Methods for treating multiple myeloma comprising an Anti-CD38 antibody combined with bortezomib, lenalidomide and dexamethasone

Abstract

The present disclosure is directed to methods of treating multiple myeloma. The present disclosure is directed to methods of treating newly diagnosed multiple myeloma in a subject in need thereof, for example, by subcutaneously administering to the subject a pharmaceutical composition comprising an anti-CD38 antibody in combination with bortezomib, lenalidomide, and dexamethasone.

Description

METHODS FOR TREATING MULTIPLE MYELOMA COMPRISING AN ANTI-CD38 ANTIBODY COMBINED WITH BORTEZOMIB, LENALIDOMIDE AND DEXAMETHASONECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 543,780, filed October 12, 2023; U.S. Provisional Application No. 63 / 627,926, filed February 1, 2024; U.S. Provisional Application No. 63 / 655,367, filed June 3, 2024; and Canadian Application No. 3234180, filed April 4, 2024, each of which is incorporated by reference in its entirety.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] This application contains a Sequence Listing, which is submitted electronically via EFS-Web as an ASCII formatted sequence listing with a file name “JBI6852WOPCT1 Sequence Listing.xml,” creation date of October 7, 2024, and having a size of 20 KB. The sequence listing submitted via Patent Center is part of the specification and is herein incorporated by reference in its entirety.TECHNICAL FIELD

[0003] The present disclosure relates generally to methods of treating multiple myeloma, particularly newly diagnosed multiple myeloma.BACKGROUND

[0004] Induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd) followed by autologous stem cell transplant (AS CT), VRd consolidation, and lenalidomide (R) maintenance therapy is a standard of care for transplant-eligible patients with newly diagnosed multiple myeloma. However, novel strategies are needed to further deepen responses and prevent relapse to achieve long-term disease control. The disclosed methods are directed to these and other important needs.SUMMARY

[0005] In certain embodiments, the present disclosure is directed to methods of treating multiple myeloma in a subject in need thereof, said method comprising administering to the subject a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38 and comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, alight chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition further comprises a hyaluronidase. In a further embodiment the pharmaceutical embodiment comprises a hyaluronidase, in particular recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0006] In certain embodiments, the multiple myeloma is newly diagnosed multiple myeloma. In further embodiments, the subject is eligible for high dose therapy. In certain embodiments, the subject is eligible for autologous stem cell transplant (ASCT).

[0007] In still further embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2. In some embodiments, the subject does not have clinical signs of meningeal involvement of multiple myeloma.

[0008] In certain embodiments, said method further comprises stem performing stem cell mobilization and autologous stem cell transplant (ASCT) on the subject. In some embodiments, the stem cell mobilization yields an improved median CD34+ cell yield.

[0009] In further embodiments, administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in the progression-free survival (PFS) of the subject relative to PFS of a reference subject or a reference population of subjects administered a combination of bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiment, the improved PFS is prolonged relative to the reference population. In certain embodiments, the improved PFS is a 58% to 60% reduction of risk of progression or death.

[0010] In certain embodiments, administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in minimal residual disease (MRD) negativity rate, sustained MRD-negativity rate, overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), time to response, duration of response, progression-free survival on the next line of therapy (PFS2), or overall survival (OS).

[0011] In some embodiments, the improvement is relative to a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition.

[0012] In certain embodiments, the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10"5. In certain embodiments, the improved MRD-negativity rate is 75.2% relative to 47.5% for the reference population. In certain embodiments, the improved overall MRD-negativity rate at or below a sensitivity threshold of 10sis 75.2% relative to 47.5% for the reference population. In certain embodiments, the improved overall MRD- negativity rate is at or below a sensitivity threshold of 10"6. In certain embodiments, the improved MRD-negativity rate is 65.1% relative to 32.2% for the reference population. In certain embodiments, the improved overall MRD-negativity rate at or below a sensitivity threshold of 10'6is 65.1% relative to 32.2% for the reference population. In certain embodiments, the improved MRD-negativity rate in high risk multiple myeloma subjects is 58% relative to 31% for the reference population. In certain embodiments, the improved overall MRD-negativity rate at or below a sensitivity threshold of 10'6is 58% relative to 31% for the reference population.

[0013] In certain embodiments, the sustained MRD-negativity rate for at least 12 months is 64.8% relative to 29.7% for the reference population. In certain embodiments, the sustained MRD-negativity rate for at least 12 months assessed at a sensitivity threshold of 10’5is 64.8% relative to 29.7% for the reference population. In certain embodiments, the sustained MRD- negativity rate for at least 12 months is 47% relative to 19% for the reference population. In certain embodiments, the sustained MRD-negativity rate for at least 12 months assessed at a sensitivity threshold of 10"6is 47% relative to 19% for the reference population. In certain embodiments, the sustained MRD-negativity rate for at least 12 months in high risk multiple myeloma subjects is 30% relative to 14% for the reference population. In certain embodiments, the sustained MRD-negativity rate for at least 12 months in high risk multiple myeloma subjects assessed at a sensitivity threshold of 10"6is 30% relative to 14% for the reference population.

[0014] In certain embodiments, the improved ORR is 96.6% relative to 93.8% for the reference population. In certain embodiments, the improved sCR is 69.3% relative to 44.6% for the reference population. In certain embodiments, the improved CR or better is 87.9% relative to 70.1% for the reference population.

[0015] In certain embodiments, the pharmaceutical composition also comprises a hyaluronidase. In certain embodiments, the hyaluronidase is a recombinant human hyaluronidase or rHuPH20.

[0016] In certain embodiments, the pharmaceutical composition comprises about 1,800 mg of said antibody and about 30,000 U rHuPH20. In further embodiments, the pharmaceutical composition comprises about 120 mg / mL of said antibody and about 2,000 U / mL rHuPH20. In still further embodiments, the pharmaceutical composition comprises one or more excipients. In some embodiments, at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0017] In further embodiments, the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of said antibody; about 30,000 U of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine. In still further embodiments, the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL of said antibody; about 2,000 U / mL of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.

[0018] In certain embodiments, the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8. In further embodiments, the antibody that specifically binds CD38 is an IgGl isotype. In still further embodiments, the antibody that specifically binds CD38 comprises a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10. In some embodiments, the antibody that specifically binds CD38 is daratumumab.

[0019] In some embodiments, the pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered at a dose of about 1,800 mg once a week, about 1,800 mg once in two weeks, about 1,800 mg once in three weeks, or about 1,800 mg once in four weeks. In certain embodiments, bortezomib is administered at a dose of about 1.3 mg / m2twice a week. In further embodiments, bortezomib is administered subcutaneously. In still further embodiments, lenalidomides administered at a dose of about 10 mg daily or about 25 mg daily. In certain embodiments, lenalidomide is administered orally. In some embodiments, dexamethasone is administered at a dose of about 40 mg daily. In further embodiments, dexamethasone is administered orally.

[0020] In certain embodiments, bortezomib, lenalidomide and dexamethasone are administered for one or more 28-day cycles. In some embodiments, the pharmaceutical composition is administered once a week in the first and the second 28-day cycle, once in two weeks in the third, the fourth, the fifth and the sixth 28-day cycle, and thereafter once in four weeks in any subsequent 28-day cycle. In further embodiments, bortezomib is administered ata dose of about 1.3 mg / m2twice a week for cycles 1-6. In still further embodiments, lenalidomide is administered at a dose of about 25 mg daily for cycles 1-6, and at a dose of 10 mg daily in any subsequent 28-day cycle. In some embodiments, dexamethasone is administered at a dose of about 40 mg on days 1-4 and 9-12 of cycles 1-6.

[0021] In further embodiments, said method further comprises performing stem cell mobilization and autologous stem cell transplant (ASCT) on the subject. In some embodiments, the ASCT is performed following cycles 1-4 but no later than 12 weeks following cycle 4. In certain embodiments, melphalan is administered at a dose of 140 mg / m2or 200 mg / m2over a period of 24 to 48 hours prior to ASCT. In further embodiments, one or more stem cell mobilization agents are administered to the subject within 6 weeks after completing cycle 4. In still further embodiments, the one or more stem cell mobilization agents are plerixafor, cyclophosphamide and / or granulocyte-colony stimulating factor.

[0022] In some embodiments, the present disclosure is directed to methods of improving progression-free survival (PFS) in a subject or a population of subjects with multiple myeloma, said method comprising administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38 and comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6 (and, in an embodiment, recombinant human hyaluronidase (rHuPH20)), wherein the improvement in PFS is relative to PFS of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0023] In certain embodiments, the improved PFS is a 58% to 60% reduction of risk of progression or death.

[0024] In certain embodiments, the subject is 50 years of age or older. In further embodiments, the subject has International Staging System (ISS) stage III disease. In still further embodiments, the subject has high cytogenetic risk.BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended drawing. For the purpose of illustrating the disclosed methods or uses, the drawing shows exemplary embodiments of the methods or uses; however, the methods or uses are not limited to the specific embodiments disclosed. In the drawing:

[0026] FIG. 1 is a schematic overview of the study described in Example 1. Abbreviations: Dara=daratumumab; R=lenalidomide; VRd=bortezomib, lenalidomide, and dexamethasone.

[0027] FIG. 2 is a Kaplan-Meier Plot for progression-free survival (PFS) by computerized algorithm; intent-to-treat (ITT) analysis set.

[0028] FIG. 3 is a Kaplan-Meier plot for PFS by independent review committee (IRC) assessment, ITT analysis set.

[0029] FIG. 4 is a Forest Plot of subgroup analyses of PFS per computerized algorithm; ITT analysis.

[0030] FIG. 5 is a Forest Plot of subgroup analyses of PFS per IRC assessment; ITT analysis set.

[0031] FIG. 6 is a graph of overall CR or better rate; ITT Analysis.

[0032] FIG. 7 is a graph of overall MRD negativity rate (10-6); ITT Analysis Set.

[0033] FIG. 8 is a Kaplan-Meier plot for overall survival; ITT Analysis Set.

[0034] FIG. 9 provides an overview of incidence rate of TEAEs; safety analysis set.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0035] In the present disclosure the singular forms “a”, “an,” and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a material” is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth.

[0036] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list and every combination of that list is to be interpreted as a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0037] It is to be appreciated that certain features of the disclosure which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiments and such a combination is considered to be another embodiment. Conversely, various features of the disclosure that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements or use of a “negative” limitation. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself.Certain Terminology

[0038] Various terms used throughout this specification shall have the definitions set out herein.

[0039] “About” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of a particular assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.

[0040] “About once a week” refers to an approximate number, and can include every 7 days ± two days, i.e., every 5 days to every 9 days. The dosing frequency of “once a week” thus can be every five days, every six days, every seven days, every eight days, or every nine days.

[0041] “About once in two weeks” refers to an approximate number, and can include every 14 days ± two days, i.e., every 12 days to every 16 days.

[0042] “About once in three weeks” refers to an approximate number, and can include every 21 days ± two days, i.e., every 19 to every 23 days.

[0043] “About once in four weeks” refers to an approximate number, and can include every 28 days ± two days, i.e., every 26 to every 30 days.

[0044] “About once in five weeks” refers to an approximate number, and can include every 35 days ± two days, i.e., every 33 to every 37 days.

[0045] “About once in six weeks” refers to an approximate number, and can include every 42 days ± two days, i.e., every 40 to every 38 days.

[0046] “About twice a week” refers to an approximate number, can include twice in one week, e.g., a first dose on day 1 and a second dose on day 2, day 3, day 4, day 5, day 6 or day 7 of the week, the fist dose on day 2 and the second dose on day 3, day 4, day 5, day 6 or day 7 of the week, the first dose on day 3 and the second dose on day 4, day 5, day 6 or day 7 of the week, the first dose on day 4 and the second dose on day 5, day 6 or day 7 of the week, the first dose on day 5 and the second dose on day 6 or day 7 of the week, the first dose on day 6 and the second dose on day 7 of the week.

[0047] The conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.”

[0048] “Antibody” includes immunoglobulin molecules belonging to any class, IgA, IgD, IgE, IgG and IgM, or sub-class IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4 and including either kappa (K) and lambda (X) light chain. Antibodies include monoclonal antibodies including human, humanized and chimeric monoclonal antibodies. Full-length antibody molecules are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CHI, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino- to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

[0049] “Biosimilar” (of an approved reference product / biological drug, i.e., reference listed drug) refers to a biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components with no clinicallymeaningful differences between the biosimilar and the reference product in terms of safety, purity and potency, based upon data derived from (a) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and / or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biosimilar. The biosimilar may be an interchangeable product that may be substituted for the reference product at the pharmacy without the intervention of the prescribing healthcare professional. To meet the additional standard of “interchangeability,” the biosimilar is to be expected to produce the same clinical result as the reference product in any given patient and, if the biosimilar is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biosimilar and the reference product is not greater than the risk of using the reference product without such alternation or switch. The biosimilar utilizes the same mechanisms of action for the proposed conditions of use to the extend the mechanisms are known for the reference product. The condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biosimilar have been previously approved for the reference product. The route of administration, the dosage form, and / or the strength of the biosimilar are the same as those of the reference product and the biosimilar is manufactured, processed, packed or held in a facility that meets standards designed to assure that the biosimilar continues to be safe, pure and potent. The biosimilar may include minor modifications in the amino acid sequence when compared to the reference product, such as N- or C-terminal truncations that are not expected to change the biosimilar performance.

[0050] “Cancer” refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread) to other areas of a patient’s body.

[0051] "CD34+” refers to human hematopoietic stem cells that are positive for the antigen CD34.

[0052] “CD38” refers to human cluster of differentiation 38 protein, a glycoprotein expressed on immune cells, including plasma cells, natural killer cells and sub-populations of B and T cells.

[0053] “Clinical efficacy endpoint” or “clinical endpoint” refers to an outcome that represents a clinical benefit, such as progression-free survival (PFS), time to disease progression (TTP), time to next treatment, overall response rate (ORR), proportion of subjects achieving partial response (PR), proportion of subjects achieving very good partial response (VGPR), proportion of subjects achieving complete response (CR), proportion of subjects achieving stringent complete response (sCR), proportion of subjects achieving a negative status for minimal residual disease (MRD), or proportion of subjects achieving both sCR and negative status for MRD.

[0054] “Clinically proven” refers to clinical efficacy results that are sufficient to meet approval standards of U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) or a corresponding national regulatory agency. For example, the clinical study may be an adequately sized, randomized, double-blinded controlled study used to clinically prove the effects of the drug and / or non-inferiority of the drug.

[0055] “Co-administration,” “administration with,” “administration in combination with,” “in combination with” or the like, encompass administration of two or more therapeutics or drugs to a single patient, and are intended to include treatment regimens in which the therapeutics or drugs are administered by the same or different route of administration or at the same or different time.

