle. In some embodiments, dexamethasone is administered before the anti-CD38 antibody, which is administered before carfilzomib on days 1, 8, and 15 of the first 28-day cycle; and wherein dexamethasone is administered before the anti-CD38 antibody on day 22 of the first 28-day cycle. In some embodiments, dexamethasone is administered before the anti-CD38 antibody, which is administered before carfilzomib on days 1 and 15 of every 28-day cycle after the first 28-day cycle; and wherein dexamethasone is administered before carfilzomib on day 8 of every 28-day cycle following the first 28-day cycle. In some embodiments, the anti-CD38 antibody is administered intravenously. In some embodiments, the carfilzomib is administered intravenously. In some embodiments, the dexamethasone is administered orally.

[0016] In some embodiments, the individual receives 10 -4 , 10 -5 , 10 -6 or MRD-negative at or below that threshold.

[0017] Also provided herein are kits containing anti-CD38 antibodies for use in combination with carfilzomib and dexamethasone to treat multiple myeloma in an individual according to any one of the methods herein.

[0018] Also, an anti-CD38 antibody (a) comprising the amino acid sequence DYWMQ (SEQ ID NO: 1) a heavy chain variable domain (V) comprising CDR-H1, CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3); H), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). L ), for use in a method of treating multiple myeloma in an individual, the method comprising administering to the individual an anti-CD38 antibody, carfilzomib, and dexamethasone, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg and the carfilzomib is administered at a dose of 20 mg / m 2 or 56 mg / m 2 and dexamethasone is administered at a dose of 20 mg, wherein the individual has received at least one prior treatment (e.g., 1 to 3 prior treatments) for multiple myeloma, and wherein the treatment prolongs the individual's progression-free survival (PFS) and / or overall survival (OS).

[0019] The anti-CD38 antibody also includes: (a) a heavy chain variable domain (V) comprising a CDR-H1 having the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 having the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 having the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3); H ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). L ), for use in a method of treating multiple myeloma in an individual, the method comprising administering to the individual an anti-CD38 antibody, carfilzomib, and dexamethasone, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg and the carfilzomib is administered at a dose of 20 mg / m 2 or 56 mg / m 2and dexamethasone is administered at a dose of 20 mg, wherein the individual has received more than three prior therapies for multiple myeloma, and wherein the treatment prolongs the individual's progression-free survival (PFS) and / or overall survival (OS).

[0020] In some embodiments, the anti-CD38 antibody comprises: (a) a heavy chain variable domain (V) comprising a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3). H ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). L ), for use in a method of treating multiple myeloma in an individual, the method comprising administering to the individual an anti-CD38 antibody, carfilzomib, and dexamethasone, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg and the carfilzomib is administered at a dose of 20 mg / m 2 or 56 mg / m 2 and dexamethasone is administered at a dose of 20 mg, wherein the individual has received at least one prior treatment for multiple myeloma, and wherein the individual has a post-treatment threshold of 10 -5 Provided below are anti-CD38 antibodies that are minimal residual disease negative.

[0021] In some embodiments, the anti-CD38 antibody comprises: (a) a heavy chain variable domain (V) comprising a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3). H), and (b) CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6) comprising a light chain variable domain (V L ), for use in a method of treating multiple myeloma in an individual, the method comprising administering to the individual an anti-CD38 antibody, carfilzomib, and dexamethasone, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg and the carfilzomib is administered at a dose of 20 mg / m 2 or 56 mg / m 2 and dexamethasone is administered at a dose of 20 mg, wherein the individual has received at least one prior treatment for multiple myeloma, and wherein the individual has renal dysfunction at the start of treatment. [Brief explanation of the drawings]

[0022] [Figure 1] 1 provides a schematic diagram of the study design of the clinical trial described in the Examples. [Figure 2] An exemplary dosing schedule for an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone is provided. [Figure 3] Kaplan-Meier curves of progression-free survival (PFS) for patients receiving isatuximab + carfilzomib + dexamethasone (IKd) versus carfilzomib + dexamethasone (Kd). [Figure 4] Forest plots of subgroup analyses of progression-free survival are shown. Circles represent hazard ratios, and bars extend from the lower to upper bounds of the 95% confidence intervals of the estimated hazard ratios. [Figure 5] 1 shows Kaplan-Meier curves of time to next treatment (TNT) for patients receiving isatuximab + carfilzomib + dexamethasone (IKd) versus carfilzomib + dexamethasone (Kd). [Figure 6] Kaplan-Meier curves of progression-free survival by minimal residual disease (MRD) status are shown for patients receiving isatuximab + carfilzomib + dexamethasone (IKd) versus carfilzomib + dexamethasone (Kd). [Figure 7] Another forest plot of the subgroup analysis of progression-free survival is shown. Circles represent hazard ratios, and bars extend from the lower to upper bounds of the 95% confidence intervals of the estimated hazard ratios. DETAILED DESCRIPTION OF THE INVENTION

[0023] Detailed Description definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural unless the content clearly dictates otherwise. Thus, for example, reference to a "molecule" optionally includes a combination of two or more such molecules, and so forth.

[0024] A "durable response" refers to a sustained effect on preventing or slowing the progression of a disease (e.g., multiple myeloma) and / or improving one or more response criteria after cessation of treatment. For example, response to treatment for multiple myeloma can be measured by the criteria of Kumar et al. (2016) "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma." Lancet Oncol. 17(8):e328-e346 and Durie et al. (2006) "International uniform response criteria for multiple myeloma." Leukemia. 20:1467-1473. (See also Table A below and Table B herein.) In some embodiments, the durable response is at least as long as the treatment period, at least 1.5x, 2.0x, 2.5x, or 3x the treatment period.

[0025] [Table 1-1] [Table 1-2]

[0026] The term "pharmaceutical formulation" refers to a preparation that is in a form that effectively utilizes the biological activity of the active ingredient and does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered. Such formulations are sterile. A "pharmaceutically acceptable" excipient (vehicle, additive) is one that can reasonably be administered to a mammalian subject to provide an effective dose of the active ingredient employed.

[0027] As used herein, the term "treatment" refers to a clinical intervention designed to alter the general course of a disease or cells (e.g., cancer cells) being treated during clinical pathology. Desirable effects of treatment include slowing the rate of disease progression, ameliorating or alleviating the disease state, and improving response or prognosis. For example, an individual is successfully "treated" if one or more symptoms associated with cancer are alleviated or eliminated, including, but not limited to, reducing (or destroying) the proliferation of cancer cells, reducing symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other medications required to treat the disease, and / or prolonging the individual's life.

[0028] As used herein, "delaying disease progression" means to prolong, prevent, slow, retard, stabilize, and / or postpone the onset of a disease (such as cancer). This delay can be of varying lengths of time depending on the disease being treated and / or the individual's medical history. As will be apparent to one skilled in the art, a sufficient or significant delay can essentially encompass prevention, in that the individual does not develop the disease. For example, late-stage cancer, such as the development of metastases, can be delayed.

[0029] An "effective amount" is at least the minimum amount required to achieve measurable improvement or prevention of a particular disorder. As used herein, an effective amount may vary depending on factors such as the individual / patient's disease state, age, sex, and weight, as well as the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic and adverse effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the development of the disease. For therapeutic use, beneficial or desired results include reducing one or more symptoms caused by the disease and preventing the disease. Clinical results include improving the quality of life of the sufferer, reducing the dose of other medications required to treat the disease, enhancing the effectiveness of another medication, for example through targeting, slowing disease progression, and / or prolonging life. In the case of cancer or tumors, an effective amount of a drug can be effective in reducing the number of cancer cells; reducing tumor size; preventing (i.e., slowing to some extent, preferably stopping) the infiltration of cancer cells into peripheral organs; preventing (i.e., slowing to some extent, preferably stopping) tumor metastasis; preventing (i.e., slowing to some extent, preferably stopping) tumor growth; and / or alleviating to some extent one or more symptoms associated with the disorder. An effective amount can be administered one or more times. For purposes of the present invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment. As understood in clinical settings, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" can be considered in the context of administering one or more therapeutic agents, and can be considered to be giving an effective amount of a single agent when a desired result can or is achieved in conjunction with one or more other agents.

[0030] As used herein, "in combination with" refers to the administration of one treatment modality in addition to another treatment modality. Thus, "in combination with" refers to the administration of one treatment modality before, during, or after the administration of the other treatment modality to an individual.

[0031] A "subject" or "individual" for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal is a human.

[0032] The term "antibody" is used herein in the broadest sense and specifically encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired biological activity.

[0033] Human light chains are typically classified as kappa and lambda light chains, while human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, defining the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, but not limited to, IgG1, IgG2, IgG3, and IgG4. IgM has subclasses, including, but not limited to, IgM1 and IgM2. IgA is similarly subdivided into subclasses, including, but not limited to, IgA1 and IgA2. Within full-length light and heavy chains, the variable and constant domains are typically joined by a "J" region of about 12 or more amino acids, and heavy chains also contain a "D" region of about 10 or more amino acids. See, e.g., FUNDAMENTAL IMMUNOLOGY (Paul, W., ed., Raven Press, 2nd ed., 1989), incorporated by reference in its entirety for all purposes. The variable regions of each light / heavy chain pair typically form an antigen-binding site. The variable domains of antibodies typically exhibit the same general structure of relatively conserved framework regions (FRs) connected by three hypervariable regions, also called complementarity-determining regions or CDRs. The CDRs from the two chains of each pair are typically aligned by the framework regions, which may enable binding to a specific epitope. From the amino terminus to the carboxyl terminus, the variable domains of both the light and heavy chains typically comprise, in order, the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0034] The term "CDR set" refers to three CDRs occurring in a single variable region that can bind to an antigen. The CDRs refer to a group of Rs. The exact boundaries of these CDRs have been defined differently in different systems. The system described by Kabat (Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any antibody variable region, but also provides precise residue boundaries defining the three CDRs. These CDRs are sometimes referred to as Kabat CDRs.

[0035] The term "Fc" as used herein refers to the sequence of a non-antigen-binding fragment resulting from antibody digestion or generated by other means, whether in monomeric or multimeric form, and may include the hinge region. The original immunoglobulin source of native Fc is preferably human and can be any immunoglobulin. Fc molecules are composed of monomeric polypeptides that can be linked by covalent (i.e., disulfide) and non-covalent bonds into dimeric or multimeric forms. The number of intermolecular disulfide bonds between the monomeric subunits of native Fc molecules ranges from one to four, depending on the class (e.g., IgG, IgA, and IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgA1, IgGA2, and IgG4). One example of an Fc is a disulfide-bonded dimer resulting from papain digestion of IgG. As used herein, the term "native Fc" refers collectively to the monomeric, dimeric, and multimeric forms.

[0036] As used herein, the term "overall response rate" or "ORR" refers to the proportion of patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR), as assessed by an IRC using the IMWG response criteria described in Kumar et al. (2016) "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma." Lancet Oncol. 17(8):e328-e346 and Durie et al. (2006) "International uniform response criteria for multiple myeloma." Leukemia. 20:1467-1473. See also Tables A and B herein.

[0037] overview Provided herein are methods for treating or delaying the progression of multiple myeloma in individuals who have received one, two, three, or more than three prior therapies for multiple myeloma. The methods include administering to the individual effective amounts of an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone. In some embodiments, the treatment extends the individual's progression-free survival (PFS) and / or overall survival (OS). In some embodiments, the treatment extends the individual's progression-free survival (PFS) and / or overall survival (OS) compared to individuals not receiving the treatment. In some embodiments, the treatment extends the individual's progression-free survival (PFS) and / or overall survival (OS) compared to individuals receiving carfilzomib and dexamethasone treatment but not an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the individual is negative for minimal residual disease (MRD) after treatment (e.g., 10 -4 Below, 10 -5 Less than or equal to 10 -6 at the threshold below).

[0038] Anti-CD38 antibody In some embodiments, the anti-CD38 antibody binds to human CD38. In some embodiments, the anti-CD38 antibody is a human antibody, a humanized antibody, or a chimeric antibody. In some embodiments, the anti-CD38 antibody comprises (a) a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and and a heavy chain variable domain (V) comprising CDR-H3 containing the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3). H ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). L In some embodiments, the anti-CD38 antibody comprises a heavy chain variable domain (V) comprising an amino acid sequence at least 90% identical (e.g., at least 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99%, including any range between these values) to SEQ ID NO:7. H Additionally, or alternatively, in some embodiments, the anti-CD38 antibody comprises a light chain variable domain (V) comprising an amino acid sequence that is at least 90% identical (e.g., at least 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99%, including any range between these values) to SEQ ID NO:8 or SEQ ID NO:9. L In some embodiments, the anti-CD38 antibody comprises a V comprising SEQ ID NO: 7. H and V comprising SEQ ID NO: 8 or SEQ ID NO: 9 L Includes. QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT IYPGDGDTGY AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD YYGSNSLDYW GQGTSVTVSS (SEQ ID NO: 7) DIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKR (SEQ ID NO: 8) DIVMAQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKR (SEQ ID NO: 9)

[0039] In some embodiments, the anti-CD38 antibody is isatuximab (CAS Registry Number: 1461640-62-9). Isatuximab, also known as hu38SB19 and SAR650984, is an anti-CD38 antibody described in WO2008 / 047242 and U.S. Patent No. 8,153,765, the contents of both of which are incorporated by reference in their entireties.

[0040] The heavy chain of isatuximab comprises the following amino acid sequence: QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT IYPGDGDTGY AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD YYGSNSLDYW GQGTSVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPG (SEQ ID NO: 10) The light chain of isatuximab comprises the following amino acid sequence: DIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 11)

[0041] Anti-CD38 antibodies can be produced using recombinant methods. For recombinant production of anti-antigen antibodies, nucleic acids encoding the antibody are isolated and inserted into a replicable vector for further cloning (amplification of the DNA) or expression. DNA encoding the antibody can be easily isolated and sequenced using conventional techniques (e.g., using oligonucleotide probes that can specifically bind to genes encoding the antibody heavy and light chains). Many vectors are available. Vector components typically include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Vectors are typically transformed into a suitable host cell for expression of the nucleic acid. Some In embodiments, the host cell is a eukaryotic or prokaryotic cell. In some embodiments, the eukaryotic host cell is a mammalian cell. Examples of useful mammalian host cell lines include SV40-transformed monkey kidney CV1 (COS-7, ATCC CRL 1651); human embryonic kidney (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK, ATCC CCL 10); mouse Sertoli cells (TM4, Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat hepatocytes (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human hepatocytes (Hep G2, HB 8065); mouse mammary tumor (MMT) 060562, ATCC CCL51); TRI cells (Mather et al., Annals NY Acad. Sci. 383:44-68 (1982); MRC 5 cells; FS4 cells; and human hepatoma line (Hep G2). Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as NS0 and Sp2 / 0. For a review of certain mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (ed. BKC Lo, Humana Press, Totowa, NJ, 2003), pp. 255-268. Anti-CD38 antibodies prepared from cells can be purified using, for example, hydroxylapatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography generally being one of the preferred purification steps. Generally, various methods for preparing antibodies for use in research, testing, and clinical applications have been established in the art and are consistent with the methods described above and / or as deemed suitable by those skilled in the art.

[0042] Carfilzomib Carfilzomib is a synthetic tetrapeptide consisting of morpholine-4-acetyl, L-2-amino-4-phenylbutanoyl, L-leucyl, and L-phenylalanyl residues joined in sequence with the C-terminus connected via an amide bond to the amino group of (2S)-2-amino-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-1-one. The chemical structure of carfilzomib is shown below: [ka]

[0043] Carfilzomib is a 40 H 57It has a molecular formula of N5O7 and a molecular weight of 719.91 g / mol. Carfilzomib's CAS Registry Number is 868540-17-4. Carfilzomib is a proteasome inhibitor formulated for intravenous administration. Irzomib is sold under the trade name KYPROLIS®.

[0044] Dexamethasone The chemical name of dexamethasone is 1-dehydro-16α-methyl-9α-fluorohydrocortisone, and dexamethasone has the following chemical structure: [ka]

[0045] Dexamethasone is C 22 H 29 It has a molecular formula of FO5 and a molecular weight of 392.461 g / mol. Dexamethasone is commercially available as a formulation for oral and intravenous administration. Exemplary trade names for dexamethasone include, for example, DECADRON, MAXIDEX, HEXADROL, DEXACORT, DEXASONE, ORADEXON, SUPERPREDNOL, and DEXALONA.

[0046] Pharmaceutical Compositions and Formulations Also provided herein are pharmaceutical compositions and formulations for, e.g., treatment of multiple myeloma (e.g., refractory multiple myeloma or relapsed and refractory multiple myeloma, etc.) comprising an anti-CD38 antibody (e.g., isatuximab), carfilzomib, or dexamethasone. In some embodiments, each of the anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone is provided as a separate pharmaceutical composition. In some embodiments, the pharmaceutical compositions and formulations further comprise a pharmaceutically acceptable carrier.

[0047] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) described herein is in a formulation comprising about 20 mg / mL (500 mg / 25 mL) of antibody, about 20 mM histidine, about 10% (w / v) sucrose, and about 0.02% (w / v) polysorbate 80 at pH 6.0. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) described herein is in a formulation comprising about 20 mg / mL of antibody, about 100 mg / mL of sucrose, 2.22 mg / mL of histidine hydrochloride monohydrate, about 1.46 mg / mL of histidine, and about 0.2 mg / mL of polysorbate 80. In some embodiments, the formulation comprises water for injection (WFI), such as sterile water for injection (SWFI). In some embodiments, the formulation is sterile. In some embodiments, the single-use formulation contains 5 ml of formulation (i.e., 100 mg of anti-CD38 antibody). In some embodiments, the single-use 5 ml formulation is provided, for example, in a 16 mL colorless, clear glass vial fitted with an elastomeric closure. In some embodiments, the vial fill volume is established to ensure removal of 5 mL. In some embodiments, the fill volume is 5.4 mL. In some embodiments, the single-use formulation contains 25 ml of formulation (i.e., 500 mg of anti-CD38 antibody). In some embodiments, the single-use 25 ml formulation is provided, for example, in a 30 mL colorless, clear glass vial fitted with an elastomeric closure. In some embodiments, the vial fill volume is established to ensure removal of 25 mL. In some embodiments, the formulation is stored at a temperature of about 2°C to about 8°C. The formulation is stable for at least about 6, 12, 18, 24, 30, or 36 months, protected from light, including any ranges between these values. In some embodiments, the formulation is diluted for infusion with 0.9% sodium chloride or 5% dextrose. In some embodiments, the diluted infusion solution is stable for up to about 6, 12, 18, 24, 30, 36, 42, or 48 hours, including any ranges between these values, between about 2°C and about 8°C. In some embodiments, the diluted infusion solution is stable for an additional 8 hours (including the infusion time) at room temperature after storage between about 2°C and about 8°C. In some embodiments, the diluted infusion solution is stable in the presence of light. In some embodiments, the bag in which the diluted infusion solution is stored is made of polyolefin (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) and di(ethylhexyl) phthalate (DEHP) or ethyl vinyl acetate (EVA). In some embodiments, the tubing used for injection is made from PE, PVC (with or without DEHP), polybutyldiene (PBD), or polyurethane (PU) with an in-line filter (polyethersulfone (PES), polysulfone, or nylon).

[0048] Pharmaceutical formulations of carfilzomib and dexamethasone are commercially available. For example, carfilzomib is known under the trade name KYPROLIS®. Dexamethasone is known under various trade names, such as DECADRON, MAXIDEX, and HEXADROL (discussed elsewhere herein). In some embodiments, carfilzomib and / or dexamethasone are provided in separate containers. In some embodiments, carfilzomib and / or dexamethasone are each used and / or prepared for administration to an individual as described in the prescribing information available for the commercially available products.

[0049] Treatment method Provided herein are methods for treating or delaying the progression of multiple myeloma (such as relapsed multiple myeloma or relapsed and refractory multiple myeloma) in an individual (e.g., a human individual), comprising administering to an individual an effective amount of an anti-CD38 antibody (e.g., a heavy chain variable domain (V) comprising: (a) a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3). H ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). L ), carfilzomib, and dexamethasone, wherein the individual has received one, two, three, or more than three prior treatments (or lines of treatment) for multiple myeloma. In some embodiments, the individual has received three or fewer prior treatments (or lines of treatment). In some embodiments, treatment with an anti-CD38 antibody described herein, carfilzomib, and dexamethasone extends the individual's progression-free survival (PFS). In some embodiments, treatment with an anti-CD38 antibody as described herein, carfilzomib, and dexamethasone extends the individual's overall survival (OS). In some embodiments, treatment with an anti-CD38 antibody as described herein, carfilzomib, and dexamethasone results in less minimal residual disease (MRD) compared to, for example, treatment with carfilzomib and dexamethasone and treatment without an anti-CD38 antibody. In some embodiments, the individual is MRD-negative after treatment with an anti-CD38 antibody as described herein, carfilzomib, and dexamethasone. In some embodiments, the individual is MRD-negative after 10 days of treatment. -4 below the threshold (e.g., "10 -4 " refers to a bone marrow sample obtained from an individual after treatment initiation that shows a 10 4 (meaning there is less than one tumor cell per 10 bone marrow cells) 10 days after treatment -5or less (e.g., "10 -5 " refers to a bone marrow sample obtained from an individual after treatment initiation that shows a 10 5 means there is less than one tumor cell per 10 bone marrow cells) or 10 days after treatment -6 or less (e.g., "10 -6 " refers to the amount of time obtained from an individual after treatment has begun. In bone marrow samples, 10 6 The individual is minimal residual disease (MRD) negative (meaning there is less than one tumor cell per bone marrow cell). In some embodiments, MRD is assessed via next generation sequencing (NGS). In some embodiments, MRD is assessed via next generation flow cytometry (NGF). Additionally or alternatively, in some embodiments, MRD is assessed via positron emission tomography-computed tomography (PET-CT) scan. In some embodiments, the individual exhibits renal dysfunction prior to (e.g., at the start of) treatment with an anti-CD38 antibody, carfilzomib, and dexamethasone as described herein. In some embodiments, the individual exhibits renal dysfunction of 60 ml / min / 1.72 m 2 If an individual has a creatine clearance less than 0.05, the individual has impaired renal function (MDRD, or "Modification of Diet in Renal Disease"). In some embodiments, treatment with an anti-CD38 antibody, carfilzomib, and dexamethasone as described herein improves the individual's renal function.

[0050] In some embodiments, a treatment is considered a new line of therapy if any of the following three conditions are met: 1. Starting a new line of treatment after discontinuing the previous line. If a treatment regimen is discontinued for any reason and a different regimen is initiated, it can be considered a new line of therapy. For example, if all drugs in a regimen are discontinued, the regimen is considered discontinued. For example, if some but not all drugs in a regimen are discontinued, the regimen is not considered discontinued. In some embodiments, the reason for discontinuation, addition, replacement, or stem cell transplant (SCT) does not affect how the line is counted. Reasons for a change may include, for example, completion of planned treatment, toxicity, progression, lack of response, or inadequate response. 2. Unplanned addition or substitution of one or more drugs in an existing regimen. The unplanned addition of a new drug or switching to a different drug (or drug combination) for any reason can be considered a new line of therapy. 3. Stem Cell Transplantation (SCT). Except in the case of planned tandem SCTs at predefined intervals (e.g., 3 months), in individuals undergoing >1 SCT, each SCT (autologous or allogeneic) may be considered a new line of treatment, regardless of whether the conditioning regimen used is the same or different. In some embodiments, planned tandem SCTs are considered one line. In some embodiments, planned induction and / or consolidation, maintenance with any SCT (frontline, relapse, autologous or allogeneic) are generally considered one line of treatment.

[0051] In some embodiments, the multiple myeloma is difficult to treat. In some embodiments, the prognosis for the individual is poor.

[0052] In some embodiments, the individual has multiple myeloma, e.g., relapsed and / or refractory multiple myeloma. In some embodiments, the individual has measurable disease according to one or more of the following criteria: serum M protein > 0.5 g / dL measured using serum protein immunoelectrophoresis and / or urine M protein > 200 mg / 24 hours measured using urine protein immunoelectrophoresis. In some embodiments, the individual with multiple myeloma (e.g., relapsed and / or refractory multiple myeloma) has received at least one, at least two, at least three, or no more than three prior treatments (or lines of treatment) for multiple myeloma. In some embodiments, the individual has received prior treatment with a proteasome inhibitor. In some embodiments, the individual has received prior treatment with an immunomodulatory agent (e.g., thalidomide, lenalidomide, and / or pomalidomide). In some embodiments, the individual has received prior treatment with a proteasome inhibitor and an immunomodulatory agent.

[0053] In some embodiments, the individual does not have primary refractory multiple myeloma. In some embodiments, an individual with primary refractory multiple myeloma is an individual who has never achieved at least a minimal response (MR) to any therapy (or line of treatment) during the course of their disease. In some embodiments, the individual does not have only free light chain (FLC) measurable disease. In some embodiments, the individual has not received previous treatment with an anti-CD38 antibody. In some embodiments, the individual has not received previous treatment (or previous line of treatment) with isatuximab. In some embodiments, the individual did not show progressive disease (PD) during previous treatment (or previous line of treatment) with an anti-CD38 antibody. In some embodiments, the individual did not show progression within 60 days after ending treatment (or line of treatment) with an anti-CD38 antibody. In some embodiments, the individual has not failed to achieve at least a minimal response to a therapy (or line of treatment) comprising an anti-CD38 antibody. In some embodiments, the individual has received a previous treatment (or line of treatment) including an anti-CD38 antibody and has not been refractory to the anti-CD38 antibody. In some embodiments, the individual has not received previous treatment with carfilzomib. In some embodiments, the individual is not allergic (or known to be allergic) to CAPTISOL® (a cyclodextrin derivative used to solubilize carfilzomib). In some embodiments, the individual is not or has not demonstrated hypersensitivity to sucrose, histidine (as the base and hydrochloride salt), polysorbate 80, or any component (active substance or excipient) of the anti-CD38 antibody, carfilzomib, and dexamethasone (not suitable for premedication with steroids), or H2 blockers (which prohibit further treatment with these agents). In some embodiments, the individual does not have a contraindication to dexamethasone. In some embodiments, the individual has not undergone a previous allogeneic hematopoietic stem cell transplant with active graft-versus-host disease (any grade and / or receiving immunosuppressive treatment within two months prior to treatment initiation). In some embodiments, the individual has no known amyloidosis or associated plasma cell leukemia.In some embodiments, the individual does not have a pleural effusion requiring thoracentesis or ascites requiring thoracentesis or any major procedure, such as plasma exchange, curative radiation therapy, or major surgery (excluding vertebroplasty). In some embodiments, the individual does not have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) >2. In some embodiments, the individual does not have platelets <50,000 cells / μL if <50% of bone marrow (BM) nucleated cells are plasma cells, or <30,000 cells / μL if ≥50% of BM nucleated cells are plasma cells. In some embodiments, the individual does not have an absolute neutrophil count (ANC) <1000 μ / L (1×109 / L). In some embodiments, the individual has a creatinine clearance of 15 mL / min / 1.73 m. 2Not less than (Modification of Diet in Renal Disease [MDRD] formula). In some embodiments, the individual does not have a total bilirubin >1.5 x upper limit of normal (ULN), excluding known Gilbert syndrome. In some embodiments, the individual does not have a corrected serum calcium >14 mg / dL (>3.5 mmol / L). In some embodiments, the individual does not have an aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) >3 x ULN. In some embodiments, the individual does not have ongoing toxicity (excluding alopecia and those described in the paragraph above) from prior antimyeloma therapy of Grade >1 (National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI-CTCAE] v4.03). In some embodiments, the individual does not have a prior malignancy. In some embodiments, patients with adequately treated basal or squamous cell skin or superficial (pTis, pTa, and pT1) bladder cancer or low-risk prostate cancer or any in situ malignancy after curative treatment, and any other cancer for which treatment was completed more than 5 years prior to initiation of treatment with an anti-CD38 antibody, carfilzomib, and dexamethasone, and who have been disease-free for more than 5 years, are not considered to have a previous malignancy. In some embodiments, the individual has not had a myocardial infarction, severe / unstable angina, coronary artery / peripheral artery bypass graft, New York Heart Association Class III or IV congestive heart failure, grade 3 or higher arrhythmia, stroke, or transient ischemic attack. In some embodiments, the individual has not suffered from myocardial infarction, severe / unstable angina, coronary artery / peripheral artery bypass graft, New York Heart Association Class III or IV congestive heart failure, grade 3 or higher arrhythmia, stroke, or transient ischemic attack within 6 months of initiating treatment with the anti-CD38 antibody, carfilzomib, and dexamethasone. In some embodiments, the individual does not have a left ventricular ejection fraction (LVEF) less than 40%. In some embodiments, the individual does not have or is not known to have acquired immunodeficiency syndrome (AIDS)-related disease or HIV disease requiring antiretroviral treatment, or active hepatitis A, hepatitis B (defined as a known positive hepatitis B surface antigen (HBsAg) result), or hepatitis C (defined as a known quantitative hepatitis C (HCV) ribonucleic acid (RNA) result greater than the lower limit of detection of an assay or positive HCV antigen). In some embodiments, the individual does not have any of the following within 3 months prior to initiation of treatment with the anti-CD38 antibody, carfilzomib, and dexamethasone: treatment-resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic disease.

[0054] In some embodiments, the treatment involves administering an anti-CD38 antibody, carfilzomib, and dexamethasone in a 28-day cycle (eg, one or more 28-day cycles).

[0055] In some embodiments, the treatment comprises administering, in a first 28-day cycle (i.e., cycle 1), an anti-CD38 antibody, carfilzomib, and dexamethasone, wherein the anti-CD38 antibody (e.g., isatuximab) is administered on days 1, 8, 15, and 22; carfilzomib is administered on days 1, 2, 8, 9, 15, and 16; and dexamethasone is administered on days 1, 2, 8, 9, 15, 16, 22, and 23. See, e.g., Figure 2. In some embodiments, the treatment involves administering an anti-CD38 antibody, carfilzomib, and dexamethasone in one or more additional 28-day cycles after the first 28-day cycle (e.g., cycle 2 onward), wherein the anti-CD38 antibody (e.g., isatuximab) is administered on days 1 and 15; carfilzomib is administered on days 1, 2, 8, 9, 15, and 16; and dexamethasone is administered on days 1, 2, 8, 9, 15, 16, 22, and 23. See, e.g., Figure 2.

[0056] In some embodiments, the treatment comprises administering an anti-CD38 antibody, carfilzomib, and dexamethasone in a first 28-day cycle (i.e., cycle 1), wherein the anti-CD38 antibody (e.g., isatuximab) is administered at a dose of 10 mg / kg on days 1, 8, 15, and 22; and carfilzomib is administered at a dose of 20 mg / kg on days 1 and 2. 2 at a dose of 56 mg / m on days 8, 9, 15, and 16. 2 and dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23. See, e.g., Table D herein. In some embodiments, treatment comprises administering an anti-CD38 antibody, carfilzomib, and dexamethasone in one or more additional 28-day cycles after the first 28-day cycle (e.g., cycle 2 onward), wherein the anti-CD38 antibody (e.g., isatuximab) is administered at a dose of 10 mg / kg on days 1 and 15; and carfilzomib is administered at a dose of 56 mg / m on days 1, 2, 8, 9, 15, and 16. 2and dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23. See, e.g., Table D herein.

[0057] In some embodiments, the anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone are administered simultaneously. In some embodiments, the anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone are administered simultaneously. In some embodiments, the anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone are administered sequentially. In some embodiments, the anti-CD38 The antibody (e.g., isatuximab), carfilzomib, and dexamethasone are administered sequentially, with dexamethasone administered before the anti-CD38 antibody, which is administered before carfilzomib on a day of each 28-day cycle, where all three of the anti-CD38 antibody, carfilzomib, and dexamethasone are administered. In some embodiments, the anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone are administered sequentially, with dexamethasone administered before carfilzomib on a day of each 28-day cycle when anti-CD38 is not administered. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered intravenously. In some embodiments, carfilzomib is administered intravenously. In some embodiments, dexamethasone is administered intravenously or orally. In some embodiments, dexamethasone is administered intravenously on a day of each 28-day cycle.

[0058] In some embodiments, an individual's PFS is measured as the time from the start of treatment to the first occurrence of progressive disease (PD). In some embodiments, PD is assessed according to the criteria of Kumar et al. (2016) "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma." Lancet Oncol. 17(8):e328-e346) and Durie et al. (2006) "International uniform response criteria for multiple myeloma. Leukemia. 20:1467-1473." (See also Table A and Table B). In some embodiments, PFS is measured as the time from the start of treatment to the time of death. In some embodiments, the methods and uses provided herein result in an improvement (e.g., prolongation) of progression-free survival (PFS) in an individual compared to an individual with multiple myeloma (such as refractory multiple myeloma or relapsed and refractory multiple myeloma) who has received a treatment comprising carfilzomib and dexamethasone without an anti-CD38 antibody. In some embodiments, the treatment increases the PFS of the individual.

[0059] In some embodiments, overall survival (OS) is measured as the time from the start of treatment to death. In some embodiments, the treatment increases the OS of an individual compared to an individual with multiple myeloma (e.g., refractory multiple myeloma or relapsed and refractory multiple myeloma) who received treatment comprising carfilzomib and dexamethasone without an anti-CD38 antibody.

[0060] In some embodiments, the time to first response in individuals receiving treatment with an anti-CD38 antibody, carfilzomib, and dexamethasone is shorter than the time to first response in individuals receiving treatment with carfilzomib and dexamethasone. In some embodiments, "time to first response" refers to the period between the date of first administration and the date of first evidence of response (see, e.g., Table A). In some embodiments, the duration of response (DOR) in individuals receiving treatment with an anti-CD38 antibody, carfilzomib, and dexamethasone is longer than the DOR in individuals receiving treatment with carfilzomib and dexamethasone. In some embodiments, DOR refers to the time from the date of response to the date of first documented progressive disease (PD) or death, whichever occurs first, in an individual (or individuals) who achieves a partial response (PR) or better.

[0061] In some embodiments, the individual is negative for minimal residual disease (MRD) or "MRD negativity" after treatment with an anti-CD38 antibody, carfilzomib, and dexamethasone. In some embodiments, MRD status is measured by next-generation flow cytometry (NGF). In some embodiments, MRD negativity as measured by NGF (or "flow MRD negativity") refers to the absence of phenotypically abnormal clonal plasma cells (such as multiple myeloma cells) in the bone marrow aspirate (e.g., as described in the EUROFLOW™ High-Throughput Flow Cytometry Standard Operating Procedure for MRD Detection in Multiple Myeloma (Flores-M (2017) Leukemia. 31:2094-2103) or equivalent method), the minimum sensitivity is, for example, 10 4 1 in 10 nucleated cells (i.e., -4 "), 10 5 1 in 10 nucleated cells (i.e., -5 "), 10 6 1 in 10 nucleated cells (i.e., -6 "), or 10 7 1 in 10 nucleated cells (i.e., -7"). In some embodiments, MRD status is measured by next-generation sequencing (NGS). In some embodiments, MRD negativity as measured by NGS (or "sequencing MRD negativity") refers to the absence of clonal plasma cells (e.g., multiple myeloma cells) in the bone marrow aspirate; the presence of a clone is determined after DNA sequencing of the bone marrow aspirate (e.g., using the LYMPHOSIGHT® high-throughput sequencing platform or equivalent method), e.g., 10 4 1 in nucleated cells (i.e., 10 -4 "), 10 5 1 in 10 nucleated cells (i.e., -5 "), 10 6 1 in 10 nucleated cells (i.e., -6 ") or better. In some embodiments, the minimum sensitivity is 10 6 One cell out of 10 nucleated cells ("10 -6"). In some embodiments, an individual is negative by both imaging and MRD (or "imaging+MRD negative"). In some embodiments, imaging+MRD negative refers to (a) being MRD negative as detected by NGF or being MRD negative as detected by NGS, and (b) disappearance of any area of ​​increased tracer uptake seen on baseline or prior positron emission tomography (PET) / computed tomography (Ct), or a decrease to below the maximum normalized uptake value of the mediastinal blood pool or less than that of surrounding normal tissue. In some embodiments, an individual is "persistently MRD negative." In some embodiments, persistent MRD negativity refers to an individual who has been confirmed as imaging+MRD negative at two time points after initiation of treatment, where those time points are more than one year apart. In some embodiments, minimal residual disease (MRD) is assessed via NGF or NGS using bone marrow samples collected from individuals treated with an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone, as described herein. In some embodiments, individuals being evaluated for MRD have achieved a complete response or better (i.e., >= CR) or a best partial response or better (i.e., >= VGPR) during or after treatment with an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone, as described herein. In some embodiments, individuals treated with an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone who achieve MRD-negative status have renal dysfunction, e.g., eGFR < 60 mL / min / 1.73 m at the start of treatment, during treatment, or after treatment. 2In some embodiments, individuals treated with an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone who achieve MRD-negative status are classified as ISS stage III at the time of diagnosis. In some embodiments, individuals treated with an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone who achieve MRD-negative status have one or more cytogenetic abnormalities selected from t(4;14) and gain(1q21). In some embodiments, individuals treated with an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone who achieve MRD-negative status are heavily pretreated, such as having received three or more prior lines of therapy for multiple myeloma. In some embodiments, an individual treated with an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone who achieves MRD-negative status was refractory to lenalidomide in their last regimen (e.g., last treatment regimen for multiple myeloma).

[0062] In some embodiments of any of the methods of anti-CD38 antibody for use described herein, the individual is under 65 years of age. In some embodiments, the individual is between 65 and under 75 years of age. In some embodiments, the individual is 75 years of age or older. In some embodiments, the individual is female (e.g., In some embodiments where the individual is female and capable of becoming pregnant, the individual may use effective methods of contraception during treatment with an anti-CD38 antibody and for 5 months after the last dose of an anti-CD38 antibody.

[0063] In some embodiments, the individual has received one prior treatment (or prior line of treatment) for multiple myeloma. In some embodiments, the individual has received two or more (e.g., two, three, or more) prior treatments (or prior lines of treatment) for multiple myeloma. In some embodiments, the individual has received more than one but not more than three prior treatments (or prior lines of treatment) for multiple myeloma. In some embodiments, the individual has received more than three prior treatments (or prior lines of treatment) for multiple myeloma. In some embodiments, the individual has stage I or stage II multiple myeloma according to the Revised International Staging System (R-ISS). In some embodiments, stage I multiple myeloma R-ISS is defined as (a) a serum beta-2 microglobulin level of less than 3.5 mg / L, (b) a serum albumin level of 3.5 g / dL or greater, (c) standard-risk chromosomal / cytogenetic abnormalities detected by interphase fluorescence in situ hybridization (iFISH), and (d) a normal serum lactate dehydrogenase (LDH) level. In some embodiments, stage II multiple myeloma R-ISS is defined as not being stage I or stage III R-ISS. In some embodiments, an individual has stage III multiple myeloma according to the Revised International Staging System (R-ISS). In some embodiments, stage III multiple myeloma according to R-ISS is defined as either (a) a serum beta-2 microglobulin level greater than about 5.5 mg / L, and (b) a high-risk cytogenetic abnormality detected by interphase fluorescence in situ hybridization (iFISH), or (c) a serum lactate dehydrogenase (LDH) level greater than the upper limit of normal. In some embodiments, the individual has a high-risk cytogenetic abnormality (CA). In some embodiments, the high-risk cytogenetic abnormality is one or more of del(17p), t(4:14), and / or t(14;16). In some embodiments, the individual is not classified by R-ISS. In some embodiments, the individual is not classified by R-ISS due to an inconclusive iFISH.

[0064] In some embodiments, the individual has one or more high-risk cytogenetic abnormalities selected from del(17p), t(4:14), and t(14:16). Additionally or alternatively, in some embodiments, the individual has del(1p), gain(1q), or both del(1p) and gain(1q) cytogenetic abnormalities.

[0065] Intravenous administration of anti-CD38 antibody In some embodiments, the anti-CD38 antibody is administered via intravenous infusion, wherein each infusion is from a volume (e.g., a fixed volume) of 250 ml. In some embodiments, the individual does not experience an infusion reaction (IR) during or after administration of the anti-CD38 antibody via intravenous infusion from a 250 ml volume. In some embodiments, the individual experiences only a mild IR during or after administration of the anti-CD38 antibody via intravenous infusion from a 250 ml volume.

[0066] In some embodiments, an anti-CD38 antibody (e.g., isatuximab) is administered to an individual in a first 28-day cycle. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to an individual at a dose of 10 mg / kg from a volume of 250 ml on each of days 1, 8, 15, and 22 of the first 28-day cycle. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to an individual via intravenous infusion at an infusion rate of 25 mL / hour for the first hour on day 1 of the first 28-day cycle, and the infusion rate is increased to 25 mL / hour every 30 minutes after the first hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to an individual via intravenous infusion at an infusion rate of 12.5 mL / hour for the first 30 minutes on day 1 of a first 28-day cycle, with the infusion rate increased by 25 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of the first 28-day cycle is less than or equal to about any one of 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.2, 6.3, 6.4, or 6.5 hours, including any range therebetween. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of the first 28-day cycle is between about 3.3 and about 6.1 hours, including any value within this range. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of the first 28-day cycle is between about 3.2 and 5.5 hours, e.g., between about 3.36 and about 5.32 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of the first 28-day cycle is between about 3.8 and 4.2 hours, e.g., about 3.94 hours. In some embodiments, the infusion duration includes a temporary interruption prior to completion of the infusion.

[0067] In some embodiments, an anti-CD38 antibody (e.g., isatuximab) is administered to an individual via intravenous infusion on day 8 of a first 28-day cycle at an infusion rate of 50 mL / hour for the first 30 minutes, 100 mL / hour for the second 30 minutes, 200 mL for the third 30 minutes, and 300 mL / hour after the third 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, an anti-CD38 antibody (e.g., isatuximab) is administered to an individual via intravenous infusion on day 8 of a first 28-day cycle at an infusion rate of 25 mL / hour for the first 30 minutes, with the infusion rate increasing by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of the first 28-day cycle is equal to or less than any one of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range therebetween. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 8 of the first 28-day cycle is between about 1.5 and about 3.5 hours, including any value within this range. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 8 of the first 28-day cycle is between about 1.4 and about 2.7 hours, e.g., between about 1.52 and about 2.6 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 8 of the first 28-day cycle is between about 1.5 and 2.0 hours, e.g., about 1.88 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption prior to completion of the infusion.

[0068] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion at an infusion rate of 200 ml / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused on day 15 of the first 28-day cycle. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion at an infusion rate of 100 ml / hour for the first 30 minutes on day 15 of the first 28-day cycle, with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused ... In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 15 of the first 28-day cycle is less than or equal to any one of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range therebetween. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of the first 28-day cycle is between about 1.2 and about 3.4 hours, including any value within this range. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 15 of the first 28-day cycle is between about 1 and 2 hours, e.g., between about 1.03 and about 1.87 hours. In some embodiments, the infusion duration on day 15 of the first 28-day cycle is between about 1 and 1.5 hours, e.g., about 1.27 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption prior to completion of the infusion.

[0069] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion at an infusion rate of 200 ml / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused on day 22 of the first 28-day cycle. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion at an infusion rate of 100 ml / hour for the first 30 minutes on day 22 of the first 28-day cycle, with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 22 of the first 28 day cycle is equal to or less than any one of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range therebetween. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 22 of the first 28 day cycle is between about 1.1 and about 2 hours, including any value within this range. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 22 of the first 28-day cycle is between about 1 and 2 hours, e.g., between about 1.18 and about 1.52 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 22 of the first 28-day cycle is between about 1 and 1.5 hours, e.g., about 1.27 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption prior to completion of the infusion.

[0070] In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is further administered via intravenous infusion at a dose of 10 mg / kg from a volume of 250 ml on each of days 1 and 15 of each subsequent 28 day cycle in one or more subsequent 28 day cycles (e.g., following the first 28 day cycle). In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion at an infusion rate of 200 ml / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused on day 1 of each subsequent 28 day cycle (e.g., following the first 28 day cycle). In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion at an infusion rate of 100 ml / hour for the first 30 minutes on day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle), with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.10, 3.11, 3.12, 3.13, 3.14, 3.15, 3.16, 3.17, 3.18, 3.19, 4.20, 4.21, 4.22, 4.23, 4.24, 4.25, 4.26, 4.27, 4.28, 4.29, 4.30, 4.31, 4.32, 4.33, 4.34, 4.35, 4.36, 4.37, 4.38, 4.39, 4.40, 4.41, 4.42, 4.43, 4.44, 4.45, 4.46, 4.47, 4.48, 4.49, 5.50, 5.51, 5.52, 5.53, 5.54, 5.55, 5.56, 5.57, 5.58, 5.59, 6.60, 6.61, 6.62, 6.6 In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1.1 and about 1.6 hours, including any value within this range. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1 and 2 hours, e.g., between about 1.19 and about 1.41 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1 and 1.5 hours, e.g., about 1.27 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption prior to completion of the infusion. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion at an infusion rate of 200 ml / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused on day 15 of each subsequent 28-day cycle (e.g., following the first 28-day cycle). In some embodiments, on day 15 of each subsequent 28-day cycle (e.g., following the first 28-day cycle), the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion at an infusion rate of 100 ml / hour for the first 30 minutes, with the infusion rate increasing by 50 ml / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) has been infused. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 15 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is less than or equal to about any one of 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range therebetween.In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1.2 and about 1.6 hours, including any value within this range. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1 and 2 hours, e.g., between about 1.2 and about 1.46 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) on day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1 and 1.5 hours, e.g., about 1.27 hours. In some embodiments, the infusion duration of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption prior to completion of the infusion.

[0071] In some embodiments, the duration of each infusion of an anti-CD38 antibody (e.g., isatuximab) after day 15 of the first 28 day cycle (e.g., including day 22 of the first 28 day cycle and days 1 and 15 of each 28 day cycle thereafter) is less than or equal to about any one of 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 hours, including any range therebetween. In some embodiments, the duration of each infusion of an anti-CD38 antibody (e.g., isatuximab) on day 15 of the first 28-day cycle and thereafter (e.g., including day 22 of the first 28-day cycle and days 1 and 15 of each subsequent 28-day cycle) is between about 0.7 and about 3.4 hours, including any value within this range. In some embodiments, the duration of each infusion of an anti-CD38 antibody (e.g., isatuximab) on day 15 of the first 28-day cycle and thereafter (e.g., including day 22 of the first 28-day cycle and days 1 and 15 of each subsequent 28-day cycle) is between about 1 and 2 hours, e.g., between about 1.13 and about 1.53 hours. In some embodiments, the duration of each infusion of an anti-CD38 antibody (e.g., isatuximab) on day 1 of each subsequent 28-day cycle (e.g., following the first 28-day cycle) is between about 1 and 2 hours, e.g., between about 1.13 and about 1.53 hours. The infusion period for the medicament (mab) is between about 1 and 1.5 hours, for example about 1.25 hours.

[0072] In some embodiments, an individual does not experience an infusion reaction (IR) during or after administration (e.g., intravenous infusion) of an anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg in a volume of 250 ml. In some embodiments, administration (e.g., by intravenous infusion) of an anti-CD38 antibody at a dose of 10 mg / kg in a volume of 250 ml does not cause an individual to experience IR during or after administration. IR refers to a disorder characterized by an adverse reaction to intravenous infusion of an anti-CD38 antibody (e.g., isatuximab). IR can occur during the infusion or within 24 hours of the infusion (e.g., 24 hours from the start of the infusion). Signs or symptoms of IR include one or more of the following: paresthesias, chest pain, cough, nasal congestion, sneezing, throat irritation, itching, fainting, flushing, chills, fever, hives, angioedema, rash, skin reactions, itching, maculopapular rash, cardiac tachycardia, decreased blood pressure, dyspnea, nausea, vomiting, headache, back pain, chest discomfort or non-cardiac chest pain, abdominal pain, abdominal cramps, bronchospasm, laryngospasm, wheezing, respiratory congestion, excessive sweating, and erythema. (For further details, see, e.g., Doessegger et al. (2015) Clin & Trans Immunol. 4(7):e39.) Accordingly, in some embodiments, an individual does not experience any one or more of these signs or symptoms.

[0073] In some embodiments, the individual does not receive (e.g., require) premedication, i.e., medication administered prior to infusion of an anti-CD38 antibody (e.g., isatuximab) for the purpose of preventing or minimizing IR. In some embodiments, the individual does not receive (e.g., require) medication to prevent or minimize IR after completion of infusion of an anti-CD38 antibody (e.g., isatuximab) (e.g., prophylactic medication). In some embodiments, the individual does not experience a delayed infusion reaction after administration (e.g., intravenous infusion) of an anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg from a volume of 250 ml. In some embodiments, the individual does not experience a delayed infusion reaction within any one of about 0.5, 1.0, 1.5, 2.0, 2.5, or 3.0 hours after administration (e.g., intravenous infusion) of an anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg from a volume of 250 ml. In some embodiments, the individual does not receive (e.g., require) a post-medication, i.e., a medication administered after infusion of an anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg from a 250 ml volume for the purpose of preventing or minimizing IR. In some embodiments, the individual does not receive (e.g., require) a post-medication within at least one or more of any of about 0.5, 1.0, 1.5, 2.0, 2.5, or 3 hours after infusion of an anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg from a 250 ml volume, for the purpose of preventing or minimizing IR, for example. In some embodiments, the individual is not pre- or post-medicated with any one or more of the following to prevent or minimize IR prior to infusion of an anti-CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg from a volume of 250 ml: analgesics (e.g., acetaminophen or paracetamol), H2 antagonists or antacids (e.g., ranitidine, cimetidine, omeprazole, or esomeprazole), anti-inflammatory agents (e.g., corticosteroids or nonsteroidal anti-inflammatory drugs), and / or antihistamines (e.g., diphenhydramine, cetirizine, promethazine, dexchlorpheniramine).

[0074] In some embodiments, the individual experiences mild IR after administration of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, mild IR is IR of Grade 1 or Grade 2 or less as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (NCI-CTCAE v.4.03). NCI-CTCAE v.4.03 is available at: evs(dot)nci(dot)nih(dot)gov / ftp1 / CTCAE / About( dot)html. In some embodiments, IR is a Grade 1 IR if the individual experiences a mild, transient reaction (e.g., one or more of the signs / symptoms described herein, e.g., within 24 hours of starting the infusion), in which interruption of the infusion is not indicated, and / or intervention is not indicated. In some embodiments, IR is a Grade 2 IR if the individual experiences a reaction (e.g., one or more of the signs / symptoms described herein, e.g., within 24 hours of starting the infusion), in which interruption of the infusion is indicated, and / or intervention is indicated, and the individual responds promptly to treatment (i.e., treatment of one or more signs or symptoms of IR, such as those described herein), e.g., within any one of about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 hours (including any ranges between these values) of treatment for IR. In some embodiments, treatment for IR includes one or more of the following: a short interruption of the infusion, administration of oxygen, administration of a bronchodilator, administration of a corticosteroid, administration of a histamine blocker, and resuming the infusion at a slower rate.

[0075] In some embodiments, the individual experiences mild IR (e.g., grade 1 or grade 2 IR) during or after a first intravenous infusion of 10 mg / kg of an anti-CD38 antibody (e.g., isatuximab) at a fixed volume of 250 ml, e.g., during the infusion on day 1 of the first 28-day cycle. In some embodiments, the individual does not experience IR (or further IR) during a second or subsequent infusion of an anti-CD38 antibody (e.g., isatuximab) at a fixed volume of 250 ml. For example, in some embodiments, the individual does not experience IR (or further IR) during an infusion of 10 mg / kg of an anti-CD38 antibody (e.g., isatuximab) at a fixed volume of 250 ml on any of days 8, 15, and 22 of the first 28-day cycle and on any of days 1 and 15 of any subsequent 28-day cycle.

[0076] In some embodiments, an individual does not experience moderate or severe IR after infusion of an anti-CD38 antibody in a volume of 250 ml, for example, according to the methods described herein. In some embodiments, an individual does not experience grade 3, 4, or 5 IR as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (NCI-CTCAE v.4.03). In some embodiments, IR is grade 3 IR if an individual experiences prolonged signs / symptoms of IR (e.g., those described herein) and does not respond promptly to discontinuation of medication and / or infusion for IR. In some embodiments, IR is grade 3 IR if an individual experiences a recurrence of signs / symptoms of IR (e.g., those described herein) after initial improvement. In some embodiments, IR is grade 3 IR if an individual requires hospitalization due to signs / symptoms of IR (e.g., those described herein). In some embodiments, if the signs / symptoms (e.g., those described herein) are life-threatening and / or require urgent intervention, the IR is Grade 4 IR. In some embodiments, if the signs / symptoms of IR result in death, the IR is Grade 5 IR.

[0077] In some embodiments, the dose of anti-CD38 antibody (eg, isatuximab) administered from a volume of 250 ml is not reduced during treatment, for example, regardless of whether the individual experiences IR.

[0078] Manufactured product or kit In another embodiment of the invention, an article of manufacture or kit is provided that comprises an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the article of manufacture or kit further comprises carfilzomib, and / or dexamethasone. In some embodiments, the article of manufacture or kit is used to treat multiple myeloma (e.g., refractory multiple myeloma or relapsed and refractory multiple myeloma) in individuals who have received 1 to 3 prior therapies (or prior lines of therapy) for multiple myeloma. The kit further comprises a package insert containing instructions for using the anti-CD38 antibody (e.g., isatuximab) in combination with carfilzomib and dexamethasone to treat or delay the progression of multiple myeloma. In some embodiments, the kit comprises isatuximab, carfilzomib, and dexamethasone.

[0079] The specification is considered to be sufficient to enable one skilled in the art to practice the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. [Example]

[0080] The present disclosure will be more fully understood by reference to the following examples, which, however, should not be construed as limiting the scope of the present invention. It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes will be suggested to those skilled in the art in light thereof, and are within the spirit and scope of the present application and the appended claims.

[0081] Example 1A: A Phase III, Randomized, Open-Label, Multicenter Study Comparing Isatuximab (SAR650984) in Combination with Carfilzomib and Low-Dose Dexamethasone Versus Carfilzomib and Low-Dose Dexamethasone in Patients with Refractory or Relapsed and Refractory Multiple Myeloma

[0082] This example describes a Phase III, multicenter, multifocal, randomized, open-label, parallel-group, two-arm study evaluating the clinical benefit of isatuximab in combination with carfilzomib and dexamethasone ("IKd" group) versus carfilzomib and dexamethasone twice weekly ("Kd" group) in patients with relapsed and / or refractory multiple myeloma who have received 1 to 3 prior lines of treatment.

[0083] I. Research Objectives A. Main Objective The primary objective (i.e., primary endpoint) of this study is to demonstrate the benefit of isatuximab in combination with carfilzomib and dexamethasone (IKd) in extending PFS using IMWG criteria compared with carfilzomib and dexamethasone (Kd) in patients with relapsed and / or refractory MM previously treated with 1–3 lines of therapy.

[0084] Progression-free survival is defined as the time from the date of randomization to the date of first documentation of progressive disease or death from any cause, whichever occurs first. Response and progression are determined according to the IMWG criteria (Kumar et al. (2016) "International (See Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 17(8):e328-e346) and Durie et al. (2006) "International uniform response criteria for multiple myeloma. Leukemia. 20:1467-1473." Paraprotein-based progression is confirmed based on two consecutive assessments.

[0085] The following disease assessment procedures should be performed during screening (for eligibility) and in the period prior to administration of study treatment. At Day 1 of Period 1 (baseline for response assessment), at Day 1 of every cycle until progression on treatment, at the end of treatment (EOT), and for patients who discontinue study treatment without PD, every month during follow-up until PD (even for patients who start further antimyeloma therapy without PD): Quantification of M protein (serum and 24-hour urine, protein immunoelectrophoresis, and immunofixation). If M protein (serum and urine) is undetectable after day 1 of cycle 1, immunofixation will be performed. Serum-free light chain quantification. · Quantitative immunoglobulins. · Bone marrow aspirate (or biopsy as clinically indicated) at baseline (bone marrow involvement, FISH, and MRD), then if VGPR or better. · Evaluation of bone disease: Skeletal survey or low-dose whole-body computed tomography (CT) scan at baseline, annually thereafter, and any time during the study if clinically indicated. Evaluation of extramedullary disease (plasmacytoma) (including bone plasmacytoma): - In cases of known extramedullary disease at baseline, CT scan or magnetic resonance imaging (MRI) should be performed at baseline and repeated every 12 weeks (± 1 week) until PD (even in patients initiating further antimyeloma treatment without PD) and as clinically indicated. - If extramedullary disease (plasmacytoma) is suspected at baseline, perform a CT scan or MRI at baseline, and if plasmacytoma is confirmed, repeat the CT scan or MRI until PD (even in patients initiating further antimyeloma therapy without PD) and every 12 weeks (± 1 week) as clinically indicated. - If progression of pre-existing plasmacytoma is suspected at any time during study treatment or as clinically indicated in patients without prior positive imaging of extramedullary disease.

[0086] For bone lesion assessment and extramedullary disease, the same modality (skeletal survey or low-dose whole-body CT scan; CT scan or MRI) will be used throughout the study for each individual patient.

[0087] Progressive disease (IMWG criteria) is defined as any one of the following for patients with measurable serum and / or urinary M protein (biological criteria on two consecutive assessments): A 25% or greater increase in serum M components from nadir (the absolute increase must be 0.5 g / dL or greater); if the starting M component is 5 g / dL or greater, an increase in serum M components of 1 g / dL or greater on two consecutive assessments is sufficient to define relapse; and / or A 25% or greater increase in urinary M components from nadir (the absolute increase must be 200 mg / 24 hours or greater); and / or - Definite onset of a new bone lesion or soft-tissue extramedullary disease, or, if more than one lesion, an increase of 50% or more from the nadir in the sum of the perpendicular diameters of existing soft-tissue extramedullary disease lesions, or an increase of 50% or more in the longest diameter of a previous soft-tissue extramedullary disease lesion that exceeds 1 cm in short axis.

[0088] If the independent review committee considers the reported clinical data to support clinical progression, clinical deterioration will be considered progression in the primary analysis of PFS. In cases of hypercalcemia, a complete disease evaluation must be performed to identify any measurable parameters of myeloma progression (e.g., serum and urine M protein, assessment of lytic lesions, and assessment of plasmacytoma) and rule out potential alternative causes of hypercalcemia. Progression is not diagnosed by FLC progression alone. Patients with only FLC-measurable disease are not permitted by the protocol. If both serum and urine M protein fall below the eligibility level on efficacy laboratories performed on Day 1 of Cycle 1, progression and overall response will be evaluated according to the criteria in Tables A and B below.

[0089] [Table 2-1] [Table 2-2]

[0090] [Table 3]

[0091] B. Key Secondary Efficacy Endpoints Key secondary efficacy endpoints were: ORR: Each patient's best overall response will be assessed to determine ORR, defined as the proportion of patients with stringent complete response (sCR), CR, VGPR, and PR as assessed using IMWG response criteria (see Table A). A bone marrow biopsy will be performed for sCR assessment as determined by the investigator. Rate of VGPR or better: defined as the proportion of patients with sCR, CR, and VGPR. MRD-negative VGPR or better: defined as the proportion of patients with MRD-negative status as assessed by sequencing at any time point after the first dose of study treatment. Minimal residual disease will be assessed by next-generation sequencing of bone marrow (BM) samples from patients who achieve VGPR or better to determine the strength of response at the molecular level. The negativity threshold is at least 10 -5 Bone marrow aspirates (BMAs) are collected at screening and upon confirmation of VGPR or better. If a patient presents with VGPR or better but is determined to be MRD-positive, another BM sample is collected 3 months (3 cycles) later to identify late negativity. If the patient remains MRD-positive and is still on treatment, a third sample is collected another 3 months later. After the third BM sample MRD-positive during VGPR, no more than three bone marrow samples are obtained during treatment unless the patient achieves CR. In this case, no more than three additional BM samples are collected. Therefore, a maximum of six BMAs are performed on patients (no more than three per response category). However, because BMAs are an invasive procedure, the following guidance is provided with the goal of limiting the number of BMAs as much as possible. - For patients with VGPR and no prior documented CR: The first bone marrow for MRD assessment is collected at the time of confirmation of CR (i.e., the second time point demonstrating CR). If the patient is determined to be MRD-positive, another BM sample is collected 3 months (3 cycles) later to identify late negativity. If the patient remains MRD-positive and undergoes treatment, a third sample is collected after another 3 months. - For patients with VGPR: The first bone marrow will be collected if VGPR is confirmed at a second or subsequent time point, as determined by the investigator based on the kinetics of M-protein decline, and / or if a plateau phase is reached (plateau defined as less than 20% fluctuation over 12 weeks). If MRD is positive on the first BMA, a second BMA will be collected 3 months later (cycle 3) to identify late negativity. If MRD is still positive on the second BMA performed while the patient is in VGPR, the timing of performing a third BMA may be postponed until CR is achieved. If the patient is in CR and the last BMA performed during VGPR was MRD-positive, a BMA will be performed for MRD assessment at the time of confirmation of CR. If the patient is MRD-positive on this BMA after the first BMA during CR, additional BMAs planned by the protocol may be discussed with the patient. CR rate: defined as the proportion of patients with sCR and CR. Patients with documented isatuximab interference will be considered in the BOR category corresponding to the M-protein assessment obtained without interference, if an antibody capture interference assay becomes available. OS: defined as the time from the date of randomization to death from any cause.

[0092] C. Other Secondary Efficacy Endpoints Other secondary efficacy endpoints will be assessed as follows: Duration of response (DOR): Defined as the time from the date of first IRC-determined response in patients who achieved PR or better to the date of first documented progressive disease (PD) or death, whichever occurs first. Time to progression (TTP): defined as the time from randomization to the date of first documented PD. PFS2: defined as the time from the date of randomization to the date of first documentation of PD after initiation of further antimyeloma treatment or death from any cause, whichever occurs first. Time to first response: The time from randomization to the date of first response (PR or better). are defined and then verified. Time to best response: defined as the time from randomization to the first subsequent confirmed best overall response (PR or better).

[0093] D. Safety Endpoints Safety will be assessed and reported throughout the study in terms of treatment-emergent adverse events (TEAEs), adverse events (AEs), serious adverse events (SAEs), infusion-related reactions (IARs), Eastern Cooperative Oncology Group performance status (ECOG PS, see Oken et al., Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-55), laboratory parameters, vital signs, and findings from physical examination.

[0094] Adverse event data will be collected throughout the study. A treatment-emergent AE is defined as an AE that develops, worsens, or becomes severe during the treatment period. The treatment period is defined as the time from the first dose of study treatment to 30 days after the last dose of study treatment. Adverse events and laboratory parameters will be assessed using NCI-CTCAE v4.03 (see, e.g., https: / / www(dot)eortc(dot)be / services / doc / ctc / CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf).

[0095] E. Patient-Reported Outcomes Patient-reported outcome measures include the 30-question European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ C30), the 20-item EORTC Myeloma Module (QLQ-MY20), and the European Quality of Life Group Index (5 dimensions and 5 levels per dimension) (EQ-5D-5L) (see, for example, https: / / qol(dot)eortc(dot)org / questionnaires / and https: / / euroqol(dot)org / eq-5d-instruments / eq-5d-5l-about / ).

[0096] All three questionnaires are designed for self-administration. All patient-reported outcomes are completed by the patient on-site. To minimize bias, patients complete the ePRO followed by a clinician's assessment and discussion of their clinical status, treatment plan, AEs, and any other relevant topics that may affect the patient's perceptions and feelings before answering the questions.

[0097] F. Pharmacokinetics Pharmacokinetic (PK) evaluation of isatuximab will be performed in all patients in the IKd group. Blood samples will be collected from all patients treated with isatuximab through cycle 10 using a sparse sampling strategy to evaluate the PK profile of isatuximab using a population PK approach. In a subset of approximately 12 patients in the IKd group, blood samples will be collected at selected time points on day 15 of cycle 1 for carfilzomib PK evaluation. PK parameters measured include, but are not limited to, those listed in Table C below.

[0098] [Table 4]

[0099] F. Immunogenicity Human anti-drug antibodies (ADA) to isatuximab will be assessed in IKd patients only on Day 1 prior to isatuximab administration from Cycle 1 to Cycle 10.

[0100] G. Exploratory Endpoints Blood samples will be collected on day 1 of cycle 1. Leukocyte DNA will be extracted and analyzed for immunogenetic determinants (such as Fcγ receptor polymorphisms) to correlate with parameters of clinical response.

[0101] In the IKd group only, additional blood samples will be collected at all time points to assess potential isatuximab interference in M-protein assessments up to cycle 30. These samples will be collected after cycle 30 only for patients who achieve at least VGPR in this cycle until disease progression. If isatuximab is discontinued before progression, interference assay samples will be collected until 3 months or PD, whichever comes first. After day 1 of cycle 1, immunofixed samples will be analyzed for all patients with M-protein of 0 g / dL. Additionally, immunofixed samples will also be analyzed in patients with serum M-protein of 0.2 g / dL or less to identify patients with potential isatuximab interference.

[0102] In addition to the three cytogenetic abnormalities (del(17p), t(4:14), and t(14:16)) assessed by fluorescence in situ hybridization (FISH) at baseline to determine the stratification factor R-ISS stage, other cytogenetic abnormalities, including but not limited to del(1p) and gain(1q) deletions, are evaluated to correlate with clinical response parameters.

[0103] Each of the above assessments was selected for use in this study and is considered well established and relevant in the hematology-oncology setting.

[0104] II. Study Design After verification of eligibility criteria (described in more detail below), patients will be randomly assigned using an interactive response technology (IRT) system in a 3:2 ratio (experimental group: control group) to one of the two groups shown in Table D below. The total number of patients expected is 300. (180 in the IKd group and 120 in the Kd group). A schematic diagram of the study design is also provided in Figure 1.

[0105] [Table 5]

[0106] Randomization was stratified by number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. unclassified). See Palumbo A, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015;33(26):3863-9. Patients will be treated until disease progression, unacceptable adverse events (e.g., unacceptable toxicity), or patient preference, whichever occurs first.

[0107] A. Duration of each patient's participation in the study Each patient will be considered in the study from the time of signing the informed consent until death, withdrawal of consent, or the cut-off date for the overall survival analysis, whichever occurs first.

[0108] The duration of the study for patients included a screening period of up to 3 weeks. Each treatment cycle was 28 days in duration. Patients continued study treatment until disease progression, unacceptable adverse events, patient preference, or other reasons occurred. All adverse events occurring after signing of informed consent were to be reported within 30 days of the last study treatment administration.

[0109] After discontinuation of study treatment, patients return to the study site 30 days after the last dose of study treatment for termination of treatment or before initiation of further anti-myeloma therapy, whichever occurs first, the end of treatment (EOT) assessment, and 90 days after administration of study treatment for HRQL questionnaires.

[0110] Associated AEs and all SAEs, regardless of their relationship to study treatment, ongoing at the time of study treatment discontinuation will be followed up during the follow-up period until resolution or stabilization. During the follow-up period, all new AEs (serious or non-serious) related to study treatment and any second primary malignancies will be collected and followed up until resolution or stabilization.

[0111] Patients who discontinue study treatment due to progressive disease (PD) will be followed up every 3 months (12 weeks) for HRQL at the first FU visit (90 days after last study treatment), further antimyeloma therapy, second primary malignancy, PFS2, and survival until death or the cutoff date for the final PFS analysis, whichever occurs first. Patients who discontinue study treatment before documentation of PD will be followed up every 4 weeks for HRQL 90 days after last study treatment until disease progression (even in patients who start further antimyeloma therapy without PD), then every 3 months (12 weeks) after confirmation of disease progression for further antimyeloma therapy, second primary malignancy, PFS2, and survival until death or the cutoff date for the final PFS analysis, whichever occurs first.

[0112] For all patients alive at the final PFS analysis cutoff date, vital status will be collected approximately one year after the final PFS analysis cutoff date and annually thereafter up to three years after the final PFS analysis cutoff date.

[0113] Patients who are still receiving treatment and benefiting from study treatment as of the final PFS or OS analysis cutoff date will continue study treatment until disease progression, unacceptable AEs, the patient's desire to discontinue further study treatment, or other reasons. For cycles administered after the cutoff date, all ongoing SAEs (regardless of whether related) and all ongoing related non-serious AEs, all new related AEs (regardless of whether serious), IP management, and reasons for EOT will continue to be collected. If a patient has received fewer than 10 cycles by the final PFS analysis cutoff date, anti-drug antibody (ADA) / PK samples will be stopped. If the last ADA is positive or indeterminate, an additional ADA will be sampled 3 months later. No further ADAs will be sampled, even if the 3-month sample is positive.

[0114] B. Decision to End Clinical Trial (All Patients) The PFS analysis (primary endpoint analysis) was event-driven, and the cutoff date for the final PFS analysis was the date on which 159 PFS events (progression or death, whichever occurred first) occurred (approximately 36 months after the first patient was randomized). The cutoff date for the OS analysis was approximately 3 years after the cutoff date for the primary PFS analysis. The primary PFS analysis corresponded to either a positive interim analysis or a final PFS analysis.

[0115] III. Patient Selection A. Inclusion criteria Eligible patients will be considered for inclusion if they meet all of the following criteria: Multiple myeloma. · Measurable disease: serum M protein ≥ 0.5 g / dL measured using serum protein immunoelectrophoresis and / or urine M protein ≥ 200 mg / 24 hours measured using urine protein immunoelectrophoresis. · Patients with relapsed and / or refractory MM with at least one prior line and no more than three prior lines including IMiDs® and proteasome inhibitors. Patients have given voluntary, written, informed consent before undergoing any research-related procedures that are not part of their usual medical care.

[0116] A line of treatment may consist of one or more complete cycles of a single drug, a combination of several drugs, or A new line of therapy consists of a different regimen or a planned sequence of different regimens. A treatment is considered a new line if any of the following three conditions are met (see, e.g., Rajkumar et al., Guidelines for the determination of the number of prior lines of therapy in multiple myeloma. Blood 2015;127(7):921-2): i. Initiation of a new line of treatment after discontinuation of a previous line. If a treatment regimen is discontinued for any reason and a different regimen is initiated, it should be considered a new line of therapy. If all agents in a regimen are discontinued, the regimen is considered discontinued. If some, but not all, agents in a regimen are discontinued, the regimen is not considered discontinued. The reason for discontinuation, addition, substitution, or stem cell transplant (SCT) does not affect how lines are counted. It is recognized that reasons for changes may include completion of planned therapy, toxicity, progression, lack of response, or inadequate response. ii. Unplanned addition or substitution of one or more drugs in an existing regimen. The unplanned addition of a new drug or switching to a different drug (or drug combination) for any reason is considered a new line of treatment. Stem Cell Transplantation (SCT): In patients with more than 1 SCT, each SCT (autologous or allogeneic) should be considered a new line of treatment, regardless of whether the conditioning regimen used is the same or different, except in the case of planned tandem SCTs at predefined intervals (e.g., 3 months). It is recommended to also capture data on the type of SCT. Planned tandem SCTs are considered 1 line. Planned induction and / or consolidation, maintenance with any SCT (frontline, relapse, autologous, or allogeneic) are considered 1 line. iii. Discontinuation and dose modification If a regimen is interrupted or discontinued for any reason and the same drug or combination is restarted without any other intervening regimen, it should be counted as a single line. However, if a regimen is interrupted or discontinued for any reason and later restarted, but in the meantime one or more other regimens are administered or the regimen is changed by adding one or more additional agents, it should be counted as two lines. A change in dosing of the same regimen should not be considered a new line of treatment.

[0117] B. Exclusion criteria Patients who meet all of the above inclusion criteria will be screened for the following exclusion criteria: · Under the age of 18 (or the legal age of majority in your country if the legal age is greater than 18). Primary refractory MM, defined as patients who have never achieved at least MR with any treatment during their disease course. Patients with serum-free light chain (FLC) measurable disease only. Patients who have received prior anti-CD38 mAb treatment who have progressed within 60 days of completing anti-CD38 mAb treatment or who have failed to achieve at least a MR to treatment (i.e., are anti-CD38 refractory). Antimyeloma treatment within 14 days prior to randomization, including dexamethasone. Patients who received any other investigational drug or prohibited treatment for this study within 28 days prior to randomization. Previous treatment with carfilzomib. History of allergy to CAPTISOL® (a cyclodextrin derivative used to solubilize carfilzomib), previous hypersensitivity to sucrose, histidine (as the base and the hydrochloride), polysorbate 80, or any component (active substance or excipient) of the study treatment that is not suitable for premedication with steroids or H2-blockers (which would contraindicate further treatment with these agents). Patients with contraindications to dexamethasone. · Previous allogeneic hematopoietic stem cell transplant with active graft-versus-host disease (any grade and / or receiving immunosuppressive treatment within 2 months prior to randomization). · Known amyloidosis or concomitant plasma cell leukemia. Pleural effusion requiring thoracentesis or ascites requiring thoracentesis or any major procedure within 14 days prior to randomization: e.g., plasma exchange, definitive radiotherapy, major surgery (vertebroplasty is not considered a major procedure). Eastern Cooperative Oncology Group (ECOG) performance status (PS) >2. Platelets <50,000 cells / μL (if <50% of BM nucleated cells are plasma cells) and <30,000 cells / μL (if ≥50% of BM nucleated cells are plasma cells). No platelet transfusions are permitted within 3 days prior to the screening blood test. Absolute neutrophil count (ANC) <1000 μ / L (1 × 10 9 / L). The use of granulocyte colony-stimulating factor (G-CSF) cannot achieve this level. Creatinine clearance <15 mL / min / 1.73 m 2 (Modification of Diet in Renal Disease [MDRD] formula: glomerular filtration rate (mL / min / 1.73m 2 ) = 175 × (Scr) − 1.154 × (age) − 0.203 × (0.742 for women) × (1.212 for African Americans); where Scr is serum creatinine in mg / dL and age in years. · Total bilirubin >1.5 x upper limit of normal (ULN), excluding known Gilbert syndrome. Corrected serum calcium >14 mg / dL (>3.5 mmol / L). · Aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) >3 × ULN. Ongoing toxicity from prior antimyeloma therapy of grade >1 (excluding alopecia and those listed in the eligibility criteria) (National Cancer Institute Common Terminology for Adverse Events [NCI-CTCAE] v4.03) Prior malignancies. Adequately treated basal or squamous cell skin or superficial (pTis, pTa, and pT1) bladder cancer or low-risk prostate cancer or any in situ malignancy after curative treatment were allowed, as well as any other cancer ≥5 years prior to randomization for which treatment was completed and the patient was disease-free for ≥5 years. Any of the following within 6 months prior to randomization: myocardial infarction, severe / unstable angina, coronary / peripheral artery bypass graft, New York Heart Association class III or IV congestive heart failure (CHF), grade 3 or greater arrhythmia, stroke, or transient ischemic attack. · Left ventricular ejection fraction (LVEF) <40%. · Known acquired AIDS-related disease or HIV disease requiring antiretroviral treatment, or known to have active hepatitis A, hepatitis B (defined as a result of a known positive hepatitis B surface antigen (HBsAg)), or hepatitis C (defined as a result of a known quantitative HCV RNA greater than the lower limit of detection of an assay or positive HCV antigen). Any of the following within 3 months prior to randomization: treatment-resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic event. Any severe acute or chronic medical condition that may impair the patient's ability to participate in the study or interfere with the interpretation of the study results (e.g., systemic infection if anti-infective treatment is not employed), or that prevents the patient from adhering to study procedures. Pregnant or breastfeeding female patients. · Women of childbearing potential (WOCBP) who are not protected by highly effective contraception and / or who are unwilling or unable to test for pregnancy. Male participants with a female partner of childbearing potential who is not protected by a highly effective method of contraception.

[0118] IV. Study Treatment A. Investigational Medicinal Products (IMPs) i. Isatuximab (IV administration) Isatuximab is formulated as a concentrated solution for injection in vials containing 20 mg / mL (500 mg / 25 mL) isatuximab in 20 mM histidine, 10% (w / v) sucrose, 0.02% (w / v) polysorbate 80, pH 6.0 buffer. Isatuximab is supplied as a sterile, non-pyrogenic, injectable, colorless 20 mg / mL concentrate for parenteral administration, which may contain white to off-white particles, packaged in a 30 mL glass vial fitted with an elastomeric closure. Each vial contains a nominal content of 500 mg isatuximab. The fill volume is set to ensure removal of 25 mL. For patient administration, the appropriate volume of isatuximab is diluted with an infusion bag of 0.9% sodium chloride solution. The final infusion volume corresponding to the dose of isatuximab depends on the dose administered and is administered over a period based on the amount of protein given per hour.

[0119] Isatuximab was administered at a dose of 10 mg / kg to patients in the IKd group via intravenous infusion on days 1, 8, 15, and 22 for the first 28-day cycle, and then on days 1 and 15 for each subsequent 28-day cycle. (All cycles were 28 days in duration.) Dose modifications (described in more detail below) were applied in the event of toxicity.

[0120] ii. Carfilzomib (IV administration) Carfilzomib (Kyprolis®) from available commercial supplies will be used in this study, if applicable. Otherwise, it will be relabeled by the sponsor in accordance with Good Manufacturing Practice (GMP) guidelines before being delivered to the investigational site. Details regarding carfilzomib formulation, storage, and handling procedures are provided in the commercial package insert. The lyophilized product will be reconstituted with water for injection to a final carfilzomib concentration of 2 mg / mL prior to administration.

[0121] iii. Dexamethasone (oral or IV administration) Dexamethasone from available commercial supplies will be used in this study, if applicable. Otherwise, it will be relabeled by the sponsor in accordance with Good Manufacturing Practice (GMP) guidelines before being supplied to the investigational site. Details regarding the formulation and handling procedures for dexamethasone are provided in the commercial package insert.

[0122] B. Non-Investigational Medicinal Products (NIMP) - Premedication for Prevention of Infusion Reactions (IR) All patients assigned to the IKd group will receive premedication prior to isatuximab infusion to reduce the risk and severity of IARs, which are commonly observed with monoclonal antibody administration. Recommended premedication medications are as follows: diphenhydramine 25–50 mg IV (or equivalent: e.g., cetirizine, promethazine, dexchlorpheniramine, depending on local approval and availability; the intravenous route is preferred for at least the first four infusions), dexamethasone oral / IV (doses shown below), ranitidine 50 mg IV (or equivalent: other approved H2 antagonists (e.g., cimetidine), oral proton pump inhibitors (e.g., omeprazole, esomeprazole), and acetaminophen 650–1000 mg oral 15–30 minutes (but no more than 60 minutes) before isatuximab infusion. Once the premedication regimen is complete, the isatuximab infusion will begin immediately.

[0123] On the day of isatuximab infusion, the following NIMPs will be administered in the following order: Acetaminophen (paracetamol) 650mg to 1000mg orally; then Ranitidine 50 mg IV (or equivalent); then Diphenhydramine 25 mg to 50 mg IV (or equivalent); then Dexamethasone 20 mg IV (also part of the study treatment).

[0124] When dexamethasone was administered intravenously, premedication was administered in the following order: Acetaminophen 650mg to 1000mg orally; then Ranitidine 50 mg IV (or equivalent); then Diphenhydramine 25 mg to 50 mg IV (or equivalent); then · Dexamethasone 40 mg IV (or 20 mg IV for patients 75 years of age or older).

[0125] In areas where IV diphenhydramine or equivalent is not available, oral administration is permitted starting with the first isatuximab infusion, which should occur 1 to 2 hours before the start of the isatuximab infusion.

[0126] If carfilzomib is administered without isatuximab (on days 2, 8, and 16 for patients assigned to the Kd group and for patients assigned to the IKd group), dexamethasone will be administered at least 30 minutes before the carfilzomib infusion.

[0127] If dexamethasone is discontinued prematurely and other study treatment is continued, steroid premedication may be considered with methylprednisolone 100 mg IV if, in the investigator's judgment, IAR premedication is still required for isatuximab and / or carfilzomib.

[0128] For patients who do not experience an IAR with four consecutive doses of isatuximab, the investigator may reconsider the need for specific isatuximab premedication for IAR.

[0129] V. Dosage and Schedule There is no limit to the number of cycles administered in the absence of major toxicity, disease progression, or any other discontinuation criteria. PD diagnosis made based on laboratory criteria is confirmed by two consecutive measurements before treatment discontinuation. Treatment continues until PD is confirmed.

[0130] Dose adjustments (with respect to dose delays, dose omissions, and carfilzomib and dexamethasone dose reductions) are permitted for subsequent treatment cycles based on individual patient tolerance. Additional details regarding dose adjustments are provided below. Dose reductions are not permitted for isatuximab infusions.

[0131] A. Study Procedure (IMP) Study treatment is defined as isatuximab / carfilzomib / dexamethasone in the IKd experimental arm and carfilzomib / dexamethasone in the Kd control arm.

[0132] Both isatuximab and carfilzomib can induce IAR and require premedication before their administration.

[0133] Patients assigned to the IKd arm will routinely receive premedication, including dexamethasone, before their isatuximab infusion to reduce the risk and severity of IARs commonly observed with mAbs and carfilzomib. Dexamethasone will be administered before carfilzomib for patients assigned to the Kd arm. For patients assigned to the IKd arm, dexamethasone will be administered before carfilzomib in the absence of an isatuximab infusion (e.g., days 2, 9, and 16 of cycle 1, and days 2, 8, 9, and 16 of subsequent cycles).

[0134] Hydration is required prior to the first two carfilzomib doses (Days 1 and 2 of Cycle 1). Hydration should begin orally at least 48 hours before Day 1 of Cycle 1. Hydration for Cycle 1 and further infusions within further cycles is at the investigator's discretion. (Details of hydration are provided below.) 2 Patients with more than 2.2 m 2 Use.

[0135] i.IKd group (experimental group) Drug administration (after premedication as described below) for patients treated with a combination of isatuximab, carfilzomib, and dexamethasone is as follows:

[0136] Dexamethasone 20 mg 15–30 minutes (but within 60 minutes) before isatuximab or at least 30 minutes before carfilzomib on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle. Dexamethasone is administered IV on days of isatuximab and / or carfilzomib administration and PO on other days. Post-infusion prophylaxis with dexamethasone is not required.

[0137] Isatuximab is administered IV at a dose of 10 mg / kg weekly for the first month (e.g., 28-day cycle), then Q2W for each 28-day cycle. The isatuximab infusion rate is initiated at 175 mg / hour. First infusion: The infusion is initiated at 175 mg / hour. If there are no IARs after 1 hour of infusion, the infusion rate is increased by 50 mg / hour every 30 minutes to a maximum of 400 mg / hour. Subsequent infusions: The infusion is initiated at 175 mg / hour. If there are no IARs after 1 hour of infusion, the infusion rate is increased by 100 mg / hour every 30 minutes to a maximum of 400 mg / hour.

[0138] Carfilzomib (after adequate hydration) was administered at 20 mg / m on days 1 and 2 of cycle 1. 256 mg / m on days 8, 9, 15, and 16 of cycle 1 2 at a dose of 56 mg / m on days 1, 2, 8, 9, 15, and 16 of all subsequent cycles. 2 The carfilzomib infusion will be administered IV over 30 minutes at 56 mg / m². The carfilzomib infusion will follow the isatuximab infusion and will be initiated immediately after the end of the isatuximab infusion. The dose will be increased to 56 mg / m² on day 8 for further administration if the patient does not experience greater than Grade 2 toxicity (excluding uncomplicated hematologic toxicity (meaning toxicity related to study treatment) and resolved tumor lysis syndrome (TLS)). 2 will be increased to.

[0139] ii. Kd group (control group) Drug administration for patients treated with a combination of carfilzomib and dexamethasone is carried out as follows:

[0140] Dexamethasone 20 mg at least 30 minutes before carfilzomib on days 1, 2, 8, 9, 15, 16, 22, and 23. Dexamethasone will be administered IV on carfilzomib days and PO on other days.

[0141] Carfilzomib (after adequate hydration) was administered at 20 mg / m on days 1 and 2 of cycle 1. 2 , 56 mg / m on days 8, 9, 15, and 16 of cycle 1 2 , then 56 mg / m on days 1, 2, 8, 9, 15, and 16 of all subsequent cycles 2 The dose is increased to 56 mg / m on Day 8 if the patient does not experience any toxicity higher than Grade 2 (excluding uncomplicated hematologic toxicity (meaning toxicity related to study treatment) or resolved TLS). 2 and increased for further administration.

[0142] B. Carfilzomib Hydration At least 48 hours prior to Day 1 of Cycle 1, oral hydration will be administered as follows: 30 mL / kg / day (approximately 6-8 cups of fluid per day) and continued until the time of treatment. Patient compliance will be assessed before treatment begins, and treatment will be postponed if oral hydration is not adequate. Oral hydration will be continued for infusions within Cycle 1 and for Cycle 2 and beyond, at the investigator's discretion. If tumor lysis syndrome (TLS) occurs after the previous study treatment administration, hydration for subsequent infusions will be administered as needed, per the investigator's discretion.

[0143] Patients with a history of cardiac disease (such as CHF and cardiomyopathy) or pulmonary edema are closely monitored for signs of fluid overload. Patients with a history of hypertension have their blood pressure controlled before initiating treatment.

[0144] Intravenous hydration will be given immediately prior to carfilzomib on Days 1 and 2 during Cycle 1 and at the investigator's discretion after Cycle 1. Intravenous hydration will consist of 500 mL of normal saline or other appropriate IV fluids prior to carfilzomib infusion over 30-60 minutes. The goal of the hydration program is to maintain a robust urine output (e.g., ≥ 2 L / day). During this period, patients will be monitored regularly for evidence of fluid overload.

[0145] On days when both isatuximab and carfilzomib are administered, the volume of the isatuximab infusion will be taken into account in the hydration required prior to the carfilzomib infusion. If the isatuximab infusion volume does not reach at least 500 mL, additional hydration will be administered until at least 500 mL is reached. In this case, the additional volume will be administered before the start of the isatuximab infusion. The total hydration volume may be less than 500 mL (250 mL or more) or may be maintained at 500 mL. Patients with borderline left ventricular ejection fraction (LVEF) and / or at risk for cardiac decompensation as determined by the investigator will receive hydration for a longer period. After the isatuximab infusion is completed, the carfilzomib infusion will begin.

[0146] C. Dose Modification Dose adjustments (dose delays, dose omissions, and dose reductions (for carfilzomib and / or dexamethasone only)) will be permitted in subsequent treatment cycles based on individual patient tolerance. Patients may omit a dose (isatuximab and / or carfilzomib and / or dexamethasone) within a cycle if toxicity occurs and the patient does not recover within 3 days of the scheduled date of infusion / administration. Administration of study treatment (isatuximab and / or carfilzomib and / or dexamethasone) will be discontinued in the event of an AE that persists despite appropriate dose modification or other AEs that warrant discontinuation in the investigator's opinion. All changes to study treatment administration will be recorded. Patients will receive the next study treatment cycle after toxicity has resolved, based on criteria assessed by the investigator.

[0147] The dose reduction steps for carfilzomib and dexamethasone are shown in Tables E1 and E2 below, respectively.

[0148] [Table 6]

[0149] [Table 7]

[0150] No dose reductions are permitted for isatuximab infusions.

[0151] V. Disease Assessment The decision made by the investigator regarding whether to allow a subject to continue treatment was based on efficacy data (obtained from local and / or central laboratories), radiological assessments, and bone marrow assessments performed throughout the study or when indicated according to IMWG criteria. The reference value for assessing treatment response was the value measured in a sample taken from each patient on Day 1 of Cycle 1 before treatment (see Section IA Primary Objective above). An overview of the assessments and schedule is provided in Table F below. Disease characteristics such as M protein subtype, extent of myeloid and extramedullary disease, cytogenetics (assessed by the central laboratory), and R-ISS will also be recorded at baseline.

[0152] [Table 8]

[0153] 2016 IMWG criteria (e.g., Kumar S, Paiva B, Anderson KC, et al., International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in myeloma) Multicenter randomized controlled trial (MDR) (see [link removed], ...

[0154] Safety assessments will include vital signs, hematology and biochemistry assessments, physical examinations, electrocardiograms, and AEs; these will be tracked throughout the study. AEs will be graded according to the National Cancer Institute's Common Terminology Criteria for AEs v4.03. Immunogenicity will be assessed during study treatment. Indirect Coombs testing will be performed only in the isatuximab plus carfilzomib / dexamethasone group at baseline and after treatment initiation.

[0155] Patient-reported outcome (PRO) assessments will be measured on day 1 of every cycle, at the end of treatment, and 90 days after study treatment administration using PRO / HRQoL and health utility instruments (European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 and MY20 [EORTCQLQ-C30 and QLQMY20] and EuroQoL questionnaire EQ-5D-5L).

[0156] Example 1B: Initial Results of the Phase III Study Described in Example 1A A total of 302 patients were randomized as follows: 179 patients were assigned to the isatuximab, carfilzomib, and dexamethasone (Isa+car+dex) group, and 123 patients were assigned to the carfilzomib and dexamethasone (car+dex) group. Patient characteristics were well balanced between groups. The median age was 64 years (range: 33-90). 25.8% of patients had R-ISS stage I disease, 59.6% had R-ISS stage II disease, and 7.9% had R-ISS stage III disease. 44% of patients had received one prior line of therapy for multiple myeloma, 33% had two prior lines of therapy, and 23% had three or more prior lines of therapy. 90% of patients had received prior treatment with a proteasome inhibitor, and 78% had received prior treatment with an immunomodulatory agent (i.e., an IMiD®). The median number of prior lines was two. Twenty-four percent of patients had high-risk cytogenetics (i.e., one or more of the following chromosomal / cytogenetic abnormalities: del(17p), t(4;14), and t(14;16)).

[0157] As discussed in Example 1A, patients in the experimental group received isatuximab at a dose of 10 mg / kg once weekly for 4 weeks, followed by carfilzomib twice weekly at 20 / 56 mg / m every other week in a 28-day cycle. 2 Patients in the control group received 20 / 56 mg / m 2 dexamethasone in combination with cefotaxime and dexamethasone at standard doses throughout the treatment period. 2 Patients received carfilzomib twice weekly at a dose of 0.001 mg / kg twice a week and standard-dose dexamethasone. The primary endpoint of the study was progression-free survival. Secondary endpoints included overall response rate (ORR), best partial response or better (≥ VGPR), minimal residual disease (MRD), complete response rate (CR), overall survival (OS), and safety.

[0158] With a median follow-up of 20.7 months and 103 progression-free survival (PFS) events per IRC (Independent Review Committee), median PFS was not reached in the isa+car+dex group. Median PFS in the car+dex group was 19.15 months (HR 0.531 (99% CI 0.318-0.889), one-sided p=0.0007). Thus, the pre-specified efficacy boundary (p=0.005) was exceeded. The PFS benefit was observed in the subgroups. Results were consistent across loops. Overall response rate (ORR) (i.e., the percentage of patients achieving a partial response (PR) or better) was 86.6% in the isa+car+dex group compared to 82.9% in the car+dex group (one-sided p=0.1930). 72.6% of patients in the isa+car+dex group achieved ≥ VGPR (best partial response) compared to 56.1% of patients in the car+dex group (p=0.0011). 39.7% of patients in the isa+car+dex group achieved a complete response (CR) compared to 27.6% of patients in the car+dex group. MRD negativity rate (10 -5 ) was 29.6% (53 / 179) in the isa+car+dex group compared with 13.0% (16 / 123) in the car+dex group.

[0159] Treatment continued in 52.0% of patients in the isa+car+dex group versus 30.9% in the car+dex group. The main reasons for treatment discontinuation were disease progression (29.1% in the isa+car+dex group vs. 39.8% in the car+dex group) and adverse events (8.4% in the isa+car+dex group vs. 13.8% in the car+dex group). Grade 3 or higher treatment-emergent adverse events (TEAEs) were observed in 76.8% of patients in the isa+car+dex group versus 67.2% in the car+dex group. Treatment-emergent serious adverse events (TE-SAEs) and fatal TEAEs were similar in both groups: 59.3% of patients in the isa+car+dex group experienced TE-SAEs compared with 57.4% in the car-dex group; and 3.4% of patients in the isa+car+dex group experienced fatal TEAEs compared with 3.3% in the car+dex group. Infusion reactions were reported in 45.8% of patients in the isa+car+dex group (0.6% grade 3-4) and 3.3% of patients in the car+dex group (0% grade 3-4). Grade 3 or higher respiratory infections (group breakdown) were observed in 32.2% of patients in the isa+car+dex group versus 23.8% of patients in the car+dex group. Grade 3 or higher heart failure (grouping) was reported in 4.1% of patients in the car+dex group compared with 4.0% of patients in the isa+car+dex group. Laboratory results showed that grade 3-4 thrombocytopenia was reported in 23.8% of patients in the car+dex group compared with 29.9% of patients in the isa+car+dex group; neutropenia was reported in 7.4% of patients in the car+dex group compared with 19.2% of patients in the isa+car+dex group.

[0160] The addition of isatuximab to carfilzomib plus dexamethasone provided a superior, statistically significant improvement in PFS with clinically meaningful improvement in response intensity (i.e., MRD) compared with standard of care carfilzomib plus dexamethasone (i.e., without isatuximab) in patients with relapsed multiple myeloma. The addition of isatuximab to carfilzomib plus dexamethasone significantly reduced the risk of disease progression or death compared with standard of care carfilzomib plus dexamethasone (i.e., without isatuximab). The combination of isatuximab plus carfilzomib plus dexamethasone was well tolerated with a manageable safety profile and a favorable benefit-risk profile. No new safety signals were identified in this study.

[0161] Example 1C: Further results from the Phase III study described in Example 1A Further details regarding interim results from the Phase III clinical trials and trials described in Example 1A are provided in this Example.

[0162] Patients with relapsed multiple myeloma who met the inclusion and exclusion criteria described in Example 1A were randomized into the two arms of the study as follows: for every three patients randomized to the IKd arm (isatuximab + carfilzomib + dexamethasone), two were randomized to the Kd arm (carfilzomib + dexamethasone). See Table D above. All patients had received one to three prior lines of treatment for multiple myeloma. None had received prior treatment with carfilzomib. None were refractory to prior anti-CD38 therapy. Patients were stratified according to prior lines of therapy (i.e., >1 line vs. 1 prior line) and R-ISS score (i.e., I or II vs. III vs. unclassified) to ensure equal allocation of participant subgroups to each arm. (For further details on the R-ISS, see Palumbo A, et al. Revised International Staging System for Multiple Myeloma: A Report From the International Myeloma Working Group. J Clin Oncol. 2015;33(26):3863-9.)

[0163] Key patient demographics and baseline characteristics are shown in Table G below. Patient characteristics were balanced in both groups. In cytogenetic analysis, del17p was defined using a 50% cutoff, and t(4;14) and 4(14;16) were defined using a 30% cutoff. Three patients (1.7%) in the IKd group and two patients (1.6%) in the Kd group had received three or more prior lines of therapy for multiple myeloma.

[0164] [Table 9]

[0165] Treatment continued until patients demonstrated progressive disease (PD), experienced unacceptable toxicity, or chose to leave the study.

[0166] The primary endpoint of the study included progression-free survival (PFS) as assessed by an independent review committee (IRC). Secondary endpoints of the study included overall response rate (ORR), rate of best partial response (VGPR) or better, minimal residual disease (MRD) negativity, complete response (CR) rate, and overall survival (OS).

[0167] result At 20.7 months follow-up, patient disposition was as follows: IKd Of 179 patients in the IKd group, 177 were treated. 84 (46.9%) patients in the IKd group discontinued treatment: 52 (29.1%) discontinued due to progressive disease (PD); 15 (8.4%) discontinued due to adverse events (AEs); and 6 (3.4%) discontinued for other reasons. 93 (52%) patients in the IKd group continued treatment. Of 123 patients in the Kd group, 122 received treatment. 84 (68.3%) patients in the Kd group discontinued treatment: 49 (39.8%) discontinued due to progressive disease (PD); 17 (13.8%) discontinued due to adverse events (AEs); and 4 (3.3%) discontinued for other reasons. 38 (30.9%) patients in the Kd group continued treatment. A higher proportion of patients in the IKd group continued treatment compared with the Kd group (i.e., approximately 37% of patients in the IKd group discontinued treatment due to PD or AE compared with approximately 54% in the Kd group).

[0168] Interim PFS analysis by an independent review committee (IRC) showed that median PFS (mPFS) had not yet been reached in the IKd group, whereas mPFS in the Kd group was 19.15 months (95% CI: 15.770-NE). HR 0.531 (99% CI: 0.318-0.889), p=0.0007. Patients receiving IKd demonstrated improved PFS compared with patients in the Kd group, with a 47% reduction in the risk of disease progression or death. See Figure 3. Subgroup analysis was performed on PFS. As shown in Figure 4, all subgroups favored IKd versus Kd. A consistent treatment effect on IKd was seen across all subgroups analyzed (e.g., age, baseline renal function (eGFR), number of previous lines of therapy, previous proteasome inhibitor treatment in last line, previous immunomodulator treatment in last line, high-risk cytogenetic status, ISS staging at study entry, and becoming refractory to lenalidomide).

[0169] Compared with patients treated with Kd, stronger responses were seen in patients treated with IKd, consistent with improved PFS. The overall response rate (ORR) for patients in the IKd group was 86%, compared with 82% for patients in the Kd group (p=0.19, stratified Cochran-Mantel-Haenszel test; one-sided significance level 0.025). 72.6% of patients in the IKd group achieved VGPR or better, compared with 56.1% of patients in the Kd group (p=0.0011). 39.7% of patients in the IKd group achieved CR, compared with 27.6% of patients in the Kd group. Furthermore, a significantly higher proportion of patients in the IKd group were MRD-negative (i.e., as assessed by next-generation sequencing (NGS)) than in the Kd group. -5 More patients were "minimal residual disease negative" at this threshold. Among intent-to-treat patients, 53 / 179 (29.6%) in the IKd group were MRD-negative compared with 16 / 123 (13%) in the Kd group. Among patients in the study who achieved VGPR or better, 53 / 128 (41.4%) in the IKd group were MRD-negative compared with 16 / 70 (22.9%) in the Kd group.

[0170] Treatment with IKd resulted in a significant delay in time to next treatment, consistent with improved PFS, compared to treatment with Kd. See Figure 5 and Table H.

[0171] [Table 10]

[0172] With a follow-up of 20.73 months, overall survival (OS) data were not yet complete at the time of analysis.

[0173] Exposure to study treatment in each treatment group is shown in Table I. The high relative dose intensity of both isatuximab and carfilzomib in the IKd group demonstrates the feasibility of the combination.

[0174] [Table 11]

[0175] More patients in the IKd group experienced grade 3 or higher treatment-emergent adverse events ( The addition of isatuximab to carfilzomib did not increase mortality, serious TEAEs, or events leading to treatment discontinuation compared with carfilzomib plus dexamethasone. IKd has a manageable safety profile with no new safety signals. Infusion reactions (IRs) occurred primarily during the first infusion and were mostly grade 1 or 2.

[0176] conclusion The addition of isatuximab to Kd resulted in a statistically significant improvement in PFS with an HR of 0.531, corresponding to a 47% reduction in the risk of progression or death. IKd demonstrated consistent benefit across multiple subgroups, including those difficult to treat with high unmet medical need (elderly, high-risk cytogenetics, renal impairment). IKd demonstrated remarkable strength of response compared with Kd, with MRD-negativity rates in the intention-to-treat population of 30% vs. 13%. IKd demonstrated a manageable safety profile and a favorable risk / benefit profile in patients with relapsed MM.

[0177] Example 1D: Magnitude and kinetics of response to isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma Prologue Achieving minimal residual disease-negative (MRD-) status in multiple myeloma (MM) is associated with improved progression-free survival (PFS) and overall survival (OS). Isatuximab (Isa) is an approved anti-CD38 IgG kappa monoclonal antibody. The intensity of response, including MRD-, long-term outcomes, and tumor response kinetics, was analyzed in the study described in Example 1A. To overcome interference with Isa in standard immunofixation assays, serum M protein was also measured by mass spectrometry.

[0178] method Example 1A describes a randomized, open-label, multicenter phase 3 study investigating Isa plus carfilzomib and dexamethasone (Isa-Kd) versus Kd in patients with relapsed MM who had received 1 to 3 lines of therapy. The primary endpoint of PFS and the secondary endpoints of overall response rate (ORR), best partial response or better (≥VGPR), and complete response (CR) rates were determined by an Independent Response Committee (IRC) based on central M protein data, central imaging review, and local bone marrow for plasma cell infiltration according to the International Myeloma Working Group (IMWG) criteria (see, e.g., Kumar et al. (2016) “International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.” Lancet Oncol. 17(8):e328-e346 and Durie et al. (2006) “International uniform response criteria for multiple myeloma. Leukemia. 20:1467-1473). MRD (i.e., minimal residual disease) was determined by a 10-point scale. -5 Next-generation sequencing at a sensitivity level of 1000 nmol / s was used to assess bone marrow aspirates from patients who achieved VGPR or better. Mass spectrometry was performed to measure serum M protein without Isa interference. Hazard ratios and corresponding confidence intervals were estimated using a Cox proportional hazards model. Secondary endpoints were compared between treatment groups using the Cochran-Mantel-Haenszel test. All patients who did not reach MRD- or were randomized without MRD assessment were analyzed as MRD+.

[0179] result As discussed in Example 1A, 302 patients (179 Isa-Kd, 123 Kd) were randomized. At a median follow-up of 20.7 months, 179 patients received Isa-Kd compared with 123 patients who received Kd. A stronger response was observed in patients receiving Isa-Kd than in those receiving Kd. 72.6% of patients in the Isa-Kd group achieved a VGPR or better, compared with 56.1% of patients in the Kd group (nominal p=0.011). 39.7% of patients in the Isa-kd group achieved a CR or better, compared with 27.6% of patients in the Kd group. MRD- occurred in 53 / 179 (30%) of patients in the Isa-Kd group versus 16 / 123 (13%) of patients in the Kd group (nominal p=0.0004). (See also, e.g., Examples 1B and 1C.) 20.1% (36 / 179) of patients in the Isa-Kd group achieved both a CR and MRD- compared with 10.6% (13 / 123) of patients in the Kd group. Progression-free survival (PFS) by MRD status in both treatment groups (i.e., Isa-Kd vs. Kd) is shown in Figure 6. Hazard ratios (HRs) favor Isa-Kd over Kd in both MRD- patients (HR 0.578, 95% CI: 0.052-6.405) and MRD+ patients (HR 0.670, 95% CI: 0.452-0.993). MRD- patients had a longer PFS than MRD+ patients. Within the Isa-Kd group, MRD-negative status can be achieved in patients with impaired renal function, i.e., eGFR < 60 mL / min / 1.73 m 2 (26.5% MRD- vs. 25.9% MRD+); ISS stage III at diagnosis (32.1% MRD- vs. 27.8% MRD+); t(4;14) (13.2% MRD- vs. 11.9% MRD+), gain(1q21) (45.3% MRD- vs. 40.5% MRD+); heavily pretreated with three or more prior lines (22.6% MRD- vs. 19.0% MRD+) or lenalidomide-refractory in the last regimen (18.9% MRD- vs. 20.6% MRD+). Within the Isa-Kd group, patients refractory to proteasome inhibitors (PIs) (18.9% MRD- vs. 36.5% MRD+) or del(17p) (3.8% MRD- vs. 12.7% MRD+) less frequently achieved MRD-negative status.

[0180] We investigated the interference of isatuximab with M protein: Samples from 27 patients with near-CR (serum immunofixation (IF) positive IgG kappa only) or potential CR (serum residual M protein ≤ 0.5 g / dL with IF positive IgG kappa) in the Isa-Kd group were tested by mass spectrometry. Among them, 11 near-CR or potential CR patients recorded less than 5% plasma cells in the bone marrow and were mass spectrometry negative (residual myeloma M protein levels below the limit of quantification (LOQ) of central lab immunofixation). Furthermore, among the 11 near-CR or potential CR patients, 7 were also MRD-negative. These results support the belief that both the current CR rate and MRD-CR rate are underestimated (potential adjusted CR rate: 45.8%; potential adjusted MRD-CR rate: 24%).

[0181] Response to treatment occurred rapidly in both groups. The median responder time to first response was 32.0 (28-259) days in the Isa-Kd group versus 33.0 (27-251) days in the Kd group. The median responder time to best response was 120.0 (29-568) days in the Isa-Kd group versus 104.5 (29-507) days in the Kd group. The median responder time to first CR was 184.0 (30-568) days in the Isa-Kd group versus 229.5 (58-507) days in the Kd group. The median responder time to first ≥ VGPR was 88.0 (28-432) days in the Isa-Kd group versus 90.0 (29-491) days in the Kd group. In addition to an increased intensity of response, quality of life as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 Global Health Status Score was maintained in patients treated with Isa-Kd on descriptive analysis.

[0182] conclusion There was a clinically meaningful improvement in the intensity of response in patients treated with Isa-Kd versus patients treated with Kd. The 39.7% CR rate in the Isa-Kd arm of the study was underestimated due to interference. Mass spectrometry results suggest that approximately half of patients with 1-3 prior lines of Isa-Kd treatment may achieve a CR. Kd arm More patients achieved MRD-negativity in the Isa-Kd group than in the Kd group (30% vs. 13%), and at least twice as many patients in the Isa-Kd group achieved CR MRD- in the Kd group (20.1% vs. 10.6%; adjusted to 24% vs. 10.6%, respectively). Achieving MRD-negativity was associated with longer PFS in both groups.

[0183] Example 1E: Further results from the Phase III study described in Example 1A Eligible patients had relapsed and / or refractory multiple myeloma with 1–3 prior lines of therapy and evidence of measurable disease (serum M protein ≥ 0.5 g / dl and / or urine M protein ≥ 200 mg / 24 h). Patients were excluded if they had primary refractory multiple myeloma according to the International Myeloma Working Group (IMWG) response criteria (e.g., Kumar et al. (2016) "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma." Lancet Oncol. 17(8):e328-e346) and Durie et al. (2006) "International uniform response criteria for multiple myeloma." Leukemia. 20:1467-1473), had serum-free light chain measurable disease only, or had an Eastern Cooperative Oncology Group performance status >2. Patients were excluded if they had received antimyeloma treatment within 14 days of randomization, had received prior treatment with carfilzomib, were refractory to anti-CD38 antibody therapy, or had a contraindication to dexamethasone. Dietary Modifications in Renal Disease (ECR) <15 ml / min / 1.73 m 2 Patients with an estimated glomerular filtration rate (eGFR) due to a low or low left ventricular ejection fraction (LVEF) <40% were also excluded. Patients with previous pulmonary complications, including chronic obstructive pulmonary disease, were enrolled. Patients were randomized as discussed above, and randomization was stratified as discussed above. Patients in each group were treated as outlined in Table D.

[0184] Efficacy endpoints and assessments The primary efficacy endpoint was progression-free survival according to a blinded independent response committee (IRC). The IRC reviewed disease assessments for response and progression (central radiological evaluation, M-protein quantification from a central laboratory, and local bone marrow aspiration for plasma cell infiltration, as needed). Key secondary efficacy endpoints included overall response rate according to IMWG response criteria, best partial response (VGPR) or better rate, minimal residual disease (MRD)-negativity rate, complete response (CR) rate, and overall survival.

[0185] MRD was 10% in patients achieving VGPR or better. 5 Next-generation sequencing was performed with a minimum sensitivity of 1 in nucleated cells. Cytogenetics was assessed by fluorescence in situ hybridization (FISH) during central screening, with cutoffs of 50% for del(17p) and 30% for t(4;14), t(14;16), and gain(1q21). High-risk cytogenetic status was defined as the presence of del(17p), t(4;14), or t(14;16).

[0186] Efficacy assessments were completed on Day 1 of every cycle and when treatment was stopped. Safety assessments included recording of adverse events, laboratory parameters (both assessed according to the National Cancer Information Center-Common Terminology Criteria (NCIC-CTC) version 4.03), vital signs, electrocardiograms, and Eastern Cooperative Oncology Group performance status. Efficacy analyses were performed in the intent-to-treat population and summarized by randomized treatment. Safety analyses and study treatment intensity were assessed and summarized by actual treatment received within the safety population.

[0187] Patients and procedures Demographic and clinical characteristics were well balanced at baseline (Table J). The median age was 64 years (range, 33–90 years). The median number of previous lines was 2 (range, 1–4), similar between groups, with 44%, 33%, and 23% receiving 1, 2, and ≥3 previous lines, respectively. One patient (isatuximab group) and two patients (control group) received 4 prior lines. Overall, 45% of patients were refractory to immunomodulatory agents, of which 32.8% were lenalidomide-refractory. In the isatuximab group, 23.5% of patients had high-risk cytogenetics, similar to the control group (25.2%). At baseline, 26.1% of patients in the isatuximab group had impaired renal function (eGFR <60 ml / min / 1.73 m). 2 ) compared with 16.2% in the control group.

[0188] [Table 12-1] [Table 12-2]

[0189] At the time of analysis, the median treatment duration was 80.0 weeks (range, 1-111) in the isatuximab group and 61.4 weeks (range, 1-114) in the control group. The median relative dose intensity of carfilzomib and dexamethasone was similar in both groups (91.2% and 84.8% in the isatuximab group vs. 91.4% and 88.4% in the control group, respectively). The median relative dose intensity of isatuximab was 94.3%. Fewer patients discontinued treatment in the isatuximab vs. control groups (46.9% vs. 68.3%).

[0190] Effectiveness With a median follow-up of 20.7 months, the addition of isatuximab to carfilzomib-dexamethasone demonstrated a statistically significant improvement in progression-free survival with a hazard ratio (HR) of 0.531 (99% CI, 0.318-0.889; one-sided P = 0.0007), corresponding to a 46.9% reduction in the risk of progression or death. The median progression-free survival (Kd) of 19.15 months (95% CI, 15.770-not reached) was consistent with the protocol assumption of 19 months. The median PFS was not reached in the IKd group. The probability of progression-free survival at 2 years was 68.9% (IKd group) versus 45.7% (Kd group).

[0191] In the intention-to-treat population, the overall response rate was 86.6% (IKd group) vs. 82.9% (Kd group), with a one-sided P value of 0.1930. Because the differences between groups were not statistically significant, P values ​​for subsequent key secondary endpoints are provided for descriptive purposes only. The rate of VGPR or better was 72.6% (IKd group) vs. 56.1% (Kd group) (P = 0.0011). The CR rate was 39.7% (IKd group) vs. 27.6% (Kd group). The addition of isatuximab to carfilzomib-dexamethasone more than doubled the MRD-negativity rate in the intention-to-treat population: 29.6% (IKd group) vs. 13.0% (Kd group) (P = 0.0004) (Table K). The proportion of patients who achieved both a CR and MRD-negative response was 20.1% (IKd group) and 10.6% (Kd group). Although overall survival was not completed at the interim analysis, 17.3% and 20.3% of patients died in the isatuximab and control groups, respectively.

[0192] [Table 13-1] [Table 13-2]

[0193] In prespecified subgroup analyses, clinical benefit favoring isatuximab and carfilzomib-dexamethasone occurred across nearly all groups (Figure 7). The median progression-free survival for patients with renal impairment was not reached in the IKd group, compared with 13.41 months (95% CI, 4.830-not reached) in the Kd group, with a hazard ratio of 0.273 [95% CI, 0.113-0.660]. A complete renal response (baseline eGFR 50 ml / min / 1.73 m) was associated with a mean renal response of 1.73 m. 2 Less than 60ml / min / 1.73m 2 Progression-free survival (PFS) benefit favoring isatuximab with carfilzomib-dexamethasone was observed in elderly patients (≥65 years), including a hazard ratio of 0.244 (95% CI, 0.060-1.000) for patients ≥75 years of age.

[0194] The median time to first response among responders was similar in both groups: 32 days (IKd group) and 33 days (Kd group); response duration was longer in the IKd group, with a hazard ratio of 0.425 (95% CI, 0.269-0.672). The combination of carfilzomib-dexamethasone in addition to isatuximab delayed the time to next treatment (hazard ratio, 0.566; 95% CI, 0.380-0.841). Of patients receiving subsequent treatment, 26.3% (IKd group) received at least one additional antimyeloma therapy compared with 43.1% (Kd group); of patients receiving subsequent treatment, 21.3% and 47.2%, respectively, received daratumumab. Health-related quality of life, as measured by the QLQ-C30 global health status score, was maintained with isatuximab in addition to carfilzomib-dexamethasone.

[0195] Consideration Results from this randomized phase 3 trial showed that the addition of isatuximab to carfilzomib-dexamethasone was associated with a significant benefit in progression-free survival compared with carfilzomib-dexamethasone alone in patients with relapsed multiple myeloma. The risk of disease progression or death was 47% lower in the isatuximab group, a very low hazard ratio. (0.531 [99% CI, 0.318-0.889]). The median progression-free survival of 19.15 months in the control group was consistent with the protocol assumptions (19 months) and a previous phase 3 study evaluating the efficacy of carfilzomib plus dexamethasone versus bortezomib plus dexamethasone in patients with relapsed / refractory multiple myeloma after one to three prior lines of therapy. Our results demonstrate that the superiority of the IKd group was not associated with an underperforming control group (i.e., the Kd group).

[0196] The progression-free survival benefit was seen in nearly all subgroups in the IKd arm, including high-risk cytogenetics, International Staging System stage III disease at study entry, elderly patients, patients with impaired renal function, patients with one or more prior lines of therapy, prior exposure to immunomodulatory agents, prior exposure to proteasome inhibitors, and prior exposure to both immunomodulatory agents and proteasome inhibitors. Importantly, cytogenetic risk was assessed centrally for all patients using an internationally accepted cutoff for FISH positivity and was conclusive in 88% of patients overall.

[0197] The intensity and quality of response were superior in the IKd group compared with the Kd group, with higher rates of VGPR, CR, MRD-negative, and CR with MRD-negative. Specifically, the rates of MRD-negative and CR with MRD-negative in the IKd group were very high, considering that the median number of prior lines for these patients was 2. Furthermore, because CR was assessed without the use of interference assays, the rate of MRD-negative CR may be underestimated (see, e.g., Example 1D).

[0198] In this study conducted in patients with relapsed multiple myeloma, the addition of isatuximab to carfilzomib-dexamethasone resulted in significantly longer progression-free survival compared with carfilzomib-dexamethasone alone. The intensity and quality of response were better in the isatuximab group, including a high rate of complete response accompanied by MRD negativity, a prognostic factor for progression-free survival and overall survival. The safety profile was manageable and encouraging, with no increase in cardiovascular events. Collectively, these results indicate that the combination of isatuximab plus carfilzomib-dexamethasone is a potential new standard of care for patients with relapsed multiple myeloma.

[0199] Each embodiment described herein may be combined with any other embodiment(s) unless expressly indicated to the contrary. In particular, any feature or embodiment indicated as being preferred or advantageous may be combined with any other feature(s) or embodiment(s) indicated as being preferred or advantageous unless expressly indicated to the contrary.

[0200] All references cited in this application are expressly incorporated herein by reference.

Claims

1. 1. An anti-CD38 antibody comprising: (a) a heavy chain variable domain (V) comprising a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3); Ｈ ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). Ｌ and for use in a method of treating multiple myeloma in an individual, the method comprising administering to the individual an anti-CD38 antibody, carfilzomib, and dexamethasone; Here, the anti-CD38 antibody was administered at a dose of 10 mg / kg and carfilzomib at a dose of 20 mg / m ２ or 56 mg / m ２ and dexamethasone is administered at a dose of 20 mg; wherein the individual has received at least one prior therapy for multiple myeloma, and the treatment prolongs the individual's progression-free survival (PFS) and / or overall survival (OS).

2. An anti-CD38 antibody, comprising: (a) a heavy chain variable domain (V) comprising a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3); Ｈ ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). Ｌ and for use in a method of treating multiple myeloma in an individual, the method comprising administering to the individual an anti-CD38 antibody, carfilzomib, and dexamethasone; Here, the anti-CD38 antibody was administered at a dose of 10 mg / kg and carfilzomib at a dose of 20 mg / m ２ or 56 mg / m ２ and dexamethasone is administered at a dose of 20 mg; wherein the individual has received at least one prior treatment for multiple myeloma, and Here, the individual is －５ Anti-CD38 antibody that is minimal residual disease negative at the following thresholds:

3. An anti-CD38 antibody, comprising: (a) a heavy chain variable domain (V) comprising a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3); Ｈ ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). Ｌ and for use in a method of treating multiple myeloma in an individual, the method comprising administering to the individual an anti-CD38 antibody, carfilzomib, and dexamethasone; Here, the anti-CD38 antibody was administered at a dose of 10 mg / kg and carfilzomib at a dose of 20 mg / m ２ or 56 mg / m ２ and dexamethasone is administered at a dose of 20 mg; wherein the individual has received at least one prior treatment for multiple myeloma, and wherein the individual has impaired renal function at the start of treatment, an anti-CD38 antibody.

4. The individual has received 1-3 prior therapies for multiple myeloma and the treatments have not resulted in progression-free survival ( 4. The anti-CD38 antibody for use according to any one of claims 1 to 3, which prolongs progression-free survival (PFS) and / or overall survival (OS).

5. The anti-CD38 antibody for use according to any one of claims 1 to 3, wherein the individual has received 1 to 3 prior treatments for multiple myeloma.

6. The anti-CD38 antibody for use according to any one of claims 1 to 3, wherein the individual has received more than three previous treatments for multiple myeloma.

7. The anti-CD38 antibody for use according to any one of claims 1 to 3, wherein the individual has undergone previous treatment with a proteasome inhibitor.

8. The anti-CD38 antibody for use according to any one of claims 1 to 3, wherein the individual has undergone previous treatment with an immunomodulatory agent.

9. 4. The anti-CD38 antibody for use according to any one of claims 1 to 3, wherein the individual is classified as stage I or stage II according to the Revised International Staging System for Multiple Myeloma (R-ISS) at the start of treatment.

10. The anti-CD38 antibody for use according to any one of claims 1 to 3, wherein the individual is classified as stage III according to R-ISS at the start of treatment.

11. The anti-CD38 antibody for use according to any one of claims 1 to 3, wherein the individual is not classified according to R-ISS at the start of treatment.

12. 4. The anti-CD38 antibody for use according to any one of claims 1 to 3, wherein the individual has one or more cytogenetic abnormalities selected from the group consisting of: del(17p), t(4;14), and t(14;16).

13. 3. The anti-CD38 antibody for use according to claim 1 or 2, wherein the individual has impaired renal function at the start of treatment.

14. The anti-CD38 antibody for use according to any one of claims 1 to 3, wherein the individual is 65 to under 75 years of age at the start of treatment.

15. The anti-CD38 antibody for use according to any one of claims 1 to 3, wherein the individual is 75 years of age or older at the start of treatment.

16. The anti-CD38 antibody comprises a heavy chain variable region (V) comprising the amino acid sequence of SEQ ID NO:

7. Ｈ ) and a light chain variable region (V Ｌ 4. The anti-CD38 antibody for use according to any one of claims 1 to 3, comprising:

17. The anti-CD38 antibody for use according to any one of claims 1 to 3, wherein the anti-CD38 antibody is isatuximab.

18. an anti-CD38 antibody, carfilzomib, and dexamethasone are administered in a first 28-day cycle; wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle, and carfilzomib is administered at a dose of 20 mg / kg on days 1 and 2 of the first 28-day cycle. ２ and 56 mg / m on days 8, 9, 15, and 16. ２ Dosage and dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of a first 28-day cycle.

19. the anti-CD38 antibody, carfilzomib, and dexamethasone are further administered in one or more 28-day cycles following the first 28-day cycle; wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg on days 1 and 15 of one or more 28-day cycles following the first 28-day cycle, and carfilzomib is administered at a dose of 56 mg / kg on each of days 1, 2, 8, 9, 15, and 16 of one or more 28-day cycles following the first 28-day cycle. ２ and dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of one or more 28 day cycles following the first 28 day cycle.

20. Individuals were treated 10 days after treatment. －５ 4. The anti-CD38 antibody for use according to claim 1 or 3, which is MRD-negative at the following thresholds:

21. A method of treating a human individual with multiple myeloma, comprising administering to the individual (a) a heavy chain variable domain (V) comprising a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3). Ｈ ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). Ｌ administering an anti-CD38 antibody comprising carfilzomib and dexamethasone; Here, the anti-CD38 antibody was administered at a dose of 10 mg / kg and carfilzomib at a dose of 20 mg / m ２ or 56 mg / m ２ and dexamethasone is administered at a dose of 20 mg; wherein the individual has received at least one prior treatment for multiple myeloma; wherein the treatment prolongs the progression-free survival (PFS) of the individual.

22. 22. The method of claim 21, wherein the treatment extends overall survival (OS) of the individual.

23. A method of treating a human individual with multiple myeloma, comprising administering to the individual (a) a heavy chain variable domain (V) comprising a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3). Ｈ ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). Ｌ administering an anti-CD38 antibody comprising carfilzomib and dexamethasone; Here, the anti-CD38 antibody was administered at a dose of 10 mg / kg and carfilzomib at a dose of 20 mg / m ２ or 56 mg / m ２ and dexamethasone is administered at a dose of 20 mg; wherein the individual has received at least one prior treatment for multiple myeloma; wherein the treatment prolongs overall survival (OS) of the individual.

24. 1. A method of treating a human individual with multiple myeloma, comprising administering to the individual: (a) administering to the individual a CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence GDYYGS A heavy chain variable domain (V) comprising CDR-H3 containing NSLDY (SEQ ID NO: 3). Ｈ ), and (b) a light chain variable domain (V) comprising a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). Ｌ administering an anti-CD38 antibody comprising carfilzomib and dexamethasone; Here, the anti-CD38 antibody was administered at a dose of 10 mg / kg and carfilzomib at a dose of 20 mg / m ２ or 56 mg / m ２ and dexamethasone is administered at a dose of 20 mg; wherein the individual has received at least one prior treatment for multiple myeloma; Here, the individual is －５ The method is minimal residual disease negative at the following thresholds:

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