Methods of treating multiple myeloma

Abstract

The present invention provides methods for treating multiple myeloma (e.g., refractory multiple myeloma or recurrent and refractory multiple myeloma) in an individual who has received at least two prior therapies for multiple myeloma. The methods comprise administering to the individual an anti-CD38 antibody, pomalidomide, and dexamethasone. Methods of ameliorating renal damage in an individual having multiple myeloma are also provided.

Description

This application is a divisional application of the invention application with the application date of January 28, 2020, Chinese application number 202080024773.7, and invention name “Method for treating multiple myeloma”. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to European Patent Application No. 19306554.7, filed December 3, 2019; U.S. Provisional Application No. 62 / 943,716, filed December 4, 2019; U.S. Provisional Application No. 62 / 931,014, filed November 5, 2019; U.S. Provisional Application No. 62 / 899,094, filed September 11, 2019; U.S. Provisional Application No. 62 / 861,954, filed June 14, 2019; U.S. Provisional Application No. 62 / 847,826, filed May 14, 2019; and U.S. Provisional Application No. 62 / 797,876, filed January 28, 2019; the contents of each of which are incorporated herein by reference in their entirety. Submission of Sequence Listings as ASCII Text Files

[0002] The contents of the following submitted ASCII text file are incorporated herein by reference in their entirety: Computer Readable Form (CRF) of the Sequence Listing (File Name: 183952031241SEQLIST.txt, Record Date: January 23, 2020, Size: 11 KB). Technical Field

[0003] The present disclosure relates to methods of treating multiple myeloma by administering an anti-CD38 antibody in combination with pomalidomide 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 excess monoclonal immunoglobulin (usually of IgG or IgA type or free light chains, i.e., paraprotein, M protein or M component). MM patients can experience bone pain, fractures, fatigue, anemia, infections, hypercalcemia, and kidney problems (Rollig et al. (2015) Lancet. 385(9983):2197-208). Expression of CD38 is particularly prominent in MM, as >98% of patients are positive for this protein (Goldmacher et al. (1994) Blood. 84(9):3017-25; Lin et al. (2004) Am J Clin Pathol. 121(4):482-8). The strong and uniform expression of CD38 on malignant clonal MM cells contrasts with the restricted expression pattern on normal cells, suggesting that this antigen can be used for specific targeting of tumor cells.

[0005] Current goals of MM therapy are to control the disease as effectively as possible, maximize quality of life, and prolong survival. Each patient's disease trajectory is unique, but relapse is inevitable, and the depth and duration of response to each treatment generally diminishes after relapse. Typically, MM patients will receive an average of 4 to 8 different regimens in their lifetime, either alone or in combination, using agents such as proteasome inhibitors (e.g., bortezomib, ixazomib, and carfilzomib) and immunomodulatory agents or (e.g., lenalidomide and thalidomide), monoclonal antibodies (e.g., elotuzumab), histone deacetylase (HDAC) inhibitors (e.g., panobinostat). However, once patients become refractory to these agents, survival is limited, and in patients who become refractory to stem cell transplant (SCT), chemotherapy, proteasome inhibitors, and immunomodulatory drugs After having experienced failures, there is a need for updated treatment options to treat them. Despite the significant improvement in patient outcomes using newer therapies, MM remains an incurable disease. Thus, there is an unmet medical need for the treatment of patients who are refractory to at least 2 different lines of therapy, including proteasome inhibitors and immunomodulatory agents, or who are refractory to proteasome inhibitors and The treatment of patients who are double refractory remains an unmet medical need.

[0006] All references cited herein, including patent applications, patent publications, and UniProtKB / Swiss-Prot Accession Nos., are hereby incorporated by reference in their entireties, as if each individual reference were expressly and individually indicated to be incorporated by reference. Summary of the Invention

[0007] Provided is an anti-CD38 antibody for use in treating multiple myeloma in an individual, the anti-CD38 antibody comprising (a) a heavy chain variable domain (V H ): CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), CDR-H2 comprising the amino acid sequence TIYPGD GDTGYAQKFQG (SEQ ID NO: 2), and CDR-H3 comprising the amino acid sequence GDYYGS NSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (V L ): a CDR-L1 comprising the amino acid sequence of KASQDVSTVVA (SEQ ID NO:4), a CDR-L2 comprising the amino acid sequence of SASYRYI (SEQ ID NO:5), and a CDR-L3 comprising the amino acid sequence of QQ HYSPPYT (SEQ ID NO:6), wherein the treatment comprises administering the anti-CD38 antibody, pomalidomide, and dexamethasone to the individual, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg, pomalidomide is administered at a dose of 4 mg, and dexamethasone is administered at a dose of 40 mg to individuals under 75 years of age or dexamethasone is administered at a dose of 20 mg to individuals 75 years of age or older, wherein the individual has received at least two prior therapies for multiple myeloma, wherein at least one of the at least two prior therapies for multiple myeloma is lenalidomide and at least one of the two prior therapies is a proteasome inhibitor, and wherein the treatment prolongs progression-free survival (PFS) and / or overall survival (OS) of the individual.

[0008] Provided is an anti-CD38 antibody for use in a method of reversing renal impairment in an individual with multiple myeloma, the anti-CD38 antibody comprising (a) a heavy chain variable domain (V H ): 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): 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), wherein the method comprises administering to the individual the anti-CD38 antibody, pomalidomide, and dexamethasone, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg, pomalidomide is administered at a dose of 4 mg, and dexamethasone is administered at a dose of 40 mg to an individual under 75 years of age or a dose of 20 mg to an individual 75 years of age or older, wherein the individual has received at least two prior therapies for multiple myeloma, and wherein at least one of the at least two prior therapies for multiple myeloma is lenalidomide and at least one of the at least two prior therapies is a proteasome inhibitor.

[0009] Also provided is a liquid pharmaceutical formulation comprising (a) isatuximab at a concentration of 5-20 mg / ml; (b) a buffer selected from histidine, acetate, and phosphate; (c) an excipient selected from sucrose and mannitol; and (d) polysorbate 80 (PS80). In some embodiments, the isatuximab is present at a concentration of 5 mg / ml, wherein the buffer is histidine and the concentration of histidine is 10 mM, wherein the excipient is sucrose and the concentration of sucrose is 10% (w / v), wherein PS80 is present at a concentration of 0.005% (w / v), and wherein the pharmaceutical formulation has a pH of about 6.0 or about 6.5. In some embodiments, the pH of the pharmaceutical formulation is about 6.5. In some embodiments, the isatuximab is present at a concentration of 20 mg / ml, wherein the buffer is histidine and the concentration of histidine is 20 mM, wherein the excipient is sucrose and is present at a concentration of 10% (w / v), wherein PS80 is present at a concentration of 0.02% (w / v), and wherein the pharmaceutical formulation has a pH of about 6.0. In some embodiments, the formulation is sterile.

[0010] A method of treating a human individual having multiple myeloma is provided, the method comprising administering to the individual an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 1, (b) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 2, and (c) an Fc domain, wherein the Fc domain comprises a S267E amino acid substitution in the CH2 domain and a L328F amino acid substitution in the CH3 domain, wherein the individual has received at least two prior therapies for multiple myeloma, and wherein at least one of the at least two prior therapies for multiple myeloma is lenalidomide and at least one of the at least two prior therapies is a proteasome inhibitor. H) 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 (VL) comprising: L ) a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SAS YRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6), wherein the treatment prolongs progression free survival (PFS) of the individual. In some embodiments, the method comprises administering the anti-CD38 antibody at a dose of 10 mg / kg; pomalidomide at a dose of 4 mg; and dexamethasone at a dose of 40 mg, wherein the individual is below 75 years old, or dexamethasone at a dose of 20 mg, wherein the individual is 75 years old or above. In some embodiments, the individual has received at least two prior therapies for multiple myeloma. In some embodiments, at least one of the at least two prior therapies for multiple myeloma is lenalidomide. In some embodiments, at least one of the two prior therapies is a proteasome inhibitor. In some embodiments, the treatment prolongs overall survival (OS) of the individual. In some embodiments, the treatment reverses renal impairment of the individual.

[0011] Also provided is a method of treating a human individual having multiple myeloma, the method comprising administering to the individual an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) comprising: H ) 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 (VL) comprising: L): 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), wherein the treatment prolongs the overall survival (OS) of the individual. In some embodiments, the anti-CD38 antibody is administered at a dose of 10 mg / kg; pomalidomide is administered at a dose of 4 mg; and dexamethasone is administered at a dose of 40 mg, wherein the individual is less than 75 years old, or dexamethasone is administered at a dose of 20 mg, wherein the individual is 75 years old or older. In some embodiments, the individual has received at least two prior therapies for multiple myeloma. In some embodiments, at least one of the at least two prior therapies for multiple myeloma is lenalidomide. In some embodiments, at least one of the two prior therapies is a proteasome inhibitor. In some embodiments, the treatment reverses the impairment of renal function in the individual.

[0012] Provided is a method for ameliorating renal impairment in a human subject with multiple myeloma, the method comprising administering to the subject an anti-CD38 antibody, pomalidomide, and dexamethasone, wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (V H ): CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), CDR-H2 comprising the amino acid sequence TIYPGDGDTGYA QKFQG (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 ): 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 QQHYSPP YT (SEQ ID NO: 6). In some embodiments, the anti-CD38 antibody is administered at a dose of 10 mg / kg; pomalidomide is administered at a dose of 4 mg; and dexamethasone is administered at a dose of 40 mg, where the individual is under 75 years of age, or at a dose of 20 mg, where the individual is 75 years of age or older.

[0013] In some embodiments of the antibodies for use herein or methods herein, the at least two prior therapies do not include treatment with an anti-CD38 antibody and / or treatment with pomalidomide. In some embodiments of the antibodies for use herein or methods herein, the individual did not respond to at least one of the at least two prior therapies, or wherein the individual relapsed after at least one of the at least two prior therapies, or wherein the individual experienced disease progression during or after treatment with at least one of the two prior therapies.

[0014] In some embodiments of the antibodies for use herein or methods herein, the individual with multiple myeloma is selected for administration of the anti-CD38 antibody, pomalidomide, and dexamethasone based on the individual having renal impairment. In some embodiments of the antibodies for use herein or methods herein, the individual with renal impairment has a renal rate of less than about 60, less than about 50, or less than about 30 mL / min / 1.73 m 2 In some embodiments of the antibodies for use herein or methods herein, the individual with renal impairment has an estimated glomerular filtration rate (eGFR) of less than about 60, less than about 50, or less than about 30 mL / min / 1.73 m before treatment begins. 2 In some embodiments of the antibodies for use herein or methods herein, the individual has received at least two prior therapies for multiple myeloma. In some embodiments of the antibodies for use herein or methods herein, at least one of the at least two prior therapies is lenalidomide. In some embodiments of the antibodies for use herein or methods herein, at least one of the at least two prior therapies is a proteasome inhibitor. In some embodiments of the antibodies for use herein or methods herein, the method prolongs the progression-free survival (PFS) of the individual. In some embodiments of the antibodies for use herein or methods herein, the method prolongs the overall survival (OS) of the individual.

[0015] Also provided herein is an anti-CD38 antibody for use in treating multiple myeloma in an individual, the anti-CD38 antibody comprising (a) a heavy chain variable domain (V H ): 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): 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), the treatment comprising administering to the individual the anti-CD38 antibody, pomalidomide, and dexamethasone, wherein the treatment prolongs progression-free survival (PFS) and / or overall survival (OS). In some embodiments of the antibodies for use herein or the methods herein, the anti-CD38 antibody is administered at a dose of 10 mg / kg; pomalidomide is administered at a dose of 4 mg; and dexamethasone is administered at a dose of 40 mg, wherein the individual is less than 75 years old, or dexamethasone is administered at a dose of 20 mg, wherein the individual is 75 years old or older. In some embodiments of the antibodies for use herein or the methods herein, the individual has received at least two prior therapies for multiple myeloma. In some embodiments of the antibodies for use herein or methods herein, at least one of the at least two prior therapies for multiple myeloma is lenalidomide. In some embodiments of the antibodies for use herein or methods herein, at least one of the two prior therapies is a proteasome inhibitor.

[0016] Also provided is an anti-CD38 antibody for use in reversing renal impairment in an individual, the anti-CD38 antibody comprising (a) a heavy chain variable domain (V H ): CDR-H1 comprising the amino acid sequence DYWMQ (SEQ ID NO: 1), CDR-H2 comprising the amino acid sequence TIYPGD GDTGYAQKFQG (SEQ ID NO: 2), and CDR-H3 comprising the amino acid sequence GDYYGS NSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (V L): 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 QQ HYSPPYT (SEQ ID NO: 6), the treatment comprising administering to the individual the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments of the antibodies for use herein or the methods herein, the individual has multiple myeloma. In some embodiments of the antibodies for use herein or the methods herein, the individual is selected to be administered the anti-CD38 antibody, pomalidomide, and dexamethasone based on having renal impairment. In some embodiments of the antibodies for use herein or the methods herein, the individual has less than about 60, less than about 50, or less than about 30 mL / min / 1.73 m 2 In some embodiments of the antibodies for use herein or methods herein, the individual has an estimated glomerular filtration rate (eGFR) of less than about 60, less than about 50, or less than about 30 mL / min / 1.73 m before the start of treatment. 2 creatinine clearance. In some embodiments of the antibodies for use herein or methods herein, the anti-CD38 antibody is administered at a dose of 10 mg / kg; pomalidomide is administered at a dose of 4 mg; and dexamethasone is administered at a dose of 40 mg, wherein the individual is less than 75 years of age, or dexamethasone is administered at a dose of 20 mg, wherein the individual is 75 years of age or older. In some embodiments of the antibodies for use herein or methods herein, the individual has received at least two prior therapies for multiple myeloma. In some embodiments of the antibodies for use herein or methods herein, at least one of the at least two prior therapies for multiple myeloma is lenalidomide. In some embodiments of the antibodies for use herein or methods herein, at least one of the two prior therapies is a proteasome inhibitor.

[0017] In some embodiments, the antibodies for use herein or methods herein extend the PFS of the individual by at least about 9 months. In some embodiments, the antibodies for use herein or methods herein extend the PFS of the individual by about 11.53 months. In some embodiments, the antibodies for use herein or methods herein extend the PFS of the individual by about 11.14 months. In some embodiments, the antibodies for use herein or methods herein extend the PFS of the individual by at least about 4.5 months relative to an individual with multiple myeloma who received a treatment comprising pomalidomide and dexamethasone without the anti-CD38 antibody.

[0018] In some embodiments, an individual receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone (e.g., according to the antibodies for use herein or the methods herein) achieves a response to the treatment more quickly than an individual with multiple myeloma who has received treatment including pomalidomide and dexamethasone but without an anti-CD38 antibody. In some embodiments, the individual achieves a renal response to the treatment (e.g., with the anti-CD38 antibody, pomalidomide, and dexamethasone (e.g., according to the antibodies for use herein or the methods herein)) more quickly than an individual with multiple myeloma who has received treatment including pomalidomide and dexamethasone but without an anti-CD38 antibody. In some embodiments, the renal response is a complete renal response. In some embodiments, the complete renal response lasts for at least 60 days.

[0019] In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region (V H ) and a light chain variable region (V L In some embodiments, the anti-CD38 antibody is isatuximab.

[0020] In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are administered in a first 28-day cycle, wherein the anti-CD38 antibody is administered on days 1, 8, 15, and 22 of the first 28-day cycle, pomalidomide is administered on each of days 1-21 of the first 28-day cycle, and dexamethasone is administered on days 1, 8, 15, and 22 of the first 28-day cycle. In some embodiments, the anti-CD38 antibody, pomalidomide, 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 on days 1 and 15 of the one or more 28-day cycles following the first 28-day cycle, pomalidomide is administered on each of days 1-21 of the one or more 28-day cycles following the first 28-day cycle, and dexamethasone is administered on days 1, 8, 15, and 22 of the one or more 28-day cycles following the first 28-day cycle. In some embodiments, pomalidomide and dexamethasone are administered before the anti-CD38 antibody on day 1 of the first 28-day cycle. In some embodiments, dexamethasone is administered before the anti-CD38 antibody on days 8, 15, and 22 of the first 28-day cycle, and wherein the anti-CD38 antibody is administered before pomalidomide on days 8 and 15 of the first 28-day cycle. In some embodiments, pomalidomide and dexamethasone are administered before the anti-CD38 antibody on day 1 of the one or more 28-day cycles after the first 28-day cycle. In some embodiments, dexamethasone is administered before the anti-CD38 antibody on day 15 of the one or more 28-day cycles after the first 28-day cycle, and wherein the anti-CD38 antibody is administered before pomalidomide. In some embodiments, the anti-CD38 antibody is administered intravenously. In some embodiments, pomalidomide is administered orally. In some embodiments, dexamethasone is administered orally. In some embodiments, dexamethasone is administered intravenously.

[0021] In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are administered in the first 28-day cycle. In some embodiments, the anti-CD38 antibody is administered once a week in the first 28-day cycle, pomalidomide is administered on day 21 of the first 28-day cycle, and dexamethasone is administered once a week in the first 28-day cycle. In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are further administered in one or more 28-day cycles after the first 28-day cycle. In some embodiments, the anti-CD38 antibody is administered once every other week in the one or more 28-day cycles after the first 28-day cycle, pomalidomide is administered on day 21 of the one or more 28-day cycles after the first 28-day cycle, and dexamethasone is administered once a week in the one or more 28-day cycles after the first 28-day cycle. In some embodiments, in the first 28-day cycle, pomalidomide and dexamethasone are administered before the anti-CD38 antibody. In some embodiments, dexamethasone is administered before the anti-CD38 antibody in the first 28-day cycle, and wherein the anti-CD38 antibody is administered before pomalidomide. In some embodiments, in the one or more 28-day cycles after the first 28-day cycle, pomalidomide and dexamethasone are administered before the anti-CD38 antibody. In some embodiments, in the one or more 28-day cycles after the first 28-day cycle, dexamethasone is administered before the anti-CD38 antibody, and wherein the anti-CD38 antibody is administered before pomalidomide. In some embodiments, the anti-CD38 antibody is administered intravenously. In some embodiments, pomalidomide is administered orally. In some embodiments, dexamethasone is administered orally. In some embodiments, dexamethasone is administered intravenously.

[0022] In some embodiments, the individual is refractory to the most recent prior therapy for multiple myeloma. In some embodiments, the most recent prior therapy is lenalidomide. In some embodiments, the most recent prior therapy is a proteasome inhibitor. In some embodiments according to any of the antibodies for use herein or methods herein, the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, and ixazomib. In some embodiments, lenalidomide and the proteasome inhibitor are administered in combination.

[0023] In some embodiments, the individual has chronic obstructive pulmonary disease (COPD). In some embodiments, the individual has asthma. In some embodiments, the individual has bronchospasm. In some embodiments, the individual has not received prior therapy with pomalidomide. In some embodiments, the individual has not received prior therapy with an anti-CD38 antibody. In some embodiments, the individual has not received prior therapy with daratumumab. In some embodiments, the individual has one or more cytogenetic abnormalities selected from the following: del(17p), t(4;14), and t(14;16). In some embodiments, the individual is at least 65 years old but less than 75 years old. In some embodiments, the individual is 75 years old or older. In some embodiments, the individual has received at least three prior therapies for multiple myeloma. In some embodiments, the individual is East Asian (e.g., a Japanese individual, a Korean individual, or a Chinese individual). In some embodiments, the individual is in stage III according to the International Staging System (ISS). In some embodiments, the individual is in stage III according to the Revised International Staging System (R-ISS). In some embodiments, the individual is in stage III after 10 -4 or less (e.g., where "10 -4 " means that in the patient's bone marrow sample, every 10 4 less than 1 tumor cell per bone marrow cell) within 10 days after treatment. -5 or less (e.g., where "10 -5 " means that in the patient's bone marrow sample, every 10 5 bone marrow cells with less than 1 tumor cell) or within 10 -6 or less (e.g., where "10 -6 " means that in the patient's bone marrow sample, every 10 6 In some embodiments, MRD is assessed by next generation sequencing (NGS). In some embodiments, MRD is assessed by next generation flow cytometry (NGF). Additionally or alternatively, in some embodiments, MRD is assessed by positron emission tomography-computed tomography (PET-CT) scanning.

[0024] A kit is provided comprising an anti-CD38 antibody for use in combination with pomalidomide and dexamethasone for treating an individual with multiple myeloma according to the methods or antibodies for use provided herein.

[0025] Also provided are liquid pharmaceutical formulations comprising isatuximab. In some embodiments, the pharmaceutical formulations herein comprise isatuximab at a concentration of 5-20 mg / ml; a buffer selected from histidine, acetate, and phosphate; and an excipient selected from sucrose and mannitol; and a non-ionic surfactant such as polysorbate 20 (PS20), polysorbate 80 (PS80), or poloxamer 188, wherein the pH of the pharmaceutical formulation is between about 5.5 to about 7.4. In some embodiments, the pharmaceutical formulation comprises about 20 mM histidine, about 10% (w / v) sucrose, about 0.2% (w / v) polysorbate 80, and about 20 mg / ml isatuximab, wherein the pH of the pharmaceutical formulation is about 6.0. BRIEF DESCRIPTION OF DRAWINGS

[0026] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0027] Figure 1 A schematic of the study design of the clinical trial described in Example 1 is provided. The IPd (experimental) arm included 154 patients. The Pd (control) arm included 153 patients.

[0028] Figure 2 A Kaplan-Meier plot of progression-free survival (PFS) of patients in the IPd arm (isatuximab + pomalidomide + dexamethasone) compared to the Pd arm (pomalidomide + dexamethasone) as assessed by the Independent Response Committee (IRC) is provided.

[0029] Figure 3 A Kaplan-Meier plot of progression-free survival (PFS) of patients in the IPd arm (isatuximab + pomalidomide + dexamethasone) compared to the Pd arm (pomalidomide + dexamethasone) as assessed by the investigator is provided.

[0030] Figure 4 A Kaplan-Meier plot of overall survival (OS) of patients in the IPd arm (isatuximab + pomalidomide + dexamethasone) compared to the Pd arm (pomalidomide + dexamethasone) is provided.

[0031] Figure 5 A forest plot showing subgroup analysis of PFS of patients in the IPd arm compared to the PD arm with various baseline characteristics (e.g., age, eGFR, prior lines of therapy, prior ASCT (autologous stem cell transplant), cytogenetic risk factors, etc.) is provided.

[0032] Figure 6A Kaplan-Meier plots of progression-free survival (PFS) for patients in the IPd group (isatuximab + pomalidomide + dexamethasone) who were minimal residual disease (MRD)-negative after the start of treatment, were MRD-positive but achieved a VGPR or better, achieved a PR, or achieved less than a PR are provided.

[0033] Figure 6B Kaplan-Meier plots of overall survival (OS) for patients in the IPd group (isatuximab + pomalidomide + dexamethasone) who were minimal residual disease (MRD)-negative after the start of treatment, were MRD-positive but achieved a VGPR or better, achieved a PR, or achieved less than a PR are provided.

[0034] Figure 7 The baseline eGFR was <50 mL / min / 1.73 m2 in the Isa-Pd group compared with the Pd group. 2 Durable C Renal (also called "sustained C Renal") is a complete renal response that lasts at least 60 days. DETAILED DESCRIPTION definition

[0035] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a molecule" optionally includes a combination of two or more such molecules, and so forth.

