[0001] This application claims the priority benefit of 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; 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 LISTING ON ASCII TEXT FILE

[0002] The content of the following submission on ASCII text file is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name:

183952031241SEQLIST.txt, date recorded: January 23, 2020, size: 11 KB).

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

[0004] Multiple myeloma (MM) is a malignant plasma cell disease that is characterized by clonal proliferation of plasma cells in the bone marrow (BM) and the production of excessive amounts of a monoclonal immunoglobulin (usually of the IgG or IgA type or free urinary light chain, i.e..

paraprotein, M-protein or M-component). Patients with MM can experience bone pain, bone fractures, fatigue, anemia, infections, hypercalcemia, and kidney problems (Rollig et al. (2015)

Lancet. 385(9983):2197-208). The expression of CD38 is especially notable 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 this antigen may be useful for specific targeting of tumor cells.

[0005] The current aim of MM therapy is to control the disease as effectively as possible, to maximize quality of life and to prolong survival. The disease trajectory varies for each patient, but relapses are inevitable, and the depth and duration of response to each treatment following relapse are generally diminished. In general, MM patients will receive an average of 4 to 8 different regimens during their lifespan using agents such as proteasome inhibitors ( e.g ., bortezomib, ixazomib, and carfilzomib) and immune modulatory agents or“IMiDs®” (e.g., lenalidomide and thalidomide),

monoclonal antibodies (e.g., elotuzumab), histone deacetylase (HDAC) inhibitors (e.g., panobinostat) alone or in combination. However, once a patient becomes refractory to those agents, survival is limited and newer treatment options are needed to treat patients after they have failed stem cell transplant (SCT), chemotherapy, proteasome inhibitors, and immunomodulatory drugs (IMiDs®). Despite the dramatic improvement in patient outcomes with newer therapies, MM remains an incurable disease. Thus, the treatment of patients who have received at least 2 different lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to a proteasome inhibitor and an IMiD® remains an unmet medical need.

[0006] All references cited herein, including patent applications, patent publications, and UniProtKB/Swiss-Prot Accession numbers are herein incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference.

SUMMARY

[0007] Provided is an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: 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) that comprises: a CDR-L1 comprising the amino acid sequence

KASQDVSTWA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6) for use in treating multiple myeloma in an individual, 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, the pomalidomide is administered at a dose of 4 mg, and the dexamethasone is administered at a dose of 40 mg individuals under 75 years of age, or the dexamethasone is administered at a dose of 20 mg to individuals 75 years of age or older, wherein the individual received at least two prior therapies for multiple myeloma, wherein at least one of the at least two prior therapies for multiple myeloma was lenalidomide and at least one of the two prior therapies was a proteasome inhibitor, and wherein the treatment extends progression free survival (PFS) and/or overall survival (OS) of the individual.

[0008] Provided is an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: 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) that comprises: a CDR-L1 comprising the amino acid sequence

KASQDVSTWA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6) for

use in method of reversing renal function impairment in an individual with multiple myeloma, 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, the pomalidomide is administered at a dose of 4 mg, and the dexamethasone is administered at a dose of 40 mg individuals under 75 years of age, or the 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 was lenalidomide and at least one of the at least two prior therapies was a proteasome inhibitor.

[0009] Also provided is a liquid pharmaceutical formulation comprising (a) isatuximab at a concentration of 5-20 mg/ml; (b) a buffering agent 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). In some embodiments, the isatuximab is present at a concentration of 5 mg/ml, wherein the buffering agent is histidine and the histidine is at a concentration of 10 mM, wherein the excipient is sucrose and the sucrose is at a concentration of 10% (w/v), wherein the 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 buffering agent is histidine and the histidine is at a concentration of 20 mM, wherein the excipient is sucrose and the sucrose is present at a concentration of 10% (w/v), wherein the 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] Provided is a method of treating a human individual having multiple myeloma, comprising administering to the individual an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: 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) that comprises: 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), pomalidomide, and dexamethasone, wherein the treatment extends 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, the pomalidomide at a dose of 4 mg, and the dexamethasone at a dose of 40 mg wherein the individual is under 75 years of age, or at a dose of 20 mg wherein the individual is 75 years of age or older. In some embodiments, the individual 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 was lenalidomide. In some embodiments, at least one of the two prior therapies was a proteasome inhibitor. In some embodiments, the treatment extends overall survival (OS) of the individual. In some embodiments, the treatment reverses renal function impairment in the individual.

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

[0012] Provided is a method of improving renal impairment in a human individual with multiple myeloma, comprising administering to the individual an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: 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) that comprises: 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), pomalidomide, and dexamethasone. In some embodiments, the anti-CD38 antibody is administered at a dose of 10 mg/kg, the pomalidomide is administered at a dose of 4 mg, and the dexamethasone is administered at a dose of 40 mg wherein the individual is less than 75 years of age or at a dose of 20 mg wherein the individual is 75 years of age or older.

[0013] In some embodiments of the antibodies for use herein or the methods herein, the at least two prior therapies did not include treatment with an anti-CD38 antibody and/or treatment with

pomalidomide. In some embodiments of the antibodies for use herein or the 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 the treatment with at least one of the two prior therapies.

[0014] In some embodiments of the antibodies for use herein or the methods herein, the individual with multiple myeloma is selected for administration with the anti-CD38 antibody, the pomalidomide, and the dexamethasone based on the individual having renal impairment. In some embodiments of the antibodies for use herein or the methods herein,, the individual with renal impairment has an estimated glomerular filtration rate (eGFR) less than about 60, less than about 50, or less than about 30 mL/min/1 73m2 prior to the start of treatment. In some embodiments of the antibodies for use herein or the methods herein,, the individual with renal impairment has creatinine clearance of less than about 60, less than about 50, or less than about 30 mL/min/1.73m2 prior to the start of treatment. In some embodiments of the antibodies for use herein or the methods herein, the individual received at least two prior therapies for multiple myeloma. In some embodiments of the antibodies for use herein or the methods herein, at least one of the at least two prior therapies was lenalidomide. In some embodiments of the antibodies for use herein or the methods herein, at least one of the at least two prior therapies was a proteasome inhibitor. In some embodiments of the antibodies for use herein or the methods herein, the method extends progression free survival (PFS) of the individual. In some embodiments of the antibodies for use herein or the methods herein, the method extends overall survival (OS) of the individual.

[0015] Also provided herein is an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: 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) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6) for use in treating multiple myeloma in an individual, the treatment comprising administering to the individual the anti-CD38 antibody, pomalidomide and dexamethasone, wherein the treatment extends 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, the pomalidomide is administered at a dose of 4 mg, and the dexamethasone is administered at a dose of 40 mg wherein the individual is less than 75 years of age, or 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 the methods herein, the individual received at least two prior therapies for multiple myeloma. In some

embodiments of the antibodies for use herein or the methods herein, at least one of the at least two prior therapies for multiple myeloma was lenalidomide. In some embodiments of the antibodies for use herein or the methods herein, at least one of the two prior therapies was a proteasome inhibitor.

[0016] Also provided is an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: 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) that comprises: a CDR-L1 comprising the amino acid sequence

KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6) for use in reversing renal function impairment in an individual, 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 for administration with the anti-CD38 antibody, the pomalidomide, and the dexamethasone based on having renal impairment. In some embodiments of the antibodies for use herein or the methods herein, the individual has an estimated glomerular fdtration rate (eGFR) of less than about 60, less than about 50, or less than about 30 mL/min/1 73m2 prior to the start of treatment. In some embodiments of the antibodies for use herein or the methods herein, the individual has a creatinine clearance of less than about 60, less than about 50, or less than about 30 mL/min/1.73m2 prior to the start of treatment. 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, the pomalidomide is administered at a dose of 4 mg, and the dexamethasone is administered at a dose of 40 mg wherein the individual is less than 75 years of age, or 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 the methods herein, the individual received at least two prior therapies for multiple myeloma. In some embodiments of the antibodies for use herein or the methods herein, at least one of the at least two prior therapies for multiple myeloma was lenalidomide. In some embodiments of the antibodies for use herein or the methods herein, at least one of the two prior therapies was a proteasome inhibitor.

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

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

[0019] In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 9. In some embodiments, the anti-CD38 antibody is isatuximab.

[0020] In some embodiments, the anti-CD38 antibody, the pomalidomide, and the

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, the pomalidomide is administered on each of Days 1-21 of the first 28-day cycle, and the dexamethasone is administered on Days 1, 8, 15, and 22 of the first 28-day cycle. In some embodiments, the anti-CD38 antibody, the pomalidomide, and the 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, the pomalidomide is administered on each of Days 1-21 of the one or more 28-day cycles following the first 28-day cycle, and the 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, the pomalidomide and the dexamethasone are administered prior to the anti-CD38 antibody on Day 1 of the first 28-day cycle. In some embodiments, the dexamethasone is administered prior to the anti-CD38 antibody Days 8, 15, and 22 of the first 28-day cycle, and wherein the anti-CD38 antibody is administered prior to the pomalidomide on Days 8 and 15 of the first 28-day cycle. In some embodiments, the pomalidomide and the dexamethasone are administered prior to the anti-CD38 antibody on Day 1 of the one or more 28-day cycles following the first 28-day cycle. In some embodiments, the dexamethasone is administered prior to the anti-CD38 antibody, and wherein the anti-CD38 antibody is administered prior to the pomalidomide on Day 15 of the one or more 28-day cycles following the first 28-day cycle. In some embodiments, the anti-CD38 antibody is administered intravenously. In some embodiments, the pomalidomide is administered orally. In some embodiments, the dexamethasone is administered orally. In some embodiments, the dexamethasone is administered intravenously.

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

embodiments, the dexamethasone is administered orally. In some embodiments, the dexamethasone is administered intravenously.

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

[0023] In some embodiments, the individual has chronic obstructive pulmonary disorder (COPD). In some embodiments, the individual has asthma. In some embodiments, the individual has bronchospams. 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 group consisting of: del(17p), t(4;14), and t(14; 16). In some embodiments, the individual is at least 65 but less than 75 years of age. In some embodiments, the individual is 75 years of age 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 Taiwanese individual). In some embodiments, the individual is Stage III according to the

International Staging System (ISS). In some embodiments, the individual is Stage III according to the Revised International Staging System (R-ISS). In some embodiments, the individual is minimal residual disease (MRD) negative at a threshold of 10 4 or less after treatment (e.g., wherein“104” means that in a patient bone marrow sample, there is less than 1 tumor cell per 104 bone marrow cells), 10 5 or less after treatment (e.g., wherein“10 5” means that in a patient bone marrow sample, there is less than 1 tumor cell per 105bone marrow cells), or 106 or less after treatment (e.g., wherein “10 6” means that in a patient bone marrow sample, there is less than 1 tumor cell per 106 bone marrow cells). In some embodiments, MRD is assessed via next generation sequencing (NGS). In some embodiments, MRD is assessed via next generation flow cytometry (NGF). Additionally or alternatively, in some embodiments, MRD is assessed via positron emission tomography-computed tomography (PET-CT) scan.

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

[0025] Also provided are liquid pharmaceutical formulations comprising isatuximab. In some embodiments, a pharmaceutical formulation herein comprises isatuximab at a concentration of 5-20 mg/ml, a buffering agent selected from the group consisting of: histidine, acetate, and phosphate, and an excipient selected from the group consisting of: sucrose and mannitol, and a nonionic 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 THE DRAWINGS

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

[0027] FIG. 1 provides a schematic of the study design of the clinical trial described in Example 1. The IPd (experimental) arm included 154 patients. The Pd (control) arm included 153 patients.

[0028] FIG. 2 provides a Kaplan-Meier Plot of progression-free survival (PFS) of patients in the IPd arm (isatuximab + pomalidomide + dexamethasone) vs. the Pd arm (pomalidomide +

dexamethasone), as assessed by the Independent Response Committee (IRC).

