Methods for treating high-risk smoldering multiple myeloma

Abstract

Described herein are methods and compositions for treating high-risk smoldering multiple myeloma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-CD38 antibody.

Description

METHODS FOR TREATING HIGH-RISK SMOLDERING MULTIPLEMYELOMACROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Application Serial number 63 / 678,278, filed August 1, 2024, and United States Provisional Application Serial number 63 / 785,325, filed April 8, 2025, the entire contents of the aforementioned applications are incorporated herein by reference in their entireties.SEQUENCE LISTING

[0002] This application contains a Sequence Listing submitted via EFS-Web, the entire content of which is incorporated herein by reference in its entirety. The file created on July 31, 2025, is named JBI6931WOPCT1 Sequence Listing.xml and is 20 kilobytes in size.FIELD

[0003] Methods of treating high-risk smoldering multiple myeloma are disclosed.BACKGROUND

[0004] Smoldering multiple myeloma (SMM) is a precursor disease state that precedes the development of active multiple myeloma, which is a cancer of the plasma cells. Patients with SMM usually do not have symptoms but are at risk for progressing to active multiple myeloma (MM). Treatment options for multiple myeloma have improved over time; however, despite recent therapeutic achievements, multiple myeloma remains an incurable malignancy with significant morbidity and mortality. There are currently no approved therapies for SMM, and there remains a need for safe and effective treatment options, in particular for patients with high-risk smoldering multiple myeloma (HR-SMM), who are at high risk of developing active multiple myeloma.SUMMARY

[0005] Herein is provided a method of treating high-risk smoldering multiple myeloma (HR-SMM) in a subject in need thereof, comprising administering to the subject atherapeutically effective amount of an anti-CD38 antibody (e.g., daratumumab or a biosimilar thereof).

[0006] All methods described herein, however expressed, may be described as corresponding uses, in particular medical uses.

[0007] In certain embodiments, the present disclosure is directed to methods of treating high-risk smoldering multiple myeloma (HR-SMM) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti- CD38 antibody.

[0008] In certain embodiments, the method provides an improvement in progression free survival (PFS), overall response rate (ORR), rate of partial response (PR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), progression-free survival on first-line treatment for multiple myeloma (PFS 2), or overall survival (OS).

[0009] In certain embodiments, the anti-CD38 antibody comprises a CD38 binding domain 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.

[0010] In certain embodiments, the CD38 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 8.

[0011] In certain embodiments, the anti-CD38 antibody is an IgGl, an IgG2, an IgG3 or an IgG4 isotype.

[0012] In certain embodiments, the anti-CD38 antibody is an IgGl isotype.

[0013] In certain embodiments, the anti-CD38 antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10.

[0014] In certain embodiments, the anti-CD38 antibody is daratumumab.

[0015] In certain embodiments, the anti-CD38 antibody is a daratumumab biosimilar.

[0016] In certain embodiments, the anti-CD38 antibody is administered as a monotherapy.

[0017] In certain embodiments, the anti-CD38 antibody is subcutaneously administered.

[0018] In a specific embodiment, the anti-CD38 antibody is administered in a pharmaceutical composition, comprising 1,800 mg of the anti-CD38 antibody. In a specific embodiment, the anti-CD38 antibody is administered in a pharmaceutical composition, comprising 1,800 mg daratumumab. In a specific embodiment, the anti- CD38 antibody is administered in a pharmaceutical composition, comprising 1,800 mg daratumumab biosimilar.

[0019] In a specific embodiment, the anti-CD38 antibody is administered in a pharmaceutical composition comprising the anti-CD38 antibody and a hyaluronidase. In a specific embodiment, the anti-CD38 antibody is daratumumab, or a daratumumab biosimilar. In a specific embodiment, the hyaluronidase comprises a recombinant human hyaluronidase.

[0020] In certain embodiments, the recombinant human hyaluronidase has an amino acid sequence of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO:15, or SEQ ID NO: 16.

[0021] In certain embodiments, the pharmaceutical composition comprises a mixture of recombinant human hyaluronidase with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

[0022] In certain embodiments, the pharmaceutical composition comprises about 1,800 mg of the anti-CD38 antibody and about 30,000 U of hyaluronidase.