[0036] "Sustained response" refers to a persistent effect on preventing or delaying progression of a disease (e.g., multiple myeloma) and / or improving one or more response criteria after cessation of treatment. For example, the response to treatment for multiple myeloma can be measured according to the criteria 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 Table A below and Table B herein). In some embodiments, the duration of the sustained response is at least the same as the duration of treatment, e.g., at least 1.5 times, 2.0 times, 2.5 times, or 3.0 times the length of the duration of treatment. Table A Standard International Myeloma Working Group (IMWG) response criteria SPD, the sum of the products of the maximum perpendicular diameters of the measured lesions

[0037] The term "pharmaceutical formulation" refers to a preparation that is in a form that permits the biological activity of the active ingredient to be effective and does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered. Such formulations are sterile. A "pharmaceutically acceptable" excipient (vehicle, additive) is an excipient that can reasonably be administered to a mammalian subject to provide an effective dose of the active ingredient employed.

[0038] As used herein, the term "treatment" refers to a clinical intervention designed to change the natural course of the disease or cell (e.g., cancer cell) being treated during the course of clinical pathology. The desired therapeutic effect includes reducing the rate of disease progression, improving or alleviating the disease state, and alleviating or improving the prognosis. For example, if one or more symptoms associated with cancer are alleviated or eliminated, including but not limited to reducing the proliferation of cancer cells (or destroying cancer cells), reducing the symptoms caused by the disease, improving the quality of life of patients with the disease, reducing the dosage of other drugs required for treating the disease, and / or prolonging the survival of the individual, the individual is successfully "treated."

[0039] As used herein, "delaying the progression of a disease" means postponing, hindering, slowing, delaying, stabilizing, and / or postponing the development of a disease (e.g., cancer). This delay can be of varying lengths of time, depending on the medical history and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can actually encompass prevention, as the individual does not develop the disease. For example, the development of advanced cancers, such as metastases, can be delayed.

[0040] An "effective amount" is at least the minimum amount required to achieve a measurable improvement or prevention of a particular disorder. The effective amount herein can vary depending on factors such as the disease state, the patient's age, sex, and weight, and the ability of the antibody to elicit the desired response in the individual. An effective amount is also an amount in which the beneficial effects of the treatment outweigh any toxic or deleterious effects of the treatment. For prophylactic uses, beneficial or desired results include results such as: eliminating or reducing the risk of a disease, reducing the severity of a disease, or delaying the onset of a disease, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the progression of the disease. For therapeutic uses, beneficial or desired results include clinical results such as: reducing one or more symptoms caused by the disease, improving the quality of life of patients suffering from the disease, reducing the dosage of other drugs required to treat the disease, such as enhancing the effect of another drug via targeting, delaying the progression of the disease, and / or prolonging survival. In the case of cancer or tumors, an effective amount of a drug can have the following effects: reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing down or desirably stopping to some extent) cancer cell infiltration into peripheral organs; inhibiting (i.e., slowing down and desirably stopping to some extent) tumor metastasis; inhibiting tumor growth to some extent; and / or alleviating to some extent one or more symptoms associated with the disorder. An effective amount can be administered in one or more administrations. For the purposes of the present invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve, directly or indirectly, a preventive or therapeutic treatment. As understood in the clinical setting, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" can be considered in the context of administering one or more therapeutic agents, and a single agent can be considered to be administered in an effective amount if the desired result can or is achieved in combination with one or more other agents.

[0041] As used herein, the term "in combination with" refers to administering one therapeutic modality in addition to another therapeutic modality. Thus, "in combination with" refers to administering one therapeutic modality before, during, or after administering another therapeutic modality to an individual.

[0042] A "subject" or "individual" for therapeutic purposes refers to any animal classified as a mammal, including humans, livestock and farm animals, and zoo, sports or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal is a human.

[0043] The term "antibody" herein is used in the broadest sense and specifically covers monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies), and antibody fragments so long as they exhibit the desired biological activity.

[0044] Human light chains are generally classified as kappa and lambda light chains, and human heavy chains are generally classified as μ, δ, γ, α or ε, and the isotype of the antibody is defined as IgM, IgD, IgG, IgA and IgE, respectively. IgG has several subclasses, including but not limited to IgG1, IgG2, IgG3 and IgG4. IgM has multiple subclasses, including but not limited to IgM1 and IgM2. IgA is similarly subdivided into multiple subclasses, including but not limited to IgA1 and IgA2. Within the full-length light and heavy chains, the variable domains and constant domains are generally joined by a "J" region of about 12 or more amino acids, and the heavy chain also includes a "D" region of about 10 or more amino acids. See, for example, Fundamental Immunology (Paul, W., ed., Raven Press, 2nd edition, 1989), which is incorporated by reference in its entirety for all purposes. The variable region of each light / heavy chain pair generally forms an antigen binding site. The variable domains of antibodies typically exhibit the same overall structure of relatively conserved framework regions (FRs) joined by three hypervariable regions (also referred to as complementary determining regions or CDRs). The CDRs from the two chains of each pair are typically aligned by the framework regions, which can enable binding to specific epitopes. From amino terminus to carboxyl terminus, both the light and heavy chain variable domains typically comprise, in sequence, the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0045] The term "CDR set" refers to a group of three CDRs present in a single variable region capable of binding to an antigen. The exact boundaries of these CDRs have been defined in different ways according to different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Maryland (1987) and (1991)) not only provides a clear residue numbering system applicable to any variable region of an antibody, but also provides the exact residue boundaries that define the three CDRs. These CDRs may be referred to as Kabat CDRs.

[0046] As used herein, the term "Fc" refers to the sequence (whether in monomeric or multimeric form) of the non-antigen binding fragment produced by antibody digestion or produced by other means, and may contain a hinge region. The original immunoglobulin source of native Fc is preferably human-derived, and may be any immunoglobulin. The Fc molecule is composed of monomeric polypeptides that can be connected into dimer or multimeric form by covalent (i.e., disulfide bond) and non-covalent association. Depending on classification (e.g., IgG, IgA, and IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgA1, IgGA2, and IgG4), the number of intermolecular disulfide bonds between the monomer subunits of native Fc molecules ranges from 1 to 4. An example of Fc is the disulfide-bonded dimer produced by papain digestion of IgG. As used herein, the term "native Fc" is universal for monomers, dimers, and multimeric forms.

[0047] As used herein, the term "overall response rate" or "ORR" refers to the proportion of patients with a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) as assessed 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. Overview

[0048] Provided herein are methods for treating multiple myeloma or delaying the progression of an individual who has received at least two prior therapies for multiple myeloma, or antibodies for the purposes of the invention. Provided herein are methods or antibodies for the purposes of the invention, including administering an effective amount of an anti-CD38 antibody (e.g., isatuximab), pomalidomide, and dexamethasone to the individual. In some embodiments, the treatment extends the progression-free survival (PFS) and / or overall survival (OS) of the individual. In some embodiments, the individual is minimal residual disease (MRD) negative after treatment. In some embodiments, the treatment extends the progression-free survival (PFS) and / or overall survival (OS) of the individual compared to treatment including administering pomalidomide and dexamethasone without the anti-CD38 antibody (e.g., isatuximab). In some embodiments, the treatment improves renal impairment. Also provided are methods or antibodies for use in improving the renal impairment of an individual with multiple myeloma. anti-CD38 antibody

[0049] In some embodiments, the anti-CD38 antibody binds to human CD38. In some embodiments, the anti-CD38 antibody is a human antibody, a humanized antibody, or a chimeric antibody. In some embodiments, the anti-CD38 antibody comprises (a) a heavy chain variable domain (V H ): 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 ): 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 ), said amino acid sequence being at least 90% identical to SEQ ID NO: 7 (e.g., at least any of 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99%, inclusive). Additionally or alternatively, in some embodiments, the anti-CD38 antibody comprises a light chain variable domain (V L), said amino acid sequence being at least 90% identical (e.g., at least any of 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99%, including any ranges therebetween) to SEQ ID NO: 8 or SEQ ID NO: 9. In some embodiments, the anti-CD38 antibody comprises a V comprising SEQ ID NO: 7. H and V containing SEQ ID NO: 8 or SEQ ID NO: 9 L .

[0050] In some embodiments, the anti-CD38 antibody is isatuximab (CAS Reg. No. 1461640-62-9). Isatuximab (also known as hu38SB19 and SAR650984) is an anti-CD38 antibody described in WO 2008 / 047242 and U.S. Pat. No. 8,153,765, the contents of both of which are incorporated herein by reference in their entirety.

[0051] The heavy chain of isatuximab comprises the amino acid sequence: And the light chain of isatuximab comprises the amino acid sequence:

[0052] The anti-CD38 antibody can be produced using recombinant methods. For recombinant production of an anti-antigen antibody, the nucleic acid encoding the antibody is isolated and inserted into a replicable vector for further cloning (amplification of the DNA) or for expression. DNA encoding the antibody is readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are specific to the genes of 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 a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. The vector is typically transformed into a host cell suitable for nucleic acid expression. In some embodiments, the host cell is a eukaryotic or prokaryotic cell. In some embodiments, the eukaryotic host cell is a mammalian cell. Examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); 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)); monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat 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 a 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, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, N.J., 2003), pp. 255-268.The anti-CD38 antibodies prepared from cells can be purified using, for example, hydroxyapatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being one of the typical preferred purification steps. Generally, various methods for preparing antibodies for use in research, testing, and clinical applications are well established in the art and are consistent with the methods described above and / or deemed appropriate by those skilled in the art. Pomalidomide

[0053] The chemical name of pomalidomide is 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, and pomalidomide has the following chemical structure

[0054] The molecular formula of pomalidomide is C 13 H 11 N3O4, and has a molecular weight of 273.24 g / mol. Pomalidomide is commercially available as POMALYST, POMALID, IMNOVID, etc. Dexamethasone

[0055] The chemical name of dexamethasone is 1-dehydro-16α-methyl-9α-fludrocortisone, and dexamethasone has the following chemical structure:

[0056] The molecular formula of dexamethasone is C 22 H 29 FO5, and a molecular weight of 392.461 g / mol. Dexamethasone is commercially available as a formulation for oral and intravenous administration. Exemplary trade names for dexamethasone include, for example, DECADRON, MAXIDEX, HEXADROL, DEXACORT, DEXASONE, ORADEXON, SUPERPREDNOL, DEXALONA, and the like. Pharmaceutical compositions and formulations

[0057] Also provided herein are pharmaceutical compositions and formulations, for example, for the treatment of multiple myeloma (such as refractory multiple myeloma or relapsed and refractory multiple myeloma), comprising anti-CD38 antibodies (such as isatuximab), pomalidomide, or dexamethasone. In some embodiments, each of the anti-CD38 antibodies (e.g., isatuximab), pomalidomide, and dexamethasone is provided as a separate pharmaceutical composition. In some embodiments, the pharmaceutical compositions and formulations further comprise a pharmaceutically acceptable carrier and / or a pharmaceutically acceptable excipient. Suitable excipients (including nonionic surfactants such as PS80) are described in the pharmacopeias of the United States and EP (USP and PhEu, respectively) and in the 2015 Chinese Pharmacopoeia (ChP, which describes, for example, polysorbate 80 for injection).

[0058] In some embodiments, the pharmaceutical formulations provided herein comprise isatuximab at a concentration of 5-20 mg / ml; a buffer selected from histidine, acetate, and phosphate; and an excipient selected from sucrose and mannitol; and 0.001%-0.03% nonionic surfactant (such as PS20, PS80, or poloxamer 188), wherein the pH of the pharmaceutical formulation is between about 5.5 and about 7.4. In some embodiments, the pharmaceutical formulation comprises 5 mg / ml isatuximab, 10 mM histidine or 10 mM acetate, 10% (w / v) sucrose or 5% mannitol, and 0.001%, 0.005%, or 0.01% (w / v) nonionic surfactant, wherein the pH of the pharmaceutical formulation is about 6.0 or about 6.5. In some embodiments, the pharmaceutical formulation comprises 5 mg / ml isatuximab, 10 mM histidine, 10% (w / v) sucrose, and 0.005% (w / v) PS80, and the pH of the pharmaceutical formulation is about 6.0 or about 6.5. In some embodiments, the nonionic surfactant is PS80.

[0059] In some embodiments, the anti-CD38 antibodies described herein (such as isatuximab) are in a pharmaceutical formulation comprising about 20 mg / mL antibody, about 20 mM histidine, about 10% (w / v) sucrose, and about 0.02% (w / v) nonionic surfactant (such as PS20, PS80, or poloxamer 188), wherein the pH of the pharmaceutical formulation is about 6.0. In some embodiments, the anti-CD38 antibodies described herein (such as isatuximab) are in a pharmaceutical formulation comprising about 20 mg / mL antibody, about 100 mg / mL sucrose, 2.22 mg / mL histidine hydrochloride monohydrate, about 1.46 mg / ml histidine, and about 0.2 mg / ml nonionic surfactant. In some embodiments, the nonionic surfactant is PS80.

[0060] In some embodiments, the pharmaceutical preparation comprises water for injection (WFI), such as sterile water for injection (SWFI). In some embodiments, the pharmaceutical preparation is sterile. In some embodiments, the single use of the preparation includes 5ml of the pharmaceutical preparation (i.e., 100mg anti-CD38 antibodies). In some embodiments, the single use 5ml pharmaceutical preparation is provided in, for example, a type 6mL colorless transparent glass bottle equipped with an elastomeric closure. In some embodiments, the fill volume of the bottle has been established to ensure that 5mL is taken out. In some embodiments, the fill volume is 5.4mL. In some embodiments, the single use of the preparation includes 25ml of the pharmaceutical preparation (i.e., 500mg anti-CD38 antibodies). In some embodiments, the single use 25ml pharmaceutical preparation is provided in, for example, a 30mL colorless transparent glass bottle equipped with an elastomeric closure. In some embodiments, the fill volume of the bottle has been established to ensure that 25mL is taken out. In some embodiments, the pharmaceutical formulation is stable at a temperature between about 2 ° C and about 8 ° C and protected from light for at least about 6, 12, 18, 24, 30 or 36 months, including any range between these values. In some embodiments, the pharmaceutical formulation is diluted for infusion in 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 between about 2 ° C and about 8 ° C, including any range between these values. In some embodiments, the dilution solution for infusion is stable for another 8 hours (for example, including the infusion time) at room temperature after storage between about 2 ° C and about 8 ° C. In some embodiments, the dilution solution for infusion is stable in the presence of light. In some embodiments, the bag in which the dilution solution for infusion is diluted is made of polyolefin (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) and diethylhexyl phthalate (DEHP) or ethylene-vinyl acetate (EVA). In some embodiments, the tubing used for infusion is made of PE, PVC (with or without DEHP), polybutadiene (PBD), or polyurethane (PU) with an inline filter (polyethersulfone (PES), polysulfone, or nylon).

[0061] Pharmaceutical formulations of pomalidomide and dexamethasone are commercially available. For example, pomalidomide is available under various trade names (as described elsewhere herein), including ) is known. Dexamethasone is known under various trade names (as described elsewhere herein), including DECADRON, MAXIDEX, and HEXADROL. In some embodiments, pomalidomide and / or dexamethasone are provided in separate containers. In some embodiments, pomalidomide and / or dexamethasone are each used and / or prepared for administration to an individual as described in the prescribing information available with the commercially available products. Methods of treatment and antibodies for use in treatment

[0062] Provided herein are methods and antibodies for use in treating or delaying progression of multiple myeloma (e.g., relapsed multiple myeloma or relapsed and refractory multiple myeloma) in an individual (e.g., a human individual), comprising administering to the individual an effective amount of an anti-CD38 antibody (e.g., 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): an anti-CD38 antibody comprising a CDR-L1 comprising the amino acid sequence KA SQDVSTVVA (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), pomalidomide, and dexamethasone, wherein the individual has received at least two prior therapies for multiple myeloma (e.g., lenalidomide and a proteasome inhibitor). In some embodiments, administration of an anti-CD38 antibody as described herein, pomalidomide, and dexamethasone results in a sustained response in the individual. In some embodiments, administration of an anti-CD38 antibody as described herein, pomalidomide, and dexamethasone prolongs progression-free survival (PFS) of the individual. In some embodiments, administration of an anti-CD38 antibody as described herein, pomalidomide, and dexamethasone prolongs overall survival (OS) of the individual. In some embodiments, the administration of anti-CD38 antibodies, pomalidomide and dexamethasone as described herein results in lower minimal residual disease (MRD). In some embodiments, the individual is MRD negative after the administration of anti-CD38 antibodies, pomalidomide and dexamethasone as described herein. In some embodiments, before the administration of anti-CD38 antibodies, pomalidomide and dexamethasone as described herein, the individual exhibits renal impairment. In some embodiments, the administration of anti-CD38 antibodies, pomalidomide and dexamethasone as described herein improves the renal function of the individual. In some embodiments, the individual is an adult, for example, at least 18 years old.

[0063] Provided herein are methods or antibodies for use in ameliorating renal impairment in an individual (e.g., a human individual) with multiple myeloma, comprising administering to the individual an effective amount of an anti-CD38 antibody comprising (a) a heavy chain variable domain (V H ): 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): 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 individual with multiple myeloma is selected to be administered the anti-CD38 antibody, pomalidomide, and dexamethasone based on having renal impairment. In some embodiments, the individual with multiple myeloma and renal impairment has a poor prognosis. In some embodiments, the individual is an adult, e.g., at least 18 years old. In some embodiments, if the individual has a renal impairment of less than about 90 mL / min / 1.73 m 2 In some embodiments, the individual has renal impairment if the individual has an estimated glomerular filtration rate (eGFR) of about 60 mL / min / 1.73 m before the start of treatment. 2 and less than about 90mL / min / 1.73m 2 In some embodiments, the individual has renal impairment if the estimated glomerular filtration rate (eGFR) is between about 60 mL / min / 1.73 m 2 and less than about 90mL / min / 1.73m 2 In some embodiments, if the individual has a renal impairment of about 30 mL / min / 1.73 m before the start of treatment, 2 and less than about 60mL / min / 1.73m 2 In some embodiments, the individual has renal impairment if the estimated glomerular filtration rate (eGFR) is between about 30 mL / min / 1.73 m 2 and less than about 60mL / min / 1.73m 2 between (e.g., such as less than about 30, less than about 50, or less than about 60 mL / min / 1.73 m 2 ) have moderate renal impairment. In some embodiments, if the individual has less than about 30 mL / min / 1.73 m 2 In some embodiments, the individual has renal impairment if the estimated glomerular filtration rate (eGFR) is less than about 30 mL / min / 1.73 m before treatment is started. 2 In some embodiments, if the individual has less than about 90 mL / min / 1.73 m 2In some embodiments, if the individual has a creatinine clearance of about 60 mL / min / 1.73 m before the start of treatment, the individual has renal impairment. 2 and less than about 90mL / min / 1.73m 2 In some embodiments, the creatinine clearance is between about 60 mL / min / 1.73 m before the start of treatment. 2 and less than about 90mL / min / 1.73m 2 In some embodiments, if the individual has a renal impairment of about 30 mL / min / 1.73 m before the start of treatment, 2 and less than about 60mL / min / 1.73m 2 In some embodiments, the creatinine clearance is between about 30 mL / min / 1.73 m before the start of treatment. 2 and less than about 60mL / min / 1.73m 2 between (e.g., such as less than about 50 or less than about 60 mL / min / 1.73 m 2 ) have moderate renal impairment. In some embodiments, if the individual has less than about 30 mL / min / 1.73 m 2 In some embodiments, the creatinine clearance is less than about 30 mL / min / 1.73 m before the start of treatment. 2 The individual has severe renal impairment. In some embodiments, the individual achieves a renal response after initiating treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual achieves a complete renal response after initiating treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, a complete renal response is characterized by a decrease in baseline eGFR or creatinine clearance from <50 mL / min / 1.73 m2 before the start of treatment. 2 ≥60 mL / min / 1.73 m2 at least once during treatment 2 In some embodiments, the subject achieves a sustained complete renal response after the start of treatment. A sustained complete renal response is also referred to as a "durable complete renal response." In some embodiments, a sustained complete renal response (or "durable complete renal response") is characterized by an improvement in eGFR or creatinine clearance from baseline to <50 mL / min / 1.73 m2 before the start of treatment. 2 to ≥ 60 mL / min / 1.73 m for at least approximately 60 days 2In some embodiments, the time to first renal response in individuals receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is shorter than the time to first renal response in individuals receiving treatment with pomalidomide and dexamethasone. In some embodiments, "time to first renal response" refers to the duration between the date of the first dose of treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone and the date of the first sign of a renal response. In some embodiments, the time to complete renal response in individuals receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is any of about 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, or 16 weeks from the start of treatment, including any ranges between these values. In some embodiments, the time to complete renal response in individuals receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is about 1, 1.5, 2, 2.5, 3, 3.5, 3.6, 3.7, 3.8, 3.9, or 4 weeks less than the time to complete renal response in individuals receiving treatment with pomalidomide and dexamethasone but not the anti-CD38 antibody. In some embodiments, the time to sustained complete renal response (also referred to as a "durable complete renal response") in individuals receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is about 1, 1.5, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3 weeks from the start of treatment, including any ranges between these values. In some embodiments, the time to complete renal response in individuals receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is less than about 1, 1.5, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3 weeks, including any ranges in between these values, compared to the time to complete renal response in individuals receiving treatment with pomalidomide and dexamethasone but without the anti-CD38 antibody.

[0064] In some embodiments, treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone according to the methods provided herein or the antibodies for such uses prevents or delays end-stage renal disease (ESRD) in the individual. In some embodiments, individuals receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone have a lower probability of developing ESRD than individuals receiving treatment with pomalidomide and dexamethasone but not the anti-CD38 antibody. In some embodiments, ESRD is delayed in an individual receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone according to the methods or uses provided herein by at least about any of 1, 2, 3, or 4 weeks; at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 42, or 48 months; or longer than 48 months (e.g., such as about any of 4.5, 5, 5.5, or 6 years), including any ranges therebetween, in comparison to an individual receiving treatment with pomalidomide and dexamethasone without the anti-CD38 antibody.

[0065] In some embodiments, provided herein are methods or antibodies for use thereof extend the progression-free survival (PFS) of the individual. In some embodiments, provided herein are methods or antibodies for use thereof extend the overall survival (OS) of the individual. In some embodiments, the individual is minimal residual disease (MRD) negative after treatment (e.g., with the anti-CD38 antibodies, pomalidomide and dexamethasone). In some embodiments, the individual has received at least two prior therapies (or prior therapy lines) for multiple myeloma (e.g., such as lenalidomide and proteasome inhibitors).