[0029] FIG. 3 provides a Kaplan-Meier Plot of progression-free survival (PFS) of patients in the IPd arm (isatuximab + pomalidomide + dexamethasone) vs. the Pd arm (pomalidomide +

dexamethasone), as assessed by the Investigator.

[0030] FIG. 4 provides a Kaplan-Meier Plot of overall survival (OS) of patients in the IPd arm (isatuximab + pomalidomide + dexamethasone) vs. the Pd arm (pomalidomide + dexamethasone).

[0031] FIG. 5 provides a Forest Plot showing subgroup analyses of PFS in patients with various baseline characteristics (e.g. , age, eGFR, prior lines of therapy, previous ASCT (autologous stem cell transplantation), cytogenetic risk factors, etc.) in the IPd arm vs. the PD arm.

[0032] FIG. 6A provides a Kaplan-Meier Plot of progression-free survival (PFS) of patients in the IPd arm (isatuximab + pomalidomide + dexamethasone) who were minimal residual disease (MRD) negative, who were MRD positive but achieved VGPR or better, who achieved PR, or who achieved less than PR following the start of treatment.

[0033] FIG. 6B provides a Kaplan-Meier Plot of overall survival (OS) of patients in the IPd arm (isatuximab + pomalidomide + dexamethasone) who were minimal residual disease (MRD) negative, who were MRD positive but achieved VGPR or better, who achieved PR, or who achieved less than PR following the start of treatment.

[0034] FIG. 7 shows the time to complete renal response (CRenal) and durable CRenal in patients with baseline eGFR <50 mL/min/1.73m2 in the Isa-Pd arm vs. the Pd arm. A durable CRenal (also known as“sustained CRenal”) is a complete renal response that is sustained for at least 60 days.

DETAILED DESCRIPTION

Definitions

[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 the like.

[0036] “Sustained response” refers to the sustained effect on preventing or delaying progression of a disease (e.g. , multiple myeloma) and/or improving one or more response criteria after cessation of a treatment. For example, response to treatment for multiple myeloma may 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 sustained response has a duration at least the same as the treatment duration, e.g., at least 1.5X, 2. OX, 2.5 X, or 3. OX length of the treatment duration.

Table A Standard International Myeloma Working Group (LMWG) Response Criteria

tSPD, sum of the products of the maximal perpendicular diameters of measured lesions

[0037] The term“pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be

administered. Such formulations are sterile.“Pharmaceutically acceptable” excipients (vehicles, additives) are those that can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed.

[0038] As used herein, the term“treatment” refers to clinical intervention designed to alter the natural course of the disease or cell (e.g., cancer cell) being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. For example, an individual is successfully“treated” if one or more symptoms associated with cancer are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, and/or prolonging survival of individuals.

[0039] As used herein,“delaying progression of a disease” means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.

[0040] An“effective amount” is at least the minimum amount required to effect a measurable improvement or prevention of a particular disorder. An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. In the case of cancer or tumor, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e.. slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (i.e.. slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an“effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

[0041] As used herein,“in conjunction with” refers to administration of one treatment modality in addition to another treatment modality. As such,“in conjunction with” refers to administration of one treatment modality before, during, or after administration of the other treatment modality to the individual.

[0042] A“subject” or an“individual” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal is 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 (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired biological activity.

[0044] Human light chains are typically classified as kappa and lambda light chains, and human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, but not limited to, IgGl, IgG2, IgG3, and IgG4. IgM has subclasses including, but not limited to, IgMl and IgM2. IgA is similarly subdivided into subclasses including, but not limited to, IgAl and IgA2. Within full-length light and heavy chains, the variable and constant domains typically are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a“D” region of about 10 more amino acids. See, e.g., FUNDAMENTAL IMMUNOLOGY (Paul, W., ed., Raven Press, 2nd ed., 1989), which is incorporated by reference in its entirety for all purposes. The variable regions of each light/heavy chain pair typically form an antigen binding site. The variable domains of antibodies typically exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair typically are aligned by the framework regions, which may enable binding to a specific epitope. From the amino-terminus to the carboxyl-terminus, both light and heavy chain variable domains typically comprise, in order, the domains FR1, CDR1, FR2, CDR2,

FR3, CDR3, and FR4.

[0045] The term“CDR set” refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Rabat (Rabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Rabat CDRs.

[0046] The term“Fc” as used herein refers to the sequence of a non-antigen-binding fragment that would result from digestion of an antibody or produced by other means, whether in monomeric or multimeric form, and can contain the hinge region. The original immunoglobulin source of the native Fc is preferably of human origin and can be any of the immunoglobulins. Fc molecules are made up of monomeric polypeptides that can be linked into dimeric or multimeric forms by covalent (i.e., disulfide bonds) and non-covalent association. The number of intermolecular disulfide bonds between monomeric subunits of native Fc molecules ranges from 1 to 4 depending on class (e.g., IgG, IgA, and IgE) or subclass (e.g., IgGl, IgG2, IgG3, IgAl, IgGA2, and IgG4). One example of a Fc is a disulfide-bonded dimer resulting from papain digestion of an IgG. The term“native Fc” as used herein is generic to the monomeric, dimeric, and multimeric forms.

[0047] As used herein, the term“overall response rate” or“ORR” refers to the proportion of patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR), as assessed by the IRC using the IMWG response criteria described in Rumar et al. (2016)“International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.” Lancet Oncol. 17(8): e328-e346 and Durie et al. (2006)“International uniform response criteria for multiple myeloma.

Leukemia. 20: 1467-1473. See also Table A and Table B.

Overview

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

Anti-CD38 Antibodies

[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 (VH) that comprises: 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) that comprises: a CDR-L1 comprising the amino acid sequence KASQDVSTVVA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6). In some embodiments, the anti-CD38 antibody comprises a heavy chain variable domain (VH) that comprises an amino acid sequence that is at least 90% identical (e.g., at least any one of 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99%, including any range between these values) to SEQ ID NO: 7. Additionally or alternatively, in some embodiments, the anti-CD38 antibody comprises a light chain variable domain (VL) that comprises an amino acid sequence that is at least 90% identical (e.g., at least any one of 91%, 92%, 94%, 95%, 96%, 97%, 98%, or 99%, including any range between these values) to SEQ ID NO: 8 or SEQ ID NO: 9. In some embodiments, the anti-CD38 antibody comprises a VH that comprises SEQ ID NO: 7 and a VL that comprises SEQ ID NO: 8 or SEQ ID NO: 9.

QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT IYPGDGDTGY AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD YYGSNSLDYW GQGTSVTVSS

(SEQ ID NO: 7)

DIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKR (SEQ ID NO: 8)

DIVMAQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKR (SEQ ID NO: 9)

[0050] In some embodiments, the anti-CD38 antibody is isatuximab (CAS Registry Number: 1461640-62-9). Isatuximab, also known as hu38SB19 and SAR650984, is an anti-CD38 antibody

described in WO 2008/047242 and US Patent No. 8,153,765, the contents of both of which are incorporated by reference herein in their entirety.

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

QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT IYPGDGDTGY AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD YYGSNSLDYW GQGTSVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPG (SEQ ID NO: 10)

and the light chain of isatuximab comprises the amino acid sequence:

DIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 11)

[0052] The anti-CD38 antibodies may be produced using recombinant methods. For recombinant production of an anti-antigen antibody, 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 may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody). Many vectors are available. The vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. The vector is typically transformed into a host cell suitable for expression of the nucleic acid. In some embodiments, the host cell is a eukaryotic cell or a prokaryotic cell. In some embodiments, the eukaryotic host cell is a mammalian cell. Examples of useful mammalian host cell lines are 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 antibody prepared from the cells can be purified using, for example, hydroxylapatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being among one of the typically preferred purification steps. In general, various methodologies for preparing antibodies for use in research, testing, and clinical applications are well-established in the art, consistent with the above-described methodologies and/or as deemed appropriate by one skilled in the art.

Pomalidomide

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

[0054] Pomalidomide has molecular formula of CYYI : I N ;OJ and a molecular weight of 273.24 g/mol. Pomalidomide is commercially available as POMALYST, POMALID, IMNOVID, and others.

Dexamethasone

[0055] The chemical name for dexamethasone is 1 -dehydro- 16alpha-methyl-9alpha-fluorohydrocortisone, and dexamethasone has the following chemical structure:

[0056] Dexamethasone has molecular formula of C H FO and a molecular weight of 392.461 g/mol. Dexamethasone is commercially available as formulations for oral and intravenous administration. Exemplary trade names for dexamethasone include, e.g., DECADRON, MAXIDEX, HEXADROL, DEXACORT, DEXASONE, ORADEXON, SUPERPREDNOL, DEXALONA and others.

Pharmaceutical Compositions and Formulations

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

[0058] In some embodiments, the pharmaceutical formulations provided herein comprise isatuximab at a concentration of 5-20 mg/ml, a buffering agent selected from the group consisting of: histidine, acetate, and phosphate, and an excipient selected from the group consisting of sucrose and mannitol, and 0.001%-0.03% of a nonionic surfactant (such as PS20, 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 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 formulations 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, an anti-CD38 antibody described herein (such as isatuximab) is 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, an anti-CD38 antibody described herein (such as isatuximab) is 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 formulation comprises water for injection (WFI), such as sterile water for injection (SWFI). In some embodiments, the pharmaceutical formulation is sterile. In some embodiments, a single use of the formulation comprises 5 ml of the pharmaceutical formulation (i.e.. 100 mg anti-CD38 antibody). In some embodiments, the single use 5 ml pharmaceutical formulation is provided in, e.g., a type I 6 mL colorless clear glass vial fitted with elastomeric closure. In some embodiments, the fill volume of the vial has been established to ensure removal of 5 mL. In some embodiments, the fill volume is 5.4 mL. In some embodiments, a single use of the formulation comprises 25 ml of the pharmaceutical formulation (i.e.. 500 mg anti-CD38 antibody). In some embodiments, the single use 25 ml pharmaceutical formulation is provided in, e.g. , a 30 mL colorless clear glass vial fitted with elastomeric closure. In some embodiments, the fill volume of the vial has been established to ensure removal of 25 mL. In some embodiments, the pharmaceutical formulation is stable for at least about 6, 12, 18, 24, 30, or 36 months, including any range in between these values, at a temperature between about 2°C and about 8°C and protected from light. 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, including any range in between these values, between about 2°C and about 8°C. In some embodiments, the diluted solution for infusion is stable following storage between about 2°C and about 8°C for a further 8 hours (e.g., including the infusion time) at room temperature. In some embodiments, the diluted solution for infusion is stable in the presence of light. In some embodiments the bag in which the diluted solution for infusion is diluted is fabricated from polyolefins (PO), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) with

di(ethylhexyl)phthalate (DEHP) or ethylene-vinyl acetate (EVA). In some embodiments, the tubing used for infusion is fabricated from PE, PVC (with or without DEHP), polybutyldiene (PBD), or polyurethane (PU) with an in-line filter (polyethersulfone (PES), polysulfone or nylon).