[0056] “Complementarity determining regions” (CDRs) are “antigen binding sites” in an antibody. CDRs may be defined based on sequence variability (Wu and Kabat, J Exp Med 132:211-250, 1970; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991) or based on alternative delineations (see Lefranc et al., Dev Comparat Immunol 27:55-77, 2003). The International ImMunoGeneTics (IMGT) database (http_ / / www_imgt_org) provides a standardized numbering and definition of antigen-binding sites.

[0057] “Comprising,” “consisting essentially of,” and “consisting of" are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of’ excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristics” of the claimed invention. Embodiments described in terms of the phrase “comprising” (or its equivalents)also provide as embodiments those independently described in terms of “consisting of' and “consisting essentially of.”

[0058] “Consolidation”, “consolidation therapy” or “consolidation period” refers to a short duration of treatment given to a subject after the subject has been treated with high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT); i.e., post-HDC and ASCT.

[0059] “Corticosteroid” refers to a class of steroid hormones that are produced in the adrenal cortex or produced synthetically refers to dexamethasone, methylprednisolone, prednisolone and prednisone. Dexamethasone is marketed under the trade name DECARON®.

[0060] “Cycle” refers to the administration schedule of one or more therapeutics or drugs and refers to the period of time when the one or more therapeutics or drugs is administered to a subject. Cycle may include days in which the drug is administered and periods of rest in which the drug is not administered. Cycle length may vary, and can be for example 2 weeks, 3 weeks, 28-days (or 4 weeks), 5 weeks or 6 weeks.

[0061] “Daratumumab” refers to an antibody that specifically binds CD38 comprising a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, a LCDR3 of SEQ ID NO: 6, a heavy chain variable region (VH) of SEQ ID NO: 7, a light chain variable region (VL) of SEQ ID NO: 8, a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10. Daratumumab is marketed under the trade names DARZALEX®, DARZALEX® SC, and DARZALEX FASPRO®.

[0062] “Dosage” refers to the information of the amount of the therapeutic or the drug to be taken by the subject and the frequency of the number of times the therapeutic is to be taken by the subject.

[0063] “Dose” refers to the amount or quantity of the therapeutic or the drug to be taken each time.

[0064] “Drug product” (DP) refers to a finished dosage form, for example, a tablet, capsule or solution that contains an active pharmaceutical ingredient (e.g., drug substance), generally, but not necessarily, in association with inactive ingredients.

[0065] “Drug substance” (DS) refers to any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in theproduction of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or function of the body.

[0066] “Duration of response” refers to the time between the date of initial documentation of a response (partial response (PR) or better) to the date of the first documented evidence of progressive disease according to International Myeloma Working Group criteria, or death due to disease progression, whichever occurred first, for patients who had a partial response or better as their best response.

[0067] “Effective” refers to a dose or dosage of a therapeutic or a drug (such as an antibody that specifically binds CD38) or a combination of therapeutics or drugs that provides a therapeutic effect for a given condition and administration regimen in a subject receiving or who has received the therapeutic or the drug or the combination of the therapeutics or drugs. “Effective” is intended to mean an amount sufficient to reduce and / or prevent a clinically significant deficit in the activity, function and response of the subject, or to cause an improvement in a clinically significant condition in the subject.

[0068] “Healthcare professional” refers to a medical doctor, a nurse, a nurse’s assistant, or a person working under direct instructions by the medical doctor or the nurse, or any person working in a hospital or a place in which treatment can be provided to the subject.

[0069] “Hyaluronidase” refers to an enzyme that degrades hyaluronic acid (EC 3.2. 1.35) and lowers the viscosity of hyaluronan in the extracellular matrix, thereby increasing tissue permeability. An exemplary hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20). rHuPH20 comprises an amino acid sequence of SEQ ID NO: 13-17. Enzymatic activity of hyaluronidase, including rHuPH20 can be defined by units per mL (U / mL) or by total enzyme activity in a particular formulation (U). The standard definition for one unit (U) of enzyme activity is the amount of enzyme that catalyzes the reaction of 1 nmol of substrate per minute.

[0070] “High dose chemotherapy” (HDC) or “high dose therapy” and “autologous stem cell transplant” (ASCT) refer to the treatment of subjects with newly diagnosed multiple myeloma who are considered fit (e.g., subjects are “eligible”). Subjects under the age of 65 years who have one or more comorbidities likely to have a negative impact on tolerability of HDC and ASCT or subjects over the age of 65 years are usually not considered eligible for HDC and ASCT due to their frail physical status which increases the risk of mortality andtransplant-related complications (e.g., subjects are “ineligible”). An exemplary comorbidity is a renal dysfunction. Exemplary HDC regimens are melphalan at a dose of 200 mg / m2body surface area with dose reductions based on age and renal function, cyclophosphamide and melphalan, carmustine, etoposide, cytarabine, and melphalan (BEAM), high-dose idarubicin, cyclophosphamide, thiotepa, busulfan, and cyclophosphamide, busulfan and melphalan, and high-dose lenalidomide (Mahajan et al., TherAdv Hematol 9:123-133, 2018).Cyclophosphamide is marketed under the trade name Cyclostin™. Melphalan is marketed under the trade name ALKERAN®. Carmustine is marketed under the trade name BiCNU®. Etoposide is marketed under the trade name VEPES1D®. Cytarabine is marketed under the trade name CYTOS AR-U®. Idarubicin is marketed under the trade name IDAMYCIN®.Thitepa is marketed under the trade name THIOPLEX®. Lenalidomide is marketed under the trade name REVLIMID®.

[0071] “High risk multiple myeloma” refers to multiple myeloma that is characterized by one or more cytogenetic abnormalities dell7p, t(4; 14), t(14;20), t(14; 16) or dell3, or any combination thereof.

[0072] “Induction”, “induction therapy” or “induction period” refers to the first treatment given for a disease with the intention of reducing the amount of malignant plasma cell burden and improving the depth of response. Induction therapy may be provided prior to treatment with high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT).

[0073] “Information” refers to reported results from clinical trials and can be provided in written or electronic form, or orally, or it can be available on internet.

[0074] “Infusion related reaction” (IRR) refers to any sign or symptom experienced by a subject during the administration of a drug or a therapeutic or any event occurring within 24- hours of administration. IRRs are typically classified as Grade 1, 2, 3 or 4.

[0075] “Maintenance therapy” refers to the treatment given for a disease after remission or best response is achieved, in order to prevent or delay relapse.

[0076] “mg / m2” refers to dosing of a drug in milligrams per square meter of body surface area.

[0077] “Minimal residual disease” (MRD) refers to a small number of clonal multiple myeloma cells that remain in the patient after treatment and / or during remission.

[0078] “MRD negative” or “negative status for MRD” refers to a ratio of 1 : IxlO5or less clonal multiple myeloma cells in a bone marrow aspirate sample obtained from the subject.

[0079] “MRD negativity rate” refers to the proportion of subjects assessed as MRD negative and achieved a complete response or better at any timepoint after the date of randomization.

[0080] “MRD positive” refers to patients for whom all tested samples were found to be MRD positive or indeterminate or were MRD negative and had not achieved CR or better status.

[0081] “Multiple myeloma” refers to a malignant disorder of plasma cells characterized by uncontrolled and progressive proliferation of one or more malignant plasma cells. The abnormal proliferation of plasma (myeloma) cells causes displacement of the normal bone marrow leading to dysfunction in hematopoietic tissue and destruction of the bone marrow architecture, resulting in progressive morbidity and eventual mortality.

[0082] “Newly diagnosed” refers to a human subject who has been diagnosed with but has not yet received treatment for a disease, such as a disease involving cells that express CD38, such as multiple myeloma.

[0083] “Overall complete response or better rate” refers to the percentage of patients in the intention-to-treat population who achieved complete response or stringent complete response status at any time during the study per the International Myeloma Working Group criteria. In addition, the specific response must have been achieved prior to the start of subsequent therapies.

[0084] “Overall minimal residual disease-negative rate” refers to the proportion of patients in the intention-to-treat population who achieved minimal residual disease negativity (at or below a sensitivity threshold of 1 tumor cell per 105white cells) by bone marrow aspirate and achieved a complete response or better at any time after the date of randomization during the study (and prior to disease progression, receipt of subsequent therapy, or both). “Sustained MRD-negativity rate” refers to the proportion of patients in the ITT population with 2 consecutive MRD-negative results at least 12 months apart, without any MRD-positive results in between.

[0085] “Overall response rate” (ORR) refers to the proportion of subjects who achieve partial response (PR), very good partial response (VGPR), complete response (CR) or stringent complete response (sCR) during or after the treatment.

[0086] “Overall survival” (OS) is defined as the time from initiation of therapy to the date of death due to any cause. For the purpose of the clinical trial described in the example, OSis defined as the time from randomization of study population to the date of the patient’ s death.

[0087] “Percent w / v” (% w / v) refers to weight in grams per 100 mL.

[0088] “Pharmaceutical combination” refers to a combination of two or more therapeutics or drugs administered either together or separately.

[0089] "Pharmaceutical composition" refers to a product that results from combining an antibody that specifically binds CD38 and a hyaluronidase as a fixed combination. "Fixed combinations" refers to a single pharmaceutical composition comprising the anti-CD38 antibody and the hyaluronidase administered simultaneously in the form of a single entity or dosage. A pharmaceutical composition typically includes a pharmaceutically acceptable carrier.

[0090] “Pharmaceutically acceptable carrier” or “excipient” refers to an ingredient in a pharmaceutical composition, other than the active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, stabilizer or preservative.

[0091] “Placebo” refers to a substance that has no therapeutic effect.

[0092] “Post-ASCT and consolidation CR rate” refers to the proportion of subjects who have achieved CR or better by the end of consolidation therapy.

[0093] “Post- ASCT and consolidation MRD negative rate” refers to the proportion of subjects who have achieved MRD negative status by the end of consolidation therapy.

[0094] ‘Post-consolidation” refers to treatment period ending at the end of consolidation therapy.

[0095] “Post-induction” refers to treatment period ending at the end of induction therapy.

[0096] “Post-induction stringent complete response rate” (post-induction sCR rate) refers to the proportion of subjects who have achieved sCR prior to HDC and ASCT.

[0097] “Post-induction overall response rate” (post-induction ORR) refers to the proportion of subjects who have achieved partial response (PR) or better by the end of induction.

[0098] “Post-induction very good partial response or better” (post-induction VGPR or better) refers to the proportion of subjects who have achieved VGPR, complete response (CR) or stringent complete response (sCR) by the end of induction.

[0099] “Progression-free survival” (PFS) means time from initiation of therapy to first evidence of disease progression or death due to any cause, whichever occurs first. For thepurpose of the clinical trial described in the example, PFS is defined as the time from the date of randomization to the date of first disease progression according to the International Myeloma Working Group response criteria or death due to any cause, whichever occurred earlier.

[0100] “Progression-free survival 2” (PFS2) refers to the time from the second randomization to time of subsequent progression on next-line of therapy after disease progression on study treatment.

[0101] “Progressive disease” (PD), “stable disease” (SD), “partial response” (PR), “very good partial response” (VGPR), “complete response” (CR) and “stringent complete response” (sCR) refer to response to treatment and take their customary meanings as will be understood by a person skilled in the art of designing, conducting, or reviewing clinical trials. Response to treatment may be assessed using International Myeloma Working Group (IMWG) uniform response criteria recommendations (International Uniform Response Criteria Consensus Recommendations) as shown in Table 1.

[0102] “Rate of complete response or better” (CR response rate or better) refers to the proportion of subjects achieving CR or stringent complete response (sCR) during or after the treatment based on the computerized algorithm according to International Myeloma Working Group (IMWG) response criteria, during or after the study treatment prior to the start of subsequent antimyeloma therapy.

[0103] “Rate of stringent complete response rate or better” (sCR rate or better) refers to the proportion of subjects achieving sCR during or after the treatment, which can be measured post-induction, post-transplant, post-consolidation, and overall.

[0104] “Reference Listed Drug” or “RLD” may also refer to an approved biological product such as DARZALEX® brand of daratumumab, DARZALEX® SC brand of daratumumab, or DARZALEX FASPRO® brand of daratumumab and hyaluronidase, in particular rHuPH20, against which a biosimilar demonstrates bioequivalence.

[0105] “Reference subject” or “reference population of subjects” refers to a subject or population of subjects having multiple myeloma who have been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. The reference subject or reference population of subjects are substantially the same as the subject or population of subjects that are treated with the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone. Exemplary reference subjects or reference population of subjects are those described in Examples 1 to 3 herein. In a specificembodiment, exemplary reference subjects or reference population of subjects are those described in Arm A of Example 1. In some embodiments, the population of subjects and reference population of subjects contain at least two subjects. In some embodiments, the population of subjects and reference population of subjects contain a number of subjects that allow for a statistically significant analysis of the improvement in safety and / or efficacy.

[0106] “Safe” as it relates to a composition, dose, dosage regimen, treatment or method with a therapeutic or a drug (such as an antibody that specifically binds CD38 or a combination of an antibody that specifically binds CD38 and one or more therapeutic agents) refers to a favorable benefit:risk ratio with an acceptable frequency and / or acceptable severity of adverse events (AEs) and / or treatment-emergent adverse events (TEAEs) compared to the standard of care or to another comparator.

[0107] “Safe and effective” refers to an amount and / or dosage of a drug (such as an antibody that specifically binds CD38) or a combination of drugs (such as a combination of an antibody that specifically binds CD38 and one or more therapeutic agents) that elicits the desired biological or medicinal response in a subject’s biological system without the risks outweighing the benefits of such response in accordance with the Federal Food, Drug, and Cosmetic Act, as amended (secs. 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. §§ 321-392). Safety is evaluated in laboratory, animal and human clinical testing to determine the highest tolerable dose or the optimal dose of the drug or the combination of drugs needed to achieve the desired benefit. Efficacy is evaluated in human clinical trials and determining whether the drug or the combination of drugs demonstrates a health benefit over a placebo or other intervention. Safe and effective drugs or a combination of drugs are granted marketing approval by the FDA for their indicated use.

[0108] An antibody that “specifically binds CD38” refers to antibody binding CD38 with greater affinity than to other antigens. Typically, the antibody binds to CD38 with an equilibrium dissociation constant (KD) of about 1x108M or less, for example about 1x109M or less, about IxlO-10M or less, about IxlO’11M or less, or about IxlO’12M or less, typically with a KD that is at least one hundred-fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein). The KD may be measured using standard procedures. Antibodies that specifically bind CD38 may, however, have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as monkey, for example Macacafascicularis (cynomolgus, cyno), Pan troglodytes (chimpanzee, chimp) or Callithrix jacchus (common marmoset, marmoset).