[0023] In a specific embodiment, the pharmaceutical composition comprises about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of hyaluronidase.

[0024] In certain embodiments, the pharmaceutical composition comprises one or more excipients.

[0025] In a specific embodiment, at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0026] In certain embodiments, the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of the anti- CD38 antibody; about 30,000 U of hyaluronidase; about 10 mM histidine; about 300 m sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.

[0027] In a specific embodiment, the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL of the anti-CD38 antibody; about 2,000 U / mL of hyaluronidase; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.

[0028] In certain embodiments, the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of daratumumab, or a daratumumab biosimilar; about 30,000 U of recombinant human hyaluronidase; about 10 mM histidine; about 300 m sorbitol; about 0.04 % (w / v) PS- 20; and about 1 mg / mL methionine.

[0029] In certain embodiments, the anti-CD38 antibody is administered at a dose of about 1,800 mg once a week, about 1,800 mg once in two weeks, or about 1,800 mg once in four weeks.

[0030] In certain embodiments, the subject is treated according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles.

[0031] In certain embodiments, the anti-CD38 antibody is administered once a week for two treatment cycles.

[0032] In certain embodiments, the anti-CD38 antibody is administered once every two weeks for four treatment cycles.

[0033] In certain embodiments, the anti-CD38 antibody is administered once every four weeks until 39 cycles or up to 36 months, or confirmed disease progression, whichever occurs first.

[0034] In certain embodiments, the anti-CD38 antibody is administered according to a regimen comprising 28-day cycles wherein the regimen comprises: in Cycles 1 to 2, administering the anti-CD38 antibody once a week, in Cycles 3 to 6, administering the anti-CD38 antibody once every two weeks, and then administering the anti-CD38 antibody once every 4 weeks.

[0035] In certain embodiments, the subject has not received prior SMM directed therapy.

[0036] In certain embodiments, the subject does not have active multiple myeloma.

[0037] In certain embodiments, the method achieves a clinical response in the subject that is a progression free survival (PFS) as defined by IRC assessment.

[0038] In certain embodiments, the method achieves a clinical response in the subject that is a partial response (PR), a very good partial response (VGPR), a complete response (CR) or a stringent complete response (sCR), as defined by International Myeloma Working Group (IMWG) response criteria.

[0039] In certain embodiments, the method achieves PFS in a population of subjects with HR-SMM of 60% or higher.

[0040] In certain embodiments, the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM of 60% or higher.

[0041] In certain embodiments, the method achieves a PFS2 rate in a population of subjects with HR-SMM of 85% or higher.

[0042] In certain embodiments, the method achieves an OS rate in a population of subjects with HR-SMM of 90% or higher.

[0043] In certain embodiments, after the subject has received at least 38 28-day cycles of treatment with the anti-CD38 antibody, the subject’s HR-SMM does not progress.

[0044] In certain embodiments, after the subject has received at least 39 28-day cycles of treatment with the anti-CD38 antibody, the subject’s HR-SMM does not progress.

[0045] In certain embodiments, administration of the anti-CD38 antibody to the subject for a maximum of 39 28-day treatment cycles prevents the subject from developing multiple myeloma.

[0046] In certain embodiments, the method prevents the subject from developing MM.

[0047] In certain embodiments, the method achieves a rate of progression free survival in a population of subjects with HR-SMM that is greater than a rate of PFS achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.

[0048] In certain embodiments, the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM that is greater than an ORR achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.

[0049] In certain embodiments, the method achieves a percentage of overall survival (OS) in a population of subjects with HR-SMM that is greater than a percentage of OS achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.

[0050] In certain embodiments, the present disclosure is directed to a method of treating HR-SMM in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of daratumumab and a hyaluronidase.

[0051] In certain embodiments, the present disclosure is directed to a method of treating HR-SMM in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of daratumumab biosimilar and a hyaluronidase.

[0052] In certain embodiments, the present disclosure is directed to a method of treating HR-SMM in a subject in need thereof, comprising administering subcutaneously to the subject a therapeutically effective and safe amount of daratumumab and a hyaluronidase.