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

Methods of Treatment and Antibodies for Use in Treating

[0062] Provided herein are methods and antibodies for use in treating or delaying progression of multiple myeloma (such as relapsed multiple myeloma or relapsed and refractory multiple myeloma) in an individual (e.g, a human individual) comprising administering to the individual an effective amount of an anti-CD38 antibody (e.g., an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: 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) that comprises: 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)), pomalidomide, and dexamethasone, wherein individual received at least two prior therapies for multiple myeloma (e.g., lenalidomide and a proteasome inhibitor). In some embodiments, the administration of the anti-CD38 antibody, pomalidomide, and dexamethasone as described herein results in a sustained response in the individual. In some embodiments, administration of the anti-CD38 antibody, pomalidomide, and dexamethasone as described herein extends the progression free survival (PFS) of the individual. In some embodiments, administration of the anti-CD38 antibody, pomalidomide, and dexamethasone as described herein extends the overall survival (OS) of the individual. In some embodiments, administration of the anti-CD38 antibody, pomalidomide, and dexamethasone as described herein results in lower minimal residual disease (MRD). In some embodiments the individual is MRD negative following administration of the anti-CD38 antibody, pomalidomide, and dexamethasone as described herein. In some embodiments, prior to

administration of the anti-CD38 antibody, pomalidomide, and dexamethasone as described herein, the individual demonstrates renal function impairment. In some embodiments, administration of the anti-CD38 antibody, pomalidomide, and dexamethasone as described herein improves renal function in the individual. In some embodiments, the individual is an adult, e.g., at least 18 years of age.

[0063] Provided herein are methods or antibodies for use in improving 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 (VH) that comprises: 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) that comprises: 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), pomalidomide, and dexamethasone. In some embodiments, the individual with multiple myeloma is selected for administration with the anti-CD38 antibody, pomalidomide, and dexamethasone based on having renal impairment. In some embodiments, the individual with multiple myeloma and renal impairment has poor prognosis. In some embodiments, the individual is an adult, e.g., at least 18 years of age. In some embodiments, the individual has renal impairment if the individual has an estimated glomerular filtration rate (eGFR) of less than about 90 mL/min/1 73m2 prior to the start of treatment. In some embodiments, the individual has renal impairment if the individual has an estimated glomerular filtration rate (eGFR) of between about 60 mL/min/1.73m2 and less than about 90 mL/min/1 73m2 prior to the start of treatment. In some embodiments, an individual with an eGFR of between about 60 mL/min/1.73m2 and less than about 90 mL/min/1.73m2 prior to the start of treatment has mild renal impairment. In some embodiments, the individual has renal impairment if the individual has an estimated glomerular filtration rate (eGFR) of between about 30 mL/min/1.73m2 and less than about 60 mL/min/1 73m2 prior to the start of treatment. In some embodiments, an individual with an eGFR of between about 30 mL/min/1.73m2 and less than about 60 mL/min/1.73m2 (e.g., such as less than about 30, less than about 50, or less than about 60 mL/min/1.73m2) prior to the start of treatment has moderate renal impairment. In some embodiments, the individual has renal impairment if the individual has an estimated glomerular filtration rate (eGFR) of less than about 30 mL/min/1 73m2 prior to the start of treatment. In some embodiments, an individual with an eGFR of less than about 30 mL/min/1 73m2 prior to the start of treatment has severe renal impairment. In some embodiments, the individual has renal impairment if the individual has creatinine clearance of less than about 90 mL/min/1 73m2 prior to the start of treatment. In some embodiments, the individual has renal impairment if the individual has creatinine clearance of between about 60 mL/min/1.73m2 and less than about 90 mL/min/1 73m2 prior to the start of treatment. In some embodiments, an individual with creatinine clearance of between about 60 mL/min/1.73m2 and less than about 90 mL/min/1.73m2 prior to the start of treatment has mild renal impairment. In some embodiments, the individual has renal impairment if the individual has creatinine clearance of between about 30 mL/min/1.73m2 and less than about 60 mL/min/1 73m2 prior to the start of treatment. In some embodiments, an individual with creatinine clearance of between about 30 mL/min/1.73m2 and less than about 60 mL/min/1.73m2 (e.g., such as less than about 50 or less than about 60 mL/min/1.73m2) prior to the start of treatment has moderate renal impairment. In some embodiments, the individual has renal impairment if the individual has creatinine clearance of less than about 30 mL/min/1.73m2 prior to the start of treatment. In some embodiments, an individual with creatinine clearance of less than about 30 mL/min/1.73m2 prior to the start of treatment has severe renal impairment. In some embodiments, the individual achieves a renal response following the start of treatment with the anti-CD38 antibody,

pomalidomide, and dexamethasone. In some embodiments the individual achieves a complete renal response following the start of treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, a complete renal response is characterized as an improvement of baseline eGFR or creatinine clearance from < 50 mL/min/1 73m2 prior to the start of treatment to > 60 mL/min/1.73m2 at least one assessment during treatment. In some embodiments the individual achieves a sustained complete renal response following the start of treatment. A sustained complete renal response is also known as a“durable complete renal response.” In some embodiments, a

sustained complete renal response (or“durable complete renal response) is characterized as an improvement of baseline eGFR or creatinine clearance from < 50 mL/min/1 73m2 prior to the start of treatment to > 60 mL/min/1 73m2 that is sustained for at least about 60 days. In some embodiments the time to first renal response in an individual receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is shorter than the time to first renal response in individual receiving treatment with pomalidomide and dexamethasone. In some embodiments,“time to renal first response” refers to the duration of time between the date of the first dose of the treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone and the date of the first sign of renal response. In some embodiments, the time to complete renal response in an individual receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is about any one of 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 range in between these values. In some embodiments, the time to complete renal response in an individual receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is about any one of 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 an individual receiving treatment with pomalidomide and dexamethasone, but without the anti-CD38 antibody, including any range in between these values. In some embodiments, the time to sustained complete renal response (also known as“durable complete renal response”) in an individual receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is about any one of 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 range in between these values. In some embodiments, the time to complete renal response in an individual 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 less, including any range between these values, than the time to complete renal response in an individual 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 a method or an antibody for use provided herein prevents or delays end-stage renal disease (ESRD) in the individual. In some embodiments, an individual receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone has a lower probability of developing ESRD than an individual receiving treatment with pomalidomide and dexamethasone, but without the anti-CD38 antibody. In some embodiments, ESRD in an individual receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone according to a method or an antibody for use provided herein is delayed by at least about any one of 1, 2, 3, or 4 weeks; by at least about any one of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 42, or 48 months; or longerthan 48 months (e.g., such as about any one of 4.5, 5, 5.5, or 6 years), including any range between these

values, as compared to an individual receiving treatment with pomalidomide and dexamethasone, but without the anti-CD38 antibody.

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

[0066] In some embodiments, the individual demonstrated progressive disease during the most recent prior therapy (or line of therapy), e.g., the therapy (or line of therapy) just before the start of treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual demonstrated progressive disease (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) just before the start of treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, a progressive disease (PD) is defined according to 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 Table A and Table B herein). In some

embodiments, a line of therapy is >1 complete cycle of a single agent, or of a combination of two or more agents, or a planned sequential therapy that includes stem cell transplantation. In some embodiments, a given treatment is considered a new line of therapy if a new line of treatment is started after discontinuation of a previous line. In some embodiments, a treatment is considered a new line of therapy if a treatment regimen is discontinued for any reason and a different treatment regimen is started. In some embodiments, a treatment regimen is considered to have been

discontinued if all the drugs in that given regimen have been stopped. In some embodiments, a regimen is not considered to have been discontinued if some of the drugs of the regimen, but not all, have been discontinued. In some embodiments, the reasons for discontinuation, addition, substitution, or SCT (stem cell transplant) do not influence how lines are counted. In some embodiments, a given treatment is considered a new line of therapy if there has been an unplanned addition or substitution of 1 or more drugs in an existing regimen. In some embodiments, in individuals undergoing >1 SCT, except in the case of a planned tandem SCT with a predefined interval (such as 3 months), each SCT (autologous or allogeneic) can be considered a new line of therapy 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 (frontline, 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, an individual with refractory multiple myeloma is one who was refractory to all prior therapies (or prior lines of therapy), but achieved at least a minimal response (MR) to one prior therapy (or line of therapy). In some embodiments, a minimal response (MR) is defined according to 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 Table A and Table B herein). In some embodiments, an individual with refractory multiple myeloma is one who was non-re sponsive to a prior therapy (or prior line of therapy). In some embodiments,“non-responsive” to a therapy (or line of therapy) for multiple myeloma means that the individual failed to achieve at least a minimal response (MR) to the therapy (or line of therapy) for multiple myeloma. In some embodiments“non-responsive” to a therapy (or line of therapy) for multiple myeloma means that the individual has demonstrated progressive disease during the therapy (or line of therapy) for multiple myeloma. In some embodiments, an individual with refractory multiple myeloma is one who demonstrated progressive disease within the 60 days from the end of the last therapy for multiple myeloma.

[0068] In some embodiments, the individual has failed prior treatment (such as treatment with lenalidomide and/or a proteasome inhibitor) for multiple myeloma. In some embodiments,“failing” a prior treatment means that the individual has demonstrated disease progression (e.g., according to the criteria in Table A and Table B) while on the treatment (such as treatment with lenalidomide and/or a proteasome inhibitor) or within 60 days from end of treatment (such as treatment with lenalidomide and/or a proteasome inhibitor). In some embodiments,“failing” a prior treatment for multiple myeloma means that the individual had demonstrated a partial response (PR) or better (e.g. , according to the criteria in Table A and Table B) to treatment (such as treatment with lenalidomide and/or a proteasome inhibitor), but exhibited disease progression within 6 months after discontinuing the treatment (e.g., as treatment with lenalidomide and/or a proteasome inhibitor). In some embodiments, “failing” a prior treatment for multiple myeloma means that the individual developed toxicity / intolerance after a minimum of 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) developing peripheral neuropathy or neuropathic pain, e.g., during or following treatment with a proteasome-containing regimen. In some embodiments, intolerance to a

lenalidomide-containing regimen means that the individual developed severe rash during or following 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 measured using serum protein immunoelectrophoresis and/or urine M protein >200 mg/24 hours measured using urine protein immunoelectrophoresis and/or serum free light chain (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, an individual with relapsed and refractory multiple myeloma is one who relapsed from at least one prior therapy (or line of therapy) for multiple myeloma and was refractory to the most recent therapy (or line of therapy) for multiple myeloma. In some

embodiments, the individual with relapsed and refractory multiple myeloma is one who relapsed from at least one prior therapy (or line of therapy) for multiple myeloma, was refractory to the most recent therapy (or line of therapy) for multiple myeloma, and was 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, an individual with relapsed or refractory multiple myeloma is one who demonstrated progressive disease within 60 days after the end of the most recent therapy (or line of therapy).

[0070] In some embodiments, the individual was 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 measured using serum protein

immunoelectrophoresis and/or urine M protein >200 mg/24 hours measured using urine protein immunoelectrophoresis) who has received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, marizomib, oprozomib, etc.) and was refractory to the last line of therapy (i.e. , most recent line of therapy). In some embodiments, the individual has adequate renal, hepatic and bone marrow function.

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

[0073] In some embodiments, the individual has undergone at least one prior therapy (or prior line of therapy) with lenalidomide. In some embodiments, the prior lenalidomide therapy (or prior line of lenalidomide therapy) comprised at least two consecutive cycles of lenalidomide. In some embodiments, the individual failed (e.g., was non-responsive to) a prior lenalidomide therapy (or a prior line of lenalidomide therapy). In some embodiments, an individual who failed a prior lenalidomide therapy (or a prior line of lenalidomide therapy) did not achieve at least a minimal

response (MR) during the therapy (or line of therapy) with lenalidomide. In some embodiments, an individual who failed a prior lenalidomide therapy (or a prior line of lenalidomide therapy) demonstrated progressive disease (PD) during the therapy (or line of therapy) with lenalidomide. As noted elsewhere herein, in some embodiments,“minimal response” and“progressive disease” are assessed 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 and Table B herein). In some embodiments, prior lenalidomide was administered during the first, second, third, fourth, fifth, sixth, and/or later therapy (or line of therapy) for multiple myeloma (i.e. , prior to treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone according to a method or an antibody for use provided herein). In some embodiments, the individual was refractory to lenalidomide. In some embodiments, the prior lenalidomide was administered to the individual as a single agent. In some embodiments, the prior lenalidomide was administered to the individual in conjunction with at least one additional agent.