[0066] In some embodiments, the individual exhibits disease progression during the most recent prior therapy (or line of therapy), e.g., the therapy (or line of therapy) immediately prior to the start of treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual exhibits disease progression (PD) within 60 days after the end of the most recent prior therapy (or line of therapy) for multiple myeloma, e.g., the therapy (or line of therapy) immediately prior to the start of treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, disease progression (PD) is defined according to the International Myeloma Working Group 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; Durie et al. (2006) “International uniform response criteria for multiple myeloma.” myeloma.Leukemia.20:1467-1473; and Tables A and B herein. In some embodiments, a line of therapy is ≥1 complete cycle of a single agent or a combination of two or more agents, or a planned sequential therapy including stem cell transplantation. In some embodiments, a given treatment is considered a new line of therapy if a new line of therapy is started after interrupting a prior line. In some embodiments, a treatment is considered a new line of therapy if a treatment regimen is interrupted for any reason and a different treatment regimen is started. In some embodiments, a given treatment regimen is considered interrupted if all drugs in the regimen have been stopped. In some embodiments, a regimen is not considered interrupted if some (but not all) drugs of the regimen have been interrupted. . In some embodiments, the reason for the interruption, addition, substitution or SCT (stem cell transplant) does not affect the way the lines are counted. In some embodiments, a given treatment is considered a new line of therapy if there is already an unplanned addition or substitution of one or more drugs in the existing regimen. In some embodiments, in individuals who have undergone >1 SCT, each SCT (autologous or allogeneic) can be considered a new line of therapy, except in the case of planned tandem SCT with predetermined intervals (such as 3 months), regardless of whether the conditioning regimen used is the same or different. In some embodiments, planned tandem SCT is considered 1 line. In some embodiments, planned induction and / or consolidation, maintenance with any SCT (first-line, relapse, autologous or allogeneic) is considered 1 line of therapy.

[0067] In some embodiments, the multiple myeloma is difficult to treat. In some embodiments, the individual has refractory multiple myeloma. In some embodiments, the individual with refractory multiple myeloma is an individual who is refractory to all previous therapies (or previous lines of therapy), but has achieved at least a minimal response (MR) to one previous therapy (or line of therapy). In some embodiments, minimal response (MR) is defined according to the International Myeloma Working Group 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; Durie et al. (2006) “International uniform response criteria for multiple myeloma.Leukemia.20:1467-1473; and Tables A and B herein). In some embodiments, an individual with refractory multiple myeloma is an individual who has not responded to a previous therapy (or a previous line of therapy). In some embodiments, being “unresponsive” to a therapy (or line of therapy) for multiple myeloma means that the individual has failed to achieve at least a minimal response (MR) to the therapy (or line of therapy) for multiple myeloma. In some embodiments, being “unresponsive” to a therapy (or line of therapy) for multiple myeloma means that the individual has exhibited disease progression during the therapy (or line of therapy) for multiple myeloma. In some embodiments, an individual with refractory multiple myeloma is an individual who has exhibited disease progression within 60 days of the end of the last therapy for multiple myeloma.

[0068] In some embodiments, the individual has failed a prior treatment for multiple myeloma (e.g., treatment with lenalidomide and / or a proteasome inhibitor). In some embodiments, "failure" of a prior treatment means that the individual has exhibited disease progression (e.g., according to the criteria in Tables A and B) while on treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor) or within 60 days of the end of treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor). In some embodiments, "failure" of a prior treatment for multiple myeloma means that the individual exhibited a partial response (PR) or better (e.g., according to the criteria in Tables A and B) to treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor), but exhibited disease progression within 6 months after discontinuing treatment (e.g., treatment with lenalidomide and / or a proteasome inhibitor). In some embodiments, "failure" of a prior treatment for multiple myeloma means that the individual developed toxicity / intolerance after at least 2 consecutive cycles of a treatment regimen (e.g., a treatment regimen containing lenalidomide and / or a proteasome inhibitor (bortezomib, carfilzomib, ixazomib, marizomib, oprozomib, etc.). In some embodiments, intolerance to a proteasome-containing regimen means that the individual (e.g., an individual who did not have peripheral neuropathy prior to starting the regimen) develops peripheral neuropathy or neuropathic pain, for example, during or after treatment with a proteasome-containing regimen. In some embodiments, intolerance to a lenalidomide-containing regimen means that the individual develops a severe rash during or after treatment with a lenalidomide-containing regimen.

[0069] In some embodiments, the individual has relapsed and 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 as measured using serum protein immunoelectrophoresis and / or urine M-protein ≥ 200 mg / 24 hours as measured using urine protein immunoelectrophoresis and / or serum free light chains (FLC) (i.e., FLC assay ≥ 10 mg / dl (≥ 100 mg / L) and an abnormal serum FLC ratio (< 0.26 or > 1.65). In some embodiments, the individual with relapsed and refractory multiple myeloma is a relapsed patient who has relapsed from at least one prior therapy (or line of therapy) for multiple myeloma and is refractory to the most recent therapy. In some embodiments, the individual with relapsed and refractory multiple myeloma is an individual who has relapsed from at least one previous therapy (or line of therapy) for multiple myeloma, is refractory to the most recent therapy (or line of therapy) for multiple myeloma, and is refractory to one or more therapies (or lines of therapy) prior to the most recent therapy (or line of therapy) for multiple myeloma. In some embodiments, the individual with relapsed or refractory multiple myeloma is an individual who has demonstrated disease progression within 60 days of the end of the most recent therapy (or line of therapy).

[0070] In some embodiments, the individual is refractory to the most recent prior therapy (or line of therapy).

[0071] In some embodiments, the individual has relapsed / refractory multiple myeloma (RRMM) with measurable disease (e.g., serum M-protein ≥ 0.5 g / dL as measured by serum protein immunoelectrophoresis and / or urine M-protein ≥ 200 mg / 24 hours as measured by urine protein immunoelectrophoresis), has received at least two prior therapies including lenalidomide and a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, marizomib, oprozomib, etc.), and is refractory to the last line of therapy (i.e., the most recent line of therapy). In some embodiments, the individual has adequate renal, liver, and bone marrow function.

[0072] In some embodiments, the individual has a poor prognosis. In some embodiments of the methods provided herein or antibodies for such use, the individual has received at least one, at least two, at least three, at least four prior therapies (or prior therapy lines), or more than four prior therapies (or prior therapy lines), such as any of at least 5, 6, 7, 8, 9, 10, or 11 prior therapies (or prior therapy lines), for multiple myeloma.

[0073] In some embodiments, the individual has experienced at least one prior therapy (or prior therapy line) with lenalidomide. In some embodiments, the prior lenalidomide therapy (or prior lenalidomide therapy line) includes at least two consecutive cycles of lenalidomide. In some embodiments, the individual has experienced failure (e.g., no response) to the prior lenalidomide therapy (or prior lenalidomide therapy line). In some embodiments, the individual who has experienced failure to the prior lenalidomide therapy (or prior lenalidomide therapy line) did not achieve at least a minimal response (MR) during the therapy (or therapy line) with lenalidomide. In some embodiments, the individual who has experienced failure to the prior lenalidomide therapy (or prior lenalidomide therapy line) exhibits disease progression (PD) during the therapy (or therapy line) with lenalidomide. As mentioned elsewhere herein, in some embodiments, the method is based on 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: "Minimal response" and "disease progression" are evaluated by the criteria in 1467-1473 (see also Table A and Table B herein). In some embodiments, lenalidomide is previously administered during the first, second, third, fourth, fifth, sixth and / or later therapy (or therapy line) for multiple myeloma (i.e., before treatment with an anti-CD38 antibody, pomalidomide and dexamethasone according to the methods provided herein or the antibody for the purposes). In some embodiments, the individual is refractory to lenalidomide. In some embodiments, lenalidomide is previously administered to the individual as a single agent. In some embodiments, lenalidomide is previously administered to the individual in combination with at least one additional agent.

[0074] In some embodiments, the individual has experienced at least one prior therapy (or at least one prior therapy line) with a proteasome inhibitor (PI). In some embodiments, the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, ixazomib, marizomib, and oprozomib. In some embodiments, the prior therapy (or prior therapy line) with the proteasome inhibitor includes at least two consecutive cycles of the proteasome inhibitor. In some embodiments, the individual has experienced failure (e.g., no response) to the prior proteasome inhibitor therapy (or prior proteasome inhibitor therapy line). In some embodiments, the individual who has experienced failure in the prior therapy (or therapy line) with the proteasome inhibitor did not achieve at least a minimal response (MR) during therapy (or therapy line) with the proteasome inhibitor. In some embodiments, the individual who has experienced failure in the prior therapy (or therapy line) with the proteasome inhibitor exhibited progressive disease (PD) during therapy (or therapy line) with the proteasome inhibitor. In some embodiments, the prior proteasome inhibitor therapy is administered during a first, second, third, fourth, fifth, sixth, and / or subsequent therapy (or line of therapy) for multiple myeloma (i.e., prior to treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone according to the methods or antibodies for use provided herein). In some embodiments, the individual is refractory to the proteasome inhibitor (e.g., one or more proteasome inhibitors). In some embodiments, the prior proteasome inhibitor therapy (or prior line of proteasome inhibitor therapy) is administered to the individual as a single agent. In some embodiments, the prior proteasome inhibitor therapy (or prior line of proteasome inhibitor therapy) is administered to the individual in combination with at least one additional agent.

[0075] In some embodiments, lenalidomide and the proteasome inhibitor are administered to the individual in combination. In some embodiments, the individual previously achieved a partial response (PR) or greater to lenalidomide and / or the proteasome inhibitor (e.g., administered alone or in combination), but exhibits progressive disease (PD) within 6 months of the end of therapy (or end of a line of therapy) with lenalidomide and / or the proteasome inhibitor.

[0076] In some embodiments, the individual is East Asian. In some embodiments, the East Asian individual is a Japanese individual, a Korean individual, or a Chinese individual.

[0077] In some embodiments, the individual has chronic obstructive pulmonary disease (COPD). In some embodiments, the individual was diagnosed with COPD before starting treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual develops and / or is diagnosed with COPD after starting treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone.

[0078] In some embodiments, the individual has asthma. In some embodiments, the individual was diagnosed with asthma before starting treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual develops and / or is diagnosed with asthma after starting treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone.

[0079] In some embodiments, the individual suffers from (e.g., experiences) bronchospasm. In some embodiments, the individual experienced bronchospasm before starting treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual developed bronchospasm after starting treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone.

[0080] In some embodiments, the bone marrow plasma cells of an individual receiving treatment according to the methods provided herein or the antibodies for use thereof have a CD38 receptor density of between about 13,000 and about 340,000 receptors per cancer cell. In some embodiments, the individual receiving treatment according to the methods provided herein or the antibodies for use thereof is heterozygous for the F158V single nucleotide polymorphism in the FCGR3A gene. In some embodiments, the individual receiving treatment according to the methods provided herein or the antibodies for use thereof is homozygous for the F158V single nucleotide polymorphism in the FCGR3A gene. In some embodiments, the individual receiving treatment according to the methods provided herein or the antibodies for use thereof does not have the F158V single nucleotide polymorphism in the FCGR3A gene.

[0081] In some embodiments, the individual does not have primary refractory multiple myeloma. In some embodiments, the individual with primary refractory multiple myeloma is an individual who has never achieved at least a minimal response (MR) under any therapy (or therapy line) during the course of the disease. In some embodiments, the individual does not have measurable disease with only free light chains (FLC). In some embodiments, the individual has not received prior treatment with an anti-CD38 antibody. In some embodiments, the individual has received prior treatment with an anti-CD38 antibody (e.g., daratumumab). In some embodiments, the individual has not received prior therapy (or prior therapy line) with isatuximab. In some embodiments, the individual did not exhibit disease progression (PD) during prior therapy (or prior therapy line) with an anti-CD38 antibody. In some embodiments, the individual did not exhibit PD within 60 days after the end of therapy (or therapy line) with an anti-CD38 antibody. In some embodiments, the individual has not received prior therapy (or prior therapy line) with pomalidomide. In some embodiments, the individual has received prior therapy (or prior line of therapy) with pomalidomide. In some embodiments, the individual has not received prior allogeneic hematopoietic stem cell transplantation.

[0082] In some embodiments, treatment comprises administering the anti-CD38 antibody at a dose of 10 mg / kg; administering pomalidomide at a dose of 4 mg; and administering dexamethasone at a dose of 40 mg (i.e., if the individual is under 75 years of age), or administering dexamethasone at a dose of 20 mg (i.e., if the individual is 75 years of age or older). In some embodiments, the anti-CD38 antibody (such as isatuximab) is administered intravenously. In some embodiments, pomalidomide is administered orally. In some embodiments, dexamethasone is administered intravenously or orally.

[0083] In some embodiments, the treatment comprises administering the anti-CD38 antibody, pomalidomide, and dexamethasone to the individual in 28-day cycles. In some embodiments, 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 (i.e., cycle 1), pomalidomide is administered at a dose of 4 mg on each of days 1-21 of the first 28-day cycle (i.e., cycle 1), and dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of the first 28-day cycle (i.e., cycle 1) if the individual is below 75 years of age, or dexamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 of the first 28-day cycle (i.e., cycle 1) if the individual is 75 years of age or older. In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are administered sequentially on days 1, 8, and 15 of the first 28-day cycle (i.e., cycle 1). In some embodiments, pomalidomide and dexamethasone are administered prior to the anti-CD38 antibody on day 1 of the first 28-day cycle (i.e., cycle 1). In some embodiments, dexamethasone is administered prior to the anti-CD38 antibody and the anti-CD38 antibody is administered prior to pomalidomide on days 8 and 15 of the first 28-day cycle (i.e., cycle 1).

[0084] In some embodiments, the treatment comprises administering the anti-CD38 antibody, pomalidomide, and dexamethasone in one or more 28-day cycles following the first 28-day cycle (i.e., Cycle 1). In some embodiments, the anti-CD38 antibody is administered at a dose of 10 mg / kg on days 1 and 15 of each cycle after Cycle 1 (e.g., Cycle 2, 3, 4, etc.), pomalidomide is administered at a dose of 4 mg on each of days 1-21 of each cycle after Cycle 1 (e.g., Cycle 2, 3, 4, etc.), and dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of each cycle after Cycle 1 (e.g., Cycle 2, 3, 4, etc.) if the individual is under 75 years of age, or at a dose of 20 mg on days 1, 8, 15, and 22 of each cycle after Cycle 1 (e.g., Cycle 2, 3, 4, etc.) if the individual is 75 years of age or older. In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are administered sequentially on days 1 and 15 of each cycle (e.g., cycle 2, 3, 4, etc.) after cycle 1. In some embodiments, pomalidomide and dexamethasone are administered before the anti-CD38 antibody on day 1 of each 28-day cycle (e.g., cycle 2, 3, 4, etc.) after cycle 1. In some embodiments, dexamethasone is administered before the anti-CD38 antibody on day 15 of each 28-day cycle (e.g., cycle 2, 3, 4, etc.) after cycle 1, and the anti-CD38 antibody is administered before pomalidomide.

[0085] In some embodiments, the treatment includes administering the anti-CD38 antibody, pomalidomide, and dexamethasone to the individual in a 28-day cycle. In some embodiments, the anti-CD38 antibody is administered once per week in the first 28-day cycle (i.e., the 1st cycle) at a dose of 10 mg / kg, pomalidomide is administered at a dose of 4 mg for 21 days of the first 28-day cycle (i.e., the 1st cycle), and if the individual is under 75 years old, dexamethasone is administered once per week in the first 28-day cycle (i.e., the 1st cycle), or if the individual is 75 years old or older, dexamethasone is administered once per week in the first 28-day cycle (i.e., the 1st cycle) at a dose of 20 mg. In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are administered sequentially in the first 28-day cycle (i.e., the 1st cycle). In some embodiments, pomalidomide and dexamethasone are administered before the anti-CD38 antibody in the first 28-day cycle (i.e., Cycle 1). In some embodiments, dexamethasone is administered before the anti-CD38 antibody, and the anti-CD38 antibody is administered before pomalidomide on days 8 and 15 of the first 28-day cycle (i.e., Cycle 1).

[0086] In some embodiments, the treatment comprises administering the anti-CD38 antibody, pomalidomide, and dexamethasone in one or more 28-day cycles following the first 28-day cycle (i.e., cycle 1). In some embodiments, the anti-CD38 antibody is administered once every other week in each 28-day cycle following cycle 1 (e.g., cycles 2, 3, 4, etc.), pomalidomide is administered on day 21 of each 28-day cycle following cycle 1 (e.g., cycles 2, 3, 4, etc.), and if the individual is under 75 years of age, dexamethasone is administered once weekly in each 28-day cycle following cycle 1 (e.g., cycles 2, 3, 4, etc.), or if the individual is 75 years of age or older, dexamethasone is administered once weekly in each 28-day cycle following cycle 1 (e.g., cycles 2, 3, 4, etc.). In some embodiments, the anti-CD38 antibody, pomalidomide, and dexamethasone are administered sequentially in each cycle after cycle 1 (e.g., cycle 2, 3, 4, etc.). In some embodiments, pomalidomide and dexamethasone are administered before the anti-CD38 antibody in each 28-day cycle after cycle 1 (e.g., cycle 2, 3, 4, etc.). In some embodiments, dexamethasone is administered before the anti-CD38 antibody in each 28-day cycle after cycle 1 (e.g., cycle 2, 3, 4, etc.), and the anti-CD38 antibody is administered before pomalidomide.

[0087] In some embodiments, the PFS of the individual is measured as the time period from the start of treatment to the first occurrence of progressive disease (PD). In some embodiments, the PFS of the individual is measured according to Kumar et al. (2016) "International MyelomaWorking 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 PD is assessed by the criteria in myeloma.Leukemia.20:1467-1473. (See also Table A and Table B). In some embodiments, PFS is measured as the time from the start of treatment to the time of death. In some embodiments, the methods and uses provided herein result in improving (e.g., extending) the progression-free survival (PFS) of the individual by at least about 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15 or more than 15 months (including any range between these values). In some embodiments, the treatment increases the progression-free survival (PFS) of the individual by at least about 11.53 months. In some embodiments, the treatment increases (e.g., extends) the progression-free survival (PFS) of the individual by at least about 11.14 months. In some embodiments, the treatment is compared with patients with multiple myeloma (e.g., refractory leukemia) who receive treatment including pomalidomide and dexamethasone without the anti-CD38 antibody. The treatment increases (e.g., prolongs) the subject's PFS by at least about any of 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or more than 11.5 months (including any ranges therebetween) compared to a subject with multiple myeloma (e.g., relapsed and refractory multiple myeloma) receiving a treatment comprising pomalidomide and dexamethasone without the anti-CD38 antibody. In some embodiments, the treatment increases (e.g., prolongs) the individual's PFS by at least about 4.5 months compared to an individual with multiple myeloma (e.g., refractory multiple myeloma or relapsed and refractory multiple myeloma) receiving a therapy comprising pomalidomide and dexamethasone without the anti-CD38 antibody.

[0088] In some embodiments, overall survival (OS) is measured as the time period from the start of treatment to death. In some embodiments, the treatment increases (e.g., prolongs) the OS of the individual compared to an individual with multiple myeloma (e.g., refractory multiple myeloma or relapsed and refractory multiple myeloma) receiving a treatment comprising pomalidomide and dexamethasone without the anti-CD38 antibody.

[0089] In some embodiments, the time to first renal reaction in an individual receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone according to the methods or antibodies for the uses provided herein is shorter than the time to first renal reaction in an individual receiving treatment with pomalidomide and dexamethasone. In some embodiments, treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone according to the methods or antibodies for the uses provided herein reduces the time to first renal reaction in an individual compared to the time to first renal reaction in an individual receiving treatment with pomalidomide and dexamethasone. In some embodiments, "time to first response" refers to the duration between the date of the first dose and the date of the first sign of a response, such as a response according to the 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).

[0090] In some embodiments, the individual is minimal residual disease (MRD) negative or "MRD negative" after treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, MRD status is measured by next generation flow cytometry (NGF). In some embodiments, MRD negativity (or "flow MRD negative") as measured by NGF refers to the absence of phenotypically abnormal clonal plasma cells (such as multiple myeloma cells) in the bone marrow aspirate (e.g., using EUROFLOW for MRD detection in multiple myeloma). TMHigh-throughput flow cytometry standard operating procedures (see Flores-Montero et al. (2017) Leukemia. 31: 2094-2103) or equivalent methods) with a minimum sensitivity of, for example, 10 4 One of the nucleated cells (10 -4 ), 10 5 One of the nucleated cells (10 -5 ), 10 6 One of the nucleated cells (10 -6 ) or 10 7 One of the nucleated cells (10 -7 In some embodiments, after treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone, the individual -4 , 10 -5 or 10 -6 The patients were MRD negative by NGF at the threshold of 10%.

[0091] In some embodiments, MRD status is measured by next generation sequencing (NGS). In some embodiments, MRD negativity as measured by NGS (or "sequencing MRD negative") refers to the absence of clonal plasma cells (e.g., multiple myeloma cells) in the bone marrow aspirate; the presence of clones is defined as obtaining at least two identical sequencing reads after DNA sequencing of the bone marrow aspirate (e.g., using high-throughput sequencing platform or equivalent method) with a minimum sensitivity of, for example, 10 4 One of the nucleated cells (10 -4 ), 10 5 One of the nucleated cells (10 -5 ), 10 6 One of the nucleated cells (10 -6 ) or higher. In some embodiments, the minimum sensitivity is 10 6 One of the nucleated cells (or 10 -6 In some embodiments, after treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone, the individual -4 , 10 -5 or 10 -6 The patients were MRD negative by NGS at the threshold of

[0092] In some embodiments, the individual is negative by both imaging and MRD (or "imaging + MRD negative"). In some embodiments, imaging + MRD negative refers to (a) MRD negative as detected by NGF or MRD negative as detected by NGS, and (b) each area of ​​increased tracer uptake found at baseline or previous positron emission tomography (PET) / computed tomography (Ct) disappears or decreases to <maximum standardized uptake value of the mediastinal blood pool or decreases to less than the uptake value of surrounding normal tissue. In some embodiments, the individual is "persistently MRD negative". In some embodiments, persistently MRD negative refers to an individual who has been confirmed as imaging + MRD negative at two time points after the start of treatment, wherein the time points are no less than 1 year apart. In some embodiments, minimal residual disease (MRD) is assessed via NGF or NGS using bone marrow samples collected from individuals who have received treatment with isatuximab, pomalidomide, and dexamethasone as described herein. In some embodiments, the individual assessed for MRD has achieved a complete response following treatment with isatuximab, pomalidomide, and dexamethasone as described herein. In some embodiments, the individual achieved a complete response following treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. -4 , 10 -5 or 10 -6 The patients were negative for MRD both by imaging and by NGS or NGF at the threshold of 1:1.

[0093] In some embodiments, the individual is less than 65 years of age. In some embodiments, the one-year overall survival rate in individuals less than 65 years of age receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least about any of 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 67.1%, 67.2%, 67.3%, 67.4%, 67.5%, 67.6%, 67.7%, 67.8%, 67.9%, or 68%, including any ranges therebetween. In some embodiments, the PFS of an individual under 65 years of age who receives treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least about 9, 9.5, 10, 10.5, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.53, 11.6 11.7, 11.8, 11.9, or 12 months, including any ranges between these values. In some embodiments, the PFS of an individual under 65 years of age who receives treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, or 7 months, including any ranges between these values, longer than the PFS of an individual under 65 years of age who receives treatment with pomalidomide and dexamethasone but not the anti-CD38 antibody. In some embodiments, PFS is calculated as described elsewhere herein.