[0109] “Subcutaneous” or “subcutaneously” refers to administration of a therapeutic under the skin, typically by injection. Administration site may be side or back of upper arm, front of thigh or abdomen.

[0110] “Subject” refers to a human patient. The terms “subject” and “patient” can be used interchangeably herein. It is understood by a person skilled in the art that a patient can also mean a population of patients. It is understood by a person skilled in the art that when a median endpoint is mentioned, for example median progression-free survival, that a patient means a population of patients

[0111] “Stem cell mobilization” refers to the process by which stem cells are stimulated out of the bone marrow space into the bloodstream, thereby making them available for collection.

[0112] “Therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics include, for example, improved well-being of the patient, reduction in a tumor burden, arrested or slowed growth of a tumor, and / or absence of metastasis of cancer cells to other locations in the body.

[0113] “Time to response” refers to the time between the randomization and the first efficacy evaluation that the subject has met all criteria for partial response (PR) or better.

[0114] “Time to complete response or better” refers to the time from the date of randomization to the date of first documentation of a confirmed response (CR) of complete response or better for patients who had a response of complete response or better.

[0115] “Treat”, “treating” or “treatment” refers to therapeutic treatment. Individuals in need of treatment include those subjects diagnosed with the disorder of a symptom of the disorder. Subject that may be treated also include those prone or susceptible to have the disorder, or those in which the disorder is to be prevented. Beneficial or desired clinical results include alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, disease remission (whether partial or total) and prolonging survival as compared to expected survival if a subject was not receiving treatment or was receiving another treatment.

[0116] “Treatment emergent adverse events” (TEAE) as used herein takes its customary meaning as will be understood by a person skilled in the art of designing, conducting, or reviewing clinical trials and the data generated in such trials and refers to an AE considered associated with the use of an antibody that specifically binds CD38 if the attribution is possible, probable, or very likely.

[0117] “Unacceptable adverse events” and “unacceptable adverse reaction” refers to all harm or undesired outcomes associated with or caused by administration of a pharmaceutical composition or a therapeutic, and the harm or undesired outcome reaches such a level of severity that a regulatory agency deems the pharmaceutical composition or the therapeutic unacceptable for the proposed use.

[0118] “Unacceptable toxicity” refers to toxicity associated with or caused by administration of a pharmaceutical composition or a therapeutic, and the harm or undesired outcome reaches such a level of severity that a regulatory agency or the treating physician deems the administration of the pharmaceutical composition or therapeutic be stopped.

[0119] “Very good partial response or better” (VGPR rate or better) refers to the proportion of subjects achieving VGPR, complete response (CR) or stringent complete response (sCR) during or after the treatment.Multiple myeloma

[0120] Multiple myeloma causes significant morbidity and mortality. It accounts for approximately 1% of all malignancies and 13% of hematologic cancers worldwide. Approximately 50,000 patients per year are diagnosed with multiple myeloma in the EU and US, and 30,000 patients per year die due to multiple myeloma.

[0121] The majority of patients with multiple myeloma produce a monoclonal protein (paraprotein, M-protein or M-component) which is an immunoglobulin (Ig) or a fragment of one that has lost its function (Kyle and Rajkumar, Leukemia 23:3-9, 2009; Palumbo and Anderson, N Engl J Med 364:1046-1060, 2011). Normal immunoglobulin levels are compromised in patients, leading to susceptibility of infections. The proliferating multiple myeloma cells displace the normal bone marrow leading to dysfunction in normal hematopoietic tissue and destruction of the normal bone marrow architecture, which is reflected by clinical findings such as anemia, paraprotein in serum or urine, and bone resorption seen as diffuse osteoporosis or lytic lesions shown in radiographs (Kyle et al., Mayo Clin Proc 78:21-33, 2003). Furthermore, hypercalcemia, renal insufficiency or failure,and neurological complications are frequently seen. A small minority of patients with multiple myeloma are non-secretory.Multiple Myeloma Diagnosis

[0122] Subjects afflicted with multiple myeloma satisfy the CRAB (calcium elevation, renal insufficiency, anemia and bone abnormalities) criteria, and have clonal bone marrow plasma cells >10% or biopsy-proven bony or extramedullary plasmacytoma, and measurable disease. Measurable disease is defined by any of the following;- IgG myeloma: Serum monoclonal paraprotein (M-protein) level >1.0 g / dL or urine M-protein level >200 mg / 24 hours; or- IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level >0.5 g / dL or urine M-protein level >200 mg / 24 hours; or- Light chain multiple myeloma without measurable disease in serum or urine: Serum immunoglobulin free light chain >10 mg / dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.

[0123] CRAB criteria• Hypercalcemia: serum calcium >0.25 mM / L (>1 mg / dL) higher than the upper limit of the normal range [ULN] or >2.75 mM / L (>11 mg / dL)• Renal insufficiency: creatinine clearance <40mL / min or serum creatinine >177 pM / L (>2 mg / dL).• Anemia: hemoglobin >2 g / dL below the lower limit of normal or hemoglobin <10 g / dL.• Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT.

[0124] Response to treatment may be assessed using International Myeloma Working Group (IMWG) uniform response criteria recommendations (International Uniform Response Criteria Consensus Recommendations) as shown in Table 1.Table 1.Abbreviations: CR=complete response; FLC=free light chain; PC=plasma cell; PR=partial response VGPR=Very good partial response; SD=stable disease.All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before the institution of any new therapy; CR, sCR, VGPR, PR, and SD categories also require no known evidence of progressive or new bone lesions if radiographic studies wereMethods of Treatment and Uses

[0125] This disclosure provides methods of treating multiple myeloma in a subject or population of subjects in need thereof, said method comprising, consisting of, or consisting essentially of administering to the subject or population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase or rHuPH20. In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0126] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for treating multiple myeloma in a subject or population of subjects in need thereof, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1 , a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. Inan embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0127] In an aspect, there is provided a pharmaceutical composition for use in treating multiple myeloma in a subject or population of subjects in need thereof, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0128] The pharmaceutical composition comprising the antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO:1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6 and recombinant human hyaluronidase is interchangeable with DARZALEX FASPRO® or DARZALEX® SC administered subcutaneously.

[0129] In certain embodiments, the antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1 , the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6 and recombinant human hyaluronidase are combined to produce a pharmaceutical composition.

[0130] In certain embodiments, the multiple myeloma is newly diagnosed multiple myeloma.

[0131] In further embodiments, the subject is eligible for high dose therapy. In certain embodiments, the subject is eligible for autologous stem cell transplant (ASCT). In certain embodiments, the subject is newly diagnosed for whom high-dose therapy and autologous stem cell transplantation is part of the intended treatment plan.

[0132] In still further embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0. In still further embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 1. In still further embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 2.

[0133] In certain embodiments, the subject is 18 to 70 years of age, inclusive.

[0134] In certain embodiments, the subject has no prior or ongoing systemic therapy or stem-cell transplant (SCT) for any plasma cell dyscrasia, with the exception of emergency use of a short course (equivalent of dexamethasone 40 mg / day for a maximum 4 days) of corticosteroids before treatment.

[0135] In certain embodiments, the subject did not receive radiation therapy for treatment of plasmacytoma within 14 days prior to randomization. In certain embodiments, the subject did not receive plasmapheresis within 28 days of randomization.

[0136] In certain embodiments, said method further comprises stem performing stem cell mobilization on the subject. In certain embodiments, said method further comprises stem performing ASCT on the subject. In some embodiments, the ASCT is performed following cycles 1-4 but no later than 12 weeks following cycle 4. In certain embodiments, melphalan is administered at a dose of 140 mg / m2or 200 mg / m2over a period of 24 to 48 hours prior to ASCT. In further embodiments, one or more stem cell mobilization agents are administered to the subject within 6 weeks after completing cycle 4. In still further embodiments, the one or more stem cell mobilization agents are plerixafor, cyclophosphamide and / or granulocytecolony stimulating factor. In certain embodiments, said method further comprises performing a second stem cell mobilization or alternatively a bone marrow harvest to ensure adequate stem cell yield.

[0137] In some embodiments, the stem cell mobilization yields an improved median CD34+ cell yield. In certain embodiments the CD34+ cell yield refers to the CD34+ cells collected during stem cell harvest. In certain embodiments, CD34+ cell yield is measured in cells / kg.

[0138] In further embodiments, administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in the progression-free survival (PFS) of the subject or population of subjects. In certain embodiments, the improvement in PFS is relative to PFS of a reference subject or a reference population of subjects administered a combination of bortezomib, lenalidomide, anddexamethasone without the pharmaceutical composition. In certain embodiment, the improved PFS is prolonged relative to the reference population. In certain embodiments, the improved PFS is a 58% to 60% reduction of risk of progression or death.

[0139] In certain embodiments, administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in minimal residual disease (MRD) negativity rate of the subject or population of subjects. In certain embodiments, the MRD negativity rate is achieved post-consolidation. In certain embodiments, the MRD negativity rate is achieved at any time during treatment. In certain embodiments, the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10'5. In certain embodiments, the improved MRD-negativity rate is 75.2% relative to 47.5% for the reference population. In certain embodiments, the improved overall MRD- negativity rate is at or below a sensitivity threshold of 10'6. In certain embodiments, the improved MRD-negativity rate is 65. 1% relative to 32.2% for the reference population.

[0140] In certain embodiments, administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in overall response rate (ORR) of the subject or population of subjects. In certain embodiments, the improved ORR is 96.6% relative to 93.8% for the reference population.

[0141] In certain embodiments, administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in rate of very good partial response (VGPR) or better of the subject or population of subjects. In further embodiments, administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in the rate of complete response (CR) or better of the subject or population of subjects. In certain embodiments, the improved CR or better is 87.9% relative to 70.1% for the reference population.

[0142] In further embodiments, administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in the rate of stringent CR (sCR) of the subject or population of subjects. In certain embodiments, the improved sCR is 69.3% relative to 44.6%% for the reference population.

[0143] In further embodiments, administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in the time to response of the subject or population of subjects.

[0144] In further embodiments, administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in the duration of response of the subject or population of subjects.

[0145] In further embodiments, administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in the progression-free survival on the next line of therapy (PFS2) of the subject or population of subjects.

[0146] In further embodiments, administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in the overall survival (OS) of the subject or population of subjects.

[0147] In further embodiments, administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in the safety of the subject or population of subjects.

[0148] In any of the foregoing embodiments, the improvement is relative to a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In any of the foregoing embodiments, the improvement is relative to a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo.

[0149] This disclosure additionally provides methods of improving progression-free survival (PFS) in a subject or a population of subjects with multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0150] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving progression-free survival (PFS) in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0151] In an aspect, there is provided a pharmaceutical composition for use in improving progression-free survival (PFS) in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0152] In certain embodiments, the improvement in PFS is relative to PFS of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in PFS is relative to PFS of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo. In certain embodiments, the subject is 50 years ofage or older. In further embodiments, the subject has International Staging System (ISS) stage III disease. In still further embodiments, the subject has high cytogenetic risk. This disclosure additionally provides methods of improving MRD negativity rate in a subject or a population of subjects with multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0153] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving MRD negativity rate in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0154] In an aspect, there is provided a pharmaceutical composition for use in improving MRD negativity rate in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically bindsCD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0155] In certain embodiments, the improvement in MRD negativity rate is relative to the MRD negativity rate of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in MRD negativity rate is relative to the MRD negativity rate of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo. In certain embodiments, the MRD negativity rate is an overall rate. In certain embodiments, the MRD negativity rate is achieved post-consolidation.

[0156] This disclosure additionally provides methods of improving ORR in a subject or a population of subjects with multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1 , a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0157] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving ORR in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib,lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0158] In an aspect, there is provided a pharmaceutical composition for use in improving ORR in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0159] In certain embodiments, the improvement in ORR is relative to the ORR of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in ORR is relative to the ORR of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo.

[0160] This disclosure additionally provides methods of improving VGPR or better in a subject or a population of subjects with multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody thatspecifically binds, in particular an antibody that and comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0161] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving VGPR in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0162] In an aspect, there is provided a pharmaceutical composition for use in improving VGPR in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0163] In certain embodiments, the improvement in VGPR or better is relative to the VGPR or better of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in VGPR or better is relative to the VGPR or better of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo.

[0164] This disclosure additionally provides methods of improving CR or better in a subject or a population of subjects with multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0165] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving CR in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase(rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0166] In an aspect, there is provided a pharmaceutical composition for use in improving CR in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0167] In certain embodiments, the improvement in CR or better is relative to the CR or better of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in CR or better is relative to the CR or better of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo.

[0168] This disclosure additionally provides methods of improving sCR in a subject or a population of subjects with multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1 , a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase(rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0169] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving sCR in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0170] In an aspect, there is provided a pharmaceutical composition for use in improving sCR in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0171] In certain embodiments, the improvement in sCR is relative to the sCR of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in sCR is relative to the sCR of a reference subject or areference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo.

[0172] This disclosure additionally provides methods of improving time to response in a subject or a population of subjects with multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0173] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving time to response in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0174] In an aspect, there is provided a pharmaceutical composition for use in improving time to response in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically bindsCD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0175] In certain embodiments, the improvement in time to response is relative to the time to response of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in time to response is relative to the time to response of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo.

[0176] This disclosure additionally provides methods of improving duration of response in a subject or a population of subjects with multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: I, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0177] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving duration of response in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical compositioncomprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0178] In an aspect, there is provided a pharmaceutical composition for use in improving duration of response in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0179] In certain embodiments, the improvement in duration of response is relative to the duration of response of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in duration of response is relative to the duration of response of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo.

[0180] This disclosure additionally provides methods of improving PFS2 in a subject or a population of subjects with multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody thatspecifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0181] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving PFS2 in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0182] In an aspect, there is provided a pharmaceutical composition for use in improving PFS2 in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0183] In certain embodiments, the improvement in PFS2 is relative to the PFS2 of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in PFS2 is relative to the PFS2 of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo.

[0184] This disclosure additionally provides methods of improving OS in a subject or a population of subjects with multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1 , a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0185] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving OS in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0186] In an aspect, there is provided a pharmaceutical composition for use in improving OS in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0187] In certain embodiments, the improvement in OS is relative to the OS of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in OS is relative to the OS of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo.

[0188] This disclosure additionally provides methods of improving safety in a subject or a population of subjects with multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0189] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving safety in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0190] In an aspect, there is provided a pharmaceutical composition for use in improving safety in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0191] In certain embodiments, the improvement in safety is relative to the safety of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in safety is relative to the safety of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo.

[0192] This disclosure additionally provides methods of improving severity of adverse events in a subject or a population of subjects with multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0193] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving severity of adverse events in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0194] In an aspect, there is provided a pharmaceutical composition for use in improving severity of adverse events in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ IDNO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0195] In certain embodiments, the improvement in severity of adverse events is relative to the severity of adverse events of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in severity of adverse events is relative to the severity of adverse events of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo.

[0196] This disclosure additionally provides methods of improving CD34+ cell yield after mobilization in a subject or a population of subjects with multiple myeloma, said method comprising, consisting of, or consisting essentially of administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered subcutaneously.

[0197] In an aspect, there is provided use of a pharmaceutical composition for the manufacture of a medicament for improving CD34+ cell yield in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprisesa heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0198] In an aspect, there is provided a pharmaceutical composition for use in improving CD34+ cell yield in a subject or a population of subjects with multiple myeloma, wherein the pharmaceutical composition is administered or to be administered to the subject or the population of subjects in combination with bortezomib, lenalidomide, and dexamethasone, and wherein said pharmaceutical composition comprises: an antibody that specifically binds CD38, in particular an antibody that comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6. In an embodiment, the pharmaceutical composition also comprises a hyaluronidase, and, in a further embodiment comprises a hyaluronidase that is recombinant human hyaluronidase (rHuPH20). In an embodiment, the pharmaceutical composition is administered or to be administered subcutaneously.

[0199] In certain embodiments, the improvement in CD34+ cell yield after mobilization is relative to the CD34+ cell yield after mobilization a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. In certain embodiments, the improvement in CD34+ cell yield after mobilization is relative to the CD34+ cell yield after mobilization of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered placebo.Pharmaceutical Composition

[0200] In certain embodiments, the pharmaceutical composition comprises about 1,800 mg of said antibody and about 30,000 U hyaluronidase, in particular rHuPH20. In furtherembodiments, the pharmaceutical composition comprises about 120 mg / mL of said antibody and about 2,000 U / mL hyaluronidase, in particular rHuPH20.

[0201] A number of suitable hyaluronidase enzymes in accordance with the present disclosure are known. In an embodiment, the hyaluronidase enzyme is a human hyaluronidase enzyme, such as a soluble human PH20 hyaluronidase. In an embodiment, the hyaluronidase enzyme is the recombinant human hyaluronidase enzyme product known as rHuPH20. The form of the hyaluronidase as defined herein is the form that is combined with the antibody in the pharmaceutical formulation. The form of the hyaluronidase as defined herein is a form that degrades hyaluronic acid. The amino acid sequence of soluble human PH20 hyaluronidases include the soluble human PH20 known as rHuPH20 and available under CAS Registry No. 757971-58-7. In some embodiments, rHuPH20 is Hylenex®. Soluble human PH20 hyaluronidases are described in Int. Pat. Publ. No. W02004 / 078140 and U.S. Pat. No. 7,767,429 incorporated herein by reference, in its entirety. In some embodiments, soluble hyaluronidases include those whose sequence are set forth in any of SEQ ID NOs: 13-17. Soluble PH20 hyaluronidase, when expressed in a cell, include a signal sequence for trafficking in the cell. In some embodiments, the amino acid sequence is the sequence of a soluble PH20 hyaluronidase SEQ ID NO: 14, namely residues 36-482 of wild type human hyaluronidase. In some embodiments, the amino acid sequence of a soluble PH20 hyaluronidase comprises SEQ ID NO: 15. In some embodiments, the amino acid sequence of a soluble PH20 hyaluronidase comprises SEQ ID NO: 16. In some embodiments, the amino acid sequence a soluble PH20 hyaluronidase rHuPH20 comprises SEQ ID NO: 17. In some embodiments, the amino acid sequence of a soluble PH20 hyaluronidase comprises SEQ ID NO: 13. In some embodiments, the soluble PH20 hyaluronidases, when expressed in a cell, comprise a mixture of species that can include any one or more of SEQ ID NO: 13 to SEQ ID NO: 17 in various abundance. The average molecular weight is 61 kDa.

[0202] rHuPH20 refers to the composition produced upon expression in a cell, such as CHO cell. As produced in the culture medium there is heterogeneity at the C-terminus such that the product, designated rHuPH20, includes a mixture of species that can include any one or more of the polypeptides of SEQ ID NO: 13-17, and some shorter polypeptides, in various abundance. Typically, rHuPH20 is produced in cells, such as CHO cells, (for example DG44 CHO cells) that facilitate correct N-glycosylation to retain activity.

[0203] In further embodiments, the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of said antibody;about 30,000 U of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine. In still further embodiments, the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL of said antibody; about 2,000 U / mL of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.

[0204] In some embodiments, the pharmaceutical composition comprises about 1,800 mg of the antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6 and about 30,000 U rHuPH20.

[0205] In some embodiments, the pharmaceutical composition comprises about 120 mg / mL of the antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO:1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6 and about 2,000 U / mL rHuPH20.

[0206] In some embodiments, the pharmaceutical composition comprises one or more excipients.

[0207] In some embodiments, the one or more excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0208] In some embodiments, the pharmaceutical composition comprises

[0209] between about 5 mM and about 15 mM histidine;

[0210] between about 100 mM and about 300 mM sorbitol;

[0211] between about 0.01% w / v and about 0.04 % w / v PS-20; and

[0212] between about 1 mg / mL and about 2 mg / mL methionine, at a pH of about 5.5-5.6.

[0213] In some embodiments, the pharmaceutical composition comprises about 10 mM histidine.

[0214] In some embodiments, the pharmaceutical composition comprises about 300 mM sorbitol.

[0215] In some embodiments, the pharmaceutical composition comprises about 0.04% (w / v) PS -20.

[0216] In some embodiments, the pharmaceutical composition comprises about 1 mg / mL methionine.

[0217] In some embodiments, the pharmaceutical composition comprises: about 1,800 mg of the antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6; about 30,000 U of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine, at a pH of about 5.6.

[0218] In some embodiments, the pharmaceutical composition comprises: about 120 mg / mL of the antibody that specifically binds CD38 comprising the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5 and the LCDR3 of SEQ ID NO: 6; about 2,000 U / mL of rHuPH20; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine, at a pH of about 5.6.

[0219] The pharmaceutical composition of the disclosure may alternatively comprise additional or alternative pharmaceutically acceptable carriers are solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible, such as salts, buffers, antioxidants, saccharides, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants or emulsifying agents, or combinations thereof.

[0220] Exemplary buffers that may be used are acetic acid, citric acid, formic acid, succinic acid, phosphoric acid, carbonic acid, malic acid, aspartic acid, histidine, boric acid, Tris buffers, HEPPSO and HEPES.

[0221] Exemplary antioxidants that may be used are ascorbic acid, methionine, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, lecithin, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol and tartaric acid.

[0222] Exemplary amino acids that may be used are histidine, isoleucine, methionine, glycine, arginine, lysine, L-leucine, tri-leucine, alanine, glutamic acid, L-threonine, and 2- phenylamine.

[0223] Exemplary surfactants that may be used are polysorbates (e.g., polysorbate-20 or polysorbate-80); polyoxamers (e.g., poloxamer 188); Triton; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyL, or isostearamidopropyl-betaine (e.g., lauroamidopropyl); myristamidopropyl-, palmidopropyL, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; and the Monaqua™ series (Mona Industries, Inc., Paterson, N.J.), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics™, PF68, etc).

[0224] Exemplary preservatives that may be used are phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof.

[0225] Exemplary saccharides that may be used are monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, nonreducing sugars such as glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, dextran, erythritol, glycerol, arabitol, sylitol, sorbitol, mannitol, mellibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, glucitol, maltitol, lactitol or iso-maltulose.

[0226] Exemplary salts that may be used are acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like. An exemplary salt is sodium chloride.

[0227] In some embodiments, the pharmaceutical composition is at pH 5.0 to 6.0.

[0228] In some embodiments, the pharmaceutical composition is at pH 5.3 to 5.8.

[0229] In some embodiments, the pharmaceutical composition is at pH 5.5.

[0230] In some embodiments, the pharmaceutical composition is at pH 5.6.

[0231] In some embodiments, the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8.

[0232] In some embodiments, the antibody that specifically binds CD38 is an IgGl isotype.

[0233] An exemplary IgGl constant domain sequence comprises an amino acid sequence of SEQ ID NO: 11. Some variation exists within the IgGl constant domain (e.g., well-known allotypes), with variation at positions 214, 356, 358, 422, 431, 435 or 436 (residue numbering according to the EU numbering) (see e.g., IMGT Web resources; IMGT Repertoire (IG and TR); Proteins and alleles; allotypes). The antibody that specifically binds CD38 may be of any IgGl allotype, such as Glml7, Glm3, Glml, Glm2, Glm27 or Glm28.

[0234] In some embodiments, the antibody that specifically binds CD38 comprises a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10.

[0235] In some embodiments, the antibody that specifically binds CD38 is daratumumab.

[0236] In some embodiments, the antibody that specifically binds CD38 is a biosimilar of DARZALEX® brand of daratumumab.Methods of Administration

[0237] In some embodiments, the pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered at a dose of about 1,800 mg of daratumumab and 30,000 U of rHuPH20 once a week. In some embodiments, the pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered at a dose of about 1,800 mg of daratumumab and 30,000 U of rHuPH20 once in two weeks. In some embodiments, the pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered at a dose of about 1,800 mg of daratumumab and 30,000 U of rHuPH20 once in three weeks. In some embodiments, the pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered at a dose of about 1,800 mg of daratumumab and 30,000 U of rHuPH20 once in four weeks.

[0238] The pharmaceutical composition of the disclosure is administered by subcutaneous administration.

[0239] The pharmaceutical composition of the disclosure may is be administered in a total volume of about 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 55 mL, 60 mL, 65 mL, 70 mL, 75 mL, 80 mL, 85 mL, 90 mL, 95 mL, 100 mL, 105 mL, 110 mL, 115 mL or 120 mL.

[0240] In some embodiments, the pharmaceutical composition of the disclosure is administered subcutaneously to the abdominal region.

[0241] Subcutaneous administration may be accomplished using a device. The device may be a syringe, a prefilled syringe, an auto-injector, either disposable or reusable, a pen injector, a patch injector, a wearable injector or an ambulatory syringe infusion pump with subcutaneous infusion sets.

[0242] The pharmaceutical composition of the disclosure may be administered over a time period of between about 1 minute (min) to about 60 min.

[0243] In certain embodiments, bortezomib is administered at a dose of about 1.3 mg / m2twice a week. In further embodiments, bortezomib is administered subcutaneously. In further embodiments, bortezomib is administered intravenously.

[0244] In certain embodiments, lenalidomide is administered at a dose of about 25 mg daily. In still further embodiments, lenalidomide is administered at a dose of about 10 mg daily. In still further embodiments, lenalidomide is administered at a dose of about 10 mg daily in the maintenance phase. After three 28-day cycles of maintenance therapy, if well tolerated, the lenalidomide dose may be increased to 15 mg daily. In certain embodiments, if a daily lenalidomide dose is missed, it may be administered if <12 hours have elapsed since the time that it should have been taken. If the next dose is scheduled to be taken within 12 hours, the missed lenalidomide dose should be skipped. In certain embodiments, lenalidomide is administered as a single dose at approximately the same time daily. In certain embodiments, lenalidomide can be taken with or without food. In certain embodiments, lenalidomide is administered orally.

[0245] In some embodiments, dexamethasone is administered at a dose of about 20 mg to about 40 mg daily. In some embodiments, dexamethasone is administered at a dose of about 20 mg daily. In some embodiments, dexamethasone is administered at a dose of about 40 mg daily. In further embodiments, dexamethasone is administered orally. In further embodiments, dexamethasone is administered intravenously. On days when dexamethasone is administered with the pharmaceutical composition, dexamethasone is administered at a dose of 40 mg orally or intravenously 1-3 hours before administration of the pharmaceutical composition. On days when the pharmaceutical composition is not administered, dexamethasone is administered orally.

[0246] Bortezomib, lenalidomide and dexamethasone doses may be reduced, or the treatment schedule may be modified for the management of the study drug-related toxicities. Subjects who need to discontinue treatment with any one component of study treatment(daratumumab, bortezomib, lenalidomide or dexamethasone) may continue to receive treatment with the other components.

[0247] In certain embodiments, the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 28-day cycles.

[0248] In some embodiments, the pharmaceutical composition is administered once a week in the first and the second 28-day cycle, once in two weeks in the third, the fourth, the fifth and the sixth 28-day cycle, and thereafter once in four weeks in any subsequent 28-day cycle.

[0249] In further embodiments, bortezomib is administered at a dose of about 1.3 mg / m2twice a week for cycles 1-6.

[0250] In still further embodiments, lenalidomide is administered at a dose of about 25 mg daily for cycles 1-6, and at a dose of 10 mg daily in any subsequent 28-day cycle. In some embodiments, dexamethasone is administered at a dose of about 40 mg on days 1-4 and 9-12 of cycles 1-6.

[0251] In further embodiments, said method further comprises performing stem cell mobilization and autologous stem cell transplant (ASCT) on the subject. In some embodiments, the ASCT is performed following cycles 1-4 but no later than 12 weeks following cycle 4.