[0074] In some embodiments, the individual has undergone at least one prior therapy (or at least one prior line of therapy) 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 line of therapy) with the proteasome inhibitor comprised at least two consecutive cycles of the proteasome inhibitor. In some

embodiments, the individual failed (e.g., was non-responsive to) a prior proteasome inhibitor therapy (or a prior line of proteasome inhibitor therapy). In some embodiments, an individual who failed a prior therapy (or a line of therapy) with the proteasome inhibitor did not achieve at least a minimal response (MR) during the therapy (or line of therapy) with the proteasome inhibitor. In some embodiments, an individual who failed a prior therapy (or a prior line of therapy) with a proteasome inhibitor demonstrated progressive disease (PD) during the therapy (or prior line of therapy) with the proteasome inhibitor. In some embodiments, the prior proteasome inhibitor therapy was administered during the first, second, third, fourth, fifth, sixth, and/or later therapy (or line of therapy) for multiple myeloma (i.e., prior to treatment with an anti-CD38 antibody, pomalidomide, and dexamethasone according to methods or antibodies for use provided herein). In some embodiments, the individual was 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) was administered to the individual as a single agent. In some embodiments, the prior proteasome inhibitor therapy (or prior line of proteasome inhibitor therapy) was administered to the individual in conjunction with at least one additional agent.

[0075] In some embodiments, the lenalidomide and the proteasome inhibitor were 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., given alone or in combination), but demonstrated progressive disease (PD) within 6 months of the end of the therapy (or end of the 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 Taiwanese individual.

[0077] In some embodiments, the individual has chronic obstructive pulmonary disorder (COPD). In some embodiments, the individual is diagnosed with COPD prior to the start of treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual develops and/or is diagnosed with COPD after the start of treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone.

[0078] In some embodiments, the individual has asthma. In some embodiments, the individual is diagnosed with asthma prior to the start of treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual develops and/or is diagnosed with asthma after the start of treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone

[0079] In some embodiments, the individual has (e.g., experiences) bronchospasms. In some embodiments, the individual experienced bronchospasms prior to the start of treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone. In some embodiments, the individual develops bronchospasms after the start of 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 methods or antibodies for use provided herein have a CD38 receptor density of between about 13000 and about 340000 receptors/cancer cell. In some embodiments, the individual receiving treatment according to methods or antibodies for use provided herein is heterozygous for the F 158V single nucleotide polymorphism in the FCGR3A gene. In some embodiments, the individual receiving treatment according to methods or antibodies for use provided herein is homozygous for the F158V single nucleotide polymorphism in the FCGR3A gene. In some embodiments, the individual receiving treatment according to methods or antibodies for use provided herein 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, an individual with primary refractory multiple myeloma is one who has never achieved at least a minimal response (MR) with any therapy (or line of therapy) during the disease course. In some embodiments, the individual does not have free light chain (FLC) measurable disease only. 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 a prior therapy (or a prior line of therapy) with isatuximab. In some embodiments, the individual has not demonstrated progressive disease (PD) during a prior therapy (or prior line of therapy) with an anti-CD38 antibody. In some embodiments, the individual has not demonstrated PD within 60 days after the end of a therapy (or line of therapy) with an anti-CD38 antibody. In some embodiments, the individual has not received a prior therapy (or a prior line of therapy) with pomalidomide. In some embodiments, the individual has received a prior therapy (or a prior line of therapy) with

pomalidomide. In some embodiments, the individual has not received prior allogenic hematopoietic stem cell transplantation.

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

[0083] In some embodiments, treatment comprises administering the anti-CD38 antibody, the pomalidomide, and the 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), the 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 the 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 under 75 years of age, or 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, the pomalidomide, and the dexamethasone are administered sequentially on Days 1, 8, and 15 of the first 28-day cycle (i.e.,

Cycle 1). In some embodiments, the pomalidomide and the 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, the dexamethasone is administered prior to the anti-CD38 antibody, and the anti-CD38 antibody is administered prior to the pomalidomide on Days 8, and 15 of the first 28-day cycle (i.e., Cycle 1).

[0084] In some embodiments, treatment comprises administering the anti-CD38 antibody, the pomalidomide, and the 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 every cycle following Cycle 1 (e.g., Cycle 2, 3, 4, etc.), the pomalidomide is administered at a dose of 4 mg on each of Days 1-21 of every cycle following Cycle 1 (e.g., Cycle 2, 3, 4, etc.), and the dexamethasone is administered at a dose of 40 mg on Days 1, 8, 15, and 22 of every cycle following 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 every cycle following 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, the pomalidomide, and the dexamethasone are administered sequentially on Days 1 and 15 of every cycle following Cycle 1 (e.g., Cycle 2, 3, 4, etc.). In some embodiments, the pomalidomide and the dexamethasone are administered prior to the anti-CD38 antibody on Day 1 of every 28-day cycle following Cycle 1 (e.g., Cycle 2, 3, 4, etc.). In some embodiments, the dexamethasone is administered prior to the anti-CD38 antibody, and the anti-CD38 antibody is administered prior to the pomalidomide on Day 15 every 28-day cycle following Cycle 1 (e.g., Cycle 2, 3, 4, etc.).

[0085] In some embodiments, treatment comprises administering the anti-CD38 antibody, the pomalidomide, and the dexamethasone to the individual in 28-day cycles. In some embodiments, the anti-CD38 antibody is administered at a dose of 10 mg/kg once every week of the first 28-day cycle (i.e.. Cycle 1), the pomalidomide is administered at a dose of 4 mg for 21 days of the first 28-day cycle (i.e., Cycle 1), and the dexamethasone is administered at a dose of 40 mg once every week of the first 28-day cycle (i.e., Cycle 1) if the individual is under 75 years of age, or at a dose of 20 mg once every week 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, the pomalidomide, and the dexamethasone are administered sequentially in the first 28-day cycle (i.e., Cycle 1). In some embodiments, the pomalidomide and the dexamethasone are administered prior to the anti-CD38 antibody in the first 28-day cycle (i.e., Cycle 1). In some embodiments, the dexamethasone is administered prior to the anti-CD38 antibody, and the anti-CD38 antibody is administered prior to the pomalidomide on Days 8, and 15 of the first 28 -day cycle (i.e., Cycle 1).

[0086] In some embodiments, treatment comprises administering the anti-CD38 antibody, the pomalidomide, and the 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 once every other week of every 28-day cycle following Cycle 1 (e.g., Cycle 2, 3, 4, etc.), the pomalidomide is administered for 21 of every 28-day cycle following Cycle 1 (e.g., Cycle 2, 3, 4, etc.), and the dexamethasone is administered at a dose of 40 mg once every week of every 28-day cycle following 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 once every week of every 28-day cycle following 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, the pomalidomide, and the dexamethasone are administered sequentially in every cycle following Cycle 1 (e.g., Cycle 2, 3, 4, etc.). In some embodiments, the pomalidomide and the dexamethasone are administered prior to the anti-CD38 antibody in every 28-day cycle following Cycle 1 (e.g., Cycle 2, 3, 4, etc.). In some embodiments, the dexamethasone is administered prior to the anti-CD38 antibody, and the anti-CD38 antibody is administered prior to the pomalidomide in every 28-day cycle following Cycle 1 (e.g., Cycle 2, 3, 4, etc.).

[0087] In some embodiments, the PFS of the individual is measured as the period of time from the start of treatment to the first occurrence of progressive disease (PD). In some embodiments, PD is assessed 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 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 improved (e.g., extended) 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 in 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 increases (e.g., extends) the PFS of the individual by at least about any one 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 range in between these values), as compared to an individual having multiple myeloma (such as refractory multiple myeloma or relapsed and refractory multiple myeloma) who received treatment comprising pomalidomide and dexamethasone without the anti-CD38 antibody. In some embodiments, the treatment increases (e.g., extends) the PFS of the individual by at least about 5 months, as compared to an individual having multiple myeloma (such as refractory multiple myeloma or relapsed and refractory multiple myeloma) who received treatment comprising pomalidomide and dexamethasone without the anti-CD38 antibody. In some embodiments, the treatment increases (e.g., extends) the PFS of the individual by at least about 4.5 months, as compared to an individual having multiple myeloma (such as refractory multiple myeloma or relapsed and refractory multiple myeloma) who received treatment comprising pomalidomide and dexamethasone without the anti-CD38 antibody.

[0088] In some embodiments, overall survival (OS) is measured as the period of time from the start of treatment to death. In some embodiments, the treatment increases (such as extends) the OS of the individual as compared to an individual having multiple myeloma (such as refractory multiple myeloma or relapsed and refractory multiple myeloma) who received treatment comprising pomalidomide and dexamethasone without the anti-CD38 antibody.

[0089] In some embodiments, the time to first response in an individual receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone according to methods or antibodies for use provided herein is shorter than the time to first response in individual receiving treatment with pomalidomide and dexamethasone. In some embodiments, treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone according to a method or antibody for use provided herein decreases the time to first response in individual, as compared to the time to first response of an

individual receiving treatment with pomalidomide and dexamethasone. In some embodiments,“time to first response” refers to the duration of time between the date of the first dose and the date of the first sign of response, e.g., 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 Table A and Table B).

[0090] In some embodiments, the individual is negative for minimal residual disease (MRD) or “MRD-negative” following 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-negative as measured by NGF (or“flow MRD-negative”) refers to the absence of phenotypically aberrant clonal plasma cells (such as multiple myeloma cells) in bone marrow aspirates (for example using the EUROFLOW™ high-throughput flow cytometry standard operation procedure for MRD detection in multiple myeloma (see Flores-Montero et al. (2017) Leukemia. 31 : 2094-2103) or an equivalent method) with a minimum sensitivity of, e.g., 1 in 104 nucleated cells (10 4), 1 in 105 nucleated cells (10 5), 1 in 106 nucleated cells (10 6), or 1 in 107 nucleated cells (10 7). In some embodiments, the individual is MRD-negative via NGF at a threshold of 10 4, 10 5, or 10 6 following treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone.

[0091] In some embodiments, MRD status is measured by next generation sequencing (NGS).

In some embodiments, MRD-negative as measured by NGS (or“sequencing MRD negative”) refers to absence of clonal plasma cells (e.g. , multiple myeloma cells) in bone marrow aspirates; the presence of a clone is defined as at least two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates (for example, using the LYMPHOSIGHT® high-throughput sequencing platform or equivalent method) with a minimum sensitivity of, e.g. , 1 in 104 nucleated cells (10 4), 1 in 105 nucleated cells(10 5), 1 in 106 nucleated cells (10 6), or higher. In some embodiments, the minimum sensitivity is 1 cell in 106 (or 10 6) nucleated cells. In some

embodiments, the individual is MRD-negative via NGS at a threshold of 10 4, 10 5, or 10 6 following treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone.

[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) being MRD-negative as detected by NGF or MRD-negative as detected by NGS and (b) disappearance of every area of increased tracer uptake found at baseline or a preceding positron emission tomography (PET)/computed tomography (Ct) or decrease to < mediastinal blood pool maximum standardized uptake value or decrease to less than that of surrounding normal tissue. In some embodiments, the individual is“sustained MRD-negative.” In some embodiments, sustained MRD negativity refers to

an individual who has been confirmed to be imaging + MRD-negative at two time points following 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 a bone marrow sample collected from an individual who has received treatment with isatuximab, pomalidomide, and dexamethasone, as described herein. In some embodiments, the individual who is assessed for MRD has achieved complete response after treatment with isatuximab, pomalidomide, and dexamethasone, as described herein. In some embodiments, the individual is negative by both imaging and MRD via NGS or NGF at a threshold of 10 4, 10 5, or 10 6 following treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone.

[0093] In some embodiments, the individual is less than 65 years of age. In some embodiments, the one-year overall survival rate of an individual less than 65 years of age receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least any one of about 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 range in between these values. In some embodiments, the PFS of an individual less than 65 years of age receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least any one of 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 range in between these values. In some embodiments, the PFS of an individual less than 65 years of age receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least any one of about 3, 3.5, 4, 4.5, 5, 5.5, 6,

6.5, or 7 months longer than the PFS of an individual less than 65 years of age receiving treatment with pomalidomide, and dexamethasone, but without the anti-CD38 antibody, including any range between these values. In some embodiments, PFS is calculated as described elsewhere herein.

[0094] In some embodiments, the individual is at least 65 but less than 75 years of age. In some embodiments, the one-year overall survival rate of an individual least 65 but less than 75 years of age receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least any one of about 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 range in between these values. In some embodiments, the PFS of an individual at least 65 but less than 75 years of age receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least any one of about 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 range between these values. In some embodiments, the PFS of an individual at least 65 but less than 75 years of age receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least any one of about 1, 1.5, 2, 2.5, 2.6, 2.7, 2.8, 2.9, 2.99, or 3 months longer than the PFS of an individual at least 65 but less than 75 years of age receiving treatment with pomalidomide, and dexamethasone, but without the anti-CD38 antibody, including any range between these values. 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 an individual 75 years of age or older receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least any one of about 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 range in between these values. In some embodiments, the one-year overall survival rate of an individual 75 years of age or older receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is higher than the one-year overall survival rate of individual 75 years of age or older receiving treatment with pomalidomide, and dexamethasone, but without the anti-CD38 antibody. In some embodiments, the one-year overall survival rate of an individual 75 years of age or older receiving treatment with the anti-CD38 antibody, pomalidomide, and dexamethasone is at least any one of about 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 higher than the one-year overall survival rate of individual 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 any one of about 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 range between these values. 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 any one of about 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 longer than the PFS of an individual 75 years of age or older receiving treatment with pomalidomide, and dexamethasone, but without the anti-CD38 antibody, including any range between these values.

In some embodiments, PFS is calculated as described elsewhere herein.

[0096] In some embodiments, the individual is female (e.g. a fertile female of childbearing age). In some embodiments, where the patient is female and is able to become pregnant, the patient may use an effective method of contraception during the treatment with the anti-CD38 antibody and for five months after the last dose of the anti-CD38 antibody. In some embodiments the individual has hepatic impairment, such as mild hepatic impairment. In some embodiments, an individual has mild hepatic impairment if the individual’s total bilirubin is between about 1 and about 1.5 times the upper limit of normal (ULN). In some embodiments, an individual has mild hepatic impairment if the individual’s aspartate aminotransferase (AST) level is greater than the upper limit of normal (ULN).

In some embodiments, the individual has received at least three (e.g., 4, 5, 6, 7, 8, etc.) prior therapies (or prior lines of therapy) for multiple myeloma. In some embodiments, the individual has a

Glomerular Filtration Rate (creatinine clearance) of less than about 60, less than about 50, or less than about 30 ml/min/1.73 m2 prior to the start of treatment. In some embodiments, the individual is Stage II or Stage III according to the Multiple Myeloma International Stating System (ISS). In some embodiments, Stage II according to the Multiple Myeloma ISS is defined as a serum beta-2

microglobulin level of between about 3.5 and about 5.5 mg/L or greater. In some embodiments, Stage II according to the Multiple Myeloma ISS is defined as a serum albumin level of less than about 3.5 g/dL. In some embodiments, Stage III according to the Multiple Myeloma ISS is defined as a serum beta-2 microglobulin level of greater than about 5.5 mg/L. In some embodiments, the individual is Stage III according to the Multiple Myeloma Revised International Stating System (R-ISS). In some embodiments, Stage III according to the Multiple Myeloma R-ISS is defined as (a) a serum beta-2 microglobulin level of greater than about 5.5 mg/L and either (b) high-risk cytogenetic abnormality detected by interphase fluorescent in situ hybridization (iPISH) 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 ofdel(17p), t(4: 14), and/or t( 14; 16).

Articles of Manufacture or Kits

[0097] In another embodiment of the invention, an article of manufacture or a kit is provided comprising an anti-CD38 antibody (such as isatuximab). In some embodiments, the article of manufacture or kit further comprising pomalidomide, and/or dexamethasone. In some embodiments, the article of manufacture or kit further comprises package insert comprising instructions for using the anti-CD38 antibody (e.g., isatuximab) in conjunction with the pomalidomide and the dexamethasone to treat or delay progression of multiple myeloma (e.g., refractory multiple myeloma or relapsed and refractory multiple myeloma) 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] The specification is considered to be sufficient to enable one skilled in the art to practice the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

EXAMPLES

[0099] The present disclosure will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

Example 1: A Phase III randomized, open-label, multicenter study comparing Isatuximab

(SAR650984) in combination with pomalidomide and low-dose dexamethasone vs. 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 that evaluated the efficacy of isatuximab in combination with

pomalidomide and low-dose dexamethasone compared with pomalidomide and low-dose

dexamethasone for the treatment of patients with refractory or relapsed and refractory multiple myeloma who had received at least 2 prior lines therapy (e.g., > 2 lines prior lines of therapy) for multiple myeloma, 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., who were refractory to the last therapy).

I. Study Objectives

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., the“IPd arm”) in the prolongation of PFS as compared to pomalidomide and low-dose dexamethasone (i.e.,“Pd arm”) 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 first documentation of progressive disease (PD), as determined by independent response committee (IRC) or the date of death from any cause, whichever came first.

[0102] PD (IMWG criteria, as described in Kumar el 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 el 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 one of the following (see also Table A and Table B) .

• increase of >25% in Serum M-component from nadir (the absolute increase must have been >0.5 g/dF) in 2 consecutive assessments; serum M component increases >1 g/dF in 2 consecutive assessments are sufficient to define relapse if starting M component is >5 g/dF and/or

• increase of >25% in Urine M-component from nadir (the absolute increase must have been >200 mg/24 h) in 2 consecutive assessments and/or

• definite development of new bone lesions or soft tissue extramedullary disease or increase >50% from nadir in the sum of perpendicular diameters of existing soft

tissue extramedullary disease lesions if >1 lesion or >50% increase in the longest diameter of a previous soft tissue extramedullary disease lesion >1 cm in short axis. (Pathological fracture or collapse of bone were not necessarily evidence of disease progression.)

B. Key Secondary Objectives

[0103] The key secondary objectives (i.e.. key secondary endpoints or key secondary efficacy endpoints) of this study were: (1) to evaluate the overall response rate (ORR) as per 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 el al. (2006)“International uniform response criteria for multiple myeloma. Leukemia. 20: 1467-1473) in each arm; and (2) to compare overall survival (OS) between the IPd and Pd arms.

[0104] ORR was defined as the proportion of patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR), as assessed by independent response committee using the IMWG response criteria. See Table A and Table B below. A plasmacytoma that had been radiated was not suitable for response assessment; however, it must have been monitored to assess for progressive disease. For patients achieving very good partial response by other criteria, a soft tissue plasmacytoma must have decreased by more than 90% in the sum of the maximal perpendicular diameter (SPD) compared with baseline.

Table A Standard International Myeloma Working Group (IMWG) Response Criteria

tSPD, sum of the products of the maximal perpendicular diameters of measured lesions

[0105] Patients continued in the last confirmed response category until there was confirmation of progression or improvement to a higher response status; patients could not move to a lower response category. Percent decreases for response calculations were from baseline values (Cycle 1, Day 1). Percent increases for progression calculations were from lowest response values or baseline values, whichever was the smaller number. The lowest value did not need to be confirmed. The lowest confirmed value before suspected progression was used as baseline for calculation of progression; if a serum and/or urine spike was considered too low to quantitate, this value could be assigned as zero as a baseline for documentation of subsequent progressive disease. Patients were considered to have progressive disease if they met the criteria for progression by a variable that was not considered measurable at baseline; however, for patients who had a measurable serum or urine M-spike at baseline, progression could not be defined by increases in serum FLC alone.

[0106] For patients who had serum and urine M-Protein below level of eligibility on efficacy laboratory performed on Cycle 1 Day 1 (e.g., patients with only FLC measurable disease according to IMWG or patients without any biological measurable disease) could only have only one of two possible overall responses: non-PD or PD. In such cases, PD could be diagnosed on the following parameters:

• for patients with only FLC measurable: M protein and plasmacytoma according to IMWG criteria described in the table above,

• for patients with non-measurable disease: M protein and plasmacytoma, or an increase of bone marrow plasma cell percentage involvement >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 (“secondary endpoints”) of this study were: (1) to evaluate the time to progression (TTP) in each arm; (2) to evaluate the PFS in high risk cytogenetic population defined as patients carrying del(17p), t(4;14), t( 14; 16) in each arm; (3) to evaluate the duration of response (DOR) in each arm; (4) to evaluate safety in both treatment arms; (5) to determine the pharmacokinetic profile of isatuximab in combination with pomalidomide; (6) to evaluate the immunogenicity of isatuximab; (7) To assess disease-specific and generic 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 first documentation of progressive disease (as determined by 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 first documentation of PD (as determined by 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 the first independent response committee (IRC)-determined response to the date of first IRC -determined PD or death, whichever happened first. DOR was determined only for patients who achieved a response of >PR.

[0112] Safety in terms of treatment-emergent adverse events (TEAEs) /serious adverse events (SAE), laboratory parameters, vital signs (blood pressure, heart rate, and temperature), weight, ECOG performance status, and physical examination were assessed throughout the study. TEAEs were defined as adverse events that develop, worsen (according to the Investigator opinion), or become serious during the TEAE period (i.e., the time from first dose of study treatments up to 30 days after last dose of study treatments). 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 patients treated with in order to assess the pharmacokinetic profile of isatuximab using population pharmacokinetic approach.

[0114] The presence of antidrug antibodies (ADA, i.e., anti-isatuximab antibodies) in patients in the IPd arm were assessed throughout the study.

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

D. Exploratory objectives

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

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

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

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

[0120] Pharmacokinetic and pharmacodynamic estimates were investigated as prognostic factors for clinical outcome including safety and efficacy endpoints, where possible.

[0121] Minimal residual disease (MRD) was assessed via next-generation sequencing (NGS) using the CLONOSEQ® NGS platform in bone marrow samples obtained only from patients who

achieved CR. MRD status was categorized as outlined in Table B below. Bone marrow aspirates were collected at baseline/screening and the time of CR confirmation. If the patient presented with CR but was determined to be MRD positive, another bone marrow sample was collected 3 months (3 cycles) later in order to identify late negativity. In certain cases, a third sample was collected after another 3 months if the patient remained MRD positive and was still being treated. No more than 3 on-treatment bone marrow samples were obtained for each patient.

Table B. International Myeloma Working Group (IMWG) Minimal Residual Disease Criteria*

*Assessed in patients achieving a CR according to the criteria in Table A

[0122] Each of the efficacy assessments described above were chosen for use in this study and are considered well established and relevant in a hemato-oncology setting.

II. Study Design

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

Table C: Study Treatment Arms

[0124] Randomization was stratified by age (<75 years vs. >75 years) and number of previous lines of therapy (2 or 3 vs. more than 3). A complete transplant procedure (induction, mobilization, conditioning, transplant, consolidation and maintenance) was considered as one line. Each additional regimen was considered as one line, whatever the reason of discontinuation (progression, adverse event or patient request). Patients continued treatment until disease progression, unacceptable adverse events (e.g., unacceptable toxicity), or patient wish, whichever came first. The study design is summarized in FIG. 1.