[0053] In certain embodiments, the present disclosure is directed to a method of treating HR-SMM in a subject in need thereof, comprising administering subcutaneously to the subject a therapeutically effective and safe amount of daratumumab biosimilar and a hyaluronidase.

[0054] In certain embodiments, the present disclosure is directed to a method of treating HR-SMM in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of daratumumab, or a daratumumab biosimilar, and a hyaluronidase, wherein the method provides an improvement in progression free survival (PFS), overall response rate (ORR), rate of partial response (PR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), progression-free survival on first-line treatment for multiple myeloma (PFS 2), or overall survival (OS) compared to a reference population.

[0055] In certain embodiments, the present disclosure is directed to a use of a pharmaceutical composition for the manufacture of a medicament for the treatment of HR-SMM in a subject in need thereof, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of an anti-CD38 antibody. In certain embodiments, the anti-CD38 antibody is daratumumab, or a daratumumab biosimilar.

[0056] In certain embodiments, the present disclosure is directed to a use of a pharmaceutical composition for the manufacture of a medicament for the treatment of HR-SMM in a subject in need thereof, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of daratumumab, or a daratumumab biosimilar.

[0057] In certain embodiments, the present disclosure is directed to a use of a pharmaceutical composition for the manufacture of a medicament for the treatment of HR-SMM in a subject in need thereof, wherein the pharmaceutical compositioncomprises a therapeutically safe and effective amount of daratumumab, or a daratumumab biosimilar, and a hyaluronidase.

[0058] In certain embodiments, the present disclosure is directed to a use of a pharmaceutical composition for the manufacture of a medicament for improving a clinical endpoint in a subject or population of subjects with HR-SMM, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of daratumumab, or a daratumumab biosimilar. In certain embodiments, the present disclosure is directed to a use of a pharmaceutical composition for the manufacture of a medicament for improving a clinical endpoint in a subject or population of subjects with HR-SMM, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of daratumumab, or a daratumumab biosimilar, and a hyaluronidase. In certain embodiments, the clinical endpoint is progression free survival (PFS), overall response rate (ORR), rate of partial response (PR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), progression-free survival on first-line treatment for multiple myeloma (PFS2), or overall survival (OS).BRIEF DESCRIPTION OF THE DRAWINGS

[0059] 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 drawings show exemplary embodiments of the methods or uses; however, the methods or uses are not limited to the specific embodiments disclosed. In the drawings:FIG. l is a schematic overview of the study described in Example 1. Key: AE=advcrsc events; CT=computcd tomography; MRI=magnetic resonance imaging; QW=oncc every week; Q2W=onc every 2 weeks; Q4W=oncc every 4 weeks; PET=positron emission tomography; SC subcutaneous; SLiM-CRAB=diagnostic criteria for symptomatic multiple myeloma; SMM=smoldcring multiple myeloma.; * or confirmed disease progression (whichever occurred first)FIG. 2 is a Kaplan-Meier Plot for Progression Free Survival (PFS) by IRC Assessment; intent-to-treat (ITT) Analysis Set. Key: HR=hazard ratio; NR=not reached; NR=not reached; PFS=progrcssion-frcc survival. Median follow-up was 65.2 months(Daratumumab 65.9 months; Active Monitoring 64.8 months). A total of 166 PFS events per IRC assessment (Daratumumab 67 ; Active Monitoring 99) were observed.FIG. 3 is a Forest Plot of subgroup analyses of PFS per computerized algorithm; ITT analysis. Key: BMPC=bonc marrow plasma clone; CI=confidcncc interval; ECOG=Eastcrn Cooperative Oncology Group; EU=European Union; EVT=cvcnt; FLC=frcc light chain; GFR=g lobular filtration rate; HR=hazard ratio; Ig=immunoglobulin; IS S international Staging System; NA=North America; NE=not estimable; SMM=smoldcring multiple myeloma;aHazard ratio and 95% CI was calculated using the Cox proportional hazards model with treatment as the sole explanatory. A hazard ratio <1 indicates an advantage for daratumumab SC.;bNormal: GFR (mL / min / 1.73m2) >90;cThe risk factors were: a. Serum M protein >30 g / L; b. IgA SMM; c. Immunoparesis with reduction of 2 uninvolved Ig isotypes (only IgA, IgM, and IgG were considered in determination for immunoparesis, IgD and IgE were not considered in this assessment); d. serum involved: uninvolved FLC ratio >8 and <100, or e. clonal BMPCs >50% to <60% with measurable disease.;dMayo 2018 risk criteria: Serum M protein >2 g / dL, I / U FLC ratio >20 and BMPC >20%. Participants with presence of 0 factors are considered as low risk, Participants with 1 factor are considered as intermediate risk and >2 factors are considered as high risk.;eYes: presence of del(17pl3), t(4; 14), or t(14; 16) at baseline; No: tested for these probes but did not have any abnormality. FIG. 3B is a Forest Plot of Sensitivity and Supplementary Analyses on Progression-free Survival; Intent-to-treat Analysis Set.FIG. 4 is a graph of Overall Response Rate divided according to stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR); ITT Analysis Set.FIG. 5 is a Kaplan-Meier Plot for Progression-free Survival on First-line Multiple Myeloma Treatment (PFS2); ITT Analysis SetFIG. 6 is a Kaplan-Meier Plot for Overall Survival; ITT Analysis SetFIG. 7 is a Kaplan-Meier Plot for the time to first line treatment of MM; ITT Analysis Set.FIG. 8A provides an overview of incidence rate of TEAEs; Safety Analysis Set. FIG. 8B is a graph of Serious Adverse Events of time (by yearly intervals); SafetyAnalysis Set. FIG. 8C is a graph of Grade 3 or 4 Adverse Events over time (by yearly intervals); Safety Analysis Set.FIG. 9 is a graph of the most common TEAEs (>= 10% in either arm); Safety Analysis Set.FIG. 10 is a graph of PFS in patients with high-risk SMM per the Mayo 2018 criteria.FIGs. 11A-C are graphs of patient-reported quality of life scores. FIG. 11A is a graph of EORTC QLQ-C30 global health status scores. FIG. 11B is a graph of EORTC QLQ-MY20 future perspective scores. FIG. 11C is a graph of EQ-5D-5L visual analog scale scores.FIG. 12 is a table showing change from baseline in key EORTC QLQ-C30 scores at Week 112.FIG. 13 is a Forest Plot of Subgroup Analysis on Overall Response Rate based on Computerized Algorithm; Intent-to-treat Analysis Set. Keys: CI = confidence interval; EU = European Union; ISS = International staging system; Overall response = sCR, CR, VGPR, or PR; US = United States, EVT = Event.DETAILED DESCRIPTION

[0060] The disclosed methods can be understood more readily by reference to the following detailed description. It is to be understood that the disclosed methods are not limited to the specific methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods. All patents, published patent applications, and publications cited herein are incorporated by reference as if set forth fully herein.

[0061] As used herein, the singular forms “a,” “an,” and “the” include the plural.

[0062] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0063] “About” when used in reference to numerical ranges, cutoffs, or specific values 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 ordetermined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of an 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.

[0064] “Antibodies” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific etc., dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity. “Full length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g. IgM). 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 can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), 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. Immunoglobulins can be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4. Antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa (K) and lambda (I), based on the amino acid sequences of their constant domains.

[0065] “Antigen binding fragment” or “antigen binding domain” refers to a portion of an immunoglobulin molecule that binds an antigen. Antigen binding fragments can be synthetic, enzymatically obtainable or genetically engineered polypeptides and include the VH, the VL, the VH and the VL, Fab, F(ab')2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, theHCDR1, the HCDR2 and / or the HCDR3 and the LCDR1, the LCDR2 and / or the LCDR3. VH and VL domains can be linked together via a synthetic linker to form various types of single chain antibody designs where the VH / VL domains can pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Int. Patent Publ. Nos. W01998 / 44001, WO1988 / 01649, WO1994 / 13804 and W01992 / 01047.

[0066] “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 clinically meaningful 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 extent 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 thebiosimilar 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 ensure 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.

[0067] ‘Cancer” refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth results in the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream. A “cancer” or “cancer tissue” can include a tumor.

[0068] “CD38” refers to human cluster of differentiation 38 protein, a glycoprotein expressed on immune cells, including plasma cells, natural killer cells and subpopulations of B and T cells.

[0069] ‘Clinical efficacy endpoint” or “clinical endpoint” refers to an outcome that represents a clinical benefit, such as progression-free survival (PFS), progression-free survival on first line of MM therapy (PFS2) time to disease progression (TTP), time to first treatment for MM, overall survival (OS), 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), or proportion of subjects achieving stringent complete response (sCR). Clinical endpoints can be determined by IMWG response criteria for MM, utilized for SMM (Table 4).

[0070] “Complementarity determining regions” (CDR) are antibody regions that bind an antigen. CDRs can be defined using various delineations such as Kabat (Wu et al. J Exp Med 132: 211-50, 1970) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. J Mol Biol 196: 901-17, 1987), IMGT (Lefranc et al. Dev Comp Immunol 27: 55-77, 2003) and AbM (Martin and Thornton J Bmol Biol 263: 800-15, 1996). The correspondence between the various delineations and variable region numbering are described (see e.g. Lefranc et al. Dev Comp Immunol 27: 55-77, 2003; Honegger and Pluckthun, J Mol Biol 309:657-70, 2001; International ImMunoGeneTics (IMGT) database; Web resources, http: / / www_imgt_org). Available programs such asabYsis by UCL Business PLC can be used to delineate CD Rs. The term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by any of the methods described supra, Kabat, Chothia, IMGT or AbM, unless otherwise explicitly stated in the specification. Preferably, the term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by the method of Kabat.

[0071] “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.”

[0072] “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.

[0073] ‘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 FASPRO®, and DARZALEX® SC. The package inserts and labels for DARZALEX®, DARZALEX FASPRO®, and DARZALEX® SC can be found at fda.gov or ema.europa.eu and are incorporated by reference herein (DARZALEX FASPRO® ((daratumumab and hyaluronidase fihj) injection [packageinsert]. Horsham, PA: Janssen Biotech, Inc; 2023; DARZALEX® (daratumumab) injection [package insert]. Horsham, PA: Janssen Biotech, Inc; 2023).

[0074] “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.

[0075] ‘Dose” refers to the amount or quantity of the therapeutic or the drug to be taken each time.

[0076] ‘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.

[0077] ‘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.

[0078] ‘Frontline” or “first line” therapy refers to the first treatment of a disease, such as smoldering multiple myeloma, administered to the subject.

[0079] “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. This enzyme is often used to increase the dispersion and absorption of other co- administered drugs into tissue (e.g., subcutaneous injections, subcutaneous infusion such as hypodermoclysis). An exemplary hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20). rHuPH20 is marketed under the trade name Hylenex®. 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.

[0080] “Identity” refers to a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by aligning and comparing the sequences. “Percent (%) sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN (DNAStar, Inc.) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0081] “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.

[0082] “Isolated” refers to a homogenous population of molecules (such as synthetic polynucleotides or a protein such as an antibody) which have been substantially separated and / or purified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been subjected to at least one purification or isolation step. “Isolated antibody” refers to an antibody that is substantially free of other cellular material and / or chemicals and encompasses antibodies that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.

[0083] “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation. Monoclonal antibodies typically bind one antigenic epitope. Abispecific monoclonal antibody binds two distinct antigenic epitopes. Monoclonal antibodies can have heterogeneous glycosylation within the antibody population.Monoclonal antibody can be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent.

[0084] “Mutation” refers to an engineered or naturally occurring alteration in a polypeptide or polynucleotide sequence when compared to a reference sequence. The alteration can be a substitution, insertion or deletion of one or more amino acids or polynucleotides.

[0085] ‘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 as determined by IMWG response criteria for MM, utilized for SMM (Table 4). In addition, the specific response must have been achieved prior to the start of subsequent therapies.

[0086] “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.

[0087] ‘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, OS is defined as the time from randomization of study population to the date of the patient’s death.

[0088] “Pharmaceutical composition” refers to composition that comprises an active ingredient and a pharmaceutically acceptable carrier.

[0089] “Pharmaceutically acceptable carrier” or “excipient” refers to an ingredient in a pharmaceutical composition, other than the active ingredient, which is nontoxic to a subject.

[0090] “Potency” 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 CD 38 and one or more therapeutic agents) refers to the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result.

[0091] “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 the purpose of the clinical trial described in the example, PFS is defined as the time from the date of randomization to the date of documented disease progression to active multiple myeloma (per IMWG diagnostic criteria) or the date of death, whichever occurred first.

[0092] “Progression-free survival 2” (PFS2) refers to the time from the randomization to time of subsequent progression on first-line of therapy after disease progression on study treatment or death, whichever comes first. “Progression-free survival on first-line treatment” refers to the time from the date of randomization to the date of documented PD on the first-line treatment for multiple myeloma or death, whichever occurred first.

[0093] “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 determined by IMWG response criteria for MM, utilized for SMM (Table 4).

[0094] ‘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.

[0095] ‘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.

[0096] ‘Recombinant” refers to DNA, antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means when segments from different sources are joined to produce recombinant DNA, antibodies or proteins.

[0097] “Refractory” multiple myeloma refers to disease that is non-responsive to therapy or stops responding to therapy.

[0098] ‘Reference subject” or “reference population of subjects” refers to a subject or population of subjects having smoldering multiple myeloma who are undergoing active monitoring. The reference subject or reference population of subjects are substantially the same as the subject or population of subjects that are treated with daratumumab.Exemplary reference subjects or reference population of subjects are those described in Example 1 herein. 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.

[0099] “Relapsed” multiple myeloma refers to disease that responded to prior treatment but then progressed and requires new therapy.

[0100] “Subcutaneous” or “subcutaneously” refers to administration of a therapeutic under the skin, typically by injection. Administration sites may be side or back of upper arm, front of thigh or abdomen.

[0101] “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.

[0102] “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 or other health care authorities for their indicated use.

[0103] “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.

[0104] “Subject” as used herein refers to a human subject. Except when noted, the terms “patient” or “subject” are used interchangeably.

[0105] “Smoldering multiple myeloma” or “SMM” refers to an asymptomatic clonal plasma cell disorder that is a precursor to active multiple myeloma (MM). Subjects with “high-risk SMM” have an approximate 50% risk of progression to MM within the first 2 years. A patient with high-risk smoldering multiple myeloma generally meets either the Mayo 2018 Criteria (“20-2-20” criteria) or the IMWG Scoring System for SMM (see, e.g., Lakshman A, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J 2018;8:59; and Mateos MV, et al. IMWG risk stratification model for smoldering multiple myeloma. Blood Cancer J 2020; 10: 102, which are incorporated by reference herein). There is no approved treatment for subjects with SMM. Outside of clinical studies, clinical management involves monitoring subjects for the development of symptomatic disease.

[0106] “Therapeutically effective amount” refers to an amount effective, at doses and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount can vary depending on 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 that include, for example, improved wellbeing of the patient.

[0107] ‘Treat” or “treatment” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder. 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, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if a subject was not receiving treatment. Those in need of treatment includethose already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0108] “Treatment dose” refers to a dose of the active agent that is administered to a subject to treat a disease. A treatment dose may be administered at a regular dosing interval on a repetitive basis (e.g., weekly, biweekly, monthly).

[0109] ‘Tumor cell” or a “cancer cell” refers to a cancerous, pre-cancerous or transformed cell, either in vivo, ex vivo, or in tissue culture, that has spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. Although transformation can arise from infection with a transforming virus and incorporation of new genomic nucleic acid, uptake of exogenous nucleic acid or it can also arise spontaneously or following exposure to a carcinogen, thereby mutating an endogenous gene. Transformation / cancer is exemplified by morphological changes, immortalization of cells, aberrant growth control, foci formation, proliferation, malignancy, modulation of tumor specific marker levels, invasiveness, