Use of Ixazomib for the treatment of relapsed and / or refractory multiple myeloma

Abstract

The present disclosure provides a method 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, comprising administering to the individual an anti-CD38 antibody, carfilzomib, and dexamethasone.

Description

Technical Field

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

[0002] Submission of a Sequence Listing in ASCII Text File The content of the following submission regarding the ASCII text file is hereby incorporated by reference in its entirety: the computer - readable format (CRF) of the sequence listing (file name: 183952033040SEQLIST.txt, recording date: December 4, 2020, size: 10 kb).

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

Background Art

[0004] Multiple myeloma (MM) is a malignant plasma cell disease characterized by clonal proliferation of plasma cells in the bone marrow (BM) and production of excessive amounts of monoclonal immunoglobulin (usually IgG or IgA or free urinary light chains, i.e., paraprotein, M protein or M component). Patients with MM may experience bone pain, fractures, fatigue, anemia, infections, hypercalcemia, and kidney problems (Non-Patent Document 1). The expression of CD38 is particularly prominent in MM since more than 98% of patients are positive for this protein (Non-Patent Document 2; Non-Patent Document 3). The strong and uniform expression of CD38 in malignant clone MM cells is in contrast to the restricted expression pattern in normal cells, suggesting that this antigen may be useful for the 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 extend survival. The disease trajectory varies from patient to patient, but relapse is inevitable, and the intensity and duration of response to each treatment after relapse generally decrease. In general, MM patients receive treatment regimens containing drugs such as proteasome inhibitors (e.g., bortezomib, ixazomib, and carfilzomib) and immunomodulatory agents or "IMiDs (registered trademark)" (e.g., lenalidomide, pomalidomide, and thalidomide), monoclonal antibodies (e.g., elotuzumab), histone deacetylase (HDAC) inhibitors (e.g., panobinostat) alone or in combination throughout their lives. However, when patients become refractory to these drugs, survival is limited, and new treatment options are needed to treat patients who have failed stem cell transplantation (SCT), chemotherapy, proteasome inhibitors, and immunomodulatory drugs (IMiDs (registered trademark)). Despite the dramatic improvement in patient outcomes with new therapies, MM remains an incurable disease. Therefore, the treatment of patients who have received 1 to 3 previous lines of multiple myeloma treatment remains an unmet medical need.

[0006] All references cited herein, including patent applications, patent publications, and UniProtKB / Swiss-Prot accession numbers, are hereby 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 Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Means for Solving the Problems

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

[0009] Also provided is a method of treating a human individual having multiple myeloma, the method comprising (a) a heavy chain variable domain (V H) and (b) a light chain variable domain (V) comprising CDR-L1 containing the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), CDR-L2 containing the amino acid sequence SASYRYI (SEQ ID NO: 5), and CDR-L3 containing the amino acid sequence QQHYSPPYT (SEQ ID NO: 6) L ) 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, 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 previous treatment (e.g., 1 to 3 previous treatments) for multiple myeloma, and this treatment prolongs the overall survival (OS) of the individual.

[0010] Also provided is a method of treating a human individual having multiple myeloma, the method comprising (a) a heavy chain variable domain (V) comprising CDR-H1 containing the amino acid sequence DYWMQ (SEQ ID NO: 1), CDR-H2 containing the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and CDR-H3 containing the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3) H ), and (b) a light chain variable domain (V) comprising CDR-L1 containing the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), CDR-L2 containing the amino acid sequence SASYRYI (SEQ ID NO: 5), and CDR-L3 containing the amino acid sequence QQHYSPPYT (SEQ ID NO: 6) L ) 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, 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 more than 3 previous treatments for multiple myeloma, and this treatment prolongs the overall survival (OS) of the individual.

[0011] In some embodiments, a method of treating a human individual having multiple myeloma is provided, the method comprising (a) a heavy chain variable domain (V H ) 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), and (b) a light chain variable domain (V L ) 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), an anti-CD38 antibody, carfilzomib, and dexamethasone are administered to the individual, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg, 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 previous treatment (e.g., 1 to 3 previous treatments) for multiple myeloma, and wherein the individual is negative for minimal residual disease at a threshold of 10 -5 or less after treatment.

[0012] In some embodiments, a method of treating a human individual having multiple myeloma is provided, the method comprising (a) a heavy chain variable domain (V H ) 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), and (b) a light chain variable domain (V Ladministering to the individual an anti-CD38 antibody, carfilzomib, and dexamethasone, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg, 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 previous treatment (e.g., 1 to 3 previous treatments) for multiple myeloma, and wherein the individual has renal dysfunction at the start of treatment.

[0013] In some embodiments, the individual has received one previous treatment for multiple myeloma. In some embodiments, the individual has received two or more previous treatments for multiple myeloma (e.g., two previous treatments or three previous treatments, etc.). In some embodiments, the individual has received more than three previous treatments for multiple myeloma. In some embodiments, the individual has received previous treatment with a proteasome inhibitor. In some embodiments, the individual has received previous treatment with an immunomodulatory agent (e.g., thalidomide, lenalidomide, and / or pomalidomide). In some embodiments, the individual has received previous 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 (R-ISS) for multiple myeloma 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 dysfunction at the start of treatment. In some embodiments, the individual is between 65 and less than 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 H ) comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (V L ) comprising the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 9. 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, 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, carfilzomib is administered at a dose of 20 mg / m 2 on days 1 and 2 of the first 28-day cycle and at a dose of 56 mg / m 2 on days 8, 9, 15, and 16, and dexamethasone is administered at a dose of 20 mg 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 2 on days 1 and 15 of one or more 28-day cycles following the first 28-day cycle, carfilzomib is administered at a dose of 56 mg / m 2administered at a dose of, 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. In some embodiments, dexamethasone is administered prior to the anti-CD38 antibody, which is administered prior to carfilzomib on days 1, 8, and 15 of the first 28-day cycle; and wherein dexamethasone is administered prior to the anti-CD38 antibody on day 22 of the first 28-day cycle. In some embodiments, dexamethasone is administered prior to the anti-CD38 antibody, which is administered prior to carfilzomib on days 1 and 15 of each 28-day cycle following the first 28-day cycle; and wherein this dexamethasone is administered prior to carfilzomib on day 8 of each 28-day cycle following the first 28-day cycle. In some embodiments, the anti-CD38 antibody is administered intravenously. In some embodiments, carfilzomib is administered intravenously. In some embodiments, dexamethasone is administered orally.

[0016] In some embodiments, the individual is MRD negative at a threshold of 10 -4 、10 -5 、10 -6 、or less.

[0017] Also provided herein is a kit comprising an anti-CD38 antibody for use in combination with carfilzomib and dexamethasone for treating an individual multiple myeloma according to any one of the methods herein.

[0018] Also, an anti-CD38 antibody comprising a heavy chain variable domain (V H) and (b) a light chain variable domain (V) comprising CDR-L1 containing the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), CDR-L2 containing the amino acid sequence SASYRYI (SEQ ID NO: 5), and CDR-L3 containing the amino acid sequence QQHYSPPYT (SEQ ID NO: 6) L ) and is 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, 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 previous treatment (e.g., 1 to 3 previous treatments) for multiple myeloma, and wherein the treatment provides an anti-CD38 antibody that prolongs progression-free survival (PFS) and / or overall survival (OS) of the individual.

[0019] Also, an anti-CD38 antibody comprising (a) a heavy chain variable domain (V) comprising CDR-H1 containing the amino acid sequence DYWMQ (SEQ ID NO: 1), CDR-H2 containing the amino acid sequence TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and CDR-H3 containing the amino acid sequence GDYYGSNSLDY (SEQ ID NO: 3) H ) and (b) a light chain variable domain (V) comprising CDR-L1 containing the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), CDR-L2 containing the amino acid sequence SASYRYI (SEQ ID NO: 5), and CDR-L3 containing the amino acid sequence QQHYSPPYT (SEQ ID NO: 6) L ) and is 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, the carfilzomib is administered at a dose of 20 mg / m 2 or 56 mg / m 2administered at a dose of, and dexamethasone is administered at a dose of 20 mg, where this individual has received more than 3 previous treatments for multiple myeloma, where this treatment provides an anti-CD38 antibody that prolongs the progression-free survival (PFS) and / or overall survival (OS) of the individual.

[0020] In some embodiments, an anti-CD38 antibody 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) in the heavy chain variable domain (V H ), and (b) 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) in the 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, where the anti-CD38 antibody is administered at a dose of 10 mg / kg, 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 this individual has received at least 1 previous treatment for multiple myeloma, where this individual is anti-CD38 antibody provided that the threshold for minimal residual disease is negative at 10 -5 or less after treatment.

[0021] In some embodiments, an anti-CD38 antibody 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) in the heavy chain variable domain (V H) and (b) a light chain variable domain (V L ) 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), 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, the carfilzomib is administered at a dose of 20 mg / m 2 or 56 mg / m 2 , and the dexamethasone is administered at a dose of 20 mg, wherein the individual has received at least one previous treatment for multiple myeloma, and wherein the individual has renal dysfunction at the start of treatment, and an anti-CD38 antibody is provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0022]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Mode for Carrying Out the Invention

[0023] Detailed Description Definitions As used in this specification and the appended claims, unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include the plural. Thus, for example, reference to "a molecule" may optionally include combinations of two or more such molecules, and the like.

[0024] "Sustained response" refers to a sustained effect on preventing or delaying the progression of a disease (e.g., multiple myeloma) and / or improving one or more response criteria after discontinuation of treatment. For example, response to treatment for multiple myeloma can be measured 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 below and Table B in this specification). In some embodiments, the sustained response has a length of at least the same period as the treatment period, at least 1.5×, 2.0×, 2.5×, or 3.0× the length of 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 enables 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 a formulation is sterile. "Pharmaceutically acceptable" excipients (vehicles, additives) are those that can be reasonably administered to the subject mammal to provide the effective dosage of the active ingredient used.

[0027] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of a disease or cells (e.g., cancer cells) being treated in a clinical pathology process. Desirable effects of treatment include reducing the rate of disease progression, improving or alleviating the disease state, and improving response or prognosis. For example, reducing (or destroying) the growth of cancer cells, reducing symptoms caused by the disease, improving the quality of life of a person suffering from the disease, reducing the dosage of other pharmaceuticals required to treat the disease, and / or increasing the lifespan of an individual, but not limited to, when one or more symptoms associated with cancer are reduced or eliminated, the individual is "treated" successfully.

[0028] As used herein, "slowing the progression of a disease" means delaying, preventing, retarding, delaying, stabilizing, and / or postponing the onset of a disease (such as cancer). This delay may be for varying lengths of time depending on the disease being treated and / or the medical history of the individual. As will be apparent to those skilled in the art, a sufficient or significant delay can encompass substantial prevention in that the individual does not develop the disease. For example, late-stage cancers such as the development of metastases can be delayed.

[0029] "Effective amount" is at least the minimal amount required to achieve a measurable improvement or prevention of a particular disorder. In the present specification, the effective amount may vary depending on factors such as the disease state, age, gender and weight of the individual / patient, as well as the ability of the antibody to elicit the desired response in the individual. The effective amount is also one in which the therapeutically beneficial effects outweigh any toxic and detrimental effects of the treatment. For prophylactic use, beneficial or desired results include removing or reducing the risk, lowering 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 resulting from the disease, improving the quality of life of those suffering from the disease, reducing the dosage of other pharmaceuticals required to treat the disease, for example enhancing the effect of another pharmaceutical through targeting, delaying the progression of the disease, and / or prolonging survival. In the case of cancer or tumor, the effective amount of the drug is effective in reducing the number of cancer cells; reducing the tumor size; preventing the invasion of cancer cells into peripheral organs (i.e., slowing down to some extent, desirably stopping); preventing tumor metastasis (i.e., slowing down to some extent, desirably stopping); preventing tumor growth to some extent; and / or reducing one or more of the symptoms associated with the disorder to some extent. The effective amount can be administered in one or more doses. For the purposes of the present invention, the effective amount of a drug, compound or pharmaceutical composition is an amount sufficient to directly or indirectly achieve a prophylactic or therapeutic treatment. As understood in the clinical setting, the 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, "effective amount" can be considered in the context of administering one or more therapeutic agents and can consider administering a single agent in an effective amount if, or when, desirable results can be 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 another treatment modality to an individual.

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

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

[0033] Human light chains are typically classified into kappa and lambda light chains, and human heavy chains are typically classified into mu, delta, gamma, alpha, or epsilon, defining the antibody isotypes 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 the full-length light and heavy chains, the variable and constant domains are typically joined by a "J" region of about 12 amino acids or more, and the heavy chain also contains a "D" region of about 10 amino acids or more. See, for example, FUNDAMENTAL IMMUNOLOGY (Paul, W. ed., Raven Press, 2nd ed., 1989), which is incorporated by reference in its entirety for all purposes. The variable regions of each light / heavy chain pair typically form the antigen-binding site. The variable domain of an antibody typically exhibits the same general structure as a relatively conserved framework region (FR) joined by three hypervariable regions, also commonly called complementarity-determining regions or CDRs. The CDRs from each pair of two chains are typically aligned by the framework regions, which may thereby enable binding to a particular epitope. From the amino terminus to the carboxyl terminus, the variable domains of both the light and heavy chains typically include, in order, domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0034] The term "CDR set" refers to a group of three CDRs arising from a single variable region capable of binding to an antigen. The exact boundaries of these CDRs are defined differently by 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))) provides not only an explicit residue numbering system applicable to any variable region of an antibody, but also the exact residue boundaries defining the three CDRs. These CDRs are sometimes referred to as Kabat CDRs.

[0035] As used herein, the term "Fc" refers to the sequence of a non-antigen-binding fragment that may contain a hinge region and is generated from digestion of an antibody, whether in monomeric or multimeric form, or is produced by other means. The original immunoglobulin source of native Fc is preferably of human origin and can be any immunoglobulin. Fc molecules are composed of monomeric polypeptides that can be joined into dimeric or multimeric forms by covalent (i.e., disulfide bonds) and non-covalent bonds. The number of intermolecular disulfide bonds between monomeric subunits of native Fc molecules ranges from 1 to 4 depending on the class (e.g., IgG, IgA, and IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgA1, IgGA2, and IgG4). An example of Fc is a disulfide-bonded dimer resulting from papain digestion of IgG. As used herein, the term "native Fc" is a general term for 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 investigated by the 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] Summary Methods are provided herein for treating or delaying the progression of multiple myeloma in an individual who has received one, two, three, or more prior treatments for multiple myeloma. The method includes administering to the individual an effective amount of an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone. In some embodiments, the treatment prolongs the progression-free survival (PFS) and / or overall survival (OS) of the individual. In some embodiments, the treatment prolongs the progression-free survival (PFS) and / or overall survival (OS) of the individual as compared to an untreated individual. In some embodiments, the treatment prolongs the progression-free survival (PFS) and / or overall survival (OS) of the individual as compared to an individual who has received treatment with carfilzomib and dexamethasone 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 Hereinafter, 10 -5 Hereinafter, or 10 -6 Hereinafter, or below a threshold of 10

[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 heavy chain variable domain (V H ) comprising (a) CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), 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), and (b) a light chain variable domain (V L ) comprising 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). In some embodiments, the anti-CD38 antibody comprises a heavy chain variable domain (V H ) having an amino acid sequence that is at least 90% (e.g., any one of at least 91%, 92%, 94%, 95%, 96%, 97%, 98% or 99%, including any range between these values) identical to SEQ ID NO: 7. Further, or alternatively, in some embodiments, the anti-CD38 antibody comprises a light chain variable domain (V L ) having an amino acid sequence that is at least 90% (e.g., any one of at least 91%, 92%, 94%, 95%, 96%, 97%, 98% or 99%, including any range between these values) identical to SEQ ID NO: 8 or SEQ ID NO: 9. In some embodiments, the anti-CD38 antibody comprises V H comprising SEQ ID NO: 7 and V L comprising SEQ ID NO: 8 or SEQ ID NO: 9. 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 entire contents of both of which are incorporated herein by reference in their entirety.

[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 Isatsukizumab contains 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 the recombinant production of anti-antigen antibodies, the nucleic acid encoding the antibody is isolated and inserted into a replicable vector for further cloning (amplification of DNA) or expression. The DNA encoding the antibody can be readily isolated and sequenced using conventional techniques (e.g., using oligonucleotide probes that can specifically bind to the genes encoding the heavy and light chains of the antibody). Many vectors are available. Vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, enhancer elements, a promoter, and a transcription termination sequence. The vector is generally transformed into a suitable host cell for the expression of the nucleic acid. In some embodiments, the host cell is a eukaryotic cell or a prokaryotic cell. In some embodiments, the eukaryotic host cell is a mammalian cell. Examples of useful mammalian host cell lines are the simian kidney CV1 line transformed by SV40 (COS-7, ATCC CRL1651); the human embryonic kidney line (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)); simian kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); dog kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51); TRI cells (Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982)); MRC 5 cells; FS4 cells; and the 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. B.K.C. Lo, Humana Press, Totowa, N.J., 2003), pp. 255-268. Anti-CD38 antibodies prepared from cells can be purified, for example, using hydroxylapatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography generally being one of the preferred purification steps. In general, various methods for preparing antibodies for use in research, testing, and clinical applications are established in the art, consistent with the methods described above, and / or as would be appropriate to one of ordinary skill in the art.

[0042] Carfilzomib Carfilzomib is a synthetic tetrapeptide consisting of a 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 and morpholine-4-acetyl, L-2-amino-4-phenylbutanoyl, L-leucyl, and L-phenylalanyl residues arranged in sequence and bound. The chemical structure of carfilzomib is shown below:

Chemical formula

[0043] Carfilzomib is C 40 H 57It has a molecular formula of N5O7 and a molecular weight of 719.91 g / mol. The CAS registration number of carfilzomib is 868540-17-4. Carfilzomib is a proteasome inhibitor formulated for intravenous administration. Carfilzomib is sold under the trade name KYPROLIS (registered trademark).

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

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

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

[0047] In some embodiments, the anti-CD38 antibodies described herein (e.g., isatuximab) are formulated to contain 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 antibodies described herein (e.g., isatuximab) contain 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 the formulation. In some embodiments, the formulation contains 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 the 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 with an elastomeric closure. In some embodiments, the fill volume of the vial 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 the 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 with an elastomeric closure. In some embodiments, the fill volume of the vial is established to ensure removal of 25 mL. In some embodiments, the formulation is stable for at least about 6, 12, 18, 24, 30, or 36 months, including any range between these values, at a temperature of about 2°C to about 8°C and protected from light. 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 range between these values, between about 2°C and about 8°C. In some embodiments, the dilution solution for infusion remains stable for an additional 8 hours (including infusion time) at room temperature after storage between about 2°C and about 8°C.In some embodiments, the diluent solution for injection is stable in the presence of light. In some embodiments, the bag in which the diluent solution for injection is stored is made of polyolefin (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) and di(2-ethylhexyl) phthalate (DEHP) or ethylene vinyl acetate (EVA). In some embodiments, the tube used for injection is made of PE, PVC (with or without DEHP), polybutadiene (PBD), or polyurethane (PU) and 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 (described elsewhere in this document). In some embodiments, carfilzomib and / or dexamethasone are provided in separate containers. In some embodiments, carfilzomib and / or dexamethasone are used and / or prepared for administration to an individual as described in the prescribing information available for commercially available products.

[0049] Method of treatment A method is provided herein 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), the method comprising administering to the individual an effective amount of an anti-CD38 antibody (e.g., (a) a heavy chain variable domain (V H) and (b) a light chain variable domain (V L ) comprising an anti-CD38 antibody), carfilzomib, and dexamethasone, wherein the individual has received one, two, three, or more than three previous treatments (or lines of treatment) for multiple myeloma. In some embodiments, the individual has received three or fewer previous treatments (or lines of treatment). In some embodiments, treatment with the anti-CD38 antibody, carfilzomib, and dexamethasone described herein prolongs progression-free survival (PFS) of the individual. In some embodiments, treatment with the anti-CD38 antibody, carfilzomib, and dexamethasone as described herein prolongs overall survival (OS) of the individual. In some embodiments, treatment with the anti-CD38 antibody, carfilzomib, and dexamethasone described herein results in less minimal residual disease (MRD), for example, compared to treatment with carfilzomib and dexamethasone and treatment without an anti-CD38 antibody. In some embodiments, the individual is MRD negative after treatment with the anti-CD38 antibody, carfilzomib, and dexamethasone as described herein. In some embodiments, the individual has a threshold of 10 -4 or less (e.g., "10 -4 " means that there is less than 1 tumor cell per 10 4 bone marrow cells in a bone marrow sample obtained from the individual after initiation of treatment), 10 -5 or less (e.g., "10 -5 " means that there is less than 1 tumor cell per 10 5 bone marrow cells in a bone marrow sample obtained from the individual after initiation of treatment), or 10 -6 or less (e.g., "10 -6 " means that there is less than 1 tumor cell per 10 6means that there are less than 1 tumor cell per bone marrow cell) and is negative for minimal residual disease (MRD). In some embodiments, MRD is evaluated via next-generation sequencing (NGS). In some embodiments, MRD is evaluated via next-generation flow cytometry (NGF). Additionally or alternatively, in some embodiments, MRD is evaluated via positron emission tomography-computed tomography (PET-CT) scan. In some embodiments, the individual exhibits renal dysfunction prior to treatment (e.g., at the start of treatment) with an anti-CD38 antibody, carfilzomib, and dexamethasone as described herein. In some embodiments, the individual has a creatinine clearance of less than 60 ml / min / 1.72 m 2 2 and has renal dysfunction (MDRD, i.e., "Modification of Diet in Renal Disease"). In some embodiments, treatment with an anti-CD38 antibody, carfilzomib, and dexamethasone as described herein improves the renal function of the individual.

[0050] In some embodiments, treatment is considered a new treatment line if any of the following three conditions are met. 1. Start treatment on a new line after discontinuation of the previous line. If the treatment regimen is discontinued for any reason and a different regimen is started, it can be considered a new treatment line. For example, if all drugs in the regimen are discontinued, the regimen is considered discontinued. For example, if some but not all drugs in the regimen are discontinued, the regimen is not considered discontinued. In some embodiments, the reasons for discontinuation, addition, substitution, or stem cell transplantation (SCT) do not affect how the lines are counted. Reasons for the change may include, for example, planned end of treatment, toxicity, progression, lack of response, inadequate response. 2. Unplanned addition or substitution of one or more agents in an existing regimen. Adding a new drug or switching to a different drug (or drug combination) unplanned for any reason can be considered a new treatment line. 3. Stem cell transplantation (SCT). Except for tandem SCT planned at predefined intervals (such as 3 months), in individuals who have received >1 SCT, each SCT (autologous or allogeneic), regardless of whether the conditioning regimen used is the same or different, can be considered a new treatment line. In some embodiments, planned tandem SCT is considered one line. In some embodiments, planned induction and / or intensification, maintenance by any SCT (front-line, relapse, autologous or allogeneic) is generally considered one treatment line.

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

[0052] In some embodiments, the individual has multiple myeloma, such as 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 urinary M protein ≥ 200 mg / 24 hours measured using urinary protein immunoelectrophoresis. In some embodiments, an individual with multiple myeloma (such as relapsed and / or refractory multiple myeloma) has received at least 1, at least 2, at least 3, or 3 or fewer previous treatments (or treatment lines) for multiple myeloma. In some embodiments, the individual has received previous treatment with a proteasome inhibitor. In some embodiments, the individual has received previous treatment with an immunomodulatory agent (such as thalidomide, lenalidomide, and / or pomalidomide). In some embodiments, the individual has received previous 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 having primary refractory multiple myeloma is an individual who has not achieved at least minimal response (MR) with any therapy (or line of treatment) during the disease course. In some embodiments, the individual does not have only disease with measurable free light chain (FLC). In some embodiments, the individual has not received prior treatment with an anti-CD38 antibody. In some embodiments, the individual has not received prior treatment (or prior line of treatment) with isatuximab. In some embodiments, the individual did not exhibit progressive disease (PD) during prior treatment (or prior line of treatment) with an anti-CD38 antibody. In some embodiments, the individual did not progress within 60 days after the end of treatment (or line of treatment) with an anti-CD38 antibody. In some embodiments, the individual has not failed to achieve at least minimal response to treatment (or line of treatment) containing an anti-CD38 antibody. In some embodiments, an individual who has received prior treatment (or a line of treatment) containing an anti-CD38 antibody was not refractory to the anti-CD38 antibody. In some embodiments, the individual has not received prior treatment with carfilzomib. In some embodiments, the individual is not allergic (or not known to be allergic) to CAPTISOL® (a cyclodextrin derivative used to solubilize carfilzomib). In some embodiments, the individual is not hypersensitive or did not show hypersensitivity to any component (active substance or excipient) of sucrose, histidine (as base and hydrochloride), polysorbate 80, or an anti-CD38 antibody, carfilzomib and dexamethasone (not suitable for steroid premedication), or an H2 blocker (further treatment with these agents is prohibited). In some embodiments, the individual is not contraindicated to dexamethasone. In some embodiments, the individual has not received a prior allogeneic hematopoietic stem cell transplant with active graft-versus-host disease (any grade and / or immunosuppressive treatment within 2 months before treatment initiation). In some embodiments, the individual is not known to have amyloidosis or associated plasmacytic leukemia.In some embodiments, the individual does not have pleural effusion requiring thoracentesis or ascites requiring paracentesis or any major procedure, such as plasma exchange, curative radiotherapy, major surgery (excluding vertebroplasty). In some embodiments, the individual does not have a performance status (PS) of >2 on the Eastern Cooperative Oncology Group (ECOG). In some embodiments, when <50% of the bone marrow (BM) nucleated cells are plasma cells, the individual does not have platelets <50,000 cells / μL, and when ≧50% of the BM nucleated cells are plasma cells, does not have <30,000 cells / μL. 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 m2. 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), except for known Gilbert's 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 from prior anti-myeloma therapy (excluding alopecia and those described in the above paragraphs) of grade > 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] v4.03). In some embodiments, the individual does not have a prior malignancy. In some embodiments, appropriately treated basal cell 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 other cancers where treatment was completed more than 5 years prior to the start of treatment with anti-CD38 antibody, carfilzomib, and dexamethasone and the patient has been disease-free for more than 5 years are not considered prior malignancies. In some embodiments, the individual has not had a myocardial infarction, severe / unstable angina, coronary / peripheral artery bypass graft, New York Heart Association class III or IV congestive heart failure, arrhythmia of grade 3 or higher, stroke, or transient ischemic attack. In some embodiments, the individual has not had a myocardial infarction, severe / unstable angina, coronary / peripheral artery bypass graft, New York Heart Association class III or IV congestive heart failure, arrhythmia of grade 3 or higher, stroke, or transient ischemic attack within 6 months of the start of treatment with 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 has an acquired immunodeficiency syndrome (AIDS)-related disease or an HIV disease that requires antiretroviral treatment, or has active hepatitis A, hepatitis B (defined as a known positive hepatitis B surface antigen (HBsAg) result), or does not have or is not known to have an infection of hepatitis C (defined as a known quantitative hepatitis C (HCV) ribonucleic acid (RNA) result greater than the lower limit of detection of the assay or a positive HCV antigen). In some embodiments, the individual does not have any of the following within 3 months prior to the initiation of treatment with an 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 thromboembolism.

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

[0055] In some embodiments, the treatment comprises administering an anti-CD38 antibody, carfilzomib, and dexamethasone in a first 28-day cycle (i.e., cycle 1), where 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., FIG. 2. In some embodiments, the 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 and later), where 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., FIG. 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), where this anti-CD38 antibody (e.g., isatuximab) is administered at a dose of 10 mg / kg on days 1, 8, 15, and 22; carfilzomib is administered at a dose of 20 mg / m 2 on days 1 and 2 and at a dose of 56 mg / m 2 on days 8, 9, 15, and 16; and dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23. See, for example, Table D herein. In some embodiments, the 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 and later), where this anti-CD38 antibody (e.g., isatuximab) is administered at a dose of 10 mg / kg on days 1 and 15; carfilzomib is administered at a dose of 56 mg / m 2 on days 1, 2, 8, 9, 15, and 16; and dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23. See, for example, Table D herein.

[0057] In some embodiments, an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone are administered simultaneously. In some embodiments, an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone are administered simultaneously. In some embodiments, an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone are administered sequentially. In some embodiments, an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone are administered sequentially, dexamethasone is administered before the anti-CD38 antibody, and the anti-CD38 antibody is administered before carfilzomib on days of each 28-day cycle, where all three of the anti-CD38 antibody, carfilzomib, and dexamethasone are administered. In some embodiments, an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone are administered sequentially, and dexamethasone is administered before carfilzomib on days of each 28-day cycle without anti-CD38. In some embodiments, an 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 days of each 28-day cycle.

[0058] In some embodiments, the PFS of an individual is measured as the period from the start of treatment to the first occurrence of progressive disease (PD). In some embodiments, PD is evaluated 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 Tables A and 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., an extension) in the progression-free survival (PFS) of an individual as compared to an individual having 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 period from the start of treatment to death. In some embodiments, the treatment increases the OS of an individual as compared to an individual having multiple myeloma (e.g., refractory multiple myeloma or relapsed and refractory multiple myeloma) who has received a treatment comprising carfilzomib and dexamethasone without an anti-CD38 antibody.

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

[0061] In some embodiments, the individual is negative for minimal residual disease (MRD) or "MRD negative" following treatment with an anti-CD38 antibody, carfilzomib, and dexamethasone. In some embodiments, the MRD status is measured by next generation flow cytometry (NGF). In some embodiments, MRD negativity (or "flow MRD negative") as measured by NGF means that there are no phenotypically abnormal clonal plasma cells (such as multiple myeloma cells) present in the bone marrow aspirate (e.g., using the standard operating procedure of EUROFLOW™ high-throughput flow cytometry for MRD detection in multiple myeloma (see Flores-Montero et al. (2017) Leukemia. 31:2094-2103) or an equivalent method), and the minimum sensitivity is, for example, 1 in 10 4 nucleated cells (i.e., "1 in 10 -4 "), 1 in 10 5 nucleated cells (i.e., "1 in 10 -5 "), 1 in 10 6 nucleated cells (i.e., "1 in 10 -6 "), or 1 in 10 7 nucleated cells (i.e., "1 in 10 -7") is meant. In some embodiments, the MRD status is measured by next-generation sequencing (NGS). In some embodiments, MRD negativity (or "sequencing MRD negativity") as measured by NGS means that there are no clonal plasma cells (e.g., multiple myeloma cells) in the bone marrow aspirate; the presence of a clone is determined, for example, after DNA sequencing of the bone marrow aspirate (e.g., using the LYMPHOSIGHT® high-throughput sequencing platform or equivalent methods), as at least two identical sequencing reads obtained with a minimum sensitivity of 1 in 10 4 nucleated cells (i.e., "10 -4 "), 1 in 10 5 nucleated cells (i.e., "10 -5 "), 1 in 10 6 nucleated cells (i.e., "10 -6 "), or more. In some embodiments, the minimum sensitivity is 1 cell out of 10 6 nucleated cells ("10 -6」). In some embodiments, the individual is negative by both imaging and MRD (or "imaging + MRD negative"). In some embodiments, imaging + MRD negative means (a) MRD negative as detected by NGF or MRD negative as detected by NGS, and (b) disappearance of any region of increased tracer uptake found on baseline or prior positron emission tomography (PET) / computed tomography (Ct), or a decrease to less than the maximum standardized uptake value of the mediastinal blood pool, or a decrease less than that of the surrounding normal tissue. In some embodiments, the individual is "persistently MRD negative". In some embodiments, persistently MRD negative refers to an individual in whom imaging + MRD negative has been confirmed at two time points after the start of treatment, the time points being more than one year apart. In some embodiments, minimal residual disease (MRD) is evaluated 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, the individuals evaluated for MRD have achieved complete response or better (i.e., ≧CR) or very good 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 an MRD-negative status may have renal dysfunction, e.g., eGFR < 60 mL / min / 1.73 m, at the start of treatment, during treatment, or after treatment. 2has. In some embodiments, an individual treated with an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone who achieves a MRD negative status is classified as ISS stage III at diagnosis. In some embodiments, an individual treated with an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone who achieves a MRD negative status has one or more cytogenetic abnormalities selected from t(4;14) and gain(1q21). In some embodiments, an individual treated with an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone who achieves a MRD negative status is highly pre-treated, such as having received three or more previous lines of treatment for multiple myeloma. In some embodiments, an individual treated with an anti-CD38 antibody (e.g., isatuximab), carfilzomib, and dexamethasone who achieves a MRD negative status was refractory to lenalidomide in its last regimen (e.g., the last treatment regimen for multiple myeloma).

[0062] In some embodiments of any method of an anti-CD38 antibody for use described herein, the individual is less than 65 years old. In some embodiments, the individual is 65 to less than 75 years old. In some embodiments, the individual is 75 years old or older. In some embodiments, the individual is female (e.g., a fertile-age, birth-capable female). In some embodiments where the individual is female and pregnancy-capable, the individual may use an effective method of contraception during treatment with the anti-CD38 antibody and for 5 months after the last administration of the anti-CD38 antibody.

[0063] In some embodiments, the individual has received one previous treatment (or previous treatment line) for multiple myeloma. In some embodiments, the individual has received two or more (e.g., two, three, or more than three) previous treatments (or previous treatment lines) for multiple myeloma. In some embodiments, the individual has received more than one but no more than three previous treatments (or previous treatment lines) for multiple myeloma. In some embodiments, the individual has received more than three previous treatments (or previous treatment lines) for multiple myeloma. In some embodiments, the individual is stage I or stage II according to the Revised International Staging System (R-ISS) for multiple myeloma. In some embodiments, stage I according to the 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 of 3.5 g / dL or more, (c) standard-risk chromosomal / cytogenetic abnormalities detected by interphase fluorescence in situ hybridization (iFISH), and (d) normal serum lactate dehydrogenase (LDH) levels. In some embodiments, stage II according to the multiple myeloma R-ISS is defined as not being stage I or stage III according to the R-ISS. In some embodiments, the individual is stage III according to the Revised International Staging System (R-ISS) for multiple myeloma. In some embodiments, stage III according to the multiple myeloma R-ISS is defined as either (a) a serum beta-2 microglobulin level greater than about 5.5 mg / L, and (b) high-risk cytogenetic abnormalities detected by interphase fluorescence in situ hybridization (iFISH), or (c) a serum lactate dehydrogenase (LDH) level above the normal upper limit. In some embodiments, the individual has high-risk cytogenetic abnormalities (CAs). In some embodiments, the high-risk cytogenetic abnormalities are one or more of del(17p), t(4:14), and / or t(14;16). In some embodiments, the individual is not classified by the R-ISS. In some embodiments, the individual is not classified by the R-ISS due to indeterminate iFISH.

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

[0065] Intravenous administration of anti-CD38 antibody In some embodiments, the anti-CD38 antibody is administered via intravenous infusion, where each infusion is from a volume of 250 ml (e.g., a fixed volume). 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, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual in a first 28-day cycle. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual at a dose of 10 mg / kg from a volume of 250 ml on days 1, 8, 15, and 22 of the first 28-day cycle, respectively. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on day 1 of the first 28-day cycle at an infusion rate of 25 mL / hour for the first hour, and the infusion rate is increased by 25 mL / hour every 30 minutes up to a maximum infusion rate of 150 mL / hour after the first hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to the individual via intravenous infusion on day 1 of the first 28-day cycle at an infusion rate of 12.5 mL / hour for the first 30 minutes, and the infusion rate is increased by 25 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the infusion period of the anti-CD38 antibody (e.g., isatuximab) on day 1 of the first 28-day cycle is any one of about 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 or less, and any range between these values is also included. In some embodiments, the infusion period 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 period 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, for example between about 3.36 and about 5.32 hours. In some embodiments, the infusion period 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, for example about 3.94 hours.In some embodiments, the infusion period includes a temporary interruption before the 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 the 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 then at an infusion rate of 300 mL / hour until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, an anti-CD38 antibody (e.g., isatuximab) is administered to an individual via intravenous infusion on day 8 of the first 28-day cycle at an infusion rate of 25 mL / hour for the first 30 minutes, and the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the infusion period of the anti-CD38 antibody (e.g., isatuximab) on day 1 of the first 28-day cycle is 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 or less, and any range between these values is also included. In some embodiments, the infusion period 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 period 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, for example, between about 1.52 and about 2.6 hours. In some embodiments, the infusion period 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, for example, about 1.88 hours. In some embodiments, the infusion period of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption before the completion of the infusion.

[0068] In some embodiments, an anti-CD38 antibody (e.g., isatuximab) is administered to an 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 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, and the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the infusion period of the anti-CD38 antibody (e.g., isatuximab) on day 15 of the first 28-day cycle is 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 or less, and any range between these values is also included. In some embodiments, the infusion period 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 period of the anti-CD38 antibody (e.g., isatuximab) on day 15 of the first 28-day cycle is between about 1 and 2 hours, for example, between about 1.03 and about 1.87 hours. In some embodiments, the infusion period on day 15 of the first 28-day cycle is between about 1 and 1.5 hours, for example, about 1.27 hours. In some embodiments, the infusion period of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption before the completion of the infusion.

[0069] In some embodiments, an anti-CD38 antibody (e.g., isatuximab) is administered to an 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 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, and the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the infusion period of the anti-CD38 antibody (e.g., isatuximab) on day 22 of the first 28-day cycle is 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 or less, and any range between these values is also included. In some embodiments, the infusion period 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 period of the anti-CD38 antibody (e.g., isatuximab) on day 22 of the first 28-day cycle is between about 1 and 2 hours, for example, between about 1.18 and about 1.52 hours. In some embodiments, the infusion period 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, for example, about 1.27 hours. In some embodiments, the infusion period of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption before the 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 (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) is 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), and the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the infusion period 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 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 or less, and any range between these values is also included. In some embodiments, the infusion period 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 period 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, for example, between about 1.19 and about 1.41 hours. In some embodiments, the infusion period 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, for example, about 1.27 hours.In some embodiments, the infusion period of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption before the completion of the infusion. In some embodiments, the anti-CD38 antibody (e.g., isatuximab) is administered to an 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, the anti-CD38 antibody (e.g., isatuximab) is administered to an individual via intravenous infusion at an infusion rate of 100 ml / hour for the first 30 minutes on day 15 of each subsequent 28-day cycle (e.g., following the first 28-day cycle), and the infusion rate is increased by 50 mL / hour every 30 minutes after the first 30 minutes until 250 ml of the anti-CD38 antibody (e.g., isatuximab) is infused. In some embodiments, the infusion period 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 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 or less, and any range between these values is also included. In some embodiments, the infusion period 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 period 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, for example between about 1.2 and about 1.46 hours. In some embodiments, the infusion period 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, for example about 1.27 hours. In some embodiments, the infusion period of the anti-CD38 antibody (e.g., isatuximab) includes a temporary interruption before the completion of the infusion.

[0071] In some embodiments, the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) after the 15th day of the first 28-day cycle (including, for example, the 22nd day of the first 28-day cycle and days 1 and 15 of each subsequent 28-day cycle) is any one or less 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, and also includes any range between these values. In some embodiments, the duration of each infusion of the anti-CD38 antibody (e.g., isatuximab) after the 15th day of the first 28-day cycle (including, for example, the 22nd day 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 the anti-CD38 antibody (e.g., isatuximab) after the 15th day of the first 28-day cycle (including, for example, the 22nd day of the first 28-day cycle and days 1 and 15 of each subsequent 28-day cycle) is between about 1 and 2 hours, for example, between about 1.13 and about 1.53 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, 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 an IR. IR refers to a disorder characterized by an adverse reaction to the intravenous infusion of an anti-CD38 antibody (e.g., isatuximab). IR can occur during the infusion or within 24 hours (e.g., 24 hours from the start time of the infusion) of the infusion. The signs or symptoms of IR include one or more of the following: paraesthesia, chest pain, cough, nasal congestion, sneezing, throat irritation, pruritus, syncope, flushing, chills, fever, urticaria, angioedema, rash, skin reaction, itching, maculopapular rash, tachycardia, hypotension, dyspnoea, nausea, vomiting, headache, back pain, chest discomfort or non-cardiac chest pain, abdominal pain, abdominal cramps, bronchospasm, laryngeal spasm, stridor, respiratory congestion, excessive sweating and erythema. (For further details, see, for example, Doessegger et al. (2015) Clin & Trans Immunol. 4(7):e39.) Thus, 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., does not require) a pre - dose, i.e., a dose administered prior to the 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., does not require) a dose (e.g., a prophylactic dose) for the purpose of preventing or minimizing IR after the completion of the infusion of an anti - CD38 antibody (e.g., isatuximab). 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., does not require) a post - dose, i.e., a dose administered after the infusion of an anti - CD38 antibody (e.g., isatuximab) at a dose of 10 mg / kg from a volume of 250 ml for the purpose of preventing or minimizing IR. In some embodiments, the individual does not receive (e.g., does not require) a pre - dose or a post - dose using any one or more of the following for the purpose of preventing or minimizing IR, e.g., prior to or after the 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 non - steroidal anti - inflammatory drugs), and / or anti - histamines (e.g., diphenhydramine, cetirizine, promethazine, dexchlorpheniramine).

[0074] In some embodiments, the individual experiences mild IR following administration of an anti-CD38 antibody (e.g., isatuximab). In some embodiments, the mild IR is grade 1 or less than grade 2 IR 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 publicly available online at evs.nci.nih.gov / ftp1 / CTCAE / About.html. In some embodiments, the IR is grade 1 IR when the individual experiences a mild transient reaction (e.g., one or more of the signs / symptoms described herein within, for example, 24 hours from the start of infusion), where interruption of the infusion is not indicated and / or intervention is not indicated. In some embodiments, the IR is grade 2 IR when the individual experiences a reaction (e.g., one or more of the signs / symptoms described herein within, for example, 24 hours from the start of infusion), where the infusion is interrupted and / or intervention is indicated and the individual responds promptly, for example, within any one of about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20 or 24 hours (including any range between these values) to treatment (i.e., treatment of one or more of the signs or symptoms of the IR such as those described herein). In some embodiments, treatment for IR includes one or more of the following: short-term 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 a mild IR (e.g., grade 1 or grade 2 IR) during or after the first intravenous infusion of 10 mg / kg of an anti-CD38 antibody (e.g., isatuximab) at a fixed volume of 250 ml, for example, 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 the second or subsequent infusions of the 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 the infusion of 10 mg / kg of the 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, the individual does not experience moderate or severe IR after infusion of the anti-CD38 antibody at a volume of 250 ml, for example, by the methods described herein. In some embodiments, the 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, if the individual experiences signs / symptoms of IR over an extended period (e.g., as described herein) and does not respond promptly to interruption of the drug and / or infusion for IR, the IR is grade 3 IR. In some embodiments, if the individual experiences recurrence of signs / symptoms of IR (e.g., as described herein) after an initial improvement, the IR is grade 3 IR. In some embodiments, if the individual requires hospitalization due to signs / symptoms of IR (e.g., as described herein), the IR is grade 3 IR. In some embodiments, if the signs / symptoms (e.g., as 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 (e.g., isatuximab) administered from a 250 ml volume is not decreased during treatment, for example, regardless of whether the individual experiences IR.

[0078] Manufactured article or kit In another embodiment of the invention, a manufactured article or kit comprising an anti-CD38 antibody (e.g., isatuximab) is provided. In some embodiments, the manufactured article or kit further comprises carfilzomib and / or dexamethasone. In some embodiments, the manufactured article or 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 (e.g., refractory multiple myeloma or relapsed and refractory multiple myeloma) in individuals who have received 1 to 3 prior treatments (or prior lines of treatment) for multiple myeloma. In some embodiments, the kit comprises isatuximab, carfilzomib, and dexamethasone.

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

Examples

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

[0081] Example 1A: A Phase III randomized, open-label, multi-center trial comparing the combination of carfilzomib and low-dose dexamethasone with the combination of isatuximab (SAR650984), carfilzomib, and low-dose dexamethasone in patients with refractory or relapsed and refractory multiple myeloma

[0082] This example describes a Phase III, multi-center, multicohort, randomized, open-label, parallel-group, two-arm trial evaluating the clinical benefit of the combination of isatuximab, carfilzomib, and dexamethasone (the “IKd” arm) versus the combination of carfilzomib and dexamethasone twice weekly (the “Kd” arm) in patients with relapsed and / or refractory multiple myeloma who had previously been treated in 1 to 3 previous lines of therapy.

[0083] I. Study Objectives A. Primary Objectives The primary objective (i.e., primary endpoint) of this trial is to demonstrate the benefit of the combination of isatuximab, carfilzomib, and dexamethasone (IKd) over the combination of carfilzomib and dexamethasone (Kd) in terms of an increase in PFS using IMWG criteria in patients with relapsed and / or refractory MM who had previously been treated in 1 to 3 lines of therapy.

[0084] Progression-free survival is defined as the time from the date of randomization to the earlier of the date of the first record of progressive disease or the date of death from any cause. Response and progression are determined according to the IMWG criteria (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). Progression based on paraprotein is confirmed based on two consecutive evaluations.

[0085] The following disease assessment procedures are performed for screening (for eligibility) on Day 1 of Cycle 1 before administration of the investigational treatment (baseline for response assessment), on Day 1 of every cycle until progression during treatment, at the end of treatment (EOT), and monthly during follow-up until PD for patients who discontinue the investigational treatment without PD (even for patients who initiate additional anti-myeloma therapy without PD): · Quantification of M protein (serum and 24-hour urine, protein immunoelectrophoresis, and immunofixation). Immunofixation is performed if M protein (serum and urine) is not detected after Day 1 of Cycle 1. · Serum-free light chain quantification. · Quantitative immunoglobulins. · Bone marrow aspiration (or biopsy if clinically indicated) at baseline (bone marrow disease involvement, FISH, and MRD), and then if VGPR or greater. · Evaluation of bone disease: - Skeletal survey or low-dose whole-body computed tomography (CT) scan at baseline, then annually, and whenever clinically necessary during the study. · Evaluation of extramedullary disease (plasmacytoma) (including osseous plasmacytoma): - In cases of extramedullary disease known at baseline, perform a CT scan or magnetic resonance imaging (MRI) at baseline, up to PD (even in patients who start additional anti-myeloma treatment without PD), and repeat every 12 weeks (±1 week) if clinically indicated. - If extramedullary disease (plasmacytoma) is suspected at baseline, perform a CT scan or MRI at baseline. If a plasmacytoma is confirmed, repeat the CT scan or MRI up to PD (even in patients who start additional anti-myeloma therapy without PD), and repeat every 12 weeks (±1 week) if clinically indicated. - At any time during the study treatment, if progression of an existing plasmacytoma is suspected, or if clinically indicated in patients without a previous positive image of extramedullary disease.

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

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

[0088] If the independent review committee considers the reported clinical data to support clinical progression, clinical deterioration is considered progression in the primary analysis of PFS. In the case of hypercalcemia, a complete disease evaluation is required to identify any measurable parameter of myeloma progression (e.g., serum and urine M proteins, evaluation of lytic lesions, and evaluation of plasmacytomas), and potential alternative causes of hypercalcemia need to be excluded. Progression is not diagnosed by FLC progression alone. Patients with only measurable FLC disease are not permitted by the protocol. If both serum and urine M proteins are below the qualified level in the efficacy laboratory performed on Day 1 of Cycle 1, progression and overall response are evaluated according to the criteria in Tables A and B below.

[0089]

Table 2-1

Table 2-2

[0090]

Table 3

[0091] B. Major secondary efficacy endpoints The major secondary efficacy endpoints are as follows. · ORR: To determine the ORR, the best overall response for each patient is evaluated. This is defined as the proportion of patients with a best overall response of stringent complete response (sCR), CR, VGPR, and PR evaluated using the IMWG response criteria (see Table A). Bone marrow biopsy is performed for sCR evaluation according to the decision of the principal investigator of the clinical trial. · Proportion of VGPR or higher: Defined as the proportion of patients with sCR, CR, and VGPR. · Percentage of patients with VGPR or better and MRD negative: Defined as the percentage of patients with MRD negative as assessed by sequencing at any time point after the first administration of the investigational treatment. Minimal residual disease is evaluated by next-generation sequencing of bone marrow (BM) samples from patients who have achieved VGPR or better to determine the intensity of response at the molecular level. The negative threshold is at least 10 -5 is. Bone marrow aspirate (BMA) is collected at screening and at confirmation of VGPR or better. If a patient is presenting 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 a patient remains MRD positive and is still on treatment, a third sample is collected 3 months later. After the third BM sample during VGPR is MRD positive, no more than 3 bone marrow samples during treatment can be obtained unless the patient achieves CR. In this case, no more than 3 additional BM samples are collected. Thus, a maximum of 6 BMAs are performed by the patient (no more than 3 per response category). However, since BMA is an invasive procedure, the following guidance is provided with the aim of limiting the number of BMAs as much as possible. - For patients with CR with no previous record of VGPR: The first bone marrow for MRD evaluation is collected at confirmation of CR (i.e., the second time point indicating CR). If a patient is determined to be MRD positive, another BM sample is collected 3 months (3 cycles) later to identify late negativity. If a patient remains MRD positive and is receiving treatment, a third sample is collected 3 months later. - For VGPR patients: The first bone marrow is collected at the second or later time point according to the judgment of the treating physician based on the dynamics of the decrease in M protein if VGPR is confirmed, and / or when the plateau stage is reached (the plateau is defined as less than 20% variation over 12 weeks). If MRD is positive in the first BMA, the second BMA is collected 3 months later (3 cycles) to distinguish late negativity. If MRD is still positive in the second BMA performed while the patient is in VGPR, the timing of the third BMA may be postponed until CR is achieved. If the patient reaches CR and was MRD positive in the last BMA performed during VGPR, a BMA is performed for MRD evaluation at the time of CR confirmation. After the first BMA during CR is performed, if the patient is MRD positive in this BMA, it may be advisable to discuss with the patient about additional BMAs planned by the protocol. · CR rate: Defined as the proportion of patients with sCR and CR. Patients in whom isatuximab interference is demonstrated are considered in the BOR category corresponding to the M protein evaluation obtained without interference if an antibody capture interference assay becomes available. · OS: Defined as the time from the date of randomization until death from any cause.

[0092] C. Other secondary efficacy endpoints Other secondary efficacy endpoints are evaluated as follows. · Duration of response (DOR): Defined as the time from the first IRC-determined response date in patients who achieved PR or above until the earlier of the date of first-recorded progressive disease (PD) or death. · Time to progression (TTP): Defined as the time from randomization until the date of first record of PD. · PFS2: Defined as the time from the date of randomization until the date of first record of PD after the earlier of the start of further anti-myeloma treatment or death from any cause. · Time to first response: Defined as the time from randomization until the date of the first response (PR or above), which is then confirmed. · Time to best response: Defined as the time from randomization to the date on which the best overall response (PR or above) that is subsequently confirmed first occurs.

[0093] D. Safety endpoints Safety is evaluated and reported throughout the study with respect to treatment-emergent adverse events (TEAEs), adverse events (AEs), serious adverse events (SAEs), infusion-related reactions (IARs), the performance status of the Eastern Cooperative Oncology Group (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 examinations.

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

[0095] E. Patient-reported outcomes As indicators of patient-reported outcomes, there are the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ C30) with 30 questions, the EORTC Myeloma Module (QLQ-MY20) with 20 items, and the indicators of the European Quality of Life Group (with 5 dimensions and 5 levels for each dimension) (EQ-5D-5L). (See, for example, https: / / qol.eortc.org / questionnaires / and https: / / euroqol.org / eq-5d-instruments / eq-5d-5l-about / ).

[0096] All three questionnaires are designed for self-completion. All patient-reported outcomes are completed by patients on-site. To minimize bias, after patients enter the ePRO, they are evaluated and considered by the clinician regarding their clinical status, treatment plan, AE, and any other relevant topics that may affect the patient's perception and feelings before answering the questions.

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

[0098]

Table 4

[0099] F. Immunogenicity Human anti-drug antibodies (ADA) against isatuximab are evaluated only in IKd patients on Day 1 before isatuximab administration from Cycle 1 to Cycle 10.

[0100] G. Exploratory endpoints Blood samples are collected on Day 1 of Cycle 1. White blood cell DNA is 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 are collected at all time points to evaluate potential interference of isatuximab in M protein assessment up to Cycle 30. These samples are collected after Cycle 30, until disease progression, only for patients who achieve at least VGPR in this cycle. If isatuximab is discontinued before progression, the sample interference assay is collected until either 3 months or PD, whichever is earlier. After Day 1 of Cycle 1, if M protein is 0 g / dL in all patients, immunofixation samples are analyzed. Additionally, immunofixation samples are analyzed even in patients with serum M protein of 0.2 g / dL or less to identify patients who may have isatuximab interference.

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

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

[0104] II. Study design After confirmation of eligibility criteria (described in more detail below), patients are randomly assigned in a 3:2 ratio (experimental group: control group) to use an interactive response technology (IRT) system in one of 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 of the study design is also provided in Figure 1.

[0105]

Table 5

[0106] Randomization was stratified by the number of previous 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 are treated until either disease progression, unacceptable adverse events (e.g., unacceptable toxicity), or patient preference, whichever comes first.

[0107] A. Study participation period for each patient Each patient is considered in the study from the signing of the informed consent until either death, withdrawal of consent, or the cutoff date for the overall survival analysis, whichever comes first.

[0108] The period of the study for patients includes a period for screening of up to 3 weeks. The period of each treatment cycle was 28 days. Patients continue the study treatment until disease progression, unacceptable AEs, patient preference, or other reasons occur. All AEs occurring after the signing of the informed consent are reported within 30 days after the last study treatment administration.

[0109] After the discontinuation of the study treatment, the patient returns to the study site at the earlier of 30 days after the last administration of the study treatment for the end of treatment, or before the initiation of further anti-myeloma therapy, at the end of the end-of-treatment (EOT) assessment, and 90 days after the administration of the study treatment for the HRQL questionnaire.

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

[0111] Patients who discontinue the study treatment due to progressive disease (PD) are followed up every 3 months (12 weeks) for HRQL, further anti-myeloma therapy, second primary malignancies, PFS2, and survival at the first FU visit (90 days after the last study treatment), until the earlier of death or the cut-off date for the final PFS analysis. Patients who discontinue the study treatment before the documentation of PD are followed up every 4 weeks for HRQL 90 days after the last study treatment until the disease progresses (even for patients who start further anti-myeloma therapy without PD), then every 3 months (12 weeks) for second primary malignancies, PFS2, and survival after confirmation of disease progression, until the earlier of death or the cut-off date for the final PFS analysis.

[0112] For all surviving patients at the final PFS analysis cut-off date, the survival status is collected annually starting approximately 1 year after the final PFS analysis cut-off date, and then up to a maximum of 3 years after the final PFS analysis cut-off date.

[0113] Patients who are still on treatment and receiving the benefits of the investigational treatment at the time of the final PFS analysis cut-off date or the OS analysis cut-off date will continue the investigational treatment until disease progression, unacceptable AE, the patient wishes to discontinue the investigational treatment further, or for other reasons. For cycles administered after the cut-off date, all ongoing SAEs (regardless of relevance) and all ongoing related non-serious AEs, all new related AEs (regardless of severity), IP management, and reasons for EOT will continue to be collected for all patients who are still on treatment and receiving the benefits of the investigational treatment at the time of the final PFS analysis cut-off date or the OS analysis cut-off date. If a patient has received less than 10 cycles by the cut-off date of the final PFS analysis, anti-drug antibody (ADA) / PK samples will be stopped. If the last ADA is positive or indeterminate, additional ADA will be sampled 3 months later. Even if this 3-month sample is positive, no further ADA will be sampled.

[0114] B. Decision to End Clinical Trial (All Patients) The PFS analysis (primary endpoint analysis) is event-driven, and the cut-off date for the final PFS analysis is the date on which 159 PFS events (either progression or death, whichever comes first) have occurred (approximately 36 months after the first patient was randomized). The cut-off date for the OS analysis is approximately 3 years after the cut-off date of the primary PFS analysis. The primary analysis of PFS corresponds to either a positive interim analysis or the 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 by serum protein immunoelectrophoresis and / or urine M protein ≥ 200 mg / 24 hours measured by urine protein immunoelectrophoresis. · Patients with relapsed and / or refractory MM with at least 1 prior line and up to 3 prior lines, including IMiDs® and proteasome inhibitors. · The patient has provided voluntary written informed consent prior to undergoing research-related procedures that are not part of their normal medical care.

[0116] A certain line of treatment consists of one or more complete cycles of a single agent, a regimen consisting of combinations of several drugs, or a planned sequential treatment of various regimens. If any of the following three conditions are met, the treatment is considered a new line (see, for example, 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 treatment line after discontinuation of a previous line. If for any reason the treatment regimen is discontinued and a different regimen is initiated, it should be considered a new treatment line. If all agents of a regimen are discontinued, that regimen is considered discontinued. If not all, but some agents of a regimen are discontinued, the regimen is not considered discontinued. The reasons for discontinuation, addition, substitution, or stem cell transplantation (SCT) do not affect the method of line counting. It is recognized that the reasons for the change may include the end of planned treatment, toxicity, progression, lack of response, or inadequate response. ii. Unplanned addition or substitution of one or more drugs in an existing regimen. Adding a new drug unplanned or switching to a different drug (or combination of drugs) for any reason is considered a new treatment line. Stem cell transplantation (SCT): For patients beyond 1 SCT, except for tandem SCT planned at pre-defined intervals (such as 3 months), each SCT (autologous or allogeneic) should be regarded as a new treatment line regardless of whether the conditioning regimen used is the same or different. It is also recommended to capture data on the type of SCT. Planned tandem SCT is regarded as 1 line. Planned induction and / or consolidation, and maintenance by any SCT (front-line, relapse, autologous, or allogeneic) are regarded as 1 line. iii. Interruptions and dose changes If a regimen is interrupted or discontinued for any reason and the same drug or combination is restarted without other intervening regimens, it should be counted as a single line. However, if a regimen is interrupted or discontinued for any reason and then restarted, but one or more other regimens are administered during that time, or one or more drugs are added and the regimen is changed, it must be counted as 2 lines. Changes in the dosing of the same regimen should not be regarded as a new treatment line.

[0117] B. Exclusion criteria Screen patients who meet all of the above inclusion criteria for the following exclusion criteria: · Under 18 years of age (or the legal age of adulthood in the country if the legal age exceeds 18). · Primary refractory MM. Defined as patients who have not achieved at least MR with any treatment during the disease course. · Patients with only measurable disease of free light chain (FLC). · Patients who progressed within 60 days after the end of anti-CD38mAb treatment or who had previously received anti-CD38mAb treatment and were unable to achieve at least MR with the treatment (i.e., refractory to anti-CD38). · Anti-myeloma drug treatment within 14 days before randomization that includes dexamethasone. · Patients who received other investigational drugs or prohibited treatments for this study within 28 days before randomization. · Previous treatment with carfilzomib. · History of allergy to CAPTISOL® (a cyclodextrin derivative used to solubilize carfilzomib), sucrose, histidine (as base and hydrochloride), polysorbate 80, or any component (active substance or excipient) of the investigational treatment not suitable for premedication with steroids or H2 blockers; previous hypersensitivity to these agents (precluding further treatment with these agents). · Patients contraindicated for dexamethasone. · Previous allogeneic hematopoietic stem cell transplantation with active graft-versus-host disease (any grade and / or immunosuppressive treatment within 2 months prior to randomization). · Known amyloidosis or associated plasmacytic leukemia. · Pleural effusion requiring thoracentesis or ascites requiring paracentesis or any major procedure within 14 days prior to randomization: e.g., plasmapheresis, radical 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). Platelet transfusions are not permitted within 3 days prior to screening blood tests. · Absolute neutrophil count (ANC) < 1000 μ / L (1×10 9 / L). The use of granulocyte colony-stimulating factor (G-CSF) is not able to reach this level. · Creatinine clearance < 15 mL / min / 1.73 m 2 (Modification of Diet in Renal Disease [MDRD] equation: glomerular filtration rate (mL / min / 1.73 m 2 ) = 175 × (Scr)-1.154 × (age)-0.203 × (0.742 if female) × (1.212 if African American); Scr is serum creatinine in mg / dL and age is in years). · Total bilirubin > 1.5 × upper limit of normal (ULN), excluding known Gilbert's syndrome. · Corrected serum calcium > 14 mg / dL (> 3.5 mmol / L). · Aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) > 3 × ULN. · Grade > 1 ongoing toxicity due to previous anti - myeloma therapy (excluding alopecia and those described in the eligibility criteria) (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI - CTCAE] v4.03). · Previous malignancy. Appropriately treated basal cell or squamous cell skin cancer or superficial (pTis, pTa, and pT1) bladder cancer or low - risk prostate cancer or any in - situ malignancy after curative treatment is possible, as well as any other cancer that was more than 5 years before randomization, the treatment was completed, and the patient has been disease - free for more than 5 years. · Any of the following within 6 months before 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 diseases 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 HCV RNA result greater than the lower limit of detection of the assay or positive HCV antigen). · Any of the following within 3 months before randomization: treatment - resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic events. · 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 study results (e.g., systemic infection if anti - infectious treatment is not employed), or that the patient cannot comply with study procedures. · Female patients who are pregnant or breastfeeding. · Women of childbearing potential (WOCBP) not protected by a highly effective method of contraception, and / or women who do not desire or are unable to have a pregnancy test. · Male participants with female partners of childbearing potential not protected by a highly effective method of contraception.

[0118] IV. Test Procedures A. Investigational Medicinal Product (IMP) i. Isatuximab (IV administration) Isatuximab is formulated as a concentrated solution for injection into 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 injection solution that may contain white to off-white particles for parenteral administration and is packaged in 30 mL glass vials with elastomeric closures. Each vial contains a nominal content of 500 mg of isatuximab. The fill volume is set to ensure removal of 25 mL. For administration to patients, an appropriate volume of isatuximab is diluted in 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 is administered intravenously at a dose of 10 mg / kg to patients in the IKd group on days 1, 8, 15, and 22 of the first 28-day cycle and then on days 1 and 15 of each subsequent 28-day cycle. (The duration of all cycles was 28 days.) In the case of toxicity, dose modifications (explained in more detail below) were applied.

[0120] ii. Carfilzomib (IV administration) Carfilzomib (Kyprolis®), if available from a commercially available supply, is used in this study. Otherwise, it is relabeled by the sponsor according to Good Manufacturing Practice (GMP) guidelines prior to being supplied to the trial sites. Details regarding the prescription, storage, and handling procedures of carfilzomib are described in the commercially available package insert. Lyophilized product is 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 a commercially available supply, if available, is used in this study. Otherwise, it is relabeled by the sponsor according to Good Manufacturing Practice (GMP) guidelines prior to being supplied to the trial sites. Details regarding the prescription and handling procedures of dexamethasone are described in the commercially available package insert.

[0122] B. Premedication for Prevention of Infusion Reactions (IR) with Non-Investigational Medicinal Products (NIMP) All patients assigned to the IKd group receive premedication prior to isatuximab infusion to reduce the risk and severity of IAR commonly observed with monoclonal antibody administration. The recommended premedication agents are as follows: diphenhydramine 25 - 50 mg IV (or equivalent: e.g., cetirizine, promethazine, dexchlorpheniramine, depending on regional approval and availability). An intravenous route is preferred for at least the first 4 infusions), dexamethasone oral / IV (dose 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 orally 15 - 30 minutes (but within 60 minutes) prior to isatuximab infusion. Once the premedication regimen is complete, the isatuximab infusion is started immediately.

[0123] On the day of isatuximab infusion, the following NIMP are administered in the following order: · Oral acetaminophen (paracetamol) 650 mg to 1000 mg; then · Ranitidine 50 mg IV (or equivalent); then · Diphenhydramine 25 mg to 50 mg IV (or equivalent); then · Dexamethasone 20 mg IV (this is also part of the test procedure).

[0124] When dexamethasone was administered intravenously, the premedication was administered in the following order. · Oral acetaminophen 650 mg to 1000 mg; 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 there is no IV formulation of diphenhydramine or equivalent, oral formulations are permitted starting from the first injection of isatuximab. In this case, it takes 1 to 2 hours before the start of isatuximab injection.

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

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

[0128] For patients who do not experience IAR with 4 consecutive administrations of isatuximab, the principal investigator may reconsider the need for specific isatuximab premedication for IAR.

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

[0130] Dose adjustments (regarding dose delay, dose omission, and reduction of carfilzomib and dexamethasone doses) are permitted for subsequent treatment cycles based on the tolerance of individual patients. Additional details regarding dose adjustments are shown below. Dose reduction is not permitted for the infusion of isatuximab.

[0131] A. Investigational Medicinal Product (IMP) The investigational medicinal product is defined as isatuximab / carfilzomib / dexamethasone in the IKd experimental group and carfilzomib / dexamethasone in the Kd control group.

[0132] Both isatuximab and carfilzomib may induce IAR, and premedication is required before their administration.

[0133] Patients assigned to the IKd group receive premedication regularly, including dexamethasone, to reduce the risk and severity of IAR commonly observed with mAb and carfilzomib before the isatuximab infusion. Dexamethasone is administered before carfilzomib to patients assigned to the Kd group. For patients assigned to the IKd group, dexamethasone is administered before carfilzomib in the absence of isatuximab infusion (such as on days 2, 9, and 16 of cycle 1, and days 2, 8, 9, and 16 of subsequent cycles).

[0134] Before the first two administrations of carfilzomib (on days 1 and 2 of cycle 1), hydration is required. Hydration should be initiated orally at least 48 hours before day 1 of cycle 1. Hydration for additional infusions during cycle 1 and further cycles is left to the discretion of the principal investigator of the clinical trial. (Details of hydration are provided below.) For patients with a body surface area (BSA) exceeding 2.2 m 2 2.2 m is used to determine the dosage of carfilzomib for patients exceeding 2 this value.

[0135] i. IKd group (experimental group) Drug administration (pre- and post-medication as described below) for patients treated with the combination of isatuximab, carfilzomib, and dexamethasone is as follows:

[0136] Dexamethasone 20 mg is administered IV 15 - 30 minutes before (but within 60 minutes) of isatuximab on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle, or at least 30 minutes before carfilzomib on days without isatuximab administration. Dexamethasone is administered IV on days of isatuximab and / or carfilzomib administration and PO on other days. No prophylaxis is required after infusion with dexamethasone.

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

[0138] Carfilzomib (after appropriate hydration) is administered at 20 mg / m on days 1 and 2 of cycle 1 2At a dose of 56 mg / m² on days 8, 9, 15, and 16 of cycle 1 2 At a dose of 56 mg / m² on days 1, 2, 8, 9, 15, and 16 of all subsequent cycles 2 and is administered IV over 30 minutes. The carfilzomib infusion is started immediately after the end of the isatuximab infusion, following the isatuximab infusion. The dose on day 8 is increased to 56 mg / m² for further administration if the patient does not experience toxicity greater than grade 2 (excluding blood toxicity without complications (meaning toxicity related to the test treatment) and resolved tumor lysis syndrome (TLS)). 2

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

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

[0141] Carfilzomib (after appropriate hydration) is administered IV over 30 minutes at a dose of 20 mg / m² on days 1 and 2 of cycle 1 2 at a dose of 56 mg / m² on days 8, 9, 15, and 16 of cycle 1 2 at a dose of 56 mg / m² on days 1, 2, 8, 9, 15, and 16 of all subsequent cycles 2 If the patient does not experience toxicity higher than grade 2 (excluding blood toxicity without complications (meaning toxicity related to the test treatment) or resolved TLS), the dose is increased to 56 mg / m² on day 8 2 and increased for further administration.

[0142] B. Hydration for carfilzomib ​Oral hydration is performed as follows at least 48 hours before the first day of Cycle 1: Continue at 30 mL / kg / day (about 6 - 8 cups of liquid per day) until the time of treatment. Patient compliance is evaluated before starting treatment, and treatment is postponed if oral hydration is not appropriate. Oral hydration is continued at the discretion of the treating investigator for infusions within Cycle 1 and subsequent cycles. If tumor lysis syndrome (TLS) occurred after previous study treatment administration, hydration for subsequent infusions is performed as needed according to the judgment of the treating investigator.

[0143] Patients with a history of heart 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 starting treatment.

[0144] Intravenous hydration is given immediately before carfilzomib on D1 and D2 during Cycle 1, and at the discretion of the treating investigator after Cycle 1. Intravenous hydration consists of 500 mL of normal saline or other appropriate IV fluid before the 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 are regularly monitored for evidence of fluid overload.

[0145] On the day both isatuximab and carfilzomib are administered, consider the volume of the isatuximab infusion in the hydration required before the carfilzomib infusion. If the isatuximab infusion volume does not reach at least 500 mL, additional hydration is performed until it reaches at least 500 mL. In this case, administer the additional volume before starting the isatuximab infusion. The total volume of hydration may be less than 500 mL (≥250 mL) or kept at 500 mL. Patients with borderline left ventricular ejection fraction (LVEF), and / or patients at risk of cardiac decompensation as determined by the treating investigator, are hydrated over a longer period. After the isatuximab infusion is completed, start the carfilzomib infusion.

[0146] C. Dose Modification Dose adjustments (dose delays, dose omissions, and dose reductions (for carfilzomib and / or dexamethasone only)) are permitted in subsequent treatment cycles based on the tolerance of the individual patient. If toxicity occurs and the patient does not recover within 3 days of the scheduled date of infusion / administration, the patient may omit the dose (isatuximab and / or carfilzomib and / or dexamethasone) within the cycle. Administration of the investigational treatment (isatuximab and / or carfilzomib and / or dexamethasone) is discontinued in the event of an AE that persists despite appropriate dose modification or other AEs that warrant discontinuation at the discretion of the study responsible physician. All changes to the investigational treatment administration are recorded. The patient receives the next investigational treatment cycle after the toxicity has recovered, based on the criteria evaluated by the study responsible physician.

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

[0148]

Table 6

[0149]

Table 7

[0150] Dose reduction is not permitted for isatuximab infusion.

[0151] V. Disease Evaluation The decision made by the principal investigator regarding whether to permit the subject to continue treatment was based on efficacy data (obtained from local and / or central laboratories), radiological evaluations, and bone marrow evaluations conducted throughout the study or as indicated according to the IMWG criteria. The reference values for evaluating treatment response were the values measured in samples collected from each patient on day 1 of cycle 1 before treatment (see section I.A. Main Objectives above). An overview of the evaluations and schedule is shown in Table F below. Disease characteristics such as M protein subtype, degree of bone marrow and extramedullary disease, cytogenetics (evaluated by the central laboratory), and R-ISS are also recorded at baseline.

[0152]

Table 8

[0153] The 2016 IMWG criteria (see, for example, Kumar S, Paiva B, Anderson KC, et al., International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. The Lancet. Oncology, 17(8), e328-e346 (2016)) are applied to evaluate response and disease progression. Evaluations are performed on the first day of every cycle and when treatment is stopped. PFS (defined as the time from randomization to either the first recorded occurrence of progressive disease or death of the patient from any cause, whichever is earlier) is the primary efficacy endpoint. Response is evaluated until disease progression in patients who discontinue treatment during follow-up and before disease progression. Subgroup analyses of PFS (by, for example, cytogenetic risk status, number of previous treatment lines) are also performed. Next-generation sequencing (NGS) is used for the evaluation of MRD.

[0154] Safety evaluations include vital signs, hematological and biochemical evaluations, physical examinations, electrocardiograms, and AEs, which are followed throughout the study. AEs are graded according to the Common Terminology Criteria for Adverse Events v4.03 of the US National Cancer Institute. Immunogenicity is evaluated during the test treatment. The indirect Coombs test is performed only at baseline and after treatment initiation in the carfilzomib / dexamethasone group in addition to isatuximab.

[0155] Patient-reported outcome (PRO) evaluations are measured on day 1 of every cycle, at the end of treatment, and 90 days after test treatment administration by using the PRO / HRQoL and health utility instruments (the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and MY20 [EORTC QLQ-C30 and QLQ-MY20] and the EuroQoL Questionnaire EQ-5D-5L).

[0156] Example 1B: Initial Results of the Phase III Trial Described in Example 1A 302 patients were randomized as follows: 179 patients were assigned to the isatuximab + carfilzomib + dexamethasone (Isa+car+dex) group and 123 patients were assigned to the carfilzomib + dexamethasone (car+dex) group. Patient characteristics were well balanced between the two groups. The median age was 64 years (range: 33 - 90). 25.8% of the patients had R-ISS stage I, 59.6% of the patients had R-ISS stage II, and 7.9% of the patients had R-ISS stage III. 44% of the patients had received one previous treatment line for multiple myeloma, 33% had received two previous treatment lines, and 23% had received three or more previous lines. 90% of the patients had received previous treatment with a proteasome inhibitor and 78% of the patients had received previous treatment with an immunomodulatory agent (i.e., IMiD®). The median number of previous lines was 2. 24% of the 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 considered in Example 1A, patients in the experimental group received isatuximab at a dose of 10 mg / kg once a week for 4 weeks, and then every other week in 28-day cycles, twice a week carfilzomib, 20 / 56 mg / m 2 dose, and dexamethasone at the standard dose were administered by intravenous infusion during the treatment period. Patients in the control group received carfilzomib twice a week at a dose of 20 / 56 mg / m 2 and dexamethasone at the standard dose during the treatment period. The primary endpoint of this study was progression-free survival. Secondary endpoints included overall response rate (ORR), very good partial response rate or better (≧VGPR), minimal residual disease (MRD), complete response rate (CR), overall survival (OS), and safety.

[0158] At the median follow-up period of 20.7 months, with 103 progression-free survival (PFS) events by the IRC (Independent Review Committee), the median PFS was not reached in the isa+car+dex group. The 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, it exceeded the pre-specified efficacy boundary (p = 0.005). The PFS benefit was consistent across subgroups. The overall response rate (ORR) (i.e., the proportion of patients achieving a partial response (PR) or better) was 86.6% in the isa+car+dex group, compared with 82.9% in the car+dex group (one-sided p = 0.1930). 72.6% of patients in the isa+car+dex group achieved ≧VGPR (very good partial response), compared with 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), while 27.6% of patients in the car+dex group achieved a complete response. The 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] For 52.0% of the patients in the isa+car+dex group, 30.9% of the patients in the car+dex group continued treatment. 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). Treatment-emergent adverse effects (TEAEs) of grade 3 or higher were observed in 76.8% of the patients in the isa+car+dex group and 67.2% of the patients in the car+dex group. Serious treatment-emergent adverse events (TE-SAEs) and fatal TEAEs were similar in both groups: 59.3% of the patients in the isa+car+dex group experienced TE-SAEs compared with 57.4% of the patients in the car-dex group; and 3.4% of the patients in the isa+car+dex group experienced fatal TEAEs compared with 3.3% of the patients in the car+dex group who were fatal. Infusion reactions were reported in 45.8% of the patients in the isa+car+dex group (0.6% grade 3-4) and 3.3% of the patients in the car+dex group (0% grade 3-4). Respiratory infections of grade 3 or higher (grouped) were seen in 32.2% of the patients in the isa+car+dex group compared with 23.8% of the patients in the car+dex group. Heart failure of grade 3 or higher (grouped) was reported in 4.0% of the patients in the isa+car+dex group compared with 4.1% of the patients in the car+dex group. According to laboratory results, grade 3-4 thrombocytopenia was reported in 29.9% of the patients in the isa+car+dex group compared with 23.8% of the patients in the car+dex group; neutropenia was reported in 19.2% of the patients in the isa+car+dex group compared with 7.4% of the patients in the car+dex group.

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

[0161] Example 1C: Further Results of the Phase III Trial Described in Example 1A Further details regarding the interim results from the Phase III clinical trial and the study 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 two groups of the study: For every three patients randomized to the IKd group (isatuximab + carfilzomib + dexamethasone), two were randomized to the Kd group (carfilzomib + dexamethasone). See Table D above. All patients had received 1 to 3 previous lines of treatment for multiple myeloma. No patients had received previous treatment with carfilzomib. No patients were refractory to previous anti-CD38 therapy. Patients were stratified according to previous treatment line (i.e., one previous line for more than 1 line) and R-ISS score (i.e., classified as I or II vs III not classified) to ensure an equal allocation of subgroups of participants to each group. (For further details on R-ISS, 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.)

[0163] The major patient demographics and baseline characteristics are shown in Table G below. Patient characteristics were balanced between the two groups. In cytogenetic analysis, del17p was defined using a 50% cutoff, and t(4;14) and t(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 more than 3 previous lines of treatment for multiple myeloma.

[0164]

Table 9

[0165] Treatment was continued until the patient demonstrated progressive disease (PD), experienced unacceptable toxicity, or elected to withdraw from the study.

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

[0167] Results At 20.7 months of follow-up, patient demographics were as follows: of the 179 patients in the IKd group, 177 were treated. Eighty-four (46.9%) patients in the IKd group discontinued treatment. Fifty-two (29.1%) discontinued due to progressive disease (PD); 15 (8.4%) discontinued due to adverse events (AE), and 6 (3.4%) discontinued for other reasons. Ninety-three (52%) patients in the IKd group continued treatment. Of the 123 patients in the Kd group, 122 received treatment. Eighty-four (68.3%) patients in the Kd group discontinued treatment. Forty-nine (39.8%) discontinued due to progressive disease (PD). Seventeen (13.8%) discontinued due to adverse events (AE), and 4 (3.3%) discontinued for other reasons. Thirty-eight (30.9%) patients in the Kd group continued treatment. A higher percentage of patients in the IKd group continued treatment compared to the Kd group (i.e., approximately 37% of patients in the IKd group discontinued treatment due to PD or AE compared to approximately 54% in the Kd group).

[0168] The interim PFS analysis by the Independent Review Committee (IRC) showed that the median PFS (mPFS) had not yet been reached in the IKd group, while the 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 administered IKd showed an improvement in PFS compared to patients in the Kd group, with a 47% reduction in the risk of disease progression or death. See Figure 3. Subgroup analyses were performed for PFS. As shown in Figure 4, all subgroups supported IKd vs Kd. A consistent treatment effect for IKd was seen across all subgroups analyzed (e.g., age, baseline renal function (eGFR), number of previous treatment lines, previous proteasome inhibitor treatment in the last line, previous immunomodulatory drug treatment in the last line, high - risk cytogenetic status, ISS stage classification at study initiation, and refractory to lenalidomide).

[0169] A stronger response was seen in patients treated with IKd compared to those treated with Kd, consistent with the improvement in PFS. The overall response rate (ORR) in the IKd group of patients was 86%, while the ORR in the Kd group of patients was 82% (p = 0.19, stratified Cochran - Mantel - Haenszel test; one - sided significance level is 0.025). 72.6% of patients in the IKd group achieved VGPR or better compared to 56.1% of patients in the Kd group (p = 0.0011). 39.7% of patients in the IKd group achieved CR compared to 27.6% of patients in the Kd group. Furthermore, in the IKd group, there were more patients who were MRD negative (i.e., "minimal residual disease negative" at a threshold of 10 -5 when evaluated by next - generation sequencing (NGS)) than in the Kd group. Among Intent To Treat patients, 53 / 179 (29.6%) in the IKd group were MRD negative compared to 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 to 16 / 70 (22.9%) in the Kd group.

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

[0171]

Table 10

[0172] With 20.73 months of follow-up, overall survival (OS) data were incomplete at the time of analysis.

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

[0174]

Table 11

[0175] More patients on IKd experienced treatment-emergent adverse events (TEAEs) due to grade 3 or higher treatment than in the Kd group (76.8% IKd vs 67.2% Kd). Adding ixazomib to carfilzomib did not increase the rate of death, serious TEAEs, or events leading to treatment discontinuation compared to carfilzomib + dexamethasone. IKd has a manageable safety profile without new safety signals. Infusion reactions (IR) occurred mainly during the first infusion and most were 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, which corresponds to a 47% reduction in the risk of progression or death. IKd demonstrated consistent benefits across multiple subgroups, including those with unmet high medical needs (elderly, high-risk cytogenetics, renal impairment) who are difficult to treat. IKd showed a significant intensity of response compared to Kd, with a MRD-negative rate of 30% vs 13% in the ITT population. IKd demonstrated a manageable safety profile and favorable risk / benefit in patients with relapsed MM.

[0177] Example 1D: Intensity and kinetics of response to carfilzomib and dexamethasone in addition to isatuximab in relapsed multiple myeloma Prologue Achievement of 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 dynamics in the study described in Example 1A, was analyzed. To overcome interference with Isa in the standard immunofixation assay, measurements by mass spectrometry of serum M protein were also performed.

[0178] Methods Example 1A describes a randomized, open-label, multi-center phase 3 trial that investigated Isa-Kd versus Kd in patients with relapsed MM who had received 1-3 lines of therapy, in addition to Isa. The primary endpoint of PFS and the secondary endpoints of overall response rate (ORR), ≥ very good partial response (≥VGPR), and complete response (CR) rate were determined by an independent response committee (IRC) based on central data of M protein, 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). Minimal residual disease (MRD), i.e., minimal residual disease, was evaluated in bone marrow aspirates from patients who achieved ≥VGPR by next-generation sequencing at a sensitivity level of 10 -5 Mass spectrometry was performed to measure serum M protein without Isa interference. Hazard ratios and corresponding confidence intervals were estimated using the Cox proportional hazards model. The Cochran-Mantel-Haenszel test was used to compare secondary endpoints between treatment groups. All patients who had not achieved MRD or who were randomized without MRD assessment were analyzed as MRD+.

[0179] Results As discussed in Example 1A, 302 patients (179 Isa-Kd, 123 Kd) were randomized. At a median follow-up of 20.7 months, a stronger response was observed in patients administered Isa-Kd than in those administered Kd. 72.6% of the patients in the Isa-Kd group achieved VGPR or better, compared with 56.1% in the Kd group (nominal p = 0.011). 39.7% of the patients in the Isa-kd group achieved CR or better, compared with 27.6% of the patients in the Kd group. MRD- occurred in 53 / 179 (30%) of the patients in the Isa-Kd group, compared with 16 / 123 (13%) of the patients in the Kd group (nominal p = 0.0004). (See also, for example, Examples 1B and 1C). 20.1% (36 / 179) of the patients in the Isa-Kd group achieved both CR and MRD-, compared with 10.6% (13 / 123) of the 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. The hazard ratio (HR) supports Isa-Kd rather than 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, a MRD-negative state may be obtained in patients with renal dysfunction, i.e., eGFR < 60 mL / min / 1.73m 2 (26.5% MRD- vs 25.9% MRD+); with 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+]; three or more previous highly pre-treated lines (22.6% MRD- vs 19.0% MRD+) or refractory to lenalidomide in the last regimen (18.9% MRD- vs 20.6% MRD+). Within the Isa-Kd group, the frequency of achieving a MRD-negative state was low in patients refractory to proteasome inhibitor (PI) [18.9% MRD- vs 36.5% MRD+] or del(17p) [3.8% MRD- vs 12.7% MRD+].

[0180] The interference between isatuximab and M protein was investigated: Samples from 27 patients with near-complete remission (CR) (serum immunofixation (IF) positive IgG kappa only) or potential CR (residual serum M protein with IF positive IgG kappa ≤ 0.5 g / dL) were tested by mass spectrometry in the Isa-Kd group. Among them, 11 near-CR or potential CR pts had < 5% plasma cells in the bone marrow and were mass spectrometry negative (residual myeloma M protein levels below the lower limit of quantification (LOQ) of central laboratory immunofixation). Additionally, 7 out of 11 near-CR or potential CR patients were also MRD-. These results support that both the current CR rate and MRD-CR rate are underestimated (potential adjusted CR rate is 45.8%; potential adjusted MRD-CR rate is 24%).

[0181] Response to treatment occurred rapidly in both groups. The median time to response for responders to the 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 time to response for responders showing the best response was 120.0 (29 - 568) days in Isa-Kd versus 104.5 (29 - 507) days in the Kd group. The median time to response for responders to the 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 time to response for responders to the 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 the increase in response intensity, 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 for descriptive analysis.

[0182] Conclusion In patients treated with Isa-Kd, there was a clinically meaningful improvement in the intensity of response compared to patients treated with Kd. A 39.7% CR rate in the Isa-Kd group of studies that were underappreciated due to interference. The results of mass spectrometry suggest that approximately half of patients in previous lines 1-3 treated with Isa-Kd may achieve CR. More patients in the Isa-Kd group reached MRD negativity than the Kd group (30% vs 13%), and at least twice as many patients in the IsaKd group reached CR MRD- as the Kd group (20.1% vs 10.6%; adjusted to 24% vs 10.6% respectively). Reaching MRD negativity was associated with longer PFS in both groups.

[0183] Example 1E: Further results of the Phase III trial described in Example 1A Eligible patients had relapsed and / or refractory multiple myeloma and had received 1-3 previous lines of treatment and evidence of measurable disease (serum M protein ≥ 0.5 g / dl and / or urine M protein ≥ 200 mg / 24 hours). In the case of having primary refractory multiple myeloma (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), only measurable disease of serum free light chain, or if the performance status of the Cancer Clinical Trials Group on the East Coast of the United States > 2, the patient was excluded. Patients were excluded if they received anti-myeloma treatment within 14 days of randomization, had received previous treatment with carfilzomib, were refractory to anti-CD38 antibody therapy, or if dexamethasone was contraindicated. Dietary modification formula in renal disease < 15 ml / min / 1.73m2 Patients with an estimated glomerular filtration rate (eGFR) due to a left ventricular ejection fraction < 40% were also excluded. Patients with previous pulmonary complications including chronic obstructive pulmonary disease were enrolled. Patients were randomized as described above, and randomization was stratified as described 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 as determined by a blinded independent response committee (IRC). The IRC reviewed disease assessments for response and progression (central radiological assessment, M protein quantification from the central laboratory, and local bone marrow aspiration for plasma cell infiltration as needed). Key secondary efficacy endpoints included overall response rate, very good partial response (VGPR) or better rate, minimal residual disease (MRD) negativity rate, complete response (CR) rate, and overall survival according to the IMWG response criteria.

[0185] MRD was evaluated by next-generation sequencing with a minimum sensitivity of 1 in 10 5 nucleated cells in patients who achieved VGPR or better. Cytogenetics was evaluated by fluorescence in situ hybridization (FISH) during screening by the central laboratory, and the cut-offs were 50% for del(17p), 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 discontinued. Safety assessments included recording of adverse events, laboratory parameters (both evaluated according to the National Cancer Institute - Common Terminology Criteria (NCIC-CTC) version 4.03), vital signs, electrocardiograms, and the performance status of the Eastern Cooperative Oncology Group. Efficacy analyses were performed in the intent-to-treat population and summarized by randomization treatment. The safety analyses and the extent of the test treatment were evaluated and summarized by the actual treatment received within the safety population.

[0187] Patients and Treatments Demographics and clinical characteristics were well balanced at baseline (Table J). The median age was 64 years (range, 33 - 90 years). The median number of prior lines was 2 (range, 1 - 4), similar between groups, and 44%, 33%, and 23% had received 1, 2, and ≥3 prior lines, respectively. One patient (in the isatuximab group) and two patients (in the control group) had received 4 prior lines. Overall, 45% of patients were refractory to immunomodulatory drugs, of which 32.8% were refractory to lenalidomide. 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 renal dysfunction (eGFR < 60 ml / min / 1.73m 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 in the isatuximab vs control group discontinued treatment (46.9% vs 68.3%).

[0190] Efficacy The median follow-up was 20.7 months, and the addition of isatuximab to carfilzomib-dexamethasone showed a statistically significant improvement in progression-free survival with a hazard ratio of 0.531 (99% CI, 0.318 - 0.889, one-sided P value = 0.0007)), corresponding to a 46.9% reduction in the risk of progression or death. The median progression-free survival at 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) vs 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 = 0.1930. Since the difference between groups was not statistically significant, P values for subsequent key secondary endpoints are provided for illustrative 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). Adding 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 achieving both CR and MRD negativity responses was 20.1% (IKd group) and 10.6% (Kd group). Overall survival was incomplete at the interim analysis, but 17.3% and 20.3% of patients died in the isatuximab group and control group, respectively.

[0192]

Table 13-1

Table 13-2

[0193] In a pre-specified subgroup analysis, clinical benefits in support of isatuximab and carfilzomib-dexamethasone occurred across almost all groups (Figure 7). The median progression-free survival in patients with renal impairment did not reach in the IKd group, whereas it was 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]. Complete renal response (improvement from baseline eGFR < 50 ml / min / 1.73m 2 2 to ≥ 60 ml / min / 1.73m 2 2) occurred in 52% (IKd group) vs 30.8% (Kd group), and persisted in 32.0% (IKd group) vs 7.7% (Kd group) of patients, respectively. Progression-free survival benefits in support of isatuximab with carfilzomib-dexamethasone were observed in elderly patients (≥ 65 years), including a hazard ratio of 0.244 (95% CI, 0.060 - 1.000) in patients 75 years and older.

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

[0195] Discussion The results of this randomized phase 3 trial showed that the addition of isatuximab to carfilzomib - dexamethasone was associated with a significant benefit in progression - free survival in patients with relapsed multiple myeloma compared with carfilzomib - dexamethasone alone. The risk of disease progression or death was shown to be 47% lower in the isatuximab group, with a very low hazard ratio (0.531 [99% CI, 0.318 - 0.889]). The median progression - free survival period of 19.15 months in the control group was consistent with the protocol assumption (19 months) and a previous phase 3 trial evaluating the efficacy of carfilzomib + dexamethasone versus bortezomib + dexamethasone in relapsed / refractory multiple myeloma patients after 1 - 3 previous lines. The results of the present invention showed that the superiority of the IKd group was not related to a control group with low performance (i.e., the Kd group).

[0196] The benefits in progression-free survival were seen in almost all subgroups of the IKd group, including high-risk cytogenetics, International Staging System stage III at study registration, elderly patients, patients with renal dysfunction, patients with one or more previous lines of treatment, prior exposure to immunomodulatory agents, prior exposure to proteasome inhibitors, and prior exposure to both immunomodulatory agents and proteasome inhibitors. Importantly, cytogenetic risk was uniformly evaluated for all patients using the FISH-positive internationally recognized cutoff and was determined in 88% of the overall patient population.

[0197] The intensity and quality of the response were superior in the IKd group compared to the Kd group, with higher rates of VGPR, CR, MRD negativity, and CR with MRD negativity. Specifically, the rates of MRD negativity and CR with MRD negativity in the IKd group were very high considering the median number of previous lines in these patients was 2. Furthermore, since CR was evaluated without using an interference assay, the rate of CR with MRD negativity may have been underestimated (see, for example, Example 1D).

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

[0199] Each embodiment described in this specification may be combined with any other optional embodiment(s), unless explicitly indicated to the contrary. In particular, any feature or embodiment shown as preferred or advantageous may be combined with any other feature(s) or embodiment(s) shown as preferred or advantageous, unless explicitly indicated to the contrary.

[0200] All references cited in this application are hereby expressly incorporated by reference into this specification.

Claims

**Claim 1** A pharmaceutical composition comprising an anti-CD38 antibody, comprising: (a) a heavy chain variable domain (V H ) 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), and (b) a light chain variable domain (V L ) comprising a CDR-L1 comprising the amino acid sequence KASQDVSVTVA (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), for use in the treatment of multiple myeloma in an individual, said treatment comprising administering to the individual an effective amount of the anti-CD38 antibody, an effective amount of carfilzomib, and an effective amount of dexamethasone, Here, the anti-CD38 antibody is administered at a dose of 10 mg / kg, 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, Here, the individual has received at least one previous treatment for multiple myeloma, the individual has renal dysfunction at the start of the treatment, and the renal dysfunction is improved by the treatment, a pharmaceutical composition. **Claim 2** The pharmaceutical composition according to claim 1, wherein the individual has received 1 to 3 previous treatments for multiple myeloma, and the treatment extends the progression-free survival (PFS) and / or overall survival (OS) of the individual. **Claim 3** The pharmaceutical composition according to claim 1, wherein the individual has received 1 to 3 previous treatments for multiple myeloma. **Claim 4** The pharmaceutical composition according to claim 1, wherein the individual has received more than 3 previous treatments for multiple myeloma. **Claim 5** The pharmaceutical composition according to claim 1, wherein the individual has received a previous treatment with a proteasome inhibitor. **Claim 6** The pharmaceutical composition according to claim 1, wherein the individual has received a previous treatment with an immunomodulatory agent. **Claim 7** The pharmaceutical composition according to claim 1, wherein the individual is classified as stage I or stage II according to the Revised International Staging System (R-ISS) for multiple myeloma at the start of the treatment. **Claim 8** The pharmaceutical composition according to claim 1, wherein the individual is classified as stage III according to R-ISS at the start of the treatment. **Claim 9** The pharmaceutical composition according to claim 1, wherein the individual is not classified according to R-ISS at the start of the treatment. **Claim 10** The pharmaceutical composition according to claim 1, wherein the individual has one or more cytogenetic abnormalities selected from the group consisting of del(17p), t(4;14), t(14;16), and gain(1q21). **Claim 11** The pharmaceutical composition according to claim 1, wherein the individual is 65 to less than 75 years old at the start of the treatment. **Claim 12** The pharmaceutical composition according to claim 1, wherein the individual is 75 years old or older at the start of the treatment. **Claim 13** The anti-CD38 antibody comprises a heavy chain variable region (V H ), which contains the amino acid sequence of SEQ ID NO: 7, and a light chain variable region (V L ), which contains the amino acid sequence of SEQ ID NO: 8 or SEQ ID NO:

9. The pharmaceutical composition according to claim 1. **Claim 14** The pharmaceutical composition according to claim 1, wherein the anti-CD38 antibody is isatuximab. **Claim 15** The anti-CD38 antibody, carfilzomib, and dexamethasone are administered in a first 28-day cycle, Here, 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 / m 2 on days 1 and 2 of the first 28-day cycle, and at a dose of 56 mg / m 2 on days 8, 9, 15, and 16, and dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of the first 28-day cycle. The pharmaceutical composition according to claim 1. **Claim 16** The anti-CD38 antibody, carfilzomib, and dexamethasone are further administered in one or more 28-day cycles following the first 28-day cycle, Here, 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 / m 2 on each of days 1, 2, 8, 9, 15, and 16 of one or more 28-day cycles following the first 28-day cycle, 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. The pharmaceutical composition according to claim 15. **Claim 17** The individual is MRD negative at a threshold of 10 or less after the treatment -5 The pharmaceutical composition according to claim 1, wherein the individual is MRD negative at a threshold of 10 or less

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