A. Duration of study participation for each vatient

[0125] Each patient was considered in the study from informed consent signature until death, consent withdrawal or cut-off date, whichever came first. The duration of the study for a patient included a period for screening of up to 3 weeks. The duration of each treatment cycle was 28 days. Patients continued study treatment until disease progression, unacceptable AEs, patient wish, or any other reason. During follow-up, patients who discontinued study treatment due to progressive disease (PD) were followed every 3 months (12 weeks) for survival until death or cut-off date, whichever came first. Patients who discontinued the study treatment prior to documentation of progressive disease (PD) were followed-up every 4 weeks until disease progression (even for patients initiated further anti -myeloma therapy without PD), and then every 3 months (12 weeks) for survival, until death or cut-off date, whichever came first.

[0126] If a patient was still on treatment at the time of the cut-off date for OS and was benefitting from the study treatment, the patient could continue the study treatment until disease progression, unacceptable AEs, patient wish, or any other reason. For cycles completed after the cut-off date, all new related AEs (serious or not), all ongoing SAE (related or not) and all ongoing related non-serious AEs, and reason of end of treatment (EOT) continued to be collected.

B. Determination of end of clinical trial (all patients)

[0127] PFS analysis (primary endpoint analysis) was event driven and the cut-off date for PFS analysis was when 162 PFS events (progression or death, whichever came first) occurred. The OS analysis was event driven and the final cut-off date was when 220 deaths occurred.

III. Selection of Patients

A. Inclusion Criteria

[0128] Eligible patients were considered for inclusion if they met all of the following criteria:

• Age: >18 years or country’s legal age of majority if the legal age is >18 years old.

• Patients must have had a documented diagnosis of multiple myeloma with evidence of measurable disease.

• Serum M protein >0.5 g/dL measured using serum protein immunoelectrophoresis and/or

• Urine M protein >200 mg/24 hours measured using urine protein

Immunoelectrophoresis.

• Patients must have received at least 2 prior lines of anti-myeloma therapy, which must have included at least 2 consecutives cycles of lenalidomide and a proteasome inhibitor (bortezomib, carfdzomib or ixazomib), given alone or in combination. (Note: An induction treatment followed by ASCT and consolidation/maintenance was considered as one line of treatment.).

• Patients must have failed treatment with lenalidomide and a proteasome inhibitor (bortezomib, carfdzomib or ixazomib) alone or in combination, defined by any of the following (failure to lenalidomide and a proteasome inhibitor can have occurred at any line of therapy):

o Progression occurred while on or within 60 days from end of the treatment with lenalidomide and/or a proteasome inhibitor.

o In cases of previous response >PR to lenalidomide and/or a proteasome inhibitor, patient must have progressed within 6 months after discontinuation of the treatment.

o Patients who have developed intolerable toxicity after a minimum of 2 consecutive cycles of a regimen containing lenalidomide and a proteasome inhibitor (bortezomib, carfdzomib or ixazomib) alone or in combination. Intolerance is defined as below:

■ For proteasome inhibitor-containing regimens: any toxicity leading to discontinuation of a proteasome inhibitor, like >Grade 2 peripheral neuropathy or >Grade 2 neuropathic pain. Peripheral neuropathy must have been 2 (as described at ecog-acrin(dot)org/resources/ecog -performance-status and/or Oken et al. (1982) “Toxicity and response criteria of the Eastern Cooperative Oncology Group.” Am J. Clin Oncol. 5: 649-655).

• Platelets <75 000 cells/pL if <50% of bone marrow (BM) nucleated cells were plasma cells, and <30 000 cells/pL if >50% of BM nucleated cells were plasma cells. Platelet transfusion was not allowed within three days before the screening visit

• ANC (absolute neutrophil count) <1000 m/L (1 x 109/L). The use of G-CSF was not allowed to reach this level.

• Creatinine clearance <30 mL/min (Modification of Diet in Renal Disease (MDRD) Equation: GFR (mL/min/1.73 m2) = 175 x (Scr) 1 154 x (Age)-0 203 x (0.742 if Female) x (1.212 if African-American)).

• Total bilirubin >2 x ULN.

• Corrected serum calcium >14 mg/dL (>3.5 mmol/L)

• AST and/or ALT >3 x ULN

• Ongoing toxicity (excluding alopecia and those listed in eligibility criteria) from any prior anti-myeloma therapy > Grade 1, as outlined in NCI-CTCAE v4.03, available at ctep(dot)cancer(dot)gov/reporting/ctc(dot)html.)

• Hypersensitivity to IMiDs® (thalidomide or lenalidomide), defined as any

hypersensitivity reaction leading to stop IMiDs within the 2 first cycles or reaction, which does meet intolerance definition (provided above in the inclusion criteria).

• Hypersensitivity to dexamethasone, sucrose histidine (as base and hydrochloride salt) and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids, or H2 blockers that would prohibit further treatment with these agents.

• Significant cardiac dysfunction; myocardial infarction within 12 months; unstable, poorly controlled angina pectoris.

• Diagnosed or treated for another malignancy within 3 years prior to randomization with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low risk prostate cancer after curative therapy.

• Known to be HIV+ or to have hepatitis A, B or C active infection.

• Malabsorption syndrome or any condition that can significantly impact the

absorption of pomalidomide.

• Active primary amyloid-light (AL) amyloidosis (evidence of end organ damage or receiving treatment for amyloidosis).

• Concomitant plasma cell leukemia

• Unable or unwilling to undergo to thromboprophylaxis.

• Daily requirement for corticosteroids (equivalent to 10 mg/day of prednisone) for more than 7 days (except for inhalation corticosteroids).

IV. Study Treatments

A. Investigational Medicinal Products (IMPs)

i. Isatuximab (IV)

[0130] Isatuximab was formulated as a concentrated solution for infusion in vials containing 20 mg/mL (500 mg/25 mL) isatuximab in 20 mM histidine, 10% (w/v) sucrose, 0.02% (w/v) polysorbate 80, pH 6.0 buffer. Isatuximab was supplied for parenteral administration as a sterile, nonpyrogenic, injectable, colorless, 20 mg/mL concentrate for solution for infusion that may contain white to off-white particulates and was packaged in 30 mL glass vials fitted with elastomeric closure. Each vial contained a nominal content of 500 mg of isatuximab. The fill volume was established to ensure removal of 25 mL. For administration to patients, the appropriate volume of isatuximab is diluted in an infusion bag of 0.9% sodium chloride solution. The final infusion volume corresponding to the dose of isatuximab was administered for a period of time that depended on dose administered and was based on protein amount given per hour.

[0131] Isatuximab was administered at a dose of 10 mg/kg to patients in the IPd arm via intravenous infusion on Days 1, 8, 15, and 22 for the first 28-day cycle, and then on Days 1 and 15 for each subsequent 28-day cycle. (All cycles were 28 days in duration.) Dose modifications (described in further detail below) were applied in cases of toxicity.

ii. Pomalidomide (Oral administration )

[0132] Pomalidomide was provided as 1 mg, 2 mg, 3 mg, and 4 mg capsules. Pomalidomide was administered orally (per os or“PO”) to patients in both the IPd and Pd arms at a dose of 4 mg on Days 1 to 21 for each 28-day cycle. (All cycles were 28 days in duration.) Dose modifications (described in further detail below) were applied in cases of toxicity.

ii. Dexamethasone (Oral or IV administration)

[0133] Dexamethasone was formulated for oral administration as 4 mg and 8 mg tablets, and for intravenous injection as a 4 mg/mL solution. Dexamethasone was 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, on Days 1, 8, 15 and 22 for each 28-day cycle. (All cycles were 28 days in duration.) Dose modifications (described in further detail below) were applied in cases of toxicity.

[0134] In the IPd arm, dexamethasone was administered with non-investigational medicinal products (NIMPs, described below) as premedication for the prevention of infusion-related reactions commonly observed with administration of monoclonal antibodies.

B. Non-Investisational Medicinal Products ( NIMPs ) - Premedication for the

Prevention of Infusion Reactions (IRs)

[0135] All patients allocated to IPd arm received 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 were: diphenhydramine 25-50 mg IV (or equivalent: e.g., cetirizine, promethazine, dexchlorpheniramine, according to local approval and availability. Intravenous route was preferred for at least the first 4 infusions), dexamethasone per os / IV (dose 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 per os 15 to 30 minutes (but no longer than 60 minutes) prior to isatuximab infusion. Once the premedication regimen was completed, the isatuximab infusion started 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, was administered as part of the premedication and part of the backbone treatment before isatuximab and pomalidomide.

[0137] When dexamethasone was administered per os, the premedications were administered in the following order:

• Dexamethasone 40 mg per os (or 20 mg PO for patients >75 years of age); then

• Acetaminophen 650 mg to 1000 mg per os; then

• Ranitidine 50 mg IV (or equivalent); then

• Diphenhydramine 25 mg to 50 mg IV (or equivalent).

[0138] When dexamethasone was administered intravenously, the premedications were administered in the following order:

• Acetaminophen 650 mg to 1000 mg per os; then

• Ranitidine 50 mg IV (or equivalent); then

• Diphenhydramine 25 mg to 50 mg IV (or equivalent); then

• Dexamethasone 40 mg IV (or 20 mg IV for patients >75 years of age).

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

[0140] No post-infusion corticosteroid or bronchodilator prophylaxis was required.

[0141] All patients received mandatory thromboprophylaxis with aspirin or low molecular

weight heparin.

C. Dosase and Schedule

i. IPd Arm (Exyerimental Arm)

[0142] Patients allocated to IPd arm received premedications prior to isatuximab infusion to reduce the risk and severity of infusion reactions (IRs) commonly observed with monoclonal antibodies ( see above).

[0143] Drug administration for patients in the IPd arm was performed as follows:

• Dexamethasone was administered about 15-30 minutes (but no longer than 60 minutes) prior to isatuximab at a dose of 40 mg (or 20 mg if the patient was >75 years old), per os (the preferred route) or intravenously (if per os route could not be used) on Days 1, 8, 15 and 22.

• Isatuximab was administered at a dose of 10 mg/kg on Days 1, 8, 15, and 22 at Cycle 1, and then at a dose of 10 mg/kg on Days 1 and 15 for 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 lh to 30 min prior to isatuximab. On Day 8, Day 15 and Day 22 of Cycle 1 and on Day 15 of subsequent cycles, pomalidomide was taken after isatuximab infusion, and at a time which was 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 given at a dose of 40 mg (or 20 mg if the patient was >75 years old ),per os or intravenously on Days 1, 8, 15 and 22.

• Pomalidomide was given at a dose of 4 mg on each of Days 1 to 21 for each 28-day cycle.

[0145] There was no limitation in the number of cycles administered to patients in the absence of major toxicity, disease progression, or any other reason (e.g., withdrawal of consent for treatment, poor compliance, intercurrent illness that prevents further administration of study treatment, etc.). In case of progressive disease (PD), diagnosis made on laboratory criteria needed to be confirmed by two consecutive measures before to treatment discontinuation. Treatment continued until confirmation of the PD.

[0146] Each patient’s weight was measured prior to each cycle to allow calculation of the isatuximab dose.

[0147] Dose adjustment (dose delay, dose omission, and dose reduction (for pomalidomide and/or dexamethasone only) was permitted for subsequent treatment cycles based on individual patient tolerance. Dose reduction steps for pomalidomide and dexamethasone are shown in Tables D1 and D2 below, respectively. One or several doses of pomalidomide could be omitted. One or several doses of dexamethasone could be omitted, or the dose of dexamethasone could be decreased to every other week (i.e., twice per 28-day cycle).

Table Dl. Dose Levels for Pomalidomide Dose Reduction

*all doses are per os

Table D2. Dose Levels for Dexamethasone Dose Reduction

*all doses are per os or IV

[0148] No dose reductions were allowed for isatuximab infusion.

V Disease Assessment

[0149] Decisions made by the investigator regarding whether or not to permit subjects to continue treatment were based on efficacy data (obtained from local and/or central laboratories), radiological assessments, and bone marrow assessments performed throughout the study or if indicated according to IMWG criteria. The reference values to assess treatment response were the values measured in samples taken from each patient on Day 1 of Cycle 1, prior to treatment.

• Serum M-protein levels were assessed via immunoelectrophoresis and, if M protein was undetectable via immunoelectrophoresis, via immunofixation.

• Urine M-protein levels were assessed via immunoelectrophoresis and, if M protein was undetectable via immunoelectrophoresis, via immunofixation.

• Free light chain (FLC) levels were centrally analyzed only in case of complete response (CR) (i.e.. M-protein undetectable via 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).

• Bone marrow plasma cell infiltration was assessed to confirm CR, or if suspicion of disease progression in the absence of biochemical progression and as clinically indicated.

• Bone marrow aspirate (or biopsy, if clinically indicated) for minimal residual disease (MRD) assessment in case of CR. If the patient was MRD positive, another bone marrow sample was collected 3 months (3 cycles) later in order to identify late MRD negativity. A third sample may have been collected after another 3 months (3 cycles), if the patient remained MRD positive and was still being treated. (No more than 3 on-treatment bone marrow samples were obtained from any patient.)

• A skeletal survey or low-dose whole-body CT scan was performed at baseline, then once a year and anytime during the study if clinically indicated. The same modality (i.e., skeletal survey or low-dose whole-body CT) was used throughout the study for each patient.

• For extramedullary disease (plasmacytoma, including bone plasmacytoma):

o If extramedullary disease was present at baseline, CT scan or MRI was

performed at baseline and repeated every 12 weeks (±1 week). (Additional CT scans or MRIs were performed, if clinically indicated.)

o If extramedullary disease was suspected at baseline, CT scan or MRI was performed at baseline to confirm extramedullary disease. In case of confirmation, CT or MRI was and repeated every 12 weeks (±1 week). (Additional CT scans or MRIs were performed, if clinically indicated.)

The same modality (CT or MRI) was throughout the study for each individual patient.

VI. Results

A. Patient Characteristics

[0150] 307 patients were randomized and included in the Intend to Treat (ITT) population (153 in Pd arm and 154 in IPd arm). Overall, patients’ demographics and characteristics at baseline were representative of the RRMM population and were in general similar in the 2 treatment arms. See Table E below.

Table E. Demographic Characteristic of Randomized Population

Pd (Control Arm) IPd (Experimental Arm) All

Age (years)

Number 153 154 307 Mean (SD) 65.2 (9.5) 66.6 (9.1) 65.9 (9.3) Median 66.0 68.0 67.0 Min ; Max 41 ; 86 36 ; 83 36 ; 86

Age group (years) [n(%)]

Number 153 154 307 <65 70 (45.8) 54 (35.1) 124 (40.4) [65-75 [ 54 (35.3) 68 (44.2) 122 (39.7)

>75 29 (19.0) 32 (20.8) 61 (19.9)

Gender [n(%)]

Number 153 154 307 Female 83 (54.2) 65 (42.2) 148 (48.2) Male 70 (45.8) 89 (57.8) 159 (51.8)

Race [n(%)]

Number 153 154 307

White 126 (82.4) 118 (76.6) 244 (79.5)

Black or African American 3 (2.0) 1 (0.6) 4 (1.3)

Asian 15 (9.8) 21 (13.6) 36 (11.7)

Native Hawaiian or other Pacific Island 1 (0.7) 2 (1.3) 3 (1.0)

Missing/Not reported 8 (5.2) 12 (7.8) 20 (6.5)

Ethnicity [n(%)]

Number 153 154 307

Hispanic or Latino 3 (2.0) 4 (2.6) 7 (2.3) Not Hispanic or Latino 134 (87.6) 130 (84.4) 264 (86.0) Unknown 2 (1.3) 2 (1.3) 4 (1.3) Not Reported 14 (9.2) 18 (11.7) 32 (10.4)

Prior history of asthma / COPD [n(%)] 16 (10.5) 16 (10.4) 32 (20.9) eGFR >60 ml/min/1.73m2 [n(%)] 96/145 (66.2) 87/142 (61.3) 183/287 (63.7) eGFR <60 ml/min/1.73m2 [n(%)] 49/145 (33.8) 55/142 (38.7) 104/287 (36.2) eGFR <50 ml/min/1.73m2 [n(%)] 24/145 (16.6) 33/142 (23.2) 57/287 (19.9) eGFR <30 ml/min/1.73m2 [n(%)] 1/145 (0.7) 1/142 (0.7) 2/287 (0.7) eGFR >45 to <60 ml/min/1.73m2 [n(%)] 32/145 (22.1) 35/142 (24.6) 67/287 (23.3) eGFR >30 to <45 ml/min/1.73m2 [n(%)] 16/145 (11.0) 19/142 (13.4) 35/287 12.2)

ECOG performance status [n(%)]

Number 153 154 307 0 69 (45.1) 55 (35.7) 124 (40.4) 1 68 (44.4) 83 (53.9) 151 (49.2) 2 16 (10.5) 16 (10.4) 32 (10.4)

Geographical region3 [n(%)]

Number 153 154 307 Western Europe 76 (49.7) 55 (35.7) 131 (42.7)

Pd (Control Arm) IPd (Experimental Arm) All

_ (N=153) _ (N=154) _ (N=307)

Eastern Europe 20 (13.1) 28 (18.2) 48 (15.6) North America 5 (3.3) 7 (4.5) 12 (3.9) Asia 15 (9.8) 21 (13.6) 36 (11.7)

Other Countries 37 (24.2) 43 (27.9) 80 (26.1) Regulatory region6 [n(%)]

Number 153 154 307

Western Countries 97 (63.4) 77 (50.0) 174 (56.7)

Other Countries_ 56 (36 6) 77 (50 0) 133 (43 3) a: Other countries=Australia, New Zealand, Turkey and Russia.

b: Other countries=Czech Republic, Hungary, Poland, Slovakia, Japan, Korea, Republic of Taiwan (Province of China), Turkey and Russia

[0151] Multiple myeloma international staging system (ISS) stage and multiple myeloma subtype at initial diagnosis were well balanced between treatment arms (see Table F). Overall, 28% of patients had ISS stage III at initial diagnosis (28.8% in Pd arm and 27.3% in IPd arm).

Table F. Disease Characteristics of Randomized Population at Initial Diagnosis

Pd (Control Arm) IPd (Experimental Arm) All _ (N=153) _ (N=154) _ (N=307)

Initial diagnosis [n(%)]

Number 153 154 307

Multiple Myeloma 153 (100) 154 (100) 307 (100)

Time from initial diagnosis of MM to randomization

(years)

Number 153 154 307 Mean (SD) 5.29 (3.69) 5.23 (3.24) 5.26 (3.46)

Median 4.09 4.46 4.23 Min ; Max 0.5 ; 20.5 0.6 ; 18.4 0.5 ; 20.5

MM subtype at initial diagnosis [n(%)]

Number 153 154 307 Ig G 100 (65.4) 102 (66.2) 202 (65.8) Ig A 41 (26.8) 34 (22.1) 75 (24.4) Ig M 0 2 (1.3) 2 (0.7) Ig D 0 0 0 Ig E 0 0 0

Kappa light chain only 7 (4.6) 8 (5.2) 15 (4.9) Lambda Light chain only 4 (2.6) 7 (4.5) 11 (3.6) Unknown/undetected 1 (0.7) 1 (0.6) 2 (0.7)

ISS stage at initial diagnosis [n(%)]

Number 153 154 307 Stage 41 (26.8) 36 (23.4) 77 (25.1) Stage 48 (31.4) 49 (31.8) 97 (31.6) Stage 44 (28.8) 42 (27.3) 86 (28.0) Unknown 20 (13 1) 27 (17.5) 47 (15.3)

Ig: Immunoglobulin, MM : Multiple Myeloma, ISS: International staging system

[0152] At study entry, the ISS criteria were classified as Stage I and II in 73.0% of the patients and stage III in 25.1% of patients (see Table G). As per the inclusion criteria, all patients were relapsed and refractory at study entry. Disease characteristics were as expected in this heavily treated RRMM population and in general similar between the treatment arms.

Table G. Disease Characteristics of Randomized Population at Study Entry

Pd (Control Arm) IPd (Experimental Arm) All (N=153) (N=154) (N=307)

MM subtype at study entry [n(%)]

Number 153 154 307 Ig G 101 (66.0) 104 (67.5) 205 (66.8) Ig A 41 (26.8) 33 (21.4) 74 (24.1) Ig M 0 2 (1.3) 2 (0.7) Ig D 0 0 0 Ig E 0 0 0

Kappa light chain only 7 (4.6) 8 (5.2) 15 (4.9) Lambda light chain only 4 (2.6) 7 (4.5) 11 (3.6)

Beta 2-microglobulin (mg/L)

Number 150 151 301 Mean (SD) 5.71 (6.72) 4.68 (3.84) 5.19 (5.49)

Median 3.75 3.40 3.60 Min ; Max 0.7 ; 54.7 0.4 ; 27.0 0.4 ; 54.7

Beta 2-microglobulin (mg/L) [n(%)]

Number 150 151 301 < 3.5 65 (43.3) 77 (51.0) 142 (47.2)

> 3.5 and <5.5 42 (28.0) 40 (26.5) 82 (27.2) > 5.5 43 (28.7) 34 (22.5) 77 (25.6)

Serum LDH [n(%)]

Number 153 154 307 < ULN 102 (66.7) 106 (68.8) 208 (67.8) > ULN 51 (33.3) 48 (31.2) 99 (32.2)

ISS stage at study entry [n(%)]

Number 153 154 307 Stage I 51 (33.3) 64 (41.6) 115 (37.5) Stage II 56 (36.6) 53 (34.4) 109 (35.5) Stage III 43 (28.1) 34 (22.1) 77 (25.1) Unknown 3 (2.0) 3 (1.9) 6 (2.0)

R-ISS stage at study entry [n(%)]

Number 153 154 307 Stage 31 (20.3) 39 (25.3) 70 (22.8) Stage 98 (64.1) 99 (64.3) 197 (64.2) Stage 24 (15.7) 16 (10.4) 40 (13.0) Unknown 0 0 0

Refractory status

Number 153 154 307

Relapsed and refractory* 153 (100) 154 (100) 307 (100)

Pd (Control Arm) IPd (Experimental Arm) All

(N=153) (N=154) (N=307)

Primary refractory 0 0 0 Relapsed 0 0 0

*: excluding primary refractory

MM: Multiple Myeloma, Ig: Immunoglobulin, LDH : Lactate Dehydrogenase, ULN : Upper Limit of Normal, ISS: International staging system, R-ISS: Revised International staging system

[0153] Overall, the 2 treatment arms were similar with regards to prior anti-myeloma therapies (see Tables HI and H2 below). As per protocol, all patients had received at least 2 prior lines of treatment including prior lenalidomide and proteasome inhibitor (PI). Overall, the median number of prior lines was 3 (range 2 to 11 lines), with 107 (34.9%) patients having received 4 or more prior lines of treatment. One patient was previously treated with daratumumab. Ninety two percent 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. Nearly all patients (98.0%) were refractory to the last regimen before study entry.

CLAIMS

1. An anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: 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) that comprises: a CDR-L1 comprising the amino acid sequence

KASQDVSTWA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6) for use in treating multiple myeloma in an individual, 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, the pomalidomide is administered at a dose of 4 mg, and the dexamethasone is administered at a dose of 40 mg individuals under 75 years of age, or the dexamethasone is administered at a dose of 20 mg to individuals 75 years of age or older,

wherein the individual received at least two prior therapies for multiple myeloma, wherein at least one of the at least two prior therapies for multiple myeloma was lenalidomide and at least one of the two prior therapies was a proteasome inhibitor, and

wherein the treatment extends progression free survival (PFS) and/or overall survival (OS) of the individual.