[0094] In some embodiments, the individual is at least 65 years of age but less than 75 years of age. In some embodiments, the one-year overall survival rate in individuals at least 65 years of age but less than 75 years of age receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least about any of 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 74.1%, 74.2%, 74.3%, 74.4%, 74.5%, 74.6%, 74.7%, 74.8%, 74.9%, or 75%, including any ranges therebetween. In some embodiments, the PFS of an individual who is at least 65 years of age but less than 75 years of age receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least about any of 9.5, 10, 10.5, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.57, 11.6, 11.7, 11.8, 11.9, or 12 months, including any ranges therebetween. In some embodiments, the PFS of an individual who is at least 65 years of age but less than 75 years of age receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least about any of 1, 1.5, 2, 2.5, 2.6, 2.7, 2.8, 2.9, 2.99, or 3 months, including any ranges therebetween, longer than the PFS of an individual who is at least 65 years of age but less than 75 years of age receiving treatment with pomalidomide and dexamethasone but not the anti-CD38 antibody. In some embodiments, PFS is calculated as described elsewhere herein.

[0095] In some embodiments, the individual is 75 years of age or older. In some embodiments, the one-year overall survival rate of individuals 75 years of age or older receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least about any of 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 73.1%, 73.2%, 73.3%, 73.4%, 73.5%, 73.6%, 73.7%, 73.8%, 73.9%, or 74%, including any ranges therebetween. In some embodiments, the one-year overall survival rate of individuals 75 years of age or older receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is greater than the one-year overall survival rate of individuals 75 years of age or older receiving treatment with pomalidomide and dexamethasone but not the anti-CD38 antibody. In some embodiments, the one-year overall survival rate of individuals 75 years of age or older receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least about any of 21, 22, 23, 24, 25, 26, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, or 27 percentage points greater than the one-year overall survival rate of individuals 75 years of age or older receiving treatment with pomalidomide and dexamethasone but without the anti-CD38 antibody. In some embodiments, the PFS of an individual 75 years of age or older receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least about any of 9.5, 10, 10.5, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, or 12 months, including any ranges therebetween. In some embodiments, the PFS of an individual 75 years of age or older receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least about any of 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7 months, including any ranges therebetween, longer than the PFS of an individual 75 years of age or older receiving treatment with pomalidomide and dexamethasone but not the anti-CD38 antibody. In some embodiments, PFS is calculated as described elsewhere herein.

[0096] In some embodiments, the individual is a female (e.g., a fertile female of childbearing age). In some embodiments, when the patient is a female and is able to become pregnant, the patient can use an effective contraceptive method during treatment with the anti-CD38 antibody and within five months after the last dose of the anti-CD38 antibody. In some embodiments, the individual suffers from liver damage, such as mild liver damage. In some embodiments, if the individual's total bilirubin is between about 1 and about 1.5 times the upper limit of normal (ULN), the individual suffers from mild liver damage. In some embodiments, if the individual's aspartate aminotransferase (AST) level is greater than the upper limit of normal (ULN), the individual suffers from mild liver damage. In some embodiments, the individual has received at least three (e.g., 4, 5, 6, 7, 8, etc.) previous therapies (or previous therapy lines) for multiple myeloma. In some embodiments, the individual has less than about 60, less than about 50, or less than about 30 ml / min / 1.73 m before the start of treatment. 2 In some embodiments, the individual is in stage II or stage III according to the International Staging System for Multiple Myeloma (ISS). In some embodiments, stage II according to the ISS for multiple myeloma is defined as a serum beta-2 microglobulin level between about 3.5 and about 5.5 mg / L or higher. In some embodiments, stage II according to the ISS for multiple myeloma is defined as a serum albumin level of less than about 3.5 g / dL. In some embodiments, stage III according to the ISS for multiple myeloma is defined as a serum beta-2 microglobulin level greater than about 5.5 mg / L. In some embodiments, the individual is in stage III according to the Revised International Staging System for Multiple Myeloma (R-ISS). In some embodiments, stage III according to the R-ISS for multiple myeloma is defined as (a) a serum beta-2 microglobulin level greater than about 5.5 mg / L, and (b) a high-risk cytogenetic abnormality detected by interphase fluorescence in situ hybridization (iFISH) or (c) a serum lactate dehydrogenase (LDH) level greater than the upper limit of normal. In some embodiments, the individual has a high-risk cytogenetic abnormality (CA). In some embodiments, the high-risk cytogenetic abnormality is one or more of del(17p), t(4:14), and / or t(14;16). Products or kits

[0097] In another embodiment of the present invention, a product or a kit is provided, comprising an anti-CD38 antibody (such as isatuximab). In some embodiments, the product or the kit further comprises pomalidomide and / or dexamethasone. In some embodiments, the product or the kit further comprises a package insert comprising instructions for using the anti-CD38 antibody (e.g., isatuximab) in combination with pomalidomide and dexamethasone to treat multiple myeloma (e.g., refractory multiple myeloma or relapsed and refractory multiple myeloma) or to delay its progression in an individual who has received at least two prior therapies for multiple myeloma. In some embodiments, the kit comprises isatuximab, pomalidomide, and dexamethasone.

[0098] This description is considered sufficient to enable one skilled in the art to practice the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. Example

[0099] 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 present invention. It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes made therefrom will be known to those skilled in the art and should be included within the spirit and scope of this application and within the scope of the appended claims. Example 1: A Phase III Randomized, Open-Label, Multicenter Study Comparing the Combination of Isartumomab (SAR650984) with Pomalidomide and Low-Dose Dexamethasone Versus Pomalidomide and Low-Dose Dexamethasone in Patients with Refractory or Relapsed and Refractory Multiple Myeloma

[0100] This example describes a phase III, multicenter, multinational, randomized, open-label, parallel-group, 2-arm study evaluating the efficacy of isatuximab in combination with pomalidomide and low-dose dexamethasone compared to pomalidomide and low-dose dexamethasone for the treatment of patients with refractory or relapsed and refractory multiple myeloma who have received at least 2 prior lines of therapy for multiple myeloma (e.g., ≥ 2 prior lines of therapy), including lenalidomide and a proteasome inhibitor (e.g., bortezomib, carfilzomib, or ixazomib), given alone or in combination, and who have demonstrated disease progression on or within 60 days of completion of the last therapy (e.g., are refractory to the last therapy). I. Purpose of the Study A. Primary Objective

[0101] The primary objective (i.e., primary endpoint) of this study was to demonstrate the benefit of isatuximab in combination with pomalidomide and low-dose dexamethasone (i.e., "IPd group") compared with pomalidomide and low-dose dexamethasone (i.e., "Pd group") in prolonging PFS in patients with refractory or relapsed and refractory multiple myeloma. PFS was defined as the time from the date of randomization to the date of the first documented progressive disease (PD) (as determined by an independent response committee (IRC)) or the date of death from any cause, whichever came first.

[0102] PD (IMWG criteria as 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) was defined for patients with measurable serum and / or urine M-protein as any of the following (see also Tables A and B): An increase of ≥25% from the nadir in the serum M component on 2 consecutive assessments (the absolute increase must have been ≥0.5 g / dL); if the initial M component was ≥5 g / dL, an increase of ≥1 g / dL in the serum M component on 2 consecutive assessments is sufficient to define a relapse, and / or An increase of ≥25% from nadir in urine M component on 2 consecutive assessments (the absolute increase must have been ≥200 mg / 24 hours), and / or Unequivocal development of a new bone lesion or soft tissue extramedullary disease, or if >1 lesion, an increase of ≥50% in the sum of the perpendicular diameters of the existing soft tissue extramedullary disease lesions from their nadir, or an increase of ≥50% in the longest diameter of a prior soft tissue extramedullary disease lesion >1 cm in the short axis. (Pathologic fracture or bone collapse is not necessarily evidence of disease progression.) B. Key Secondary Objectives

[0103] The key secondary objectives of this study (i.e., key secondary endpoints or key secondary efficacy endpoints) were: (1) to evaluate the overall response rate (ORR) in each group according to the International Myeloma Working Group (IMWG) criteria (as 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); and (2) to compare overall survival (OS) between the IPd group and the Pd group.

[0104] ORR is defined as the proportion of patients with a strict complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) as assessed by an independent response committee using the IMWG response criteria. See Tables A and B below. Irradiated plasmacytomas are not suitable for response assessment; however, they must be monitored to assess disease progression. For patients who achieve a very good partial response based on other criteria, the sum of the largest perpendicular diameters (SPD) of the soft tissue plasmacytomas must have decreased by more than 90% compared to baseline. Table A Standard International Myeloma Working Group (IMWG) response criteria SPD, the sum of the products of the maximum perpendicular diameters of the measured lesions

[0105] Patients are continued into the last confirmed response category until progression is confirmed or improvement to a higher response state is achieved; patients cannot move to a lower response category. The percentage reduction used for response calculations is relative to the baseline value (Cycle 1, Day 1). The percentage increase used for progression calculations is relative to the lowest response value or baseline value (whichever is smaller). The lowest value does not need to be confirmed. The lowest confirmed value before suspected progression is used as a baseline for calculating progression; if the serum and / or urine peak value is considered too low to be quantified, the value can be assigned to zero as a baseline for recording subsequent disease progression. If a patient meets the progression criteria based on a variable that is considered unmeasurable at baseline, they are considered to have disease progression; however, for patients with a measurable serum or urine M peak at baseline, progression cannot be defined solely by an increase in serum FLC.

[0106] For patients with serum and urine M-protein below qualifying levels based on efficacy labs performed on Cycle 1 Day 1 (e.g., patients with only FLC-measurable disease or patients without any biomeasurable disease according to the IMWG), there can be only one of two possible overall responses: no PD or PD. In such cases, PD can be diagnosed based on the following parameters: For patients with measurable FLC only: M-protein and plasmacytoma according to the IMWG criteria described in the table above, For patients with non-measurable disease: M-protein and plasmacytoma, or an increase in bone marrow plasma cell involvement of ≥10%.

[0107] Overall survival (OS) was defined as the time from the date of randomization to death from any cause. C. Other Secondary Objectives

[0108] Other secondary objectives of this study ("secondary endpoints") are: (1) to evaluate the time to progression (TTP) in each group; (2) to evaluate the PFS of the high-risk cytogenetic population defined as patients carrying del(17p), t(4;14), t(14;16) in each group; (3) to evaluate the duration of response (DOR) in each group; (4) to evaluate the safety profile in both treatment groups; (5) to determine the pharmacokinetic profile of the combination of isatuximab and pomalidomide; (6) to evaluate the immunogenicity of isatuximab; and (7) to assess disease-specific and general health-related quality of life (HRQL), disease- and treatment-related symptoms, health state utility, and health status.

[0109] Time to progression (TTP) was defined as the time from the date of randomization to the date of the first documented disease progression (as determined by an independent response committee). The same definition of progression as for the PFS endpoint (see above) was used.

[0110] PFS in the high-risk cytogenetic population was defined as the time from the date of randomization to the date of the first documented PD (as determined by an independent response committee) or the date of death from any cause, whichever came first, in the subgroup of patients carrying high-risk cytogenetic changes (including del(17p), t(4;14), or t(14;16)) as assessed by fluorescence in situ hybridization (FISH).

[0111] Duration of response (DOR) was defined as the time from the date of response determined by the first independent response committee (IRC) to the date of PD or death determined by the first IRC, whichever occurred first. DOR was determined only for patients who achieved a response ≥ PR.

[0112] Safety in terms of treatment-emergent adverse events (TEAEs) / serious adverse events (SAEs), laboratory parameters, vital signs (blood pressure, heart rate, and temperature), weight, ECO G performance status, and physical examination was assessed throughout the study. TEAEs were defined as adverse events that occurred, worsened (according to the investigator's opinion), or became serious during the TEAE period (i.e., from the first dose of study treatment to 30 days after the last dose of study treatment). Adverse events and laboratory parameters were graded using NCI-CTCAE v4.03, available at ctep(dot)cancer(dot)gov / reporting / ctc(dot)html.

[0113] Blood samples were collected from all treated patients to assess the pharmacokinetic profile of isatuximab using a population pharmacokinetic approach.

[0114] Patients in the IPd group were assessed throughout the study for the presence of anti-drug antibodies (ADA, i.e., anti-isatuximab antibodies).

[0115] The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) with 30 questions, the EORTC Myeloma Module (MY20) with 20 items, and the European Quality of Life Group Scale (EQ-5D-5L) assessment with 5 dimensions and 5 levels per dimension were designated to be self-completed by all patients (IPD group and Pd group). All patient-reported outcomes (PROs) were completed by patients at the center before discussing their health / disease status, before administering study treatment or other study-related procedures during treatment, at the end of treatment visit (EOT; 30 [± 5] days after the last study treatment administration) and 60 days (± 5 days) after the last study treatment administration. D. Exploratory Objectives

[0116] The exploratory objectives of this study were to: (1) explore the relationship between immunogenetic determinants and efficacy endpoints; (2) explore pharmacokinetic (PK) and pharmacodynamic (PD) relationships; and (3) explore minimal residual disease (MRD) rates in both treatment groups.

[0117] For consenting patients, blood samples were collected on Cycle 1, Day 1. These samples were used to determine whether there was a relationship between the genetic markers and (a) treatment with isartuximab, (b) how the body processes isartuximab, and / or (c) possible side effects of isartuximab. The samples were transferred to a separate location. DNA was extracted from each sample and stored until further analysis.

[0118] Blood samples were collected on Cycle 1, Day 1 or for exploratory biomarker analysis (which was a mandatory part of the study and was not performed under separate pharmacogenetic consent). Leukocyte DNA was extracted from each blood sample and analyzed for immunogenetic determinants such as FcγR polymorphisms, human leukocyte antigen (HLA), and killer cell inhibitory receptor (KIR) genotypes and correlated with clinical response parameters including, for example, ORR, DOR, PFS, and OS.

[0119] Additional serum samples were collected to evaluate the potential interference of isatuximab with M protein assessment in immunoelectrophoresis and immunofixation assays. These samples were collected from patients in the IPd group at all time points analyzed for M protein.

[0120] Where possible, pharmacokinetic and pharmacodynamic estimates were investigated as prognostic factors for clinical outcomes, including safety and efficacy endpoints.

[0121] In bone marrow samples obtained only from patients who achieved CR, the The NGS platform assesses minimal residual disease (MRD) via next generation sequencing (NGS). MRD status is classified as outlined in Table B below. Bone marrow aspirates are collected at baseline / screening and when CR is confirmed. If the patient shows CR but is determined to be MRD positive, another bone marrow sample is collected after 3 months (3 cycles) to identify late negatives. In some cases, if the patient remains MRD positive and is still in treatment, a third sample is collected after 3 months. No more than 3 bone marrow samples in treatment are obtained for each patient. Table B. International Myeloma Working Group (IMWG) Minimal Residual Disease Criteria* *Assessed in patients who achieved a CR according to the criteria in Table A

[0122] Each of the efficacy assessments described above was selected for use in this study and is considered well-established and relevant in the hematology-oncology setting. II. Research Design

[0123] After confirmation of eligibility criteria (which are described in further detail below), patients were randomized in a 1:1 ratio using an interactive response technology (IRT) system to one of the two groups shown in Table C below. Table C: Study Treatment Groups

[0124] Randomization was stratified by age (<75 years vs ≥75 years) and number of prior lines of therapy (2 or 3 vs more than 3). The complete transplant sequence (induction, mobilization, conditioning, transplant, consolidation, and maintenance) was considered one line. Each additional regimen was considered one line, regardless of the reason for discontinuation (progression, adverse events, or patient request). Patients continued treatment until disease progression, unacceptable adverse events (e.g., unacceptable toxicity), or patient preference, whichever came first. The study design is summarized in Figure 1 middle. A. Duration of study participation per patient

[0125] Each patient is considered to be in the study from the signature of informed consent until death, withdrawal of consent or deadline (whichever comes first). The patient's study duration includes a screening period of up to 3 weeks. The duration of each treatment cycle is 28 days. The patient continues to study treatment until disease progression, unacceptable AEs, patient wishes or any other reason. During the follow-up period, patients who interrupt study treatment due to disease progression (PD) are followed up every 3 months (12 weeks) for survival until death or deadline (whichever comes first). Patients who interrupt study treatment before recording disease progression (PD) are followed up every 4 weeks until disease progression (even for patients who start further anti-myeloma therapy in the absence of PD), and then followed up every 3 months (12 weeks) for survival until death or deadline (whichever comes first).

[0126] If the patient was still on treatment at the cutoff date for OS and was benefiting from study treatment, the patient could continue study treatment until disease progression, unacceptable AEs, patient preference, or any other reason. For cycles completed after the cutoff date, all new relevant AEs (serious or non-serious), all ongoing SAEs (related or non-related), and all ongoing relevant non-serious AEs, as well as the reason for end of treatment (EOT), continued to be collected. B. Determination of end of clinical trial (all patients)

[0127] The PFS analysis (primary endpoint) was event-driven, with the cutoff date being 162 PFS events (progression or death, whichever occurred first). The OS analysis was event-driven, with the final cutoff date being 220 deaths. III. Patient Selection A. Inclusion Criteria

[0128] Eligible patients were considered for inclusion if they met all of the following criteria: Age: ≥18 years or the legal age of majority in the country where the legal age is >18 years. Patients must have a documented diagnosis of multiple myeloma with evidence of measurable disease. Serum M-protein ≥ 0.5 g / dL as measured by serum protein immunoelectrophoresis, and / or Urine M-protein ≥ 200 mg / 24 hours as measured by urine protein immunoelectrophoresis. Patients must have received at least 2 prior lines of anti-myeloma therapy, which must have included at least 2 consecutive cycles of lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib), given alone or in combination. (Note: induction therapy followed by ASCT and consolidation / maintenance is considered one line of treatment.) Patients must have experienced failure of treatment with lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib), alone or in combination, as defined by any of the following (failure of lenalidomide and a proteasome inhibitor can have occurred on any line of therapy): oProgression occurred on or within 60 days of completion of lenalidomide and / or proteasome inhibitor treatment. o In the case of a prior response ≥ PR to lenalidomide and / or a proteasome inhibitor, patients must have progressed within 6 months of discontinuing treatment. o The patient has experienced intolerable toxicity after at least 2 consecutive cycles of a regimen containing lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib), alone or in combination. Intolerance is defined as follows: For regimens containing a proteasome inhibitor: Any toxicity leading to discontinuation of the proteasome inhibitor, such as Grade 2 or higher peripheral neuropathy or Grade 2 or higher neuropathic pain. Peripheral neuropathy must have been Grade 1 or lower before study entry (according to the National Cancer Institute Common Terminology for Adverse Events (NCI-CTCAE) v4.03, available at ctep(dot)cancer(dot)gov / reporting / ctc(dot)html). For regimens containing lenalidomide, any toxicity leading to lenalidomide discontinuation, such as Grade 3 rash. Rash must not have been Grade 4, and other non-hematologic toxicities should not have been Grade 4. All non-hematologic toxicities must have been ≤ Grade 1 prior to study entry. o Patients must have progressed on or within 60 days of the end of their previous therapy prior to study entry, i.e., be refractory to the last line of treatment. This patient population includes the following two categories: ■ Relapsed and refractory disease: Patients who are refractory to all prior lines of therapy but should have achieved at least a minimal response (MR) in one prior line. ■ Relapsed and refractory disease: Patients who have relapsed from at least one prior line of treatment and are refractory to the last line of treatment. Patients may have been refractory to one or more other prior lines of treatment. NOTE: Patients must have achieved MR or better to at least one prior line of therapy (ie, primary refractory disease is ineligible). B. Exclusion Criteria

[0129] Patients who met all the above inclusion criteria were screened for the following exclusion criteria: Primary refractory multiple myeloma, defined as patients who have never achieved at least MR with any therapy during the course of their disease. Only free light chains can measure disease. - Patients treated with prior anti-CD38 monoclonal antibody therapy (progressed on or within 60 days after completion of anti-CD38 monoclonal antibody therapy, e.g., refractory to prior therapy with anti-CD38 monoclonal antibody therapy). Prior therapy with pomalidomide. Any anti-myeloma drug treatment, including dexamethasone, within 14 days before randomization. Previous allogeneic HSC transplantation with active graft-versus-host disease (GvHD) (any grade of GvHD and / or immunosuppressive therapy within the last 2 months). Any major procedure within 14 days before the start of study treatment: plasma exchange, major surgery (kyphoplasty is not considered a major procedure), radiation therapy. Patients who have received any other investigational drug or contraindicated therapy for this study within 28 days or 5 half-lives (whichever is longer) from randomization. Eastern Cooperative Oncology Group (ECOG) performance status >2 (as described at ecog-acrin(dot)org / res ources / ecog-performance-status and / or Oken et al. (1982) “Toxicity and responsibility criteria of the Eastern Cooperative Oncology Group.” Am J. Clin Oncol. 5:649-655). Platelets <75 000 cells / μL if <50% of bone marrow (BM) nucleated cells are plasma cells, and platelets <30 000 cells / μL if ≥50% of BM nucleated cells are plasma cells. Platelet transfusions were not permitted within three days prior to the screening visit. ANC (absolute neutrophil count) <1000 μ / L (1 x 10 9 / L). G-CSF is not allowed to reach this level. Creatinine clearance <30 mL / min (Modification of Diet in Renal Disease (MDRD) formula: GFR (mL / min / 1.73 m 2 )=175x(Scr) -1.154 x(age) -0.203 x(0.742, if female) x(1.212, if African American)). Total bilirubin >2x ULN. Corrected serum calcium >14 mg / dL (>3.5 mmol / L) AST and / or ALT > 3x ULN • Ongoing toxicity of grade >1 from any prior anti-myeloma therapy (excluding alopecia and those listed in the eligibility criteria) as outlined in the NCI-CTCAE v4.03 available at ctep(dot)cancer(dot)gov / reporting / ctc(dot)html. ·right Hypersensitivity reactions to thalidomide or lenalidomide were defined as any hypersensitivity reaction that met the definition of intolerance (provided above in the inclusion criteria) leading to discontinuation of the IMiD within the first 2 cycles or reactions. Hypersensitivity to dexamethasone, sucrose, histidine (as base and hydrochloride), and polysorbate 80, or any component of the study therapy that is inappropriate for premedication with steroids or H2 blockers (such that further treatment with these agents would be contraindicated). Significant cardiac dysfunction; myocardial infarction within 12 months; unstable, poorly controlled angina. Diagnosis or treatment of another malignancy within 3 years before randomization, excluding completely resected basal cell or squamous cell carcinoma of the skin, malignant neoplasm in situ, or low-risk prostate cancer following curative therapy. Known to be HIV + or have active hepatitis A, B, or C infection. Malabsorption syndrome or any condition that could significantly affect the absorption of pomalidomide. Active primary amyloid light chain (AL) amyloidosis (evidence of end-organ damage or receiving treatment for amyloidosis). · Associated plasma cell leukemia Unable or unwilling to undergo thromboprophylaxis. Requirement of daily corticosteroids (equivalent to 10 mg / day of prednisone) for more than 7 days (except inhaled corticosteroids). IV. Study Treatment A. Investigational medicinal product (IMP) i. Isatuximab (IV)

[0130] Isatuximab is formulated as a concentrated solution for infusion in a vial containing 20 mg / mL (500 mg / 25 mL) of Isatuximab in 20 mM histidine, 10% (w / v) sucrose, 0.02% (w / v) polysorbate 80, pH 6.0 buffer. Isatuximab is provided for parenteral administration as a sterile, pyrogen-free, injectable, colorless 20 mg / mL infusion solution concentrate that may contain white to off-white particles and is packaged in 30 mL glass vials equipped with elastomeric closures. Each vial contains 500 mg of the nominal amount of Isatuximab. A fill volume is established to ensure that 25 mL is removed. For administration to a patient, an appropriate volume of Isatuximab is diluted in an infusion bag of 0.9% sodium chloride solution. The final infusion volume corresponding to the isatuximab dose is administered over a period of time that depends on the dose administered and is based on the amount of protein given per hour.