[0252] In certain embodiments, melphalan is administered at a dose of 140 mg / m2or 200 mg / m2over a period of 24 to 48 hours prior to ASCT. In further embodiments, one or more stem cell mobilization agents are administered to the subject within 6 weeks after completing cycle 4. In still further embodiments, the one or more stem cell mobilization agents are plerixafor, cyclophosphamide and / or granulocyte-colony stimulating factor.EMBODIMENTS

[0253] This invention provides the following non- limiting embodiments:

[0254] Embodiments Section 11) A method of treating multiple myeloma in a subject in need thereof, said method comprising subcutaneously administering to the subject a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises:• an antibody that specifically binds CD38 and comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementaritydetermining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6, and recombinant human hyaluronidase (rHuPH20). ) The method of embodiment 1 , wherein the multiple myeloma is newly diagnosed multiple myeloma. ) The method of embodiment 1 , wherein the subject is eligible for high dose therapy.) The method of embodiment 1, wherein the subject is eligible for autologous stem cell transplant (ASCT). ) The method of embodiment 1, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2. ) The method of embodiment 1 , wherein said method further comprises stem performing stem cell mobilization and autologous stem cell transplant (ASCT) on the subject. ) The method of embodiment 6, wherein the stem cell mobilization yields an improved median CD34+ cell yield. ) The method of embodiment 1 , wherein administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in the progression-free survival (PFS) of the subject. ) The method of embodiment 1 , wherein administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in minimal residual disease (MRD) negativity rate, overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), time to response, duration of response, progression-free survival on the next line of therapy (PFS2), or overall survival (OS). 0) The method of any one of embodiments 7-9, wherein the improvement is relative to a reference population of subjects with multiple myeloma, said reference populationhaving been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. ) The method of embodiment 1 , wherein the pharmaceutical composition comprises about 1 ,800 mg of said antibody and about 30,000 U rHuPH20. ) The method of embodiment 11, wherein the pharmaceutical composition comprises about 120 mg / mL of said antibody and about 2,000 U / mL rHuPH20. ) The method of embodiment 1, wherein the pharmaceutical composition comprises one or more excipients. ) The method of embodiment 13, wherein at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof. ) The method of embodiment 1 , wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises:• about 1,800 mg of said antibody;• about 30,000 U of rHuPH20;• about 10 mM histidine;• about 300 mM sorbitol;• about 0.04 % (w / v) PS -20; and• about 1 mg / mL methionine. ) The method of embodiment 15, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises:• about 120 mg / mL of said antibody;• about 2,000 U / mL of rHuPH20;• about 10 mM histidine;• about 300 mM sorbitol;• about 0.04 % (w / v) PS -20; and• about 1 mg / mL methionine. ) The method of embodiment 1, wherein the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8.) The method of embodiment 1, wherein the antibody that specifically binds CD38 is an IgGl isotype. ) The method of embodiment 1, wherein the antibody that specifically binds CD38 comprises a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10. ) The method of embodiment 1, wherein the antibody that specifically binds CD38 is daratumumab. ) The method of embodiment 1, wherein the pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered at a dose of about 1,800 mg once a week, about 1,800 mg once in two weeks, about 1 ,800 mg once in three weeks, or about 1,800 mg once in four weeks. ) The method of embodiment 1 , wherein bortezomib is administered at a dose of about 1.3 mg / m2twice a week. ) The method of embodiment 1, wherein bortezomib is administered subcutaneously.) The method of embodiment 1 , wherein lenalidomide is administered at a dose of about 10 mg daily or about 25 mg daily. ) The method of embodiment 1, wherein lenalidomide is administered orally. ) The method of embodiment 1 , wherein dexamethasone is administered at a dose of about 40 mg daily. ) The method of embodiment 1 , wherein dexamethasone is administered orally. ) The method of embodiment 1 , wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 28-day cycles.) The method of embodiment 28, wherein the pharmaceutical composition is administered once a week in the first and the second 28-day cycle, once in two weeks in the third, the fourth, the fifth and the sixth 28-day cycle, and thereafter once in four weeks in any subsequent 28-day cycle.) The method of embodiment 28, wherein bortezomib is administered at a dose of about 1.3 mg / m2twice a week for cycles 1-6. ) The method of embodiment 28, wherein lenalidomide is administered at a dose of about 25 mg daily for cycles 1 -6, and at a dose of 10 mg daily in any subsequent 28- day cycle. ) The method of embodiment 28, wherein dexamethasone is administered at a dose of about 40 mg on days 1-4 and 9-12 of cycles 1-6. ) The method of embodiment 28, wherein said method further comprises performing stem cell mobilization and autologous stem cell transplant (ASCT) on the subject.) The method of embodiment 33, wherein the ASCT is performed following cycles 1-4 but no later than 12 weeks following cycle 4. ) The method of embodiment 33, wherein melphalan is administered at a dose of 140 mg / m2or 200 mg / m2over a period of 24 to 48 hours prior to ASCT. ) The method of embodiment 33, wherein one or more stem cell mobilization agents are administered to the subject within 6 weeks after completing cycle 4. ) The method of embodiment 36, wherein the one or more stem cell mobilization agents are plerixafor, cyclophosphamide and / or granulocyte-colony stimulating factor.) A method of improving progression-free survival (PFS) in a subject or a population of subjects with multiple myeloma, said method comprising subcutaneously administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises:• an antibody that specifically binds CD38 and comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6, and• recombinant human hyaluronidase (rHuPH20),wherein the improvement in PFS is relative to PFS of a reference population of subjects with multiple myeloma, said reference population having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition.39) The method of embodiment 38, wherein the subject is 50 years of age or older.40) The method of embodiment 38, wherein the subject has International Staging System (ISS) stage III disease.41) The method of embodiment 38, wherein the subject has high cytogenetic risk.

[0255] Embodiments Section 2:1) A method of treating multiple myeloma in a subject in need thereof, said method comprising administering to the subject a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises an antibody that specifically binds CD38 and comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6.2) The method of embodiment 1 , wherein the multiple myeloma is newly diagnosed multiple myeloma.3) The method of embodiment 1 or 2, wherein the subject is eligible for high dose therapy.4) The method of any one of the preceding embodiments, wherein the subject is eligible for autologous stem cell transplant (ASCT).5) The method of any one of the preceding embodiments, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.6) The method of any one of the preceding embodiments, wherein said method further comprises stem performing stem cell mobilization and autologous stem cell transplant (ASCT) on the subject.) The method of any one of the preceding embodiments, wherein the stem cell mobilization yields an improved median CD34+ cell yield. ) The method of any one of the preceding embodiments, wherein administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in progression-free survival (PFS) of the subject relative to PFS of a reference population administered a combination of bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. ) The method of embodiment 8, wherein the improved PFS is prolonged relative to the reference population. 0) The method of embodiment 8 or 9, wherein the improved PFS is a 58% to 60% reduction of risk of progression or death. 1) The method of any one of the preceding embodiments, wherein administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in minimal residual disease (MRD) negativity rate, sustained MRD-negativity rate, overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), time to response, duration of response, progression- free survival on the next line of therapy (PFS2), or overall survival (OS). 2) The method of embodiment 11, wherein the improvement is relative to a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. 3) The method of embodiment 11 or embodiment 12, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10'5. 4) The method of any one of embodiments 11 to 13, wherein the improved MRD- negativity rate is 75.2% relative to 47.5% for the reference population. 5) The method of any one of embodiments 11 to 14, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 106.) The method of any one of embodiments 11 to 15, wherein the improved MRD- negativity rate is 65.1% relative to 32.2% for the reference population. ) The method of any one of embodiments 11 to 16, wherein the sustained MRD- negativity rate is at or below a sensitivity threshold of 10’6. ) The method of any one of embodiments 11 to 17, wherein the sustained MRD- negativity rate for at least 12 months is 64.8% relative to 29.7% for the reference population. ) The method of any one of embodiments 11 to 18, wherein the improved MRD- negativity rate in high risk multiple myeloma subjects is 58% relative to 31% for the reference population having high risk multiple myeloma. ) The method of any one of embodiments 11 to 19, wherein the sustained MRD- negativity rate for at least 12 months in high risk multiple myeloma subjects is 64.8% relative to 29.7% for the reference population having high risk multiple myeloma.) The method of any one of embodiments 11 to 18, wherein the improved ORR is 96.6% relative to 93.8% for the reference population. ) The method of any one of embodiments 11 to 21 , wherein the improved sCR is 69.3% relative to 44.6%% for the reference population. ) The method of any one of embodiments 11 to 22, wherein the improved CR or better is 87.9% relative to 70.1% for the reference population. ) The method of any one of the preceding embodiments, wherein the pharmaceutical composition also comprises a hyaluronidase ) The method of embodiment 24, wherein the hyaluronidase is a recombinant human hyaluronidase or rHuPH20. ) The method of any one of the preceding embodiments, wherein the pharmaceutical composition is administered subcutaneously.) The method of any one of the preceding embodiments, wherein the pharmaceutical composition comprises about 1,800 mg of said antibody and about 30,000 U rHuPH20. ) The method of any one of the preceding embodiments, wherein the pharmaceutical composition comprises about 120 mg / mL of said antibody and about 2,000 U / mL rHuPH20. ) The method of any one of the preceding embodiments, wherein the pharmaceutical composition comprises one or more excipients. ) The method of embodiment 29, wherein at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof. ) The method of any one of the preceding embodiments, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises:• about 1,800 mg of said antibody;• about 30,000 U of rHuPH20;• about 10 mM histidine;• about 300 mM sorbitol;• about 0.04 % (w / v) PS-20; and• about 1 mg / mL methionine. ) The method of embodiment 31 , wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises:• about 120 mg / mL of said antibody;• about 2,000 U / mL of rHuPH20;• about 10 mM histidine;• about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.) The method of any one of the preceding embodiments, wherein the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8. ) The method of any one of the preceding embodiments, wherein the antibody that specifically binds CD38 is an IgGl isotype. ) The method of any one of the preceding embodiments, wherein the antibody that specifically binds CD38 comprises a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10. ) The method of any one of the preceding embodiments, wherein the antibody that specifically binds CD38 is daratumumab. ) The method of any one of the preceding embodiments, wherein the pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered at a dose of about 1,800 mg once a week, about 1,800 mg once in two weeks, about 1,800 mg once in three weeks, or about 1,800 mg once in four weeks.) The method of any one of the preceding embodiments, wherein bortezomib is administered at a dose of about 1.3 mg / m2twice a week. ) The method of any one of the preceding embodiments, wherein bortezomib is administered subcutaneously. ) The method of any one of the preceding embodiments, wherein lenalidomide is administered at a dose of about 10 mg daily or about 25 mg daily. ) The method of any one of the preceding embodiments, wherein lenalidomide is administered orally. ) The method of any one of the preceding embodiments, wherein dexamethasone is administered at a dose of about 40 mg daily. ) The method of any one of the preceding embodiments, wherein dexamethasone is administered orally.) The method of any one of the preceding embodiments, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 28-day cycles. ) The method of embodiment 44, wherein the pharmaceutical composition is administered once a week in the first and the second 28-day cycle, once in two weeks in the third, the fourth, the fifth and the sixth 28-day cycle, and thereafter once in four weeks in any subsequent 28-day cycle. ) The method of embodiment 44 or 45, wherein bortezomib is administered at a dose of about 1.3 mg / m2twice a week for cycles 1-6. ) The method of any one of embodiments 44 to 46, wherein lenalidomide is administered at a dose of about 25 mg daily for cycles 1-6, and at a dose of 10 mg daily in any subsequent 28-day cycle. ) The method of any one of embodiments 44 to 47, wherein dexamethasone is administered at a dose of about 40 mg on days 1-4 and 9-12 of cycles 1-6. ) The method of any one of embodiments 44 to 48, wherein said method further comprises performing stem cell mobilization and autologous stem cell transplant (ASCT) on the subject. ) The method of embodiment 49, wherein the ASCT is performed following cycles 1-4 but no later than 12 weeks following cycle 4. ) The method of embodiment 49 or 50, wherein melphalan is administered at a dose of 140 mg / m2or 200 mg / m2over a period of 24 to 48 hours prior to ASCT. ) The method of any one of embodiments 49 to 51, wherein one or more stem cell mobilization agents are administered to the subject within 6 weeks after completing cycle 4. ) The method of embodiment 52, wherein the one or more stem cell mobilization agents are plerixafor, cyclophosphamide and / or granulocyte-colony stimulating factor.) A method of improving progression-free survival (PFS) in a subject or a population of subjects with multiple myeloma, said method comprising subcutaneously administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises:• an antibody that specifically binds CD38 and comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6, and• recombinant human hyaluronidase, wherein the improvement in PFS is relative to PFS of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. ) The method of embodiment 54, wherein the improved PFS is a 58% to 60% reduction of risk of progression or death. ) The method of embodiment 54 or 55, wherein the subject is 50 years of age or older.) The method of any one of embodiments 54 to 56, wherein the subject has International Staging System (ISS) stage III disease. ) The method of any one of embodiments 54 to 57, wherein the subject has high cytogenetic risk. ) A pharmaceutical composition for use in treating multiple myeloma wherein the pharmaceutical composition is for administration, or to be administered, in combination with bortezomib, lenalidomide, and dexamethasone, and further wherein said pharmaceutical composition comprises an antibody that specifically binds CD38 and comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6) The pharmaceutical composition for use as embodied in embodiment 59, wherein the multiple myeloma is newly diagnosed multiple myeloma. ) The pharmaceutical composition for use as embodied in embodiment 59 or embodiment 60, wherein the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8 ) The pharmaceutical composition for use as embodied in any of embodiment 59 to 61 , wherein the antibody that specifically binds CD38 is an IgGl isotype. ) The pharmaceutical composition for use as embodied in any of embodiments 59 to 62, wherein the antibody that specifically binds CD38 comprises a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10. ) The pharmaceutical composition for use as embodied in any of embodiments 59 to 63, wherein the antibody that specifically binds CD38 is daratumumab. ) The pharmaceutical composition for use as embodied in any of embodiments 59 to 64, wherein administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in progression-free survival (PFS) of the subject relative to PFS of a reference population administered a combination of bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. ) The pharmaceutical composition for use as embodied in embodiment 65, wherein the improved PFS is prolonged relative to the reference population. ) The pharmaceutical composition for use as embodied in embodiment 65 or embodiment 66, wherein the improved PFS is a 58% to 60% reduction of risk of progression or death. ) The pharmaceutical composition for use as embodied in any of embodiments 59 to 67, wherein administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in minimal residual disease (MRD) negativity rate, sustained MRD negativity rate, overallresponse rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), time to response, duration of response, progression-free survival on the next line of therapy (PFS2), or overall survival (OS). ) The pharmaceutical composition for use as embodied in any of embodiments 65 to 68, wherein the improvement is relative to a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition. ) The pharmaceutical composition for use as embodied in embodiment 68 or embodiment 69, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10"5. ) The pharmaceutical composition for use as embodied in any of embodiments 68 to 70, wherein the improved MRD-negativity rate is 75.2% relative to 47.5% for the reference population. ) The pharmaceutical composition for use as embodied in any of embodiments 68 to 71, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10'6. ) The pharmaceutical composition for use as embodied in any of embodiments 68 to 72, wherein the improved MRD-negativity rate is 65.1% relative to 32.2% for the reference population. ) The pharmaceutical composition for use as embodied in any of embodiments 68 to 73, wherein the sustained MRD-negativity rate is at or below a sensitivity threshold of IO’6. ) The pharmaceutical composition for use as embodied in any of embodiments 68 to 74, wherein the sustained MRD-negativity rate for at least 12 months is 64.8% relative to 29.7% for the reference population.) The pharmaceutical composition for use as embodied in any of embodiments 68 to 75, wherein the improved MRD-negativity rate in high risk multiple myeloma subjects is 58% relative to 31% for the reference population having high risk multiple myeloma.) The pharmaceutical composition for use as embodied in any of embodiments 68 to 76, wherein the sustained MRD-negativity rate for at least 12 months in high risk multiple myeloma subjects is 64.8% relative to 29.7% for the reference population having high risk multiple myeloma. ) The pharmaceutical composition for use as embodied in any of embodiments 68 to 75, wherein the improved ORR is 96.6% relative to 93.8% for the reference population.) The pharmaceutical composition for use as embodied in any of embodiments 68 to 75, wherein the improved sCR is 69.3% relative to 44.6%% for the reference population.) The pharmaceutical composition for use as embodied in any of embodiments 68 to 75, wherein the improved CR or better is 87.9% relative to 70.1% for the reference population. ) The pharmaceutical composition for use as embodied in any of embodiments 59 to 80, wherein the pharmaceutical composition also comprises a hyaluronidase. ) The pharmaceutical composition for use as embodied in any of embodiments 59 to 81, wherein the hyaluronidase is a recombinant human hyaluronidase or rHuPH20.) The pharmaceutical composition for use as embodied in any of embodiments 59 to 82, wherein the pharmaceutical composition is administered subcutaneously. ) The pharmaceutical composition for use as embodied in any of embodiments 59 to 83, wherein the pharmaceutical composition comprises (i) about 1,800 mg of said antibody and about 30,000 U rHuPH20; or (ii) about 120 mg / mL of said antibody and about 2,000 U / mL rHuPH20. ) The pharmaceutical composition for use as embodied in any of embodiments 59 to 84, wherein the pharmaceutical composition comprises one or more excipients.86) The pharmaceutical composition for use as embodied in any of embodiment 59 to 85, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises:• about 1,800 mg of said antibody;• about 30,000 U of rHuPH20;• about 10 mM histidine;• about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.EXAMPLES

[0256] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.EXAMPLE 1: Perseus-3 Clinical Study

[0257] An ongoing, non-limiting example of a phase 3, randomized, open-label, multicenter study evaluating subjects with newly diagnosed multiple myeloma who are deemed eligible for high-dose therapy (Perseus), is provided herein.Overview:

[0258] In Arm A, subjects will receive VELCADE® (bortezomib), lenalidomide, and dexamethasone (VRd) for induction and consolidation, followed by lenalidomide (R) maintenance until disease progression. Subjects in Arm B will receive daratumumab (DARZALEX FASPRO®; DARZALEX® SC), VELCADE®, lenalidomide, and dexamethasone (D-VRd) for induction and consolidation followed by daratumumab and lenalidomide maintenance until disease progression. Subjects in Arm B who have a response of complete response (CR) or better will stop therapy with daratumumab after sustained minimal residual disease (MRD) negativity (at or below the threshold of 10-6) for 12 months and a minimum of 24 months of maintenance therapy. Study ID numbers include: NCT03710603, EMN17 / 54767414MMY3014, and 2018-002992-16 (EudraCT).

[0259] The primary objective is to determine if the addition of daratumumab (DARZALEX FASPRO®; DARZALEX® SC) to VRd will prolong progression-free survival (PFS) defined as the time from the date of randomization to the date of disease progression(assessed by International Myeloma Working Group [IMWG] criteria) or death, compared with VRd alone. Secondary objective include determining if the addition of daratumumab (DARZALEX FASPRO®; DARZALEX® SC) to VRd will improve clinical outcomes and assessing the safety profile of D-VRd.Study Design:

[0260] The original study design of Perseus had approximately 690 subjects stratified by International Staging System (ISS) Stage I, II, or III disease (P-2 microglobulin and albumin) and cytogenetics (standard risk or high risk as defined by presence of dell7p, t[4; 14] or t[ 14; 16]) and then randomized in a 1 :1 ratio.

[0261] In Arm A, subjects received VRd for induction and consolidation, followed by lenalidomide (R) maintenance until disease progression or unacceptable toxicity. Subjects in Arm B received D-VRd for induction and consolidation followed by daratumumab and lenalidomide maintenance until disease progression or unacceptable toxicity. Subjects in Arm B that had a response of CR or better stopped therapy with daratumumab after sustained MRD negativity (at the threshold of 10"6) for 12 months and after a minimum of 24 months of maintenance therapy. These subjects continued lenalidomide maintenance therapy until disease progression or unacceptable toxicity. After stopping daratumumab therapy, subjects with sustained MRD negativity restarted therapy with daratumumab if there was a recurrence of MRD at 10"4or higher or a confirmed loss of CR without International Myeloma Working Group (IMWG)-defined disease progression as evidenced by the reappearance of serum or urine monoclonal protein (M-protein) by immunofixation or electrophoresis by central laboratory or development of >5% plasma cells in bone marrow. When a participant had a loss of CR, confirmation was required by the central laboratory prior to restarting daratumumab. After reinitiating daratumumab, the subject continued daratumumab and lenalidomide therapy until disease progression or unacceptable toxicity.

[0262] Primary analysis set for efficacy: Intent-to-treat (ITT) analysis set is defined as subjects who have been randomly assigned to the D-VRd or VRd group.

[0263] A diagram of the study design is provided in FIG. 1.Inclusion Criteria:

[0264] Each potential subject must satisfy all of the following criteria to be enrolled in the study:18 to 70 years of age, inclusive.• Monoclonal plasma cells in the bone marrow >10% or presence of a biopsy proven plasmacytoma and documented multiple myeloma satisfying at least one of the calcium, renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria: o CRAB criteria: Hypercalcemia: serum calcium >0.25 mmol / L (>1 mg / dL) higher than upper limit of normal (ULN) or >2.75 mmol / L (>11 mg / dL); Renal insufficiency: creatinine clearance <40mL / min or serum creatinine >177 pmol / L (>2 mg / dL); Anemia: hemoglobin >2 g / dL below the lower limit of normal or hemoglobin <10 g / dL; or Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT; o Biomarkers of Malignancy: Clonal bone marrow plasma cell percentage >60%; Involved: uninvolved serum FLC ratio >100; or > 1 focal lesion on magnetic resonance imaging (MRI) studies; o Measurable disease as defined by any of the following: Serum monoclonal paraprotein (M-protein) level >1.0 g / dL or urine M-protein level >200 mg / 24 hours; or Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin free light chain (FLC) >10 mg / dL and abnormal serum immunoglobulin kappa lambda FLC ratio;• Newly diagnosed subjects for whom high-dose therapy and autologous stem cell transplantation is part of the intended treatment plan.• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, l, or 2.• Clinical laboratory values meeting the following criteria during the Screening Phase (Screening hematology and chemistry tests should be repeated if done more than 3 days before C1D1): o Adequate bone marrow function: Hemoglobin >7.5 g / dL (>4.65 mmol / L; prior red blood cell [RBC] transfusion or recombinant human erythropoietin use is permitted however transfusions are not permitted within 7 days of randomization to achieve this minimum hemoglobin count); Absolute neutrophil count (ANC) >1.0 x 109 / L (G-CSF use is permitted); or Platelet count >50 x 109 / L if bone marrow is >50% involved in myeloma. Otherwise >75 x 109 / L o Adequate liver function: Aspartate aminotransferase (AST) <2.5 x ULN; Alanine aminotransferase (ALT) <2.5 x ULN; or Total bilirubin <1.5 x ULN(except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubin <1.5 x ULN) o Adequate renal function: Estimated creatinine clearance >30 mL / min. Creatinine clearance may be calculated using Cockcroft-Gault, eGFR (Modified Diet in Renal Disease [MDRD]), or chronic kidney disease (CKD)- epi formula; or Corrected serum calcium <13.5 mg / dL (<3.4 mmol / L); or free ionized calcium <6.5 mg / dL (<1.6 mmol / L);• Female subjects of reproductive childbearing potential (defined as post- menarche until post-menopause unless permanently sterilized) must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during the treatment period, during any dose interruptions, and for 3 months after the last dose of any component of the treatment regimen. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug and is consistent with the usual lifestyle of the subject. This birth control method must include one highly effective form of contraception (tubal ligation, intrauterine device [IUD], hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy with confirmation of procedure) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.• A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing.• A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 3 months after receiving the last dose of any component of the treatment regimen.• Male subjects of reproductive potential who are sexually active with females of reproductive potential must always use a latex or synthetic condom during the study and for 3 months after discontinuing study treatment (even after a successful vasectomy).• Male subjects of reproductive potential must not donate sperm during the study or for 3 months after the last dose of study treatment.• Signed an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study. Subjects in emergency situations that do not allow for collection of informed consent are excluded.• Able to adhere to the prohibitions and restrictions specified herein.Exclusion Criteria:• Prior or current systemic therapy or stem-cell transplant (SCT) for any plasma cell dyscrasia, with the exception of emergency use of a short course (equivalent of dexamethasone 40 mg / day for a maximum 4 days) of corticosteroids before treatment.• Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI- CTCAE) Version 5.• Prior or concurrent invasive malignancy (other than multiple myeloma) within 5 years of date of randomization (exceptions are adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other non- invasive lesion that in the opinion of the investigator, with concurrence with the sponsor’s medical monitor, is considered cured with minimal risk of recurrence within 3 years).• Radiation therapy for treatment of plasmacytoma within 14 days of randomization (palliative radiation for pain control secondary to lytic lesion is allowed within 14 days of randomization).• Plasmapheresis within 28 days of randomization.• Clinical signs of meningeal involvement of multiple myeloma.• Pulmonary: Subjects <65 years old with chronic obstructive pulmonary disease (COPD) with Forced Expiratory Volume in 1 second (FEVi) <50% of predicted normal; or Subjects >65 years old with a FEVI <50% or diffusing capacity of the lungs for carbon monoxide [DLCO] <50%• Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).• Known to be seropositive for human immunodeficiency virus (HIV). HIV antibody testing at screening should be performed per local health guidelines. Seropositive forhepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [Anti-HBc] and / or antibodies to hepatitis B surface antigen [Anti-HBs]) must be screened using real-time PCR measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. Known to be seropositive for hepatitis C, (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).• Concurrent medical or psychiatric condition or disease (such as, but not limited to, systemic amyloidosis, POEMS, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.• Myocardial infarction within 6 months before randomization, or an unstable or uncontrolled disease / condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV); uncontrolled cardiac arrhythmia; screening 12-lead ECG showing a baseline QT interval >470 msec (exception: subjects with pacemaker); screening ECHO or MUGA scan for subjects aged >65-70: left ventricular ejection fraction (LVEF) <40%.• Received a strong CYP3A4 inducer within 5 half-lives prior to randomization.• Allergy, hypersensitivity, or intolerance to boron or mannitol, corticosteroids, monoclonal antibodies or human proteins, or sensitivity to mammalian-derived products or lenalidomide or its excipients.• Not able to comply with the study protocol (e.g., because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol- specified assessments. Subject is taking any prohibited medications. Subject is deprived of their freedom by a judicial or administrative decision, or subject is in psychiatric care. Subject is subjected to a legal protection measure or unable to provide their consent.• Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of any component of the treatmentregimen. Or subject is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen.• Major surgery within 2 weeks before randomization or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or Vertebroplasty is not considered major surgery.• Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks or 5 half-lives of the respective drug / investigational medicinal product (IMP) (whichever is longer) before randomization or is currently enrolled in an interventional investigational study.• Contraindications to the use of any components of the backbone treatment regimens, per local prescribing information.• Gastrointestinal disease that may significantly alter the absorption of oral drugs.• Vaccination with live attenuated vaccines within 4 weeks of first study agent administration.• Unable or unwilling to undergo antithrombotic prophylactic treatment.Treatment duration / Trial duration:

[0265] The study consisted of 3 phases; a Screening Phase, a Treatment Phase, and a Follow-up Phase. The Screening Phase started up to 28 days before randomization. The Treatment Phase extended from Cycle 1 Day 1 to discontinuation of all study treatment. The Treatment Phase consisted of six 28-day cycles, 4 cycles of induction, followed by ASCT, then 2 cycles of consolidation, followed by maintenance therapy until disease progression or unacceptable toxicity.Main Study Arms:Arm A

[0266] Subjects received 6 cycles of treatment (4 cycles of treatment for induction and 2 cycles of treatment for consolidation) followed by maintenance (Cycle 7+).

[0267] Bortezomib 1.3 mg / m2SC, twice a week for 6 cycles.

[0268] Lenalidomide 25 mg orally for 6 cycles.

[0269] Subjects will start maintenance therapy (Cycle 7+), during which they will receive lenalidomide 10 mg daily orally on Days 1 to 28 (continuously) of each 28-day cycle until disease progression or unacceptable toxicity.

[0270] Dexamethasone 40 mg orally on Days 1-4 and 9-12 during Cycles 1-6 as part of the VRd backbone regimen.Arm B

[0271] Daratumumab will be given subcutaneously (SC) at 1800 mg to subjects in Arm B once every week for Cycles 1 to 2, then every 2 weeks for Cycles 3-6. For maintenance Cycles 7+, subjects will receive daratumumab (1800 mg) once every 4 weeks until documented disease progression or unacceptable toxicity.

[0272] Bortezomib, Lenalidomide, and Dexamethasone as in Arm A.TABLE 2: Primary and Secondary EndpointsTopline Results:

[0273] These topline results include the results from the PFS Interim Analysis #1.Subject and Treatment Information

[0274] A total of 709 subjects (D-VRd: 355, VRd: 354) were randomized across 113 sites of 14 countries (Europe and Australia). Of the 709 randomized subjects, 11 subjects did not receive any study treatment and are therefore not included in the safety analysis set (e.g., 351 and 347 subjects were treated in the D-VRd and VRd groups, respectively). At the time of the clinical cut-off, a total of 91 (25.9%) subjects in the D-VRd treatment group discontinued study treatment, compared to 188 (54.2%) subjects in the VRd treatment group; similarly, the study treatment discontinuation rate for AEs was substantially less for D-VRd subjects as compared to VRd subjects (D-VRd: 9.1% vs VRd: 22.5%).

[0275] Demographic and baseline characteristics were well balanced between the two treatment groups. D-VRd group has a median age of 61.0 years old and 26.5% of the subjects >65 years of age while VRd group has a median age of 59.0 and 24.6% of subjects >65 years. In D-VRd group, 52.4%, 32.1%, and 15.5% were ISS stage I, II, and III, respectively versus 50.4%, 35.4% and 14.2% in VRd group. 154 subjects had a high-risk cytogenetic abnormality (D-VRd: 21.4%; VRd: 22.0%).Efficacy- 1 -

[0276] A hierarchical testing approach was pre-specified for the primary endpoint (PFS) and key secondary endpoints to control family- wise Type I error rate at 0.05. As of the PFS IA # 1 cut-off date, the median follow-up was 47.5 months.Primary efficacy endpoint (PFS):PFS by computerized algorithm

[0277] A total of 153 (D-VRd: 50; VRd: 103) PFS events were observed. The hazard ratio (D-VRd vs. VRd) was 0.42 (95% confidence interval [CI]: 0.30, 0.59), demonstrating a 58% reduction in the risk of progression or death in subjects randomized to D-VRd, the p-value was <0.0001, crossing the stopping boundary of 0.0126 in favor of D-VRd group. The median PFS was not reached in either D-VRd group (48-month PFS rate: 84.3%) or VRd group (48-month PFS rate: 67.7%). FIG. 2 provides a Kaplan-Meier plot for PFS by computerized algorithm, ITT analysis set.PFS by IRC assessment per the US-specific SAP addendum

[0278] A total of 154 (D-VRd: 49; VRd: 105) PFS events were observed. The hazard ratio (D-VRd vs. VRd) was 0.40 (95% CI: 0.29, 0.57), demonstrating a 60% reduction in the risk of progression or death in subjects randomized to D-VRd, the p-value was <0.0001, crossing the stopping boundary of 0.0246 in favor of D-VRd group. The median PFS was not reached in both D-VRd group (48-month PFS rate: 84.6%) and VRd group (48-month PFS rate: 67.2%). FIG. 3 provides a Kaplan-Meier plot for PFS by IRC assessment, ITT analysis set.

[0279] The level of agreement on disease progression assessment (PD and no PD) between IRC and computerized algorithm, demonstrated a high concordance: Prevalence Adjusted and Bias Adjusted Kappa (PABAK) and 95% CI = 0.98 [0.97, 0.99]; observed agreement of 99.0%).

[0280] In addition, treatment effect on PFS (D-VRd over VRd) is generally consistent across pre-specified subgroups as demonstrated in FIG. 4 (by computerized algorithm) and FIG. 5 (by IRC assessment), in favor of D-VRd group.Key secondary endpoints:

[0281] Overall CR or better rate (FIG. 6), demonstrated a statistically significant and clinically meaningful treatment difference:• By computerized algorithm: the odds ratio (D-VRd vs. VRd) was 3.13 (95% CI: 2.11, 4.65) and the p-value was <0.0001, in favor of D-VRd group, with an absolute increase of 17.8% over VRd (87.9% vs 70.1%).• By IRC assessment per the US-specific SAP addendum: the odds ratio (D-VRd vs. VRd) was 3.01 (95% CI: 2.02, 4.49) and the p-value was <0.0001, in favor of D-VRd group, with an absolute increase of 16.7% over VRd (88.2% vs 71.5%).

[0282] The level of agreement on response assessment (CR or better response and less than CR) between IRC and computerized algorithm, demonstrated high concordance (PABAK [95%CI]= 0.98 [0.97, 1.00]; observed agreement of 99.2%).

[0283] Overall MRD negativity rate (achieving both CR / sCR and MRD negativity by NGS at the threshold of 106, was 65.1% in D-VRd versus 32.2% in VRd (FIG. 7). 47% of patients achieved sustained MRD negativity (10-6) for 12 months versus 19% with VRd + R. In high risk: 58% of patients achieved MRD negativity (10-6) and 30% achieved sustained MRD negativity (10-6) versus 31% and 14% with VRd + R.

[0284] Overall Survival (OS): OS analysis was descriptive only at this IA due to immature data with a total of 78 deaths (D-VRd: 34; VRd: 44) and showed a trend toward beneficial treatment effect with an estimated HR of 0.73 (95% CI: [0.47, 1.14]). FIG. 8 provides a Kaplan-Meier plot for overall survival, ITT analysis set.

[0285] During D-R maintenance the rate of MRD-negativity (10-6) increased by 30% versus 15% with R alone. The percentage of MRD-positive patients converted to sustained MRD negativity (10“6) was 31% versus 10% with R alone. During maintenance 64% of patients stopped DARA after achieving sustained MRD negativity (10-5).Exposure:

[0286] Among 698 subjects treated with either D-VRd (351) or VRd (347), the median duration of treatment was 43 cycles in the D-VRd group and 38 cycles in the VRd group, including induction, consolidation, and maintenance. The median duration of induction and consolidation were 4 cycles and 2 cycles respectively in both groups as protocol specified.

[0287] According to the protocol, 207 (59%) of 351 D-VRd subjects stopped daratumumab after completing 24 months of maintenance treatment and achieving both CR / sCR and sustained MRD negativity.Safety:

[0288] The safety data for daratumumab given in combination with VRd demonstrated a clinically manageable safety profile, consistent with the known safety profiles of daratumumab monotherapy and the VRd regimen. No new safety signals were identified (refer to FIG. 9).

[0289] The most frequently reported (>20% in either group) TEAEs included Neutropenia (D-VRd: 69.2%; VRd: 58.8%), Diarrhoea (D-VRd: 61.0%; VRd: 54.2%), Peripheral sensory neuropathy (D-VRd: 53.6%; VRd: 51.6%), Thrombocytopenia (D-VRd: 48.4%; VRd: 34.3%), COVID- 19 (D-VRd: 35.0%; VRd: 23.9%), Constipation (D-VRd: 33.9%; VRd: 34.0%), Pyrexia (D-VRd: 31.6%; VRd: 31.4%), Upper respiratory tract infection (D-VRd: 31.6%; VRd: 25.1%), Insomnia (D-VRd: 27.1%; VRd: 17.6%), Asthenia (D-VRd: 26.8%; VRd: 25.6%), Cough (D-VRd: 24.2%; VRd: 14.7%), Fatigue (D-VRd: 23.9%; VRd: 26.5%), Rash (D-VRd: 23.4%; VRd: 27.1%), Back pain (D-VRd: 22.8%; VRd: 19.0%), Anaemia (D- VRd: 22.2%; VRd: 20.7%), Oedema peripheral (D-VRd: 20.5%; VRd: 21.3%), Nausea (D- VRd: 20.2%; VRd: 16.7%).

[0290] The most common (>5% in either group) Grade 3 or 4 TEAEs included Neutropenia (D-VRd: 62.1%; VRd: 51.0%), Thrombocytopenia (D-VRd: 29.1%; VRd: 17.3%), Diarrhoea (D-VRd: 10.5%; VRd: 7.8%), Pneumonia (D-VRd: 10.5%; VRd: 6.1%), Febrile neutropenia (D-VRd: 9.4%; VRd: 10.1%), Anaemia (D-VRd: 6.0%; VRd: 6.3%), Stomatitis (D-VRd: 6.0%; VRd: 5.8%), Alanine aminotransferase increased (D-VRd: 5.1%; VRd: 5.2%), Fatigue (D-VRd: 2.8%; VRd: 5.2%).

[0291] The incidence rate of treatment-emergent serious adverse event (SAE) was 57.0% in D-VRd group and 49.3% in VRd group. The most common (>2%) SAE reported was Pneumonia (D-VRd: 11.4%; VRd: 6.1%), Febrile neutropenia (D-VRd: 4.6%; VRd: 4.6%), Pyrexia (D-VRd: 3.7%; VRd: 4.6%), COVID-19 (D-VRd: 3.7%; VRd: 1.7%), COVID-19 pneumonia (D-VRd: 3.1%; VRd: 1.4%), Atrial fibrillation (D-VRd: 2.6%; VRd: 0.6%), Lower respiratory tract infection (D-VRd: 2.6%; VRd: 0.9%), Pulmonary embolism (D-VRd: 2.6%; VRd: 1.4%), Diarrhoea (D-VRd: 2.0%; VRd: 2.6%), Sepsis (D-VRd: 2.0%; VRd: 2.6%), Upper respiratory tract infection (D-VRd: 2.0%; VRd: 2.3%).

[0292] IRRs (injection related reactions) were reported in 6.0% of subjects in the D-VRd group.

[0293] Infections and infestations were reported in 305 (86.9%) subjects in the D-VRd group compared to 266 (76.7%) subjects in the VRd group. Overall TEAEs of COVID-19 infections (grouped term) were more frequent in the D-VRd group (D-VRd 37.9% vs VRd 25.1%). Overall SAEs of COVID-19 infections were also more frequent in the D-VRd group (D-VRd 6.6% vs 2.9%). Five subjects had grade 5 COVID (D-VRd 4 vs. VRd 1).

[0294] HBV reactivation was reported at low frequencies in both groups: D-VRd: 5 (1.4%) vs VRd:5 (1.4%).

[0295] The incidence of second primary malignancies was 10.5% in D-VRd and 7.2% in VRd group.

[0296] Addition of daratumumab to VRd treatment demonstrated a clinically meaningful and statistically significant improvement over VRd alone with regards to the primary endpoint (progression-free survival) and key secondary endpoints (overall CR or better rate, and overall MRD negativity rate at the threshold of 10"6). Overall survival showed a trend toward beneficial treatment effect with a HR of 0.73. The D-VRd safety profile was clinically manageable, consistent with the known safety profiles of daratumumab monotherapy and the VRd regimen.Indications and Recommended Dosage and Administration:United States

[0297] Indication: DARZALEX FASPRO® (DARZALEX® SC) is indicated for the treatment of adult patients with multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone, followed by maintenance treatment in combination with lenalidomide, in newly diagnosed patients who are eligible for autologous stem cell transplant.

[0298] Recommended Dosage and Administration: The recommended dosing schedule of DARZALEX FASPRO® (DARZALEX® SC), when used in combination with bortezomib, lenalidomide, and dexamethasone, followed by maintenance treatment in combination with lenalidomide (4-week cycle) for treatment of newly diagnosed multiple myeloma patients eligible for ASCT, is provided below (Table 3).TABLE 3aFirst dose of the every-2-week dosing schedule is given at Week 9bWeek 17 corresponds to re-initiation of treatment following recovery from ASCTcDiscontinue DARZALEX FASPRO® (DARZALEX® SC) for patients who have achieved MRD negativity that is sustained for 12 months and have been treated on maintenance for at least 24 monthsEuropean Union (EU)

[0299] Indication: DARZALEX FASPRO® (DARZALEX® SC) is indicated in combination with bortezomib, lenalidomide, and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.

[0300] Recommended Dosage and Administration: The recommended dosing schedule of DARZALEX FASPRO® (DARZALEX® SC), when used in combination with bortezomib, lenalidomide, and dexamethasone, followed by maintenance treatment in combination with lenalidomide (4-week cycle) for treatment of newly diagnosed multiple myeloma patients eligible for ASCT, is provided below (Table 4).TABLE 4aFirst dose of the every-2-week dosing schedule is given at week 9bWeek 17 corresponds to re-initiation of treatment following recovery from ASCT

[0301] FASPRO®- VRd arm as compared to the VRd arm; the median PFS had not been reached in either arm. Treatment with DARZALEX FASPRO®- VRd resulted in a reduction in the risk of disease progression or death by 60% compared to VRd alone (HR [95% CI]: 0.40 [0.29, 0.57]; p-value < 0.0001) (FIG. 3) assessed by IRC assessment per the US-specific SAP addendum.

[0302] Serious adverse reactions occurred in 37% of patients who received DARZALEX FASPRO®- VRd. The most frequent serious adverse reaction in >5% of patients who receivedDARZALEX FASPRO®-VRd was pneumonia (6%). Fatal adverse reactions occurred in 1.7% of patients who received DARZALEX FASPRO®-VRd.

[0303] Permanent treatment discontinuation due to an adverse reaction occurred in 2% of patients who received DARZALEX FASPRO®-VRd. An adverse reaction which resulted in permanent discontinuation of DARZALEX FASPRO®-VRd in more than 1 patient included sepsis.

[0304] The most common adverse reactions (>20%) were peripheral neuropathy, fatigue, edema, pyrexia, upper respiratory infection, constipation, diarrhea, musculoskeletal pain, insomnia, and rash.

[0305] Table 5 summarizes the adverse reactions in patients who received DARZALEX FASPRO® in PERSEUS. The D-VRd safety profile was clinically manageable, consistent with the known safety profiles of daratumumab monotherapy and the VRd regimen.Table 5key : V Rd=bortezomib-lenahdomide -dexamethasone a Peripheral neuropathy includes neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy. b Includes other related terms. c Upper respiratory tract infection includes fungal pharyngitis, hlnl influenza, influenza, influenza like illness, laryngitis, nasopharyngitis, oral candidiasis, oropharyngeal candidiasis, parainfluenzae virus infection, pharyngitis, respiratory moniliasis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, sinusitis, tonsillitis, upper respiratory tract infection, viral tonsillitis, and viral upper respiratory tract infection. Pneumonia includes bronchopulmonary aspergillosis, lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia influenzal, pneumonia klebsiella, pneumonia legionella, and pneumonia streptococcal. e Hepatotoxicity includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic cytolysis, hepatic failure, hepatic function abnormal, hepatoxicity, hyperbilirubinemia, hypertransaminasemia, and liver disorder *Only Grade 3 adverse reactions occurred.®Fatal adverse reactions included Pneumonia: n=l (0.3%) in the VRd arm.

[0306] Clinically relevant adverse reactions in <10% of patients who receivedDARZALEX FASPRO® with bortezomib, lenalidomide and dexamethasone include:• Gastrointestinal disorders: vomiting, hemorrhoids• Musculoskeletal and connective tissue disorders: arthralgia• Infections: bronchitis, sepsis, urinary tract infection, herpes zoster, Covid-19, cytomegalovirus infection• Respiratory, thoracic, and mediastinal disorders: dyspnea, pulmonary edema• Metabolism and nutrition disorders: hypocalcemia, decreased appetite, hyperglycemia, dehydration• Vascular disorders: hypotension, hypertension, orthostatic hypotension• General disorders and administration site conditions: infusion reactions, injection site reaction, chills• Nervous system disorders: dizziness, headache, syncope• Cardiac disorders: thrombosis, atrial fibrillation, tachycardia• Skin and subcutaneous tissue disorders: pruritusExample 2: Combination treatment with bortezomib, lenalidomide and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma eligible for autologous stem cell transplant (AS CT)

[0307] Study MMY3014 was an open-label, randomized, active-controlled phase III study that compared induction and consolidation treatment with DARZALEX subcutaneous formulation ( 1800 mg) (DARZALEX® SC) in combination with bortezomib, lenalidomide and dexamethasone (D-VRd), followed by maintenance with DARZALEX (DARZALEX® SC) in combination with lenalidomide, to treatment with bortezomib, lenalidomide and dexamethasone (VRd), followed by maintenance with lenalidomide, in patients 70 years of age and younger with newly diagnosed multiple myeloma eligible for ASCT until documented disease progression or unacceptable toxicity. An emergency short course of corticosteroid (equivalent of dexamethasone 40 mg / day for a maximum 4 days) was permitted before treatment. Patients received DARZALEX subcutaneous formulation (DARZALEX® SC) (1800 mg) administered subcutaneously once weekly (days 1, 8, 15, and 22) for cycles 12 followed by once every two weeks (days 1 and 15) for cycles 36. For maintenance (cycles 7+), patients received DARZALEX subcutaneous formulation (DARZALEX® SC) (1800 mg) once every four weeks. Patients who achieved MRD negativity that was sustained for 12 months and had been treated on maintenance for at least 24 months discontinued treatment with DARZALEX subcutaneous formulation (DARZALEX® SC) (1800 mg). Bortezomib was administered by subcutaneous (SC) injection at a dose of 1.3 mg / m2body surface area twice weekly for two weeks (days 1, 4, 8, and 11) of repeated 28day (4week) cycles 16. Lenalidomide was administered orally at 25 mg daily on days 1 to 21 during cycles 16. For maintenance (cycles 7+), patients received 10 mg lenalidomide daily on days 128 (continuously) of each cycle until documented disease progression or unacceptable toxicity. Dexamethasone (oral or intravenous) was administered at 40 mg on days 14 and days 912 of cycles 16. On the days of DARZALEX subcutaneous formulation (DARZALEX® SC) (1800 mg) injection, the dexamethasone dose was administered orally or intravenously as a preinjection medicinal product. Dose adjustmentsfor bortezomib, lenalidomide and dexamethasone were applied according to manufacturer’s prescribing information.

[0308] A total of 709 patients were randomised: 355 to the D-VRd arm and 354 to the VRd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 60 (range: 31 to 70 years). The majority were male (59%), 64% had an ECOG performance score of 0, 31% had an ECOG performance score of 1 and 5% had an ECOG performance score of 2. Additionally, 51% had ISS stage I, 34% had ISS stage II, 15% had ISS stage III disease, 75% had a standard cytogenetic risk, 22% had a high cytogenetic risk (dell7p, t[4;14J, t[ 14; 16J), and 3% had an indeterminate cytogenetic risk.

[0309] With a median follow-up of 47.5 months, the primary analysis of PFS in study MMY3014 demonstrated an improvement in PFS in the D-VRd arm as compared to the VRd arm (HR=0.42; 95% CI: 0.30, 0.59; p<0.0001) (FIG. 2) assessed with the use of a validated computerized algorithm in accordance with International Myeloma Working Group response criteria. The median PFS was not reached in either arm. Additional efficacy results from study MMY3014 are presented in table 6 below.Table 6: Efficacy results from study MMY3014aD-VRd=daratumumab-bortezomib-lenalidomide-dexamethasone; VRd=bortezomib-lenalidomide-dexamethasone;MRD=minimal residual disease; CI=confidence intervalaBased on intent-to-treat populationbp-value from Cochran Mantel-Haenszel Chi-Squared test c Patients achieved both MRD negativity (threshold of 10 -5 ) and CR or betterllMantel-Haenszel estimate of the common odds ratio for stratified tables is used

Claims

What is claimed:1) A method of treating multiple myeloma in a subject in need thereof, said method comprising administering to the subject a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises an antibody that specifically binds CD38 and comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6.2) The method of claim 1 , wherein the multiple myeloma is newly diagnosed multiple myeloma.3) The method of claim 1 or 2, wherein the subject is eligible for high dose therapy.4) The method of any one of the preceding claims, wherein the subject is eligible for autologous stem cell transplant (ASCT).5) The method of any one of the preceding claims, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.6) The method of any one of the preceding claims, wherein said method further comprises stem performing stem cell mobilization and autologous stem cell transplant (ASCT) on the subject.7) The method of any one of the preceding claims, wherein the stem cell mobilization yields an improved median CD34+ cell yield.8) The method of any one of the preceding claims, wherein administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in progression-free survival (PFS) of the subject relative to PFS of a reference population administered a combination of bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition.9) The method of claim 8, wherein the improved PFS is prolonged relative to the reference population.10) The method of claim 8 or 9, wherein the improved PFS is a 58% to 60% reduction of risk of progression or death.11) The method of any one of the preceding claims, wherein administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in minimal residual disease (MRD) negativity rate, sustained MRD negativity rate, overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), time to response, duration of response, progression- free survival on the next line of therapy (PFS2), or overall survival (OS).12) The method of claim 11 , wherein the improvement is relative to a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition.13) The method of claim 11 or claim 12, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10'5.14) The method of any one of claims 11 to 13, wherein the improved MRD-negativity rate is 75.2% relative to 47.5% for the reference population.15) The method of any one of claims 11 to 14, wherein the improved overall MRD- negativity rate is at or below a sensitivity threshold of 10"6.16) The method of any one of claims 11 to 15, wherein the improved MRD-negativity rate is 65.1% relative to 32.2% for the reference population.17) The method of any one of claims 11 to 16, wherein the sustained MRD-negativity rate is at or below a sensitivity threshold of 10‘6.18) The method of any one of claims 11 to 17, wherein the sustained MRD-negativity rate for at least 12 months is 64.8% relative to 29.7% for the reference population.19) The method of any one of claims 11 to 18, wherein the improved MRD-negativity rate in high risk multiple myeloma subjects is 58% relative to 31% for the reference population having high risk multiple myeloma.20) The method of any one of claims 11 to 19, wherein the sustained MRD-negativity rate for at least 12 months in high risk multiple myeloma subjects is 64.8% relative to 29.7% for the reference population.21) The method of any one of claims 11 to 18, wherein the improved ORR is 96.6% relative to 93.8% for the reference population.22) The method of any one of claims 11 to 21, wherein the improved sCR is 69.3% relative to 44.6%% for the reference population.23) The method of any one of claims 11 to 22, wherein the improved CR or better is 87.9% relative to 70.1% for the reference population.24) The method of any one of the preceding claims, wherein the pharmaceutical composition also comprises a hyaluronidase25) The method of claim 20, wherein the hyaluronidase is a recombinant human hyaluronidase or rHuPH20.26) The method of any one of the preceding claims, wherein the pharmaceutical composition is administered subcutaneously.27) The method of any one of the preceding claims, wherein the pharmaceutical composition comprises about 1,800 mg of said antibody and about 30,000 U rHuPH20.28) The method of any one of the preceding claims, wherein the pharmaceutical composition comprises about 120 mg / mL of said antibody and about 2,000 U / mL rHuPH20.29) The method of any one of the preceding claims, wherein the pharmaceutical composition comprises one or more excipients.30) The method of claim 29, wherein at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.31) The method of any one of the preceding claims, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises:• about 1,800 mg of said antibody;• about 30,000 U of rHuPH20;• about 10 mM histidine;• about 300 mM sorbitol;• about 0.04 % (w / v) PS -20; and• about 1 mg / mL methionine.32) The method of claim 31 , wherein the pharmaceutical composition is at a pH of about5.6, and wherein the pharmaceutical composition comprises:• about 120 mg / mL of said antibody;• about 2,000 U / mL of rHuPH20;• about 10 mM histidine;• about 300 mM sorbitol;• about 0.04 % (w / v) PS-20; and• about 1 mg / mL methionine.33) The method of any one of the preceding claims, wherein the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8.34) The method of any one of the preceding claims, wherein the antibody that specifically binds CD38 is an IgGl isotype.35) The method of any one of the preceding claims, wherein the antibody that specifically binds CD38 comprises a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10.36) The method of any one of the preceding claims, wherein the antibody that specifically binds CD38 is daratumumab.37) The method of any one of the preceding claims, wherein the pharmaceutical composition comprising the antibody that specifically binds CD38 and rHuPH20 is administered at a dose of about 1,800 mg once a week, about 1,800 mg once in two weeks, about 1,800 mg once in three weeks, or about 1,800 mg once in four weeks.38) The method of any one of the preceding claims, wherein bortezomib is administered at a dose of about 1.3 mg / m2twice a week.39) The method of any one of the preceding claims, wherein bortezomib is administered subcutaneously.40) The method of any one of the preceding claims, wherein lenalidomide is administered at a dose of about 10 mg daily or about 25 mg daily.41) The method of any one of the preceding claims, wherein lenalidomide is administered orally.42) The method of any one of the preceding claims, wherein dexamethasone is administered at a dose of about 40 mg daily.43) The method of any one of the preceding claims, wherein dexamethasone is administered orally.44) The method of any one of the preceding claims, wherein the pharmaceutical composition, bortezomib, lenalidomide and dexamethasone are administered for one or more 28-day cycles.45) The method of claim 44, wherein the pharmaceutical composition is administered once a week in the first and the second 28-day cycle, once in two weeks in the third, the fourth, the fifth and the sixth 28-day cycle, and thereafter once in four weeks in any subsequent 28-day cycle.46) The method of claim 44 or 45, wherein bortezomib is administered at a dose of about 1.3 mg / m2twice a week for cycles 1-6.47) The method of any one of claims 44 to 46, wherein lenalidomide is administered at a dose of about 25 mg daily for cycles 1-6, and at a dose of 10 mg daily in any subsequent 28-day cycle.48) The method of any one of claims 44 to 47, wherein dexamethasone is administered at a dose of about 40 mg on days 1-4 and 9-12 of cycles 1-6.49) The method of any one of claims 44 to 48, wherein said method further comprises performing stem cell mobilization and autologous stem cell transplant (ASCT) on the subject.50) The method of claim 49, wherein the ASCT is performed following cycles 1-4 but no later than 12 weeks following cycle 4.51) The method of claim 49 or 50, wherein melphalan is administered at a dose of 140 mg / nr or 200 mg / m2over a period of 24 to 48 hours prior to ASCT.52) The method of any one of claims 49 to 51 , wherein one or more stem cell mobilization agents are administered to the subject within 6 weeks after completing cycle 4.53) The method of claim 52, wherein the one or more stem cell mobilization agents are plerixafor, cyclophosphamide and / or granulocyte-colony stimulating factor.54) A method of improving progression-free survival (PFS) in a subject or a population of subjects with multiple myeloma, said method comprising subcutaneously administering to the subject or the population of subjects a pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone, wherein said pharmaceutical composition comprises:• an antibody that specifically binds CD38 and comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 6, and• recombinant human hyaluronidase,wherein the improvement in PFS is relative to PFS of a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition.55) The method of claim 54, wherein the improved PFS is a 58% to 60% reduction of risk of progression or death.56) The method of claim 54 or 55, wherein the subject is 50 years of age or older.57) The method of any one of claims 54 to 56, wherein the subject has International Staging System (ISS) stage III disease.58) The method of any one of claims 54 to 57, wherein the subject has high cytogenetic risk.59) A pharmaceutical composition for use in treating multiple myeloma wherein the pharmaceutical composition is for administration, or to be administered, in combination with bortezomib, lenalidomide, and dexamethasone, and further wherein said pharmaceutical composition comprises an antibody that specifically binds CD38 and comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5 and a LCDR3 of SEQ ID NO: 660) The pharmaceutical composition for use as claimed in claim 59, wherein the multiple myeloma is newly diagnosed multiple myeloma.61) The pharmaceutical composition for use as claimed in claim 59 or claim 60, wherein the antibody that specifically binds CD38 comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 862) The pharmaceutical composition for use as claimed in any of claims 59 to 61, wherein the antibody that specifically binds CD38 is an IgGl isotype.63) The pharmaceutical composition for use as claimed in any of claims 59 to 62, wherein the antibody that specifically binds CD38 comprises a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10.64) The pharmaceutical composition for use as claimed in any of claims 59 to 63, wherein the antibody that specifically binds CD38 is daratumumab.65) The pharmaceutical composition for use as claimed in any of claims 59 to 64, wherein administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in progression-free survival (PFS) of the subject relative to PFS of a reference population administered a combination of bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition.66) The pharmaceutical composition for use as claimed in claim 65, wherein the improved PFS is prolonged relative to the reference population.67) The pharmaceutical composition for use as claimed in claim 65 or claims 59 to 66, wherein the improved PFS is a 58% to 60% reduction of risk of progression or death.68) The pharmaceutical composition for use as claimed in any of claims 59 to 67, wherein administration of the pharmaceutical composition in combination with bortezomib, lenalidomide, and dexamethasone provides an improvement in minimal residual disease (MRD) negativity rate, sustained MRD negativity rate, overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), time to response, duration of response, progression-free survival on the next line of therapy (PFS2), or overall survival (OS).69) The pharmaceutical composition for use as claimed in any of claims 65 to 68, wherein the improvement is relative to a reference subject or a reference population of subjects with multiple myeloma, said reference subject or said reference population of subjects having been administered bortezomib, lenalidomide, and dexamethasone without the pharmaceutical composition.70) The pharmaceutical composition for use as claimed in claim 68 or claim 69, wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10" 571) The pharmaceutical composition for use as claimed in any of claims 68 to 70, wherein the improved MRD-negativity rate is 75.2% relative to 47.5% for the reference population.72) The pharmaceutical composition for use as claimed in any of claims 68 to 71 , wherein the improved overall MRD-negativity rate is at or below a sensitivity threshold of 10" 673) The pharmaceutical composition for use as claimed in any of claims 68 to 72, wherein the improved MRD-negativity rate is 65.1% relative to 32.2% for the reference population.74) The pharmaceutical composition for use as claimed in any of claims 68 to 73, wherein the sustained MRD-negativity rate is at or below a sensitivity threshold of 10'6.75) The pharmaceutical composition for use as claimed in any of claims 68 to 74, wherein the sustained MRD-negativity rate for at least 12 months is 64.8% relative to 29.7% for the reference population.76) The pharmaceutical composition for use as claimed in any of claims 68 to 75, wherein the improved MRD-negativity rate in high risk multiple myeloma subjects is 58% relative to 31 % for the reference population having high risk multiple myeloma.77) The pharmaceutical composition for use as claimed in any of claims 68 to 76, wherein the sustained MRD-negativity rate for at least 12 months in high risk multiple myeloma subjects is 64.8% relative to 29.7% for the reference population.78) The pharmaceutical composition for use as claimed in any of claims 68 to 69, wherein the improved ORR is 96.6% relative to 93.8% for the reference population.79) The pharmaceutical composition for use as claimed in any of claims 68 to 78, wherein the improved sCR is 69.3% relative to 44.6%% for the reference population.80) The pharmaceutical composition for use as claimed in any of claims 68 to 79, wherein the improved CR or better is 87.9% relative to 70.1% for the reference population.81) The pharmaceutical composition for use as claimed in any of claims 59 to 80, wherein the pharmaceutical composition also comprises a hyaluronidase.82) The pharmaceutical composition for use as claimed in any of claims 59 to 81, wherein the hyaluronidase is a recombinant human hyaluronidase or rHuPH20.83) The pharmaceutical composition for use as claimed in any of claims 59 to 82, wherein the pharmaceutical composition is administered subcutaneously.84) The pharmaceutical composition for use as claimed in any of claims 59 to 83, wherein the pharmaceutical composition comprises (i) about 1,800 mg of said antibody and about 30,000 U rHuPH20; or (ii) about 120 mg / mL of said antibody and about 2,000 U / mL rHuPH20.85) The pharmaceutical composition for use as claimed in any of claims 59 to 84, wherein the pharmaceutical composition comprises one or more excipients.86) The pharmaceutical composition for use as claimed in any of claim 59 to 85 wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises:• about 1,800 mg of said antibody;• about 30,000 U of rHuPH20;• about 10 mM histidine;• about 300 mM sorbitol;• about 0.04 % (w / v) PS-20; and• about 1 mg / mL methionine.

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