2. An anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: 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) that comprises: a CDR-L1 comprising the amino acid sequence

KASQDVSTWA (SEQ ID NO: 4), a CDR-L2 comprising the amino acid sequence SASYRYI (SEQ ID NO: 5), and a CDR-L3 comprising the amino acid sequence QQHYSPPYT (SEQ ID NO: 6) for use in method of reversing renal function impairment in an individual with multiple myeloma, 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, the pomalidomide is administered at a dose of 4 mg, and the dexamethasone is administered at a dose of 40 mg individuals under 75 years of age, or the 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 was lenalidomide and at least one of the at least two prior therapies was a proteasome inhibitor.

3. A liquid pharmaceutical formulation comprising

(a) isatuximab at a concentration of 5-20 mg/ml;

(b) a buffering agent 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).

4. The liquid pharmaceutical formulation of claim 3, wherein isatuximab is present at a concentration of 5 mg/ml, wherein the buffering agent is histidine and the histidine is at a

concentration of 10 mM, wherein the excipient is sucrose and the sucrose is at a concentration of 10% (w/v), wherein the 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. The liquid pharmaceutical formulation of claim 3, wherein isatuximab is present at a concentration of 20 mg/ml, wherein the buffering agent is histidine and the histidine is at a concentration of 20 mM, wherein the excipient is sucrose and the sucrose is present at a concentration of 10% (w/v), wherein the 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, comprising administering to the individual an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: 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) that comprises: 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), pomalidomide, and

dexamethasone,

wherein the anti-CD38 antibody is administered at a dose of 10 mg/kg, the pomalidomide is administered at a dose of 4 mg, and the dexamethasone is administered at a dose of 40 mg wherein the individual is under 75 years of age, or at a dose of 20 mg wherein the individual 75 years of age or older,

wherein the individual received at least two prior therapies for multiple myeloma, wherein at least one of the at least two prior therapies for multiple myeloma was lenalidomide and at least one of the two prior therapies was a proteasome inhibitor, and

wherein the treatment extends progression free survival (PFS) and/or the treatment extends over all survival (OS) of the individual.

8. A method of improving renal impairment in an individual in need thereof, wherein the individual has multiple myeloma, comprising administering to the individual an anti-CD38 antibody comprising (a) a heavy chain variable domain (VH) that comprises: 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) that comprises: 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), pomalidomide, and dexamethasone,

wherein the anti-CD38 antibody is administered at a dose of 10 mg/kg, the pomalidomide is administered at a dose of 4 mg, and the dexamethasone is administered at a dose of 40 mg wherein the individual is under 75 years of age, or 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 was lenalidomide and at least one of the at least two prior therapies was a proteasome inhibitor.

9. The antibody for use according to claim 1 or 2 or method according to claim 7 or 8, wherein the at least two prior therapies did not include treatment with an anti-CD38 antibody and/or treatment with pomalidomide.

10. The antibody for use according to claim 1, 2, or 9, or the method according to any one of claim 7-9, wherein 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 the treatment with at least one of the two prior therapies.

11. The antibody for use according to claim 2, 9, or 10, or the method according to any one of claims 8-10, wherein the individual with multiple myeloma is selected for the administration based on the individual having renal impairment.

12. The antibody for use or the method according to claim 11, wherein the individual has an estimated glomerular filtration rate (eGFR) less than about 60 mL/min/1.73m2.

13. The antibody for use according to any one of claims claim 2 and 9-12, or the method according to any one of claims 8-12, wherein the treatment extends progression free survival (PFS) of the individual.

14. The antibody for use according to any one of claims claim 2 and 9-13, or the method according to any one of claims 8-13, wherein the treatment extends overall survival (OS) of the individual.

15. The antibody for use according to any one of claims claim 1, 9-10, and 13, or the method according to any one of claims 7, 9-10, and 13, wherein the treatment extends the PFS of the individual by at least about 9 months.

16. The antibody for use according to any one of claims claim 1, 9-10, and 13, or the method according to any one of claims 7, 9-10, and 13, wherein the treatment extends the PFS of the individual by at least about 4.5 months relative to an individual having 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 claims 1, 9, 10 and 15-16 or the method according to any one of claims 7, 9, 10, 15 and 16 wherein treatment reverses renal function impairment.

18. The antibody for use according to any one of claims 1-2 and 9-17, or the method according to any one of claims 7-17, wherein the individual achieves a response to the treatment faster than an individual having multiple myeloma who received a treatment comprising pomalidomide and dexamethasone without the anti-CD38 antibody.

19. The antibody for use according to any one of claims 2 and 9-17, or the method of any one of claims 8-17, wherein the individual achieves a renal response to the treatment faster than an

individual having multiple myeloma who received a treatment comprising pomalidomide and dexamethasone without the anti-CD38 antibody.

20. The antibody for use or the method according to claim 19, wherein the renal response is a complete renal response.

21. The antibody for use or the method according to claim 19 or 20, wherein the complete renal response is sustained for at least 60 days.

22. The antibody for use according to any one of claims 1-2 and 9-21, or the method according to any one of claims 7-21, wherein the anti-CD38 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 8 or SEQ ID NO: 9.

23. The antibody for use according to any one of claims 1-2 and 9-22, or the method according to any one of claims 7-22, wherein the anti-CD38 antibody is isatuximab.

24. The antibody for use according to any one of claims 1-2 and 9-23, or the method according to any one of claims 7-23, wherein the anti-CD38 antibody, the pomalidomide, and the 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, the pomalidomide is administered on each of Days 1-21 of the first 28-day cycle, and the dexamethasone is administered on Days 1, 8, 15, and 22 of the first 28-day cycle.

25. The antibody for use or the method according to claim 24, wherein the anti-CD38 antibody, the pomalidomide, and the 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, the pomalidomide is administered on each of Days 1-21 of the one or more 28-day cycles following the first 28-day cycle, and the 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 for use or the method according to claim 24 or 25, wherein the

pomalidomide and the dexamethasone are administered prior to the anti-CD38 antibody on Day 1 of the first 28 -day cycle.

27. The antibody for use or the method according to any one of claims 24-26, wherein the dexamethasone is administered prior to the anti-CD38 antibody on Days 8, 15, and 22 of the first 28 -day cycle, and wherein the anti-CD38 antibody is administered prior to the pomalidomide on Days 8 and 15 of the first 28 -day cycle.

28. The antibody for use or the method according to any one of claims 24-27 wherein the pomalidomide and the dexamethasone are administered prior to the anti-CD38 antibody on Day 1 of the one or more 28 -day cycles following the first 28 -day cycle.

29. The antibody for use or the method according to any one of claims 24-28, wherein the dexamethasone is administered prior to the anti-CD38 antibody, and wherein the anti-CD38 antibody is administered prior to the pomalidomide on Day 15 of the one or more 28-day cycles following the first 28 -day cycle.

30. The antibody for use according to any one of claims 1-2 and 9-23, or the method according to any one of claims 7-23, wherein the anti-CD38 antibody, the pomalidomide, and the dexamethasone are administered in a first 28-day cycle,

wherein the anti-CD38 antibody is administered once every week of the first 28-day cycle, the pomalidomide is administered for 21 days of the first 28-day cycle, and the dexamethasone is administered once every week of the first 28-day cycle.

31. The antibody for use or the method according to claim 30, wherein the anti-CD38 antibody, the pomalidomide, and the dexamethasone are further administered in one or more 28-day cycles following the first 28 -day cycle,

wherein the anti-CD38 antibody is administered once every other week of the one or more 28-day cycles following the first 28-day cycle, the pomalidomide is administered for 21 days of the one or more 28-day cycles following the first 28-day cycle, and the dexamethasone is once every week of the one or more 28 -day cycles following the first 28 -day cycle.

32. The antibody for use or the method according to claim 30 or 31, wherein the

pomalidomide and the dexamethasone are administered prior to the anti-CD38 antibody in the first 28 -day cycle.

33. The antibody for use or the method according to any one of claims 30-32, wherein the dexamethasone is administered prior to the anti-CD38 antibody and wherein the anti-CD38 antibody is administered prior to the pomalidomide in the first 28-day cycle.

34. The antibody for use or the method according to any one of claims 30-33 wherein the pomalidomide and the dexamethasone are administered prior to the anti-CD38 antibody in the one or more 28-day cycles following the first 28-day cycle.

35. The antibody for use or the method according to any one of claims 30-34, wherein the dexamethasone is administered prior to the anti-CD38 antibody, and wherein the anti-CD38 antibody is administered prior to the pomalidomide in the one or more 28-day cycles following the first 28-day cycle.

36. The antibody for use according to any one of claims 1-2 and 9-35, or the method according to any one of claims 7-29, wherein the anti-CD38 antibody is administered intravenously.

37. The antibody for use according to any one of claims 1-2 and 9-36, or the method according to any one of claims 7-30, wherein the pomalidomide is administered orally.

38. The antibody for use according to any one of claims 1-2 and 9-37, or the method according to any one of claims 7-37, wherein the dexamethasone is administered orally.

39. The antibody for use according to any one of claims 1-2 and 9-37 or the method according to any one of claims 7-37, wherein the dexamethasone is administered intravenously.

40. The antibody for use according to any one of claims 1-2 and 9-39 or the method according to any one of claims 7-39, wherein the individual was refractory to the most recent prior therapy for multiple myeloma.

41. The antibody for use or the method according to claim 40, wherein the most recent prior therapy was lenalidomide.

42. The antibody for use or the method according to claim 40, wherein the most recent prior therapy was a proteasome inhibitor.

43. The antibody for use according to any one of claims 1-2 and 9-42, or the method according to any one of claims 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 claims 1-2 and 9-43, or the method according to any one of claims 7-37, wherein the lenalidomide and the proteasome inhibitor were administered in combination.

45. The antibody for use according to any one of claims 1-2 and 9-44, or the method according to any one of claims 7-38, wherein the individual has chronic obstructive pulmonary disorder (COPD).

46. The antibody for use according to any one of claims 1-2 and 9-45, or the method according to any one of claims 7-39, wherein the individual has asthma.

47. The antibody for use according to any one of claims 1-2 and 9-46, or the method according to any one of claims 7-40, wherein the individual has bronchospams.

48. The antibody for use according to any one of claims 1-2 and 9-47, or the method according to any one of claims 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 claims 1-2 and 9-48, or the method according to any one of claims 7-42, wherein the individual is at least 65 but less than 75 years of age.

50. The antibody for use according to any one of claims 1-2 and 9-48, or the method according to any one of claims 7-42, wherein the individual is 75 years of age or older.

51. The antibody for use according to any one of claims 1-2 and 9-50, or the method according to any one of claims 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 claims 1-2 and 9-51, or the method according to any one of claims 7-51, wherein the individual is East Asian.

53. The antibody for use according to any one of claims 1-2 and 9-52, or the method according to any one of claims 7-52, wherein the individual is Stage III according to the International Staging System (ISS).

54. The antibody for use according to any one of claims 1-2 and 9-53, or the method according to any one of claims 7-53, wherein the individual is Stage III according to the Revised International Staging System (R-ISS).

55. The antibody for use according to any one of claims 1-2 and 9-54, or the method according to any one of claims 7-54, wherein the individual is minimal residual disease (MRD) negative at a threshold of 10 4 or less after treatment.

56. The antibody for use or the method according to claim 55, wherein the individual is MRD negative at a threshold of 10 5 or less after treatment.

57. The antibody for use or the method according to claim 56, wherein the individual is MRD negative at a threshold of 10 6 or less after treatment.

58. The antibody for use or the method according to any of claims 55-57, wherein MRD is assessed via next generation sequencing (NGS).

59. The antibody for use or the method according to any of claims 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 multiple myeloma according to the antibody for use according to any one of claims 1-2 and 9-59 or the method of any one of claims 7-59.