[0131] Isarituximab was administered to patients in the IPd group at a dose of 10 mg / kg via intravenous infusion 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. (All cycles were 28 days in duration.) Dose modifications were applied in the event of toxicity (described in further detail below). ii. Pomalidomide (oral administration)

[0132] Pomalidomide is supplied as 1 mg, 2 mg, 3 mg, and 4 mg capsules. Pomalidomide is administered orally (per os or "PO") to patients in both the IPd and Pd groups at a dose of 4 mg on Days 1-21 of each 28-day cycle. (The duration of all cycles is 28 days.) Dose modifications are applied in the case of toxicity (described in further detail below). ii. Dexamethasone (oral or IV administration)

[0133] Dexamethasone is formulated for oral administration as 4 mg and 8 mg tablets, and for intravenous injection as a 4 mg / mL solution. On Days 1, 8, 15, and 22 of each 28-day cycle, dexamethasone is administered at a dose of 40 mg for patients < 75 years of age, or at a dose of 20 mg for patients > 75 years of age. (The duration of all cycles is 28 days.) Dose modifications are applied in the case of toxicity (described in further detail below).

[0134] In the IPd group, dexamethasone is administered with a non-investigational medicinal product (NIMP, described below) as a premedication for the prevention of infusion-related reactions commonly observed with administration of monoclonal antibodies. B. Non-investigational medicinal product (NIMP) - Pre-medication for prevention of infusion reactions (IR)

[0135] All patients assigned to the IPd group receive premedication prior to isatuximab infusion in order to reduce the risk and severity of IARs commonly observed with administration of monoclonal antibodies. The recommended premedication agents are: diphenhydramine 25-50 mg IV (or equivalent: e.g., cetirizine, promethazine, dexchlorpheniramine, as per local approval and availability. Intravenous route is preferred for at least the first 4 infusions), dexamethasone PO / IV (doses provided 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 PO, 15 to 30 minutes (but not longer than 60 minutes) prior to isatuximab infusion. Once the premedication regimen is completed, the isatuximab infusion is initiated immediately.

[0136] On the day of isatuximab infusion, a total of 40 mg of dexamethasone (i.e., the regular dose of dexamethasone when used in combination with pomalidomide) or 20 mg in patients > 75 years of age is administered as part of the premedication and as part of the backbone therapy prior to isatuximab and pomalidomide.

[0137] When dexamethasone is administered orally, the premedication is administered in the following order: Dexamethasone 40 mg orally (or 20 mg PO for patients ≥ 75 years); then Acetaminophen 650 mg to 1000 mg orally; then Ranitidine 50 mg IV (or equivalent); then Diphenhydramine 25 mg to 50 mg IV (or equivalent).

[0138] When dexamethasone is administered intravenously, premedication should be given in the following order: Acetaminophen 650 mg to 1000 mg orally; then Ranitidine 50 mg IV (or equivalent); then Diphenhydramine 25 mg to 50 mg IV (or equivalent); then Dexamethasone 40 mg IV (or 20 mg IV for patients ≥ 75 years).

[0139] Regardless of the route of administration (IV or PO), dexamethasone was administered only once (ie, a single administration was used for both premedication and study treatment).

[0140] Post-infusion corticosteroid or bronchodilator prophylaxis was not required.

[0141] All patients received mandatory thromboprophylaxis with aspirin or low-molecular-weight heparin. C. Dose and schedule i. IPd arm (experimental arm)

[0142] Patients assigned to the IPd group received premedication prior to isatuximab infusion to reduce the risk and severity of infusion reactions (IR) commonly observed with monoclonal antibodies (see above).

[0143] Drug administration for patients in the IPd group was performed as follows: On Days 1, 8, 15, and 22, administer dexamethasone at a dose of 40 mg (or 20 mg if the patient is ≥75 years of age) orally (preferred route) or intravenously (if the oral route cannot be used) approximately 15-30 minutes (but not longer than 60 minutes) before isatuximab. • Administer 10 mg / kg on days 1, 8, 15, and 22 of cycle 1, then on days 1 and 15 of subsequent cycles. Pomalidomide was administered at a dose of 4 mg on each of Days 1 to 21 of each 28-day cycle. On Day 1 of each cycle, pomalidomide was taken 1 hour to 30 minutes before isatuximab. On Days 8, 15, and 22 of the first cycle and Day 15 of subsequent cycles, pomalidomide was taken after the isatuximab infusion and at a time most convenient for the patient (preferably at the same time for each dose). ii. Pd arm (control arm)

[0144] Drug administration for patients treated with pomalidomide + dexamethasone was performed as follows: Dexamethasone was administered orally or intravenously at a dose of 40 mg (or 20 mg if the patient was ≥75 years of age) on days 1, 8, 15, and 22. Pomalidomide was administered at a dose of 4 mg on each of days 1 to 21 of each 28-day cycle.

[0145] In the absence of major toxicity, disease progression, or any other reason (e.g., withdrawal of treatment consent, poor compliance, intercurrent illness that prevents further administration of study treatment, etc.), there is no limit to the number of cycles administered to a patient. In the event of progressive disease (PD), a diagnosis made according to laboratory criteria requires confirmation by two consecutive measurements before discontinuing treatment. Treatment continues until PD is confirmed.

[0146] Each patient's body weight was measured before each cycle to allow calculation of the isatuximab dose.

[0147] For subsequent treatment cycles, dose adjustments (dose delays, dose omissions, and dose reductions (for pomalidomide and / or dexamethasone only) were allowed based on individual patient tolerability. The dose reduction steps for pomalidomide and dexamethasone are shown in Tables D1 and D2 below, respectively. One or several doses of pomalidomide may be omitted. One or several doses of dexamethasone may be omitted, or the dose of dexamethasone may be reduced to every other week (i.e., twice per 28-day cycle). Table D1. Pomalidomide dose reduction levels Starting dose Dose level -1 Dose level -2 Dose level -3 4 mg 3 mg 2 mg 1 mg *All doses are oral Table D2. Dexamethasone dose reduction levels *All doses are oral or IV

[0148] Dose reductions were not permitted for the isatuximab infusion. V. Disease Assessment

[0149] The investigator's decision on whether to allow a subject to continue treatment was based on efficacy data (obtained from local and / or central laboratories), radiographic evaluations, and bone marrow assessments performed throughout the study or according to IMWG criteria (if indicated). The reference value for assessing treatment response was the value measured in a sample obtained from each patient before treatment on Day 1 of Cycle 1. • Serum M-protein levels were assessed by immunoelectrophoresis and, if undetectable by immunoelectrophoresis, by immunofixation. • Assess urine M-protein levels by immunoelectrophoresis and, if M-protein is undetectable by immunoelectrophoresis, by immunofixation. • Free light chain (FLC) levels were analyzed centrally only in case of complete response (CR) (ie, undetectable M protein by serum protein electrophoresis / urine protein electrophoresis and negative immunofixation). Immunoglobulins: IgG, IgA, IgM, IgD, and IgE (IgD or E only if the heavy chain component of the disease is known to be E or D). Assess bone marrow plasma cell infiltration to confirm CR or if progressive disease is suspected in the absence of biochemical progression and as clinically indicated. In the case of CR, a bone marrow aspirate (or biopsy if clinically indicated) is used for minimal residual disease (MRD) assessment. If the patient is MRD-positive, another bone marrow sample is collected after 3 months (3 cycles) to identify late MRD negativity. If the patient remains MRD-positive and is still on treatment, a third sample can be collected after another 3 months (3 cycles). (No more than 3 on-treatment bone marrow samples are obtained from any patient.) A skeletal survey or low-dose whole-body CT scan was performed at baseline, then annually, and at any time during the study (if clinically indicated). The same modality (i.e., skeletal survey or low-dose whole-body CT) was used for each patient throughout the study. For extramedullary disease (plasmacytoma, including bone plasmacytoma): o If extramedullary disease is present at baseline, perform a CT scan or MRI at baseline and repeat every 12 weeks (± 1 week). (Additional CT scans or MRIs will be performed if clinically indicated.) o If extramedullary disease is suspected at baseline, perform a CT scan or MRI at baseline to confirm extramedullary disease. If confirmed, repeat the CT or MRI every 12 weeks (± 1 week). (Additional CT scans or MRIs will be performed if clinically indicated.) The modality (CT or MRI) was the same for each individual patient throughout the study. VI. Results A. Patient Characteristics

[0150] 307 patients were randomized and included in the intention-to-treat (ITT) population (153 in the Pd group and 154 in the IPd group). Overall, patient demographics and characteristics at baseline were representative of the RRMM population and were generally similar in the two treatment groups. See Table E below. Table E. Demographic Characteristics of the Randomized Population a : Other countries = Australia, New Zealand, Türkiye and Russia. b : Other countries = Czech Republic, Hungary, Poland, Slovakia, Japan, South Korea, China, Türkiye and Russia

[0151] International Staging System (ISS) stage and subtype of multiple myeloma at initial diagnosis were well balanced between treatment groups (see Table F). Overall, 28% of patients had ISS stage III at initial diagnosis (28.8% in the Pd group and 27.3% in the IPd group). Table F. Disease Characteristics of the Randomized Population at Initial Diagnosis Ig: immunoglobulin, MM: multiple myeloma, ISS: International Staging System

[0152] At study entry, ISS criteria classified 73.0% of patients as stage I and II and 25.1% as stage III (see Table G). All patients were relapsed and refractory at study entry according to the inclusion criteria. Disease characteristics were as expected in this heavily treated RRMM population and were generally similar between treatment groups. Table G. Disease Characteristics of the Randomized Population at Study Entry * :Excluding primary refractory MM: multiple myeloma, Ig: immunoglobulin, LDH: lactate dehydrogenase, ULN: upper limit of normal, ISS: Revised International Staging System, R-ISS: Revised International Staging System

[0153] Overall, the two treatment groups were similar with respect to prior anti-myeloma therapy (see Tables H1 and H2 below). According to the protocol, all patients had received at least 2 prior lines of treatment, including prior lenalidomide and a proteasome inhibitor (PI). Overall, the median number of prior lines was 3 (range 2 to 11 lines), of which 107 (34.9%) patients had received 4 or more prior lines of treatment. One patient had previously been treated with daratumumab. 92% of patients were refractory to lenalidomide, 75.9% of patients were refractory to PI, and 72.6% of patients were refractory to lenalidomide and PI. Almost all patients (98.0%) were refractory to the last regimen before entering the study. Table H1. Overall summary of prior anti-myeloma treatment by randomized population. Table H2. Refractory status to prior anti-myeloma therapy by randomized population. PI: proteasome inhibitor, IMiD: immunomodulator

[0154] More than one-third of the study population (i.e., 36.2%) entered the study with impaired renal function (defined as GFR < 60 ml / min / 1.73 m2). There was a trend toward more patients with impaired renal function entering the IPd group (38.7%) than the Pd group (33.8%).

[0155] It has been well documented that multiple myeloma patients who carry at least one high-risk chromosomal abnormality (CA), such as del(17p), translocation t(4;14), and / or translocation t(14;16), have a worse prognosis than patients without high-risk CA. Therefore, high-risk chromosomal abnormalities were assessed at baseline in some patients. CA could not be evaluated in 21% of patients, which is within the range typically reported for assessments in MM studies. The percentage of patients with high-risk CA was lower in the IPd group compared with the Pd group (15.6% vs. 23.5%). Eight (2.6%) patients (five in the Pd group and three in the IPd group) had two high-risk cytogenetic abnormalities (see Table I). This patient population has a very poor prognosis. Table I: Cytogenetics of the randomized population at study entry CA: Chromosomal abnormality a : High-risk CA is defined as the presence of del(17p) and / or translocation t(4;14) and / or translocation t(14;16) b : Abnormalities were considered positive if present in at least 30% of analyzed plasma cells, with the exception of del(17p) which had a threshold of at least 50% B. Dose and duration of exposure to study treatment

[0156] Compared to the Pd group, the duration of exposure in the IPd group was almost twice as long. The median duration of exposure was 41 weeks (range 1.3 to 76.7) in the IPd group and 24 weeks (range 1 to 73.7) in the Pd group. 55 patients (36.2%) in the IPd group and 38 patients (25.5%) in the Pd group received ≥12 cycles. In the IPd group, the median number of asiltuximab cycles was 10 (range 1 to 19), with the median duration of asiltuximab exposure being 40.9 weeks (range 1.0 to 75.1 weeks), and 35.5% of patients received ≥12 cycles of asiltuximab. See Table J. The median relative dose intensity (RDI) of asiltuximab was 92.3% (range = 19.7%-111.1%). The median RDIs for pomalidomide and dexamethasone were 85.1% (pomalidomide) and 87.8% (dexamethasone) in the IPd group, and 93.3% (pomalidomide) and 96.3% (dexamethasone) in the Pd group.

[0157] Dose omissions and dose delays of isatuximab were reported in 52% and 10.5% of patients, respectively. Infusion interruptions of isatuximab occurred in 34.9% of patients, and 2.1% of isatuximab infusions were as part of the management of infusion reactions. With the exception of 6 patients, dose interruptions generally occurred only once. Almost all infusion interruptions occurred during the first infusion. The median RDI for pomalidomide was slightly lower in the IPd group compared to the Pd group (85.1% (range = 22.9%-103.7%) in the IPd group and 93.3% (range = 37.2%-118.5%) in the Pd group). The median RDI for dexamethasone was slightly lower in the IPd group compared to the Pd group (87.8% (range = 15.9%-130%) in the IPd group and 96.3% (range = 30.3%-300%) in the Pd group). The RDIs for pomalidomide and dexamethasone were driven by dose reductions and omissions for management of neutropenia and infection. Table J. Duration of Exposure to Study Treatment C. Efficacy i. Progression-free survival (PFS)

[0158] Patients treated with isatuximab + pomalidomide + dexamethasone (IPd) exhibited significantly increased progression-free survival (PFS) compared to patients treated with pomalidomide + dexamethasone (Pd), as assessed by an independent response committee (IRC). Figure 2 . The stratified log-rank test obtained by comparing PFS between the two groups was statistically significant, with a p-value of 0.001. 89 (58.2%) and 73 (47.4%) PFS events were reported in the Pd and IPd groups, respectively. Respectively, the median PFS was longer in the IPd group (11.53 months, 95% CI: 8.936 to 13.897) than in the Pd group (6.47 months, 95% CI: 4.468 to 8.279). The stratified hazard ratio was 0.596 (95% CI: 0.436 to 0.814, p = 0.0010), which represents a 40% reduction in the risk of disease progression or death in the case of IPd compared to Pd. IRC assessment of progression and response was based on central laboratory evaluation of M protein and central radiological examination of imaging, and the International Myeloma Working Group (IMWG) criteria were applied (see Tables A and B).

[0159] Sensitivity analyses were performed to assess the robustness of the primary endpoint analysis using different efficacy assessment methods (investigator) or different review rules. The results of all sensitivity analyses of PFS were very consistent with the results of the primary PFS analysis, with statistical significance favoring the IPd group. In particular, the PFS based on the investigator assessment (see Figure 3 ) is consistent with the PFS assessed based on IRC. The investigator assessment of progression is based on local laboratory M protein analysis and local radiological evaluation of plasmacytoma / bone lesions (if any). As assessed by the investigators, the median PFS was 11.14 months (95% CI: 7.491 to 14.784) in the IPd group, compared to 6.54 months (95% CI: 4.468 to 7.885) in the Pd group. The stratified hazard ratio was 0.602 (95% CI: 0.444 to 0.816; p = 0.0009). ii. Subgroup Analysis of PFS

[0160] The consistency of treatment effect on PFS was evaluated with respect to predefined demographics, baseline characteristics, and prognostic factors. Prespecified subgroup analyses showed no significant interaction between treatment groups and stratification factors, between treatment groups and demographic characteristics, or between treatment groups and patient baseline characteristics at the 10% level, suggesting overall consistency of treatment effect across these subgroups. Subgroup analyses on PFS showed positive treatment effects consistent with the overall treatment effect in all subgroups, including subgroups with poor prognosis, such as age >75; HR=0.479; >3 prior lines of therapy: HR=0.59; impaired renal function: HR=0.51; ISS stage III: HR=0.635; R-ISS stage III: HR=0.605; high risk cytogenetics HR=0.655, as shown in Table K. Table K. Progression-free survival - Subgroup analysis summary

[0161] PFS benefit with isatuximab was seen in all subgroups, including patients with poor prognosis. PFS benefit was shown in patients refractory to lenalidomide (median PFS was 11.4 months in the IPd group vs. 5.6 months in the Pd control group), patients refractory to proteasome inhibitors (median PFS was 11.4 months in the IPd group vs. 5.6 months in the Pd group), patients refractory to both lenalidomide and proteasome inhibitors (median PFS was 11.2 months in the IPd group vs. 4.8 months in the Pd group), and patients refractory to the last line of lenalidomide prior to study entry (median PFS was 11.6 months in the IPd group vs. 5.7 months in the Pd group). Patients with high risk cytogenetics treated with IPd also exhibited a PFS benefit compared to patients with high risk cytogenetics in the Pd group. (High risk cytogenetics was defined by FISH as del(17p), t(4;14), or t(14;16); cutoff values for cytogenetics obtained by central laboratory were 50% for del 17, and 30% for t(4,14) and t(14,16).) In patients with high risk cytogenetics, median PFS was 7.5 (95% CI: 2.628 to NC) in the IPd group and 3.745 (95% CI: 2.793 to 7.885) in the Pd group. See also Figure 5, which provides a forest plot showing subgroup analyses of PFS in the IPd group compared to the PD group with various baseline characteristics (e.g., age, eGFR, previous line of therapy, prior ASCT, etc.). An improved PFS benefit was also observed in the IPd group in patients who were ≥75 years old, had ISS stage III at study entry, had a dapoxetine level <60 ml / min / 1.73 m 2 patients with a baseline estimated creatinine clearance (eGFR), patients on >3 prior lines of therapy, patients refractory to prior therapy with lenalidomide or a proteasome inhibitor, and patients refractory to the last line of lenalidomide before study entry. iii. Overall response rate (ORR)

[0162] In an analysis based on investigator assessment, the ORR (i.e., partial response (PR) or better) in the IPd group was significantly higher than in the Pd group (60.4% vs. 35.3%, respectively). The stratified Cochran-Mantel-Haenszel (CMH) p value was <0.0001, which demonstrated a significant difference in ORR between the two groups in favor of IPd at the 0.025 level. The depth of response in the IPd group was improved. VGPR or better was achieved in 31.8% and 8.5% of the IPd and Pd groups, respectively (P < 0.0001), and more patients in the IPd group had a complete response or better (4.5% vs. 2.0%) than in the Pd group. See Table L1, which provides the results of further analysis of the ORR in the IPd and Pd groups. Table L1. Overall response rate according to IRC assessment - ITT population aEstimated using the Clopper-Pearson method; CI: confidence interval, IRC: independent response committee

[0163] Response rates based on investigator assessment (overall response rate: 63.0% in the IPd group and 32.0% in the Pd group; and at least VGPR rate: 33.8% in the IPd group and 7.2% in the Pd group) were consistent with IRC assessments.

[0164] As shown in Table L2, subgroup analysis of ORR showed a trend toward a positive treatment effect in the IPd group across all tested subgroups, which was consistent with the overall treatment effect (including subgroups with poorer prognosis, such as age > 75; > 3 prior lines of therapy; impaired renal function; ISS stage III; R-ISS stage III; and high-risk cytogenetics). Patients with impaired renal function (i.e., creatinine clearance < 60 ml / min / 1.73 m2) in the IPd group had a significantly higher ORR than those with poor prognosis (i.e., creatinine clearance < 60 ml / min / 1.73 m2). 2The number of patients achieving VGPR or better was higher in the IPd arm than in the Pd arm (32.7% in the IPd arm vs. 4.1% in the Pd arm). Table L2. Response rates by subgroup. iv. Effect of treatment on renal dysfunction

[0165] Patients with renal impairment are often excluded from or underrepresented in clinical trials. Furthermore, there are few data exploring renal impairment in patients receiving monoclonal antibody therapy. Renal impairment is an independent predictor of poor prognosis in patients with RRMM, and there is an unmet need for anti-myeloma therapies that also improve renal function.

[0166] In the present study, the number of patients with impaired renal function at baseline (i.e., baseline creatinine clearance (MDRD)) was evenly balanced between the two arms (49 in the Pd arm vs. 55 in the IPd arm). See Table L3, which provides baseline demographic and clinical characteristics of patients with renal impairment at study start. Table L3. Baseline demographic and clinical characteristics of patients with renal impairment a ISS staging was derived based on a combination of serum beta2-microglobulin and albumin bHigh risk was defined by fluorescence in situ hybridization as del(17p), t(4;14), or t(14;16). Cytogenetics was performed by a central laboratory with a cutoff of 50% for del(17p) and 30% for t(4;14) and t(14;16) eGFR estimates glomerular filtration rate, Ig immunoglobulin, Isa isatuximab, ISS international staging system, IMiD immunomodulatory drug, Pd pomalidomide and dexamethasone, PI proteasome inhibitor

[0167] The number of patients in the IPd group who showed improvement in renal function after the start of treatment was significantly higher than in the Pd group. 23 patients (16.4%) in the IPd group achieved a complete renal response, compared to 8 patients (5.7%) in the Pd group. Another patient (0.7) in the IPd group achieved a mild renal response, i.e., an increase in eGFR of >50%, from <15 mL / min to 15-<30 mL / min or from 15-<30 mL / min to 30-<60 mL / min. Fewer patients in the IPd group experienced deterioration to severe or end-stage renal function than in the Pd group (23% in the IPd group and 35% in the Pd group). Table M1. Effects of treatment on renal function *Number of patients who had both baseline and at least one postbaseline assessment. CrCl = creatinine clearance; d = dexamethasone; Isa = isatuximab; P = pomalidomide Complete renal response: defined as improvement from <50 ml / min / 1.73 m2 at baseline to ≥60 ml / min on at least one assessment during treatment Sustained complete renal response: defined as improvement from <50 ml / min / 1.73 m2 at baseline to ≥60 ml / min on at least one assessment during treatment and sustained for at least 60 days

[0168] As shown in Table M1, the creatinine clearance in the IPd group was <50 ml / min / 1.73 m at baseline. 2 Of the 32 patients in the Pd group, 23 (71.9%) showed complete renal response, and 10 (31.3%) showed sustained complete renal response. In contrast, creatinine clearance was <50 ml / min / 1.73 m2 at baseline in the Pd group. 2 Of the 21 patients enrolled, 8 (38.1%) showed a complete renal response, and 4 (19%) showed a sustained complete renal response. A complete renal response (C renal) was characterized by a creatinine clearance of <50 mL / min / 1.73 m 2 ≥60 mL / min / 1.73 m2 at ≥1 post-baseline assessment 2 Improvement in C-nephropathy. A durable (persistent) C-nephropathy response is characterized by a response that lasts ≥ 60 days (see Dimopoulos et al., Blood, 2013; 122: 3176). The median time to first complete renal response (C-nephropathy) was 4.1 weeks in the IPd group and 7.3 weeks in the Pd group. C-nephropathy lasted a median of 57.0 days in the IPd group and 59.5 days in the Pd group.

[0169] For patients with impaired renal function at baseline, the median PFS was 9.5 months in the IPD group and 3.7 months in the Pd group (HR, 0.50; 95% CI, 0.30-0.85). 2 For patients with renal impairment at baseline, the median PFS for patients in the IPD group was 7.5 months, while the median PFS for patients in the Pd group was 2.8 months (HR 0.50; 95% CI 0.22-1.13). In patients without renal impairment at baseline, the median PFS for patients in the IPD group (n=87) was 12.7 months, while the median PFS for patients in the Pd group (n=96) was 7.9 months (HR 0.58; 95% CI 0.38-0.88).

[0170] Regardless of the renal function at baseline, the overall response rate (ORR) of patients treated with IPd was higher than that of patients treated with Pd. For patients without renal impairment at baseline, the ORR was 67.8% (4.6% CR, 29.9% VGPR and 33.3% PR) in the IPd group (n=87) and 42.7% (1% sCR, 1% CR, 9.4% VGPR and 31.3% PR) in the Pd group (n=96). For patients with renal impairment at baseline (eGFR<60ml / min / 1.73m 2 For patients with an eGFR ≥ 45-< 60 ml / min / 1.73 m2 at baseline, the ORR was 56.4% (5.5% CR, 27.3% VGPR, 23.6% PR) in the IPd group (n = 55) and 24.5% (2% CR, 2% VGPR, 20.4% PR) in the Pd group (n = 49) (odds ratio [OR] 3.98; 95% CI 1.60-10.17). 2 For patients with an eGFR < 45 mL / min / 1.73 m2 at baseline, the ORR was 68.6% (5.7% CR, 31.4% VGPR, 31.4% PR) in the IPd group (n = 35) and 25% (3.1% CR, 3.1% VGPR, 18.8% PR) in the Pd group (n = 32). 2 In patients with eGFR < 45 mL / min / 1.73 m2 at baseline, the ORR was 35.0% (5% CR, 20% VGPR, 10% PR) in the IPd group (n = 20) and 23.5% (23.5% PR) in the Pd group (n = 17) (OR 1.75; 95% CI 0.34-10.11). 2Among the patients, one patient in each group had an eGFR < 30 ml / min / 1.73 m 2 ; Patients in the IPd group had SD (stable disease), while patients in the Pd group had PD (progressive disease).

[0171] Three patients with renal impairment in the IPd group achieved minimal residual disease (MRD) negativity (sensitivity level 10 5 1 of them).

[0172] The median OS for patients with renal impairment at baseline was not reached in the IPd group, whereas it was 11.6 months in the Pd group (HR 0.53; 95% CI 0.30-0.96). 2 For patients who received IPd, median OS was 10.7 months and 6.6 months in the Pd group (HR 0.62; 95% CI 0.26-1.45). Among patients without renal impairment at baseline, median OS was not reached in either group (HR 0.62; 95% CI 0.33-1.19).

[0173] In the IPd group, patients developed end-stage renal disease (ESRD; eGFR < 15 mL / min / 1.73 m 2 The number of patients with moderate RI at baseline was lower in the Isa-Pd group (2.9%) than in the Pd group (7.9%). Among patients with moderate RI at baseline, renal function worsened to severe RI or ESRD in 22.6% (12 / 53) of patients in the Isa-Pd group and 34.8% (16 / 46) of patients in the Pd group [OR 0.55; 95% CI, 0.20-1.45].

[0174] Treatment with IPd improved renal function in patients with renal impairment at baseline (including patients with eGFR < 45 mL / min / 1.73 m 2 The PFS and disease response rate of patients with renal impairment were significantly improved (PFS and disease response rate of patients with renal impairment). These results are consistent with the benefits observed in the overall study population. Compared with the treatment with Pd, the treatment with IPd was also associated with an increase in the number of patients with renal impairment reversal and with a durable renal response. The pharmacokinetic parameters between patients with renal impairment and those without renal impairment were comparable, which shows that no dose adjustment is needed for patients with renal impairment. Based on these data, it is expected that adding isatuximab to pomalidomide + dexamethasone will be beneficial for patients with RRMM and renal impairment. v. Effect of treatment on patients with high-risk cytogenetic abnormalities

[0175] The overall response rate (ORR) benefit observed in the IPd group compared to the Pd group was maintained in patients with at least one high-risk cytogenetic abnormality (i.e., one or more of del(17p), t(4;14), and t(14;16)) at baseline. In patients with standard-risk cytogenetics at baseline, the ORR in the IPd group (n=103) was 65% (3.9% CR, 28.2% VGPR, 33% PR), while the ORR in the Pd group (n=78) was 42.3% (1.3% CR, 7.7% VGPR, and 33.3% PR). In patients with at least one high-risk cytogenetic abnormality at baseline, the ORR in the IPd group (n=24) was 50.0% (29.2% VGPR, 20.8% PR), while the ORR in the Pd group (n=36) was 16.7% (2.8% VGPR, 13.9% PR). Among patients with del(17p) and 4(4;14) cytogenetic abnormalities at baseline, one patient in the IPd group (n=3) achieved a VGPR, and one patient in the Pd group (n=4) achieved a PR. Data on the odds ratios for response rates are provided in Table M2 below: Table M2.

[0176] Regardless of the high-risk cytogenetic cutoff definition used, the ORR benefit of treatment with IPd compared to Pd was maintained in patients with at least one high-risk cytogenetic abnormality at baseline. An ORR benefit of treatment with IPd compared to Pd was observed in patients classified as del(17p) according to any of the following cutoff definitions: at least 5% of plasma cells, at least 20% of plasma cells, at least 40% of plasma cells, at least 50% of plasma cells, or at least 60% of plasma cells. An ORR benefit of treatment with IPd compared to Pd was observed in patients classified as t(4;14) according to any of the following cutoff definitions: at least 3% of plasma cells, at least 20% of plasma cells, at least 30% of plasma cells, at least 40% of plasma cells, or at least 60% of plasma cells.

[0177] The PFS benefit observed in the IPd group compared to the Pd group was maintained in patients who had at least one high-risk cytogenetic abnormality at baseline (i.e., one or more of del(17p), t(4;14), and t(14;16)). In the IPd group, the median PFS for patients with standard-risk cytogenetics at baseline was 11.6 months, while in the Pd group, the median PFS for patients with standard-risk cytogenetics at baseline was 7.4 months. In the IPd group, the median PFS for patients with high-risk cytogenetics at baseline was 7.5 months, while in the Pd group, the median PFS for patients with high-risk cytogenetics at baseline was 3.7 months. For patients with del(17p) at baseline, the median PFS was 9.1 months in the IPd group and 7.4 months in the Pd group. For patients with t(4;14) at baseline, the median PFS was 7.5 months in the IPd group and 2.8 months in the Pd group. A PFS benefit with IPd compared to Pd was observed in patients classified as del(17p) according to any of the following cutoff definitions: at least 5% of plasma cells, at least 20% of plasma cells, at least 40% of plasma cells, at least 50% of plasma cells, or at least 60% of plasma cells. A PFS benefit with IPd compared to Pd was observed in patients classified as t(4;14) according to any of the following cutoff definitions: at least 3% of plasma cells, at least 20% of plasma cells, at least 30% of plasma cells, at least 40% of plasma cells, or at least 60% of plasma cells. vi. Safety in cytogenetic subgroups

[0178] The number of TEAEs experienced by high-risk and standard-risk patients treated with IPd or Pd is shown in Table M3. Table M3

[0179] Despite more grade ≥3 TEAEs occurring in high-risk patients, the addition of Isa to Pd did not increase events leading to treatment discontinuation. There was no increase in treatment-related mortality in either subgroup.

[0180] The numbers of Grade ≥3 events of the indicated laboratory abnormalities and TEAEs experienced in >5% of patients for high-risk and standard-risk patients treated with IPd or Pd are shown in Table M4. Table M4 *n-33; d, dexamethasone; Isa, isatuximab; P, pomalidomide; TEAE, treatment-emergent adverse event.

[0181] In patients with at least one high-risk cytogenetic abnormality at baseline, isatuximab + pomalidomide + dexamethasone has a manageable safety profile. The ORR benefit of Isa-Pd compared to Pd was maintained in patients with high-risk cytogenetics, and the benefit was independent of the cytogenetic cutoff definition used. Similar PFS benefits were observed with Isa-Pd compared to Pd for high-risk (del[17p], t[4;14] and / or t[14;16]) and standard-risk patients. Isa-Pd provides consistent benefits compared to Pd in ​​a difficult-to-treat subgroup of patients with high-risk cytogenetics and may be a new treatment option for RRMM. vii. Overall survival (OS)

[0182] As defined in the protocol, the efficacy margin for OS will be derived from the actual number of deaths observed at the interim analysis of OS based on the O'Brien and Fleming alpha spending function. At the interim analysis of OS, a trend towards longer OS was observed with the addition of isatuximab to Pd treatment, with the survival curves clearly separating from the baseline. Median OS had not yet been reached in either treatment group. At the time of analysis, the probability of surviving 12 months was 0.633 (95% CI: 0.545 to 0.709) in the Pd group and 0.720 (95% CI: 0.636 to 0.787) in the IPd group. The addition of isatuximab to Pd resulted in a statistically significant (one-sided p=0.001) and clinically meaningful improvement (according to IRC) in the primary endpoint of PFS. See Figure 4 . viii. Time to subsequent therapy

[0183] At the time of this analysis, 54% of patients in the Pd group and 39% of patients in the IPd group had started subsequent therapy. The median time to subsequent therapy was 9.1 months in the Pd group and not reached in the IPd group (HR: 0.538; 95% CI: 0.382 to 0.758). ix. Other endpoints

[0184] Response to treatment occurred more quickly and was more durable in the IPd group than in the Pd group.

[0185] Duration of Response (DOR): The median duration of response was longer in the IPd group than in the Pd group (13.27 months [10.612 to NC (ie, not calculated)] vs. 11.07 months [8.542 to NC], respectively). See Table N below.

[0186] Time to First Response: Among patients who achieved a response, the median time to first response was shorter in the IPd group (1.1 months / 35 days) than in the Pd group (1.9 months / 58 days). In the ITT analysis, the median time to first response was slightly shorter in the IPd group than in the Pd group (1.94 months [1.314 to 2.004] vs. 3.02 months [2.825 to 5.060], respectively). See Table N. Table N. Summary of reactions The HR for duration of response was 0.828 (95% CI: 0.464-1.474).

[0187] Improved response rates were observed across all subgroups. Among patients who had received two or three prior lines of therapy for multiple myeloma, the response rate was 56.9% in the IPd group and 38.6% in the Pd group. Among patients who had received more than three prior lines of therapy for multiple myeloma, the response rate was 67.3% in the IPd group and 28.8% in the Pd group.

[0188] Interference Assay Evaluation: Under the VGPR category, the IRC identified patients who met the CR criteria but had residual immunofixation positivity (historical near-CR category, undetectable M protein and immunofixation positivity). 24 patients (15.6%) in the IPd group and 5 patients (3.3%) in the Pd group had a near-CR as their best response. Serum samples from 22 of these patients in the IPd group were tested by mass spectrometry after separating the isatuximab signal from the myeloma M protein signal. In 11 of the 22 patients (50%), there was no longer detectable residual myeloma M protein at the sensitivity level of the immunofixation test (as performed in the central laboratory for this study (25 mg / dL, Hydragel, Sebia)), which means that the immunofixation was due to the presence of isatuximab. Due to the potential interference of isatuximab on the assessment of M protein by immunofixation, the depth of response, especially the complete response, may be underestimated.

[0189] Minimal residual disease (MRD): Adaptive Minimal residual disease (MRD) was assessed using the Bone Marrow Aspirate assay (version 2.0; Adaptive Biotechnologies, Seattle, WA, USA) at screening (ID calibrator sample), at confirmation of complete response or stringent complete response, and after three months in the case of MRD positivity. If the patient remains MRD positive, an additional sample can be collected. No more than three post-treatment samples are obtained.

[0190] The clonoSEQ assay is a next-generation sequencing (NGS)-based assay that identifies rearranged IgH (VDJ), IgH (DJ), IgK, and IgL receptor gene sequences, as well as translocated BCL1 / IgH (J) and BCL2 / IgH (J) sequences. The assay also includes primers that amplify specific genomic regions present as diploid copies in normal genomic DNA (gDNA) to allow determination of total nucleated cell content.

[0191] Testing begins with genomic DNA (gDNA) extracted from bone marrow aspirates. Multiplexed PCR is used to assess the quality of extracted gDNA and to amplify rearranged immune receptors. Reaction-specific index barcode sequences are added to the receptor sequences amplified by PCR for sample identification. Sequencing libraries are prepared from the barcoded amplified DNA, which is then sequenced using NGS with sequencing-by-synthesis. Raw sequence data is uploaded from the sequencing instrument to the Adaptive analysis pipeline. These sequence data are analyzed in a multi-step process: first, sequence data for a sample are identified using sample index sequences. Next, the data are processed using proprietary algorithms with online controls to remove amplification bias.

[0192] When a clonoSEQ clonality (ID) assessment is performed, the sample is examined for the presence of DNA sequences specific to one or more “dominant” clonotypes (that are consistent with the presence of a lymphoid malignancy). Clonal sequences are evaluated for suitability as ID sequences (for subsequent tracking) by first clustering highly similar sequences and requiring the frequency of the sequence to be at least 3% as a percentage of all sequences in the locus. In samples with sufficient abundance and differentiation from polyclonal background, a clonotype must have a frequency of at least 0.2% of all nucleated cells. Each sequence considered for MRD tracking is compared to the B-cell repertoire database and assigned a uniqueness value, which is used along with the abundance of the sequence relative to other sequences to assign the sequence to a sensitivity bin, which is used to estimate the reported limits of detection and quantification on patient reports.

[0193] During clonoSEQ tracking (MRD) assessment, the complete immunoglobulin receptor repertoire is again evaluated, and one or more dominant clonal sequences previously identified are detected and quantified to determine the sample MRD level.

[0194] MRD negative rate is defined as the proportion of patients with negative MRD by bone marrow aspirate at any time point after the first dose. For analysis purposes, patients in the intent-to-treat population who did not have a MRD assessment are considered MRD positive.

[0195] Bone marrow samples for MRD assessment were collected by the investigator for patients with an investigator-assessed complete response or if clinically indicated. 16 patients, including all patients with confirmed CR or sCR according to IRC examination (7 patients in the isatuximab group and 3 patients in the control group), were analyzed. It should be noted that responses other than CR may have been attributed by the IRC because the investigators based their assessment on local M-protein laboratory results, while the IRC assessment was based on central M-protein results.

[0196] In the IPd group, -4 (i.e., 10 4 In 10 (6.5%) patients, the sensitivity of 1 multiple myeloma cell in 1 nucleated cell was 2. -5 (i.e., 10 5 in 8 (5.2%) patients with a sensitivity of 1 multiple myeloma cell in 10 -6 (i.e., 10 6 MRD negativity in the ITT population was observed in 2 patients (1.3%) at a sensitivity of 1 multiple myeloma cell in 1 nucleated cell. No MRD negativity was observed in patients in the Pd (control) group.

[0197] Quality of life: Overall quality of life (as measured by the QLQ-C30 global health status score) persisted over time and was similar in both treatment groups. Adding isatuximab to Pom+Dex did not negatively impact patients' quality of life. Further analysis showed that adding isatuximab to Pom+Dex maintained health-related quality of life in patients.

[0198] Efficacy analysis according to previous lines of treatment and refractory status: Regardless of the number of previous lines of treatment or refractory status, the PFS benefit of IPd compared to Pd was maintained in all analyzed subgroups (see Table O below). This included patients with 4 previous lines of treatment (8.54 vs. 3.29 months; HR 0.498; 95% CI 0.258-0.962), patients who were refractory to Len and PI (11.20 vs. 4.76 months; HR 0.579; 95% CI 0.401-0.835), and patients who were refractory to the last line of Len (11.6 vs. 5.7 months; HR 0.50; 95% CI 0.34-0.76). In subsequent analyses, the number of patients who were refractory to lenalidomide on the last line of treatment in the IPd group was 93, and the number of patients who were refractory to lenalidomide on the last line of treatment in the Pd group was 88. Table O. Progression-free survival in the IPd and Pd groups according to refractory status and number of previous lines of therapy

[0199] In addition, regardless of the number of previous therapy lines, more patients responded to treatment with IPd compared to Pd. In patients who had received 2-3, >3, and 4 previous therapies, the overall response rate (ORR) in the IPd group was higher than that in the Pd group. In patients who had received 2-3 previous therapy lines, the ORR was 56.9% (of which 32.4% achieved VGPR or better) in the IPd group (n=102), compared to 38.6% (of which 10.9% achieved VGPR or better) in the Pd group (n=101). In patients who had received >3 previous therapy lines, the ORR was 67.3% (of which 30.8% achieved VGPR or better) in the IPd group (n=52), compared to 28.8% (of which 3.8% achieved VGPR or better) in the Pd group (n=52). Among patients who had received four prior lines of therapy, the ORR was 56.3% in the IPd group (n=32) (31.3% achieved a VGPR or better) compared to 28.6% in the Pd group (n=28) (7.1% achieved a VGPR or better).

[0200] In patients who were refractory to lenalidomide (Len), refractory to proteasome inhibitors (PIs), refractory to both Len and PIs, and refractory to Len in the last line of treatment, the ORR in the IPd group was higher than that in the Pd group. In patients refractory to Len, the ORR in the IPd group (n=144) was 59.0% (of which 30.6% achieved VGPR or better), while the ORR in the Pd group (n=140) was 31.4% (of which 7.1% achieved VGPR or better). In patients refractory to PIs, the ORR in the IPd group (n=118) was 60.2% (of which 30.5% achieved VGPR or better), while the ORR in the Pd group (n=115) was 32.2% (of which 7.8% achieved VGPR or better). In patients who were refractory to both Len and PI, the ORR in the IPd group (n=111) was 58.6% (of which 29.7% achieved VGPR or better), while the ORR in the Pd group (n=107) was 29.9% (of which 8.4% achieved VGPR or better). In patients who were refractory to Len on the last line of treatment, the ORR in the IPD group (n=93) was 55.9% (of which 32.3% achieved VGPR or better), while the ORR in the IPd group (n=88) was 29.5% (of which 4.5% achieved VGPR or better).

[0201] The PFS benefit of IPd compared to Pd was consistent with that seen in the overall population, regardless of the number of prior lines of therapy or refractory status. Adding isatuximab to pomalidomide + dexamethasone improved treatment response rates in all subgroups analyzed by prior therapy. Notably, the benefit of IPd compared to Pd was maintained in patients who were refractory to their last line of Len. D. Safety

[0202] Safety is assessed by the following: treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to treatment interruption, other significant AEs (e.g., infusion reactions, second primary malignancies, respiratory AEs, neutropenia and neutropenia complications, infections, thrombocytopenia and bleeding, tumor lysis syndrome, hemolytic disorders and blood cell transfusions, autoimmune disorders), standard hematology and blood chemistry. The safety population includes patients from the ITT population who have actually received at least one or partial dose of study treatment. All analyses using this population are based on the treatment actually received. The overall safety profile of IPd is well characterized and manageable and does not interfere with treatment duration and sustained clinical benefit. Adding aisatuximab to Pd is primarily associated with an increase in low-grade infusion reactions and neutropenia and infection. Positive ADA (i.e., anti-drug antibodies, particularly anti-isatuximab antibodies) has not been identified.

[0203] The addition of esatuximab to pomalidomide and dexamethasone demonstrated a statistically significant and clinically meaningful benefit in PFS in heavily pretreated patients with relapsed and refractory multiple myeloma. Kaplan-Meier curves ( Figure 2 and Figure 3 ) showed early and sustained separation, which translated into a 41% reduction in the risk of death or progression in patients in the isatuximab group. PFS benefits were seen in all subgroups, including patients with high-risk cytogenetics (HR 0.66), patients over 75 years of age, patients with renal impairment, and patients who had received 2-3 previous lines, patients who had received>3 previous lines, patients who were refractory to lenalidomide and proteasome inhibitors, and patients who were refractory to lenalidomide in the last line. The PFS in the case of isatuximab, pomalidomide, and dexamethasone was the longest observed in this patient population to date. High-risk cytogenetics were determined using an internationally recognized positive threshold by central laboratory FISH analysis. In addition, the overall response benefit was seen in all subgroups. The results of the subgroup analysis also provided the first evidence of improving renal function with CD38-targeted therapy in RRMM patients.

[0204] Compared with Pd (i.e., pomalidomide and dexamethasone), IPd (i.e., isatuximab with pomalidomide and dexamethasone) significantly improved the response rate and depth of response. IPd treatment also led to the reversal of renal impairment. 5.2% of patients in the isatuximab group and 0% of patients in the control group achieved remission within 10 days. -5 Minimal residual disease negative status (ITT) at the lowest level. Example 2: Subgroup analysis of East Asian patients in a phase III randomized, open-label, multicenter study comparing the combination of isatuximab (SAR650984) with pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with refractory or relapsed and refractory multiple myeloma.

[0205] This example describes a subgroup analysis of East Asian patients in the Phase III, multicenter, multinational, randomized, open-label, parallel-group, 2-arm study described in Example 1. This subgroup analysis evaluated the safety and efficacy of isatuximab in combination with pomalidomide and low-dose dexamethasone compared with pomalidomide and low-dose dexamethasone for the treatment of East Asian patients with refractory or relapsed and refractory multiple myeloma (RRMM) who had received at least 2 prior lines of therapy for multiple myeloma (e.g., > 2 prior lines of therapy), including lenalidomide and a proteasome inhibitor (e.g., bortezomib, carfilzomib, or ixazomib), given alone or in combination, and are refractory to their last therapy.

[0206] East Asian patients were randomized to either the Isa-Pd (IPd) experimental group or the Pd control group as described in detail in Example 1. Patients in the IPd group received isatuximab at a dose of 10 mg / kg on days 1, 8, 15, and 22 of cycle 1, and then at a dose of 10 mg / kg on days 1 and 15 of subsequent 28-day cycles. Patients in the IPd and Pd groups received pomalidomide at a dose of 4 mg on each of days 1 to 21 of each 28-day cycle, and dexamethasone at a dose of 40 mg (20 mg if the patient was ≥75 years old) orally or intravenously on days 1, 8, 15, and 22. Results A. Patient Characteristics

[0207] 36 East Asian patients (13 Japanese patients, 9 Korean patients and 14 Chinese patients) were included in this subgroup analysis. 21 patients in the East Asian subgroup were assigned to the IPd experimental treatment group, and 15 patients were assigned to the Pd control treatment group. Of the 13 Japanese patients in this subgroup, 9 patients were assigned to the IPd experimental treatment group, and 4 patients were assigned to the Pd control treatment group.

[0208] Patient characteristics in the East Asian subgroup were similar to those of the entire population of the Phase III study described in Example 1. The median age was 65 years (range: 41-85 years). The median number of prior lines of therapy was 3 (range: 2-7). 91.7% of patients in this subgroup were refractory to prior lenalidomide therapy, and 69.4% of patients in this subgroup were refractory to prior PI therapy. 13.9% of East Asian patients had high-risk cytogenetics. B. Efficacy i. Progression-free survival (PFS)

[0209] After a median follow-up of 11.6 months, median PFS was not reached for the IPd group.For the Pd group, median PFS was 7.9 months (HR 0.517 [95% CI 0.19-1.39]). ii. Overall response rate (ORR)

[0210] ORR (≥PR) was 71.4% in the IPd group and 60% in the Pd group.

[0211] The VGPR rate or better was 61.9% in the IPd group and 13.3% in the Pd group.

[0212] The median time to first reaction was 32 days in the IPd group and 59 days in the Pd group. C. Safety

[0213] Grade ≥3 AEs were observed in 90.5% and 93.3% of patients in the IPd and Pd arms, respectively. Grade ≥3 AEs led to treatment discontinuation in 9.5% of patients in the IPd arm.

[0214] Infusion reactions were reported in 57.1% of patients receiving IPd. No infusion reactions were Grade 3-4. Conclusions

[0215] A subgroup analysis of 36 East Asian patients from the Phase III study described in Example 1 demonstrated that the efficacy and safety of Isa-Pd in ​​the East Asian population (including Japanese patients) were comparable to the entire population studied in Example 1. Isa-Pd is a novel treatment option for East Asian patients with RRMM. Example 3: Depth of Response and Response Kinetics in a Study of Isarituximab + Pomalidomide + Dexamethasone in Patients with Relapsed / Refractory Multiple Myeloma

[0216] In multiple myeloma (MM), deep responses have been associated with improvements in progression-free survival (PFS) and overall survival (OS). Response kinetics data (including renal response time) are rarely reported, which is very important for patients with renal impairment (RI). Data from the randomized, open-label, active-controlled, Phase 3 study described in Example 1 were used to analyze the association between depth of response (including minimal residual disease (MRD) negativity) plus response kinetics and long-term outcomes. Methods

[0217] As described in Example 1, all patients received standard doses of pomalidomide + dexamethasone ("Pd"), and patients randomized to the Isa-Pd group received Pd and 10 mg / kg isatuximab IV on days 1, 8, 15, and 22 (cycle 1) and on days 1 and 15 of subsequent 28-day cycles until progression. The depth and kinetics of response were analyzed for each treatment group. -5 Minimal residual disease ("MRD") was assessed (tested by next-generation sequencing in patients with complete response [CR] / stringent CR [sCR]). Time to biochemical response, improvement in renal response (Crenal; estimated glomerular filtration rate (eGFR) using the MDRD GFR equation (see www(dot)kidney(dot)org / content / mdrd-study-equation) from <50 mL / min / 1.73 m2 at baseline) were recorded. 2 ≥60 mL / min / 1.73 m2 at ≥1 post-baseline assessment 2 ) and time to persistent C nephron (C nephron lasting ≥ 60 days). Neutralization assays were not used for patients with IgGκ clonality. Results

[0218] Overall, 307 patients were randomized to Isa-Pd (n=154) or Pd (n=153), of whom 33 / 142 (23.2%) and 24 / 145 (16.6%) had an eGFR <50 mL / min / 1.73 m2 measured at baseline. 2 Patients had received a median of 3 prior lines of therapy (range 2-11), and 73.4% and 71.9% of patients in the Isa-Pd and Pd arms, respectively, were double refractory (i.e., to and proteasome inhibitor refractory). Median PFS was 11.53 months with Isa-Pd and 6.47 months with Pd (hazard ratio [HR] 0.596 [95% confidence interval (CI) 0.436-0.814]). Biochemical responses were more frequent and deeper with Isa-Pd than with Pd. Overall response rate (ORR) was 60.4% vs. 35.3% (odds ratio [OR] 2.80; 95% confidence interval [CI] 1.72-4.56; p < 0.0001); > very good partial response rate (VGPR) was 31.8% vs. 8.5% (OR 5.03; 95% CI 2.51-10.59; p < 0.0001). Near complete response rate (immunofixation remained positive) was reported due to no Interferometry assay performed: 15.6% in the Isa-Pd group vs. 3.3% in the Pd group (OR 5.47; 95% CI 1.96-18.78; p = 0.0002). MRD-negative rate (at a sensitivity of 10 -5 in the Isa-Pd group vs. 0% in the Pd group. In both groups, depth of response was associated with improved long-term outcome. After a median follow-up of 11.6 months in the Isa-Pd group, 100% of MRD-negative (MRDneg) patients were progression-free and alive. Median PFS was longer in the Isa-Pd group with increasing depth of response. In MRDneg patients (n = 8) in the Isa-Pd group, median PFS was not reached (NR). In > VGPR patients (n = 42) in the Isa-PD group who were MRD±, median PFS was 15.21 months. In patients (n = 44) in the Isa-Pd group who achieved PR, median PFS was 11.53 months. In patients (n = 57) in the Isa-Pd group who achieved less than PR, median PFS was 3.29 months (see Figure 6A ) In the Pd group, median PFS was not calculable in patients who achieved > PR response, while in patients with < PR, median PFS was 2.86 months (range: 2.6-3.81 months).

[0219] In the Isa-Pd group, 1 -year OS rate was highest in MRD- patients and was associated with depth of response. In MRDneg patients in the Isa-Pd group, 1 -year OS rate was 100%. In > VGPR patients in the Isa-Pd group who were MRD±, 1 -year OS rate was 92.9%. In patients in the Isa-Pd group who achieved PR, 1 -year OS rate was 82.4%. In patients in the Isa-Pd group who achieved less than PR, 1 -year OS rate was 46.4% (see Figure 6BIn the Pd arm, the one-year OS rate also correlated with the depth of response. Among patients in the Pd arm who achieved a VGPR or greater with MRD±, the one-year OS rate was 88.9%. Among patients in the Pd arm who achieved a PR, the one-year OS rate was 90.6%. Among patients in the Pd arm who achieved less than a PR, the one-year OS rate was 54.3%.

[0220] Biochemical responses occurred faster with Isa-Pd than with Pd. Among patients who achieved a ≥PR response (93 in the Isa-Pd group and 54 in the Pd group), the median time to first response was shorter with Isa-Pd (1.1 months) than with Pd (1.9 months). Among patients who achieved a ≥VGPR response (49 and 13 in the Isa-Pd and Pd groups, respectively), the time to first VGPR or better was similar, 2.9 months for Isa-Pd and 3.0 months for Pd. Among patients who achieved a ≥CR response (7 in the Isa-Pd group and 3 in the Pd group), the median time to first CR or better was shorter with Isa-Pd (5.7 months) than with Pd (7.9 months). The time to best response was 2.5 months in the Isa-Pd group, compared to 2.8 months in the Pd group.

[0221] Renal responses occurred faster in patients receiving Isa-Pd than in the case of Pd. Complete renal responses (C renal) were observed in 23 / 32 (71.9%) patients in the Isa-Pd group (median time to first complete renal response was 4.1 weeks) and in 8 / 21 (38.1%) patients in the Pd group (median time to first response was 7.3 weeks). Persistent C renal (i.e., C renal ≥ 60 days, also referred to as "persistent C renal") was observed in 10 / 32 (31.3%) patients in the Isa-Pd group (median time to first response was 2.4 weeks) and in 4 / 21 (19.0%) patients in the Pd group (median time to first response was 4.8 weeks). In addition, renal responses occurred faster in patients in the Isa-Pd group than in the Pd group. See Figure 7 As mentioned above, the median time to C nephron was 4.1 weeks in the Isa-Pd group and 7.3 weeks in the Pd group. The median time to sustained C nephron (i.e., C nephron ≥ 60 days) was 2.4 weeks in the Isa-Pd group and 4.8 weeks in the Pd group. The median time to first renal response (including mild and partial responses) was 3.1 weeks in the IPd group and 7.3 weeks in the IPd group. Conclusions

[0222] In the heavily pretreated population studied in Example 1, Isa-Pd induced more frequent and faster biochemical responses (i.e., tumor responses) and renal responses compared to Pd. Response depth (including MRD negativity) was improved with Isa-Pd and was associated with better long-term survival outcomes (i.e., PFS and OS). The results of the subgroup analysis also provide the first evidence of improved renal function with CD38-targeted therapy in RRMM patients. Example 4: Efficacy of Isartumomab with Pomalidomide and Dexamethasone in Elderly Patients with Relapsed / Refractory Multiple Myeloma

[0223] Multiple myeloma (MM) is most commonly diagnosed in individuals aged 65-74 years, and approximately one-third of patients are aged ≥75 years. Advanced age negatively impacts the prognosis of patients with MM. Example 1 Treatment with the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with pomalidomide and dexamethasone (Pd) was compared with Pd. Patients had relapsed / refractory MM (RRMM) after ≥2 prior lines of therapy (including lenalidomide and a proteasome inhibitor). This subgroup analysis examined the efficacy and safety of Isa in elderly patients (≥75 years) compared with younger patients. Methods

[0224] Patients were randomized (1:1) to receive Isa-Pd or Pd. Isa (10 mg / kg IV) was administered on days 1, 8, 15, and 22 (cycle 1) and on days 1 and 15 of subsequent 28-day cycles. All patients received pomalidomide 4 mg on days 1 to 21 of each cycle and dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) on days 1, 8, 15, and 22 of each cycle. The primary endpoint was progression-free survival (PFS) assessed by an independent response committee. Subgroup analyses were performed for patients aged < 65 years, 65-74 years, and ≥ 75 years. Results

[0225] Overall, 307 patients were randomized to Isa-Pd (n=154) or Pd (n=153) and included in the intention-to-treat population. The median age of patients was 68.0 years in the Isa-Pd group and 66.0 years in the Pd group. In the Isa-Pd and Pd groups, 54 (35%) and 70 (46%) patients, respectively, were <65 years old, 68 (44%) and 54 (35%) patients were 65-74 years old, respectively, and 32 (21%) and 29 (19%) patients, respectively, were ≥75 years old.

[0226] In the overall population, a significant improvement in median PFS was obtained with Isa-Pd compared to Pd (11.53 vs 6.47 months; hazard ratio [HR] 0.596 [95% confidence interval (CI) 0.436-0.814], p=0.001). Consistently, median PFS was 11.40 months with Isa-Pd and 4.47 months with Pd for patients >75 years old (HR 0.479 [95% CI, 0.242-0.946]). Similarly, PFS was 11.57 and 8.58 months in the Isa-Pd and Pd groups, respectively, for patients 65-74 years old (HR 0.638 [0.385-1.059]) and 11.53 months vs 5.03 months for patients <65 years old (HR 0.656 [95% CI, 0.401-1.074]). See Table P. Table P: Median PFS for patients <65 years old, 65-74 years old, and >75 years old in the two treatment groups. <65 years old 65-74 years ≥ 75 years Isa-Pd arm 11.53 months 11.57 months 11.40 months Pd arm 5.03 months 8.58 months 4.47 months

[0227] Overall response rate (ORR) was 60.4% with Isa-Pd and 35.3% with Pd, with an odds ratio (OR) of 2.80 (95% CI, 1.72-4.56). ORR by age group among patients receiving Isa-Pd vs Pd: 53.1% and 31.0% in the >75 years old group (OR 2.52 [95% CI, 0.79-8.26]); 64.7% and 38.9% in the 65-74 years old group (OR 2.88 [95% CI, 1.29-6.46]); and 59.3% and 34.3% in the <65 years old group (OR 2.79 [95% CI, 1.26-6.20]).

[0228] Very good partial response (VGPR) was achieved by 31.8% of patients with Isa-Pd and 8.5% of patients with Pd, with an OR of 5.03 (95% CI, 2.51-10.59). The rate of >VGPR by age among patients receiving Isa-Pd vs Pd: 31.3% and 0% in the >75 years old group (OR not calculated); 32.4% and 13.0% in the 65-74 years old group (OR 3.21 [95% CI, 1.17-9.70]); and 31.5% and 8.6% in the <65 years old group (OR 4.90 [95% CI, 1.64-16.35]).

[0229] Overall, 8 patients in the Isa-Pd group had a CR or VGPR at 10 -5All had minimal residual disease negative. 2 / 8 were >75 years old and 2 / 8 were aged 65-74 years. The remaining 4 patients were <65 years old. No patients in the Pd arm achieved MRD negative.

[0230] At the time of the interim analysis, overall survival (OS) data were immature. However, in the older population, 8 / 32 (25%) of patients in the Isa-Pd arm had died with a median OS not reached and in the Pd arm, 15 / 29 (51.7%) of patients had died with a median OS of 10.25 months (HR 0.404 (95% CI 0.171-0.956).

[0231] In a subsequent analysis of OS in patients aged 65-74 years, the median OS was not reached in the Isa-Pd arm and OS in the Pd arm was 14.5 months (HR 0.75; 95% CI 0.38-1.45). For patients <65 years of age, the median OS was not reached for either treatment arm (HR for Isa-Pd vs Pd was 0.85 (95% CI 0.46-1.59).

[0232] The one-year OS rate was similar for patients aged >75 years, aged 65-74 years and <65 years in the Isa-Pd arm. See Table Q below. Table Q: One-year overall survival rate for patients <65 years, 65-74 years and >75 years in the two treatment arms. <65 years old 65-74 years ≥ 75 years Isa-Pd arm 67.7％ 74.7％ 73.5％ Pd arm 63％ 72.9％ 47.2％

[0233] In the Isa-Pd arm, the incidence of treatment-emergent adverse events (TEAEs) was similar across age groups: <65 years, 98.1%; 65-74 years, 100%; and >75 years, 100%. The incidence of TEAEs was comparable in both arms.

[0234] In the case of Isa-Pd, there were more grade ≥3 TEAEs in patients aged ≥75 years (93.8%) compared to patients <65 years (85.2%), and a similar trend was observed in the Pd group (75.0% and 64.7%, respectively). There were also more treatment discontinuations due to TEAEs in patients aged ≥75 years compared to patients <65 years in the Isa-Pd group (15.6% and 7.4%) and the Pd group (14.3% and 10.3%). In both groups, the incidence of serious TEAEs (SAEs) was higher in patients aged ≥75 years compared to patients <65 years (Isa-Pd, 68.8% and 57.4%; Pd, 57.1% and 47.1%). The incidence of TEAEs with fatal outcomes was lower in patients aged ≥75 years (6.3%) compared with those aged <65 years (11.1%) in the Isa-Pd group, while the opposite trend was observed with Pd (14.3% vs. 5.9%). Conclusions

[0235] Adding Isa to Pd improved PFS, ORR, ≥VGPR, and OS rates in elderly patients, consistent with the benefits observed in the overall study population. In the Isa-Pd arm, PFS and one-year OS rates were similar in patients aged <65 years, 65-74 years, and ≥75 years. There was a consistent trend toward higher SAE rates and discontinuation rates due to TEAEs in patients aged ≥75 years compared with younger patients in both the Isa-Pd and Pd arms, but there was no increase in fatal AEs in the Isa-Pd arm. Example 5: Relationship between baseline biomarkers and the efficacy of isatuximab in combination with pomalidomide and dexamethasone in RRMM

[0236] Baseline biomarker analysis was performed on samples from two clinical studies: a Phase I study evaluating the safety and maximum tolerated dose of isatuximab in combination with pomalidomide and dexamethasone in patients with relapsed / refractory multiple myeloma, and a Phase III study described in Example 1. CD38 receptor density (RD), FCGR3A (Fc immunoglobulin receptor) genotype, and bone marrow or peripheral blood immune phenotype were assessed to provide information on response to the Isa-Pd regimen. Methods

[0237] Both studies recruited similar populations of RRMM patients who had received ≥2 prior lines of therapy, including lenalidomide and a proteasome inhibitor. In both studies, baseline blood samples were obtained before the first treatment administration; in addition, bone marrow samples were obtained during screening in the Phase I study. In the Phase I study, bone marrow plasma cells were analyzed for CD38 RD. Blood samples and bone marrow aspirates were used to characterize immune cell populations (CD19 + B cells, CD3 + T cells, CD4 + T cells, regulatory T cells (Treg) and natural killer (NK) cells [CD56 + Bright CD16 + Low subpopulation and CD56 + Dark CD16 + Blood samples from both studies were analyzed for FCGR3A genotyping (V158 and F158 high- and low-affinity alleles). Biomarker results correlated with response, defined as at least partial response according to the International Myeloma Working Group criteria. Results

[0238] The Phase I study recruited 45 patients and treated them with Isa-Pd. As discussed in Example 1, the Phase III study randomized 154 patients to Isa-Pd and 153 patients to Pd. The baseline patient demographics of the two studies were similar, and the median number of previous therapy lines was 3 (range: 1-10) for the Phase I study and 3 (2-11) for the Phase III study. The overall response rate (ORR) with Isa-Pd was 62.2% (28 / 45) in the Phase I study and 60.4% (93 / 154) in the Phase III study. In the Phase I study, for 31 treated patients with evaluable results, the median CD38 RD was 108,172 receptors / cancer cell (range: 12,950-337,335). In patients who responded to Isa-Pd (n=21), the median CD38 RD value was 120,931 (48,770-337,335) receptors / cancer cell; in patients who did not respond to Isa-Pd (n=10), the median CD38 RD value was 85,370 (range 12,950-309,003) receptors / cancer cell. In five Phase I / II clinical studies with Isa, 4 / 198 patients (2.0%) had CD38 RD levels below 48,770, the lowest value among responding patients.

[0239] FCGR3A genotyping results were available for both studies. In both studies, as found in the general population, the distribution of the F158V single nucleotide polymorphism of the FCGR3A gene was 42% for F / F, 42% for F / V, and 16% for V / V. In both studies, responses were observed for all 3 genotypes (Table R). In the Phase I study, the ORR observed for the 3 genotypes ranged from 50.0% to 80.0% for the Isa-Pd regimen, while in the larger Phase III study, the ORR for the Isa-Pd regimen was more similar between genotypes (ranging from 56.9% to 65.5%). Progression-free survival (PFS) ranged from 8.97 months to 14.78 months, and Isa-Pd showed a PFS benefit over Pd for all 3 genotypes (see Table R). Table R: Response data by FCGR3A genotype

[0240] In the Phase I study, 42 patients had at least one baseline peripheral blood immune biomarker value, and of these patients, 17 patients were non-responders and 25 patients were responders. In addition, 41 patients had at least one baseline bone marrow immune biomarker measurement (16 were non-responders and 25 were responders). During screening, no significant differences were observed between responders and non-responders for the immune biomarkers tested in the bone marrow. P values were 0.2817 (CD19+ B cells), 0.6446 (CD3 + T cells), 0.7780 (CD4 + T cells), 0.1620 (Tregs), 0.9591 (NK cells), 0.8275 (CD56 + bright / CD16 + low NK cells), and 0.7389 (CD56 + dim / CD16 + bright NK cells). Similarly, no significant differences were observed between responders and non-responders for the immune biomarkers in the blood. Conclusions

[0241] Biomarker analysis of samples from patients treated with Isa-Pd showed that a treatment benefit of Isa-Pd was seen in all groups regardless of baseline bone marrow plasma cell CD38 RD, FCGR3A genotype, or immune phenotype in bone marrow plasma cells or peripheral blood. Example 6: Development of a pharmaceutical formulation comprising isatuximab for intravenous administration. Development of Formulation 1 (containing 5 mg / ml of isatuximab)

[0242] Formulation 1 was developed with a concentration of 5 mg / mL of isatuximab to achieve the desired pH, osmolarity, and stability requirements. Several different formulations were developed and tested under various stress conditions designed to simulate those encountered during manufacturing, shipping, storage, and handling. The stress conditions tested for each formulation included: Mechanical stress by shaking (350 rpm during 15 hours), Heat stress at 40°C or 45°C, Freeze-thaw cycles (3 to 5 cycles from -20°C or -30°C to room temperature), Light exposure (sunlight testing), and Dilute with infusion solution.

[0243] Formulations containing one of the following buffers at one of the following pH values ​​were also tested: Citrate 10 mM, pH 5.0, 5.5, 6.0, 6.5, or 7.0; Histidine 10 mM, pH 5.5, 6.0, or 6.5; Phosphate 10 mM, pH 6.5, 7.0, or 7.4; Succinate 10 mM, pH 5.0, 5.5 or 6.0; and Acetate 10 mM, pH = 5.0 or 5.5.

[0244] The buffer-pH system was selected based on its buffering capacity in the pH range of interest. The buffer-pH system was evaluated for its effect on the aggregation of isatuximab (in terms of the formation of visible and invisible particles and the formation of high molecular weight species (HMWS, e.g., soluble aggregates)) after shaking and thermal stress.

[0245] Compared with the formulations containing citrate, phosphate or succinate buffers, it was found that the formulations containing histidine or acetate buffers provided higher stability. In addition, it was found that citrate and succinate buffers reduced the solubility of isatuximab because the solution became milky white with each of the two buffers. Dynamic light scattering (DLS) showed a gradual increase in the Z-average value, and static light scattering (SLS) showed molecular attraction in the formulations comprising sodium citrate or sodium succinate and molecular repulsion in the formulation comprising histidine under the condition of virial coefficient A22. In addition, compared with citrate and succinate buffers, during ultrafiltration / diafiltration, the HMWS of isatuximab produced by the histidine buffer was less (as measured via size exclusion high performance liquid chromatography (SE-HPLC)).

[0246] The effects of formulations containing histidine and acetate buffers on stability against charge heterogeneity under thermal stress were further tested and showed similar stability. Based on the results, the following buffer-pH system for stabilization of isatuximab was selected for further development steps: histidine 10 mM, pH = 5.5 to pH 6.5; acetate 10 mM, pH = 5.0 and pH 5.5.

[0247] The ability of NaCl (0.8% w / v), sucrose (5% w / v) and mannitol (3% w / v) in combination with selected pH buffer systems to improve the stability of isatuximab (as measured by the aggregation of isatuximab) was tested. Aggregation was assessed by measuring the amount of visible and invisible particles, soluble aggregates (HMWS) and debris (low molecular weight species (LMWS)) after shaking, thermal stress and / or freeze / thaw cycles.

[0248] In the case of the formulation containing NaCl, isatuximab was found to be significantly destabilized under heat, freeze-thaw and oscillation stress (as indicated by increased levels of invisible particles).

[0249] Formulations containing sucrose or mannitol were found to have a stabilizing effect on isatuximab.

[0250] Formulations containing acetate buffer showed higher post-translational modifications (PTMs) under heat stress compared to formulations with histidine. Higher deamidation was found in formulations containing acetate buffer.

[0251] In formulations containing histidine and sucrose or mannitol at pH values ​​between 6.0 and 6.5, no significant differences in the behavior of isatuximab were observed (e.g., using the assays discussed above, according to the criteria discussed above). Therefore, the histidine pH 6.5 buffer was selected for further development testing. In formulation 1, the concentration of mannitol was increased to 5% (w / v) and the concentration of sucrose was increased to 10% (w / v) to achieve the target isotonicity. Sucrose 10% (w / v) corresponds to 292 mOsm / kg osmotic pressure, and mannitol 5% (w / v) corresponds to 330 mOsm / kg osmotic pressure.

[0252] Next, different concentrations of various surfactants were evaluated. Polysorbate 80 (PS80) was tested at concentrations ranging from 0.001% to 0.01% with histidine 10 mM pH 6.5, 5% mannitol. The test formulations were subjected to shaking stress (15 h at 350 rpm) or diluted to 2 mg / mL in NaCl 0.9% or dextrose 5% solutions. Non-visible particles under light obscuration (LO) were estimated. Equivalent results were obtained with formulations containing all the tested concentrations of PS80, even at the lowest level of 0.001% PS80, which shows the high stabilizing efficiency of PS80 on isatuximab under the applied stress. The 0.005% concentration of PS80 was chosen to allow potential adsorption of PS80 during manufacturing steps (i.e. compounding, filtration and filling operations of the formulated drug substance).

[0253] Two formulations were selected from the formulation development study: histidine 10 mM, PS80 0.005% (w / v) pH 6.5 with 5% (w / v) mannitol or 10% (w / v) sucrose and tested for six months stability as shown in Table S. Table S a Suntest exposure: total illuminance not less than 1.2 million lux hours and integrated near ultraviolet energy not less than 200 watt hours / square meter. Dark control samples were stored under the same conditions to eliminate any effect due to local temperature variations.

[0254] Based on the variability of the different analytical procedures, no significant difference was observed between any of the formulations, except under suntest exposure, where the prototype containing mannitol had more acidic form. In addition, mannitol can crystallize at freezing temperature. Therefore, sucrose was chosen as stabilizer.

[0255] Therefore, a pharmaceutical formulation 1 containing the following was developed: • 5 mg / mL isatuximab • 10 mM histidine • 10% (w / v) sucrose • 0.005% (w / v) polysorbate 80 • pH 6.5.

[0256] Isatuximab formulated in formulation 1 has a 24 months shelf life at +5°C ± 3°C. The 5 mg / ml concentration of isatuximab is compatible with very low dose isatuximab to meet the minimum anticipated biological effect level (MABEL) dosing regimen; however, to allow administration of higher doses, a formulation containing a higher concentration of isatuximab is also needed. Development of Formulation 2 (containing 20 mg / ml of isatuximab)

[0257] The pH and molar concentration of the histidine buffer were tested to achieve potential stability improvements and higher buffering capacity. Histidine was tested at the following concentrations and pH values: 10 mM, pH = 6.0; 10 mM, pH = 6.5; 20 mM, pH = 6.0; and 20 mM, pH 6.5. The stability of aisatuximab in each test formulation was evaluated by measuring the following under thermal stress conditions (i.e., 1 month at 40 ° C): aggregation (HMWS and LMWS measured by SE-HPLC), invisible particle counts (using flow cytometry (FCM)), charge heterogeneity (using weak cation exchange chromatography (WCX)), hydrodynamic radius values ​​(Z average values) and polydispersity index (PdI) measured by DLS. Surprisingly, better aisatuximab stabilization was observed in pH 6.0 formulations (10 mM or 20 mM histidine) compared to pH 6.5 formulations. Therefore, 20 mM histidine at pH 6.0 was selected for Formulation 2 due to increased isatuximab stability and higher buffering capacity. Effect of PS80 surfactant content

[0258] The effect of PS80 content was evaluated in formulations containing between 0.015% (w / v) and 0.025% (w / v) PS80. Oscillation and dilution in the infusion solution were applied as stress conditions.

[0259] After subjecting the test formulations to shaking, no differences in the number of invisible particles were observed by flow cytometry for PS80 contents ranging between 0.015% (w / v) and 0.025% (w / v).

[0260] The stability of formulations with PS80 contents between 0.015% (w / v) and 0.025% (w / v) was tested after dilution in a 0.9% NaCl solution. The formulations were diluted to 2 mg / mL of isatuximab in a 0.9% NaCl infusion bag. The samples were measured for invisible particles. No differences between the formulations were observed. Thus, it was found that for 20 mg / ml of isatuximab, formulations with PS80 concentrations between 0.015% (w / v) and 0.025% (w / v) had similar stability profiles.

[0261] Under long-term storage, PS80 may degrade over time. To simulate the effects of long-term storage, a formulation with a PS80 concentration of 0.0057% (w / v) was evaluated by applying stirring, shaking, and freeze / thaw stress conditions. These conditions correspond to storing a sample initially containing 0.020% or 200 ppm PS80 at 5°C for 50 months.

[0262] No changes in aggregation characteristics were observed after exposure to agitation stress (stirring and shaking) or after freeze / thaw stress. This demonstrates that when 20 mg / ml ixatuximab is formulated with 20 mM histidine, 10% (w / v) sucrose at pH 6.0, ixatuximab stability is not affected by reduction of PS80 content to as low as 57 ppm, even after exposure to agitation or freeze / thaw stress.

[0263] Therefore, a pharmaceutical formulation was developed containing: 20 mg / mL isatuximab 20 mM histidine 10% (w / v) sucrose 0.02% (w / v) polysorbate 80 pH 6.0.

[0264] Although the present disclosure has been described in detail by way of illustration and example for purposes of clarity of understanding, the description and example should not be construed as limiting the scope of the present disclosure. The disclosures of all patents and scientific literature cited herein are expressly incorporated by reference in their entirety.

[0265] The present disclosure relates to the following embodiments. 1. An anti-CD38 antibody for use in treating multiple myeloma in an individual, the anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) 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 (VL) 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), wherein the treatment comprises administering to the individual the anti-CD38 antibody, pomalidomide, and dexamethasone, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg; pomalidomide is administered at a dose of 4 mg; and dexamethasone is administered at a dose of 40 mg to individuals under 75 years of age, or dexamethasone is administered at a dose of 20 mg to individuals 75 years of age or older, wherein the individual has received at least two prior therapies for multiple myeloma, wherein at least one of the at least two prior therapies for multiple myeloma is lenalidomide and at least one of the two prior therapies is a proteasome inhibitor, and wherein the treatment prolongs progression-free survival (PFS) and / or overall survival (OS) of the individual. 2. An anti-CD38 antibody for use in a method of reversing renal impairment in an individual with multiple myeloma, the anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) comprising a CDR-H1 comprising the amino acid sequence of DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence of TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) comprising a CDR-L1 comprising the amino acid sequence of KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence of SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6), wherein the method comprises administering to the individual the anti-CD38 antibody, pomalidomide, and dexamethasone, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg; pomalidomide is administered at a dose of 4 mg; and dexamethasone is administered at a dose of 40 mg to individuals under 75 years of age, or dexamethasone is administered at a dose of 20 mg to individuals 75 years of age or older, wherein the individual has received at least two prior therapies for multiple myeloma, and wherein at least one of the at least two prior therapies for multiple myeloma is lenalidomide, and at least one of the at least two prior therapies is a proteasome inhibitor. 3. A liquid pharmaceutical preparation comprising (a) Isatuximab at a concentration of 5-20 mg / ml; (b) a buffer selected from the group consisting of histidine, acetate, and phosphate; (c) an excipient selected from sucrose and mannitol; and (d) Polysorbate 80 (PS80). 4. A liquid pharmaceutical formulation according to claim 3, wherein isatuximab is present at a concentration of 5 mg / ml, wherein the buffer is histidine and the concentration of histidine is 10 mM, wherein the excipient is sucrose and the concentration of sucrose is 10% (w / v), wherein PS80 is present at a concentration of 0.005% (w / v), and wherein the pharmaceutical formulation has a pH of about 6.0 or about 6.5. 5. The liquid pharmaceutical formulation of claim 4, wherein the pH is about 6.5. 6. A liquid pharmaceutical formulation according to claim 3, wherein isatuximab is present at a concentration of 20 mg / ml, wherein the buffer is histidine and the concentration of histidine is 20 mM, wherein the excipient is sucrose and sucrose is present at a concentration of 10% (w / v), wherein PS80 is present at a concentration of 0.02% (w / v), and wherein the pharmaceutical formulation has a pH of about 6.0. 7. A method of treating multiple myeloma in an individual, the method comprising administering to the individual an anti-CD38 antibody, pomalidomide, and dexamethasone, wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) comprising a CDR-H1 comprising the amino acid sequence of DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence of TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) comprising a CDR-L1 comprising the amino acid sequence of KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence of SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6), wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg; pomalidomide is administered at a dose of 4 mg; and dexamethasone is administered at a dose of 40 mg, wherein the individual is under 75 years of age, or dexamethasone is administered at a dose of 20 mg, wherein the individual is 75 years of age or older, wherein the individual has received at least two prior therapies for multiple myeloma, wherein at least one of the at least two prior therapies for multiple myeloma is lenalidomide and at least one of the two prior therapies is a proteasome inhibitor, and wherein the treatment prolongs progression-free survival (PFS) of the individual and / or the treatment prolongs overall survival (OS) of the individual. 8. A method for improving renal impairment in an individual in need thereof, wherein the individual has multiple myeloma, the method comprising administering to the individual an anti-CD38 antibody, pomalidomide, and dexamethasone, wherein the anti-CD38 antibody comprises (a) a heavy chain variable domain (VH) comprising a CDR-H1 comprising the amino acid sequence of DYWMQ (SEQ ID NO: 1), a CDR-H2 comprising the amino acid sequence of TIYPGDGDTGYAQKFQG (SEQ ID NO: 2), and a CDR-H3 comprising the amino acid sequence of GDYYGSNSLDY (SEQ ID NO: 3), and (b) a light chain variable domain (VL) comprising a CDR-L1 comprising the amino acid sequence of KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence of SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6), wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg; pomalidomide is administered at a dose of 4 mg; and dexamethasone is administered at a dose of 40 mg, wherein the individual is under 75 years of age, or dexamethasone is administered at a dose of 20 mg, wherein the individual is 75 years of age or older, thereby improving renal impairment, wherein the individual has received at least two prior therapies for multiple myeloma, and wherein at least one of the at least two prior therapies for multiple myeloma is lenalidomide, and at least one of the at least two prior therapies is a proteasome inhibitor. 9. The antibody for use according to item 1 or 2 or the method according to item 7 or 8, wherein the at least two prior therapies do not include treatment with an anti-CD38 antibody and / or treatment with pomalidomide. 10. The antibody for use according to item 1, 2 or 9, or the method according to any one of items 7 to 9, wherein the individual has not responded to at least one of the at least two prior therapies, or wherein the individual has relapsed after at least one of the at least two prior therapies, or wherein the individual has experienced disease progression during or after treatment with at least one of the two prior therapies. 11. The antibody for use according to item 2, 9 or 10, or the method according to any one of items 8 to 10, wherein the individual suffering from multiple myeloma is selected for administration based on the individual suffering from renal impairment. 12. The antibody or method for use according to claim 11, wherein the subject has an estimated glomerular filtration rate (eGFR) of less than about 60 mL / min / 1.73 m2. 13. The antibody for use according to any one of items 2 and 9-12 or the method according to any one of items 8-12, wherein the treatment prolongs progression-free survival (PFS) of the individual. 14. The antibody for use according to any one of items 2 and 9-13, or the method according to any one of items 8-13, wherein the treatment prolongs the overall survival (OS) of the individual. 15. The antibody for use according to any one of items 1, 9-10 and 13, or the method according to any one of items 7, 9-10 and 13, wherein the treatment prolongs the PFS of the subject by at least about 9 months. 16. The antibody for use of any one of items 1, 9-10 and 13, or the method of any one of items 7, 9-10 and 13, wherein the treatment prolongs the PFS of the individual by at least about 4.5 months relative to an individual with multiple myeloma who received a treatment comprising pomalidomide and dexamethasone without the anti-CD38 antibody. 17. The antibody for use according to any one of items 1, 9, 10 and 15-16 or the method according to any one of items 7, 9, 10, 15 and 16, wherein the treatment reverses the impairment of renal function. 18. The antibody for use of any one of items 1-2 and 9-17 or the method of any one of items 7-17, wherein the individual achieves a response to the treatment more quickly than an individual with multiple myeloma who received a treatment comprising pomalidomide and dexamethasone without the anti-CD38 antibody. 19. The antibody for use of any one of items 2 and 9-17 or the method of any one of items 8-17, wherein the individual achieves a renal response to the treatment more quickly than an individual with multiple myeloma who has received a treatment comprising pomalidomide and dexamethasone without the anti-CD38 antibody. 20. The antibody or method for use according to item 19, wherein the renal response is a complete renal response. 21. The antibody or method for use according to item 19 or 20, wherein the complete renal response persists for at least 60 days. 22. The antibody for use according to any one of items 1-2 and 9-21 or the method according to any one of items 7-21, wherein the anti-CD38 antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8 or SEQ ID NO: 9. 23. The antibody for use according to any one of items 1-2 and 9-22, or the method according to any one of items 7-22, wherein the anti-CD38 antibody is isatuximab. 24. The antibody for use according to any one of items 1-2 and 9-23, or the method according to any one of items 7-23, wherein the anti-CD38 antibody, pomalidomide and dexamethasone are administered in a first 28-day cycle, wherein the anti-CD38 antibody is administered on days 1, 8, 15, and 22 of the first 28-day cycle, pomalidomide is administered on each of days 1-21 of the first 28-day cycle, and dexamethasone is administered on days 1, 8, 15, and 22 of the first 28-day cycle. 25. The antibody or method for use according to item 24, wherein the anti-CD38 antibody, pomalidomide 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 on days 1 and 15 of the one or more 28-day cycles following the first 28-day cycle, pomalidomide is administered on each of days 1-21 of the one or more 28-day cycles following the first 28-day cycle, and dexamethasone is administered on days 1, 8, 15, and 22 of the one or more 28-day cycles following the first 28-day cycle. 26. The antibody or method for use according to item 24 or 25, wherein pomalidomide and dexamethasone are administered before the anti-CD38 antibody on day 1 of the first 28-day cycle. 27. The antibody or method for use of any one of items 24-26, wherein dexamethasone is administered before the anti-CD38 antibody on days 8, 15 and 22 of the first 28-day cycle, and wherein the anti-CD38 antibody is administered before pomalidomide on days 8 and 15 of the first 28-day cycle. 28. The antibody or method for use according to any one of items 24 to 27, wherein pomalidomide and dexamethasone are administered before the anti-CD38 antibody on day 1 of the one or more 28-day cycles following the first 28-day cycle. 29. The antibody or method for use of any one of items 24-28, wherein dexamethasone is administered before the anti-CD38 antibody on day 15 of the one or more 28-day cycles following the first 28-day cycle, and wherein the anti-CD38 antibody is administered before pomalidomide. 30. The antibody for use according to any one of items 1-2 and 9-23, or the method according to any one of items 7-23, wherein the anti-CD38 antibody, pomalidomide and dexamethasone are administered in a first 28-day cycle, wherein the anti-CD38 antibody is administered once a week in the first 28-day cycle, pomalidomide is administered on day 21 of the first 28-day cycle, and dexamethasone is administered once a week in the first 28-day cycle. 31. The antibody or method for use according to item 30, wherein the anti-CD38 antibody, pomalidomide 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 every other week in the one or more 28-day cycles following the first 28-day cycle, pomalidomide is administered on day 21 of the one or more 28-day cycles following the first 28-day cycle, and dexamethasone is administered once a week in the one or more 28-day cycles following the first 28-day cycle. 32. The antibody or method for use according to item 30 or 31, wherein in the first 28-day period, pomalidomide and dexamethasone are administered before the anti-CD38 antibody. 33. The antibody or method for use according to any one of items 30 to 32, wherein in the first 28-day cycle, dexamethasone is administered before the anti-CD38 antibody, and wherein the anti-CD38 antibody is administered before pomalidomide. 34. The antibody or method for use according to any one of items 30 to 33, wherein pomalidomide and dexamethasone are administered before the anti-CD38 antibody in the one or more 28-day cycles following the first 28-day cycle. 35. The antibody or method for use of any one of items 30-34, wherein in the one or more 28-day cycles following the first 28-day cycle, dexamethasone is administered before the anti-CD38 antibody, and wherein the anti-CD38 antibody is administered before pomalidomide. 36. The antibody for use according to any one of items 1-2 and 9-35 or the method according to any one of items 7-29, wherein the anti-CD38 antibody is administered intravenously. 37. The antibody for use according to any one of items 1-2 and 9-36 or the method according to any one of items 7-30, wherein pomalidomide is administered orally. 38. The antibody for use according to any one of items 1-2 and 9-37 or the method according to any one of items 7-37, wherein dexamethasone is administered orally. 39. The antibody for use according to any one of items 1-2 and 9-37 or the method according to any one of items 7-37, wherein dexamethasone is administered intravenously. 40. The antibody for use according to any one of items 1-2 and 9-39 or the method according to any one of items 7-39, wherein the individual is refractory to the most recent prior therapy for multiple myeloma. 41. The antibody or method for use according to item 40, wherein the most recent prior therapy is lenalidomide. 42. The antibody or method for use according to item 40, wherein the most recent prior therapy is a proteasome inhibitor. 43. The antibody for use according to any one of items 1-2 and 9-42, or the method according to any one of items 7-36, wherein the proteasome inhibitor is selected from the group consisting of: bortezomib, carfilzomib, and ixazomib. 44. The antibody for use according to any one of items 1-2 and 9-43 or the method according to any one of items 7-37, wherein lenalidomide and the proteasome inhibitor are administered in combination. 45. The antibody for use according to any one of items 1-2 and 9-44 or the method according to any one of items 7-38, wherein the individual suffers from chronic obstructive pulmonary disease (COPD). 46. ​​The antibody for use according to any one of items 1-2 and 9-45 or the method according to any one of items 7-39, wherein the individual suffers from asthma. 47. The antibody for use according to any one of items 1-2 and 9-46 or the method according to any one of items 7-40, wherein the subject suffers from bronchospasm. 48. The antibody for use according to any one of items 1-2 and 9-47 or the method according to any one of items 7-41, wherein the individual has one or more cytogenetic abnormalities selected from the group consisting of del(17p), t(4;14) and t(14;16). 49. The antibody for use according to any one of items 1-2 and 9-48 or the method according to any one of items 7-42, wherein the individual is at least 65 years old but less than 75 years old. 50. The antibody for use according to any one of items 1-2 and 9-48 or the method according to any one of items 7-42, wherein the individual is 75 years of age or older. 51. The antibody for use according to any one of items 1-2 and 9-50 or the method according to any one of items 7-44, wherein the individual has received at least three prior therapies for multiple myeloma. 52. The antibody for use according to any one of items 1-2 and 9-51 or the method according to any one of items 7-51, wherein the individual is East Asian. 53. The antibody for use according to any one of items 1-2 and 9-52 or the method according to any one of items 7-52, wherein the individual is in stage III according to the International Staging System (ISS). 54. The antibody for use according to any one of items 1-2 and 9-53 or the method according to any one of items 7-53, wherein the individual is in stage III according to the Revised International Staging System (R-ISS). 55. The antibody for use according to any one of items 1-2 and 9-54 or the method according to any one of items 7-54, wherein the individual is minimal residual disease (MRD) negative at a threshold of 10-4 or less after treatment. 56. The antibody or method for use according to claim 55, wherein the individual is MRD negative after treatment at a threshold of 10-5 or less. 57. The antibody or method for use according to claim 56, wherein the individual is MRD negative after treatment at a threshold of 10-6 or less. 58. The antibody or method for use of any one of items 55-57, wherein MRD is assessed via next generation sequencing (NGS). 59. The antibody or method for use of any one of items 55-58, wherein MRD is assessed via next generation flow cytometry (NGF). 60. A kit comprising an anti-CD38 antibody for use in combination with pomalidomide and dexamethasone for treating an individual with multiple myeloma according to the antibody for use according to any one of items 1-2 and 9-59 or the method according to any one of items 7-59.

Claims

1. A liquid pharmaceutical preparation comprising (a) Isatuximab at a concentration of 5-20 mg / ml; (b) a buffer selected from the group consisting of histidine, acetate and phosphate; (c) an excipient selected from the group consisting of sucrose and mannitol; and (d) Polysorbate 80 (PS80).

2. The liquid pharmaceutical formulation of claim 1, wherein isatuximab is present at a concentration of 5 mg / ml, wherein the buffer is histidine and the concentration of histidine is 10 mM, wherein the excipient is sucrose and the concentration of sucrose is 10% (w / v), wherein PS80 is present at a concentration of 0.005% (w / v), and wherein the pharmaceutical formulation has a pH of about 6.0 or about 6.

5.

3. The liquid pharmaceutical formulation of claim 1, wherein the pH is about 6.

5.

4. The liquid pharmaceutical formulation of claim 1 , wherein isatuximab is present at a concentration of 20 mg / ml, wherein the buffer is histidine and the concentration of histidine is 20 mM, wherein the excipient is sucrose and sucrose is present at a concentration of 10% (w / v), wherein PS80 is present at a concentration of 0.02% (w / v), and wherein the pharmaceutical formulation has a pH of about 6.

0.

5. The liquid pharmaceutical formulation of claim 1 , wherein isatuximab is present at a concentration of 20 mg / ml, wherein the buffer is histidine and the concentration of histidine is 1.46 mg / ml, wherein the excipient is sucrose and the sucrose is present at a concentration of 100 mg / ml, wherein PS80 is present at a concentration of 0.2 mg / ml, and wherein the pharmaceutical formulation further comprises histidine hydrochloride monohydrate at a concentration of 2.22 mg / mL.

6. Use of an anti-CD38 antibody in the preparation of a medicament for treating multiple myeloma in an individual, the anti-CD38 antibody comprising (a) a heavy chain variable domain (V H ): 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 ): 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), wherein the medicament is formulated for administration with pomalidomide and dexamethasone, wherein the anti-CD38 antibody is administered at a dose of 10 mg / kg; pomalidomide is administered at a dose of 4 mg; and dexamethasone is administered at a dose of 40 mg to individuals under 75 years of age, or dexamethasone is administered at a dose of 20 mg to individuals 75 years of age or older, wherein the individual has received at least two prior therapies for multiple myeloma, wherein at least one of the at least two prior therapies for multiple myeloma is lenalidomide, and at least one of the two prior therapies is a proteasome inhibitor, and wherein said drug, pomalidomide and dexamethasone prolongs progression-free survival (PFS) of said subject and / or said treatment prolongs overall survival (OS) of said subject.

7. The use according to claim 6, wherein the subject suffers from chronic obstructive pulmonary disease (COPD).

8. A kit comprising an anti-CD38 antibody for use according to claim 6 or 7 for treating an individual with multiple myeloma in combination with pomalidomide and dexamethasone.

9. Use of an anti-CD38 antibody in the preparation of a medicament for treating renal injury in an individual, the anti-CD38 antibody comprising (a) a heavy chain variable domain (V H ), and (b) a light chain variable domain (V L ), wherein the drug is formulated for administration with pomalidomide and dexamethasone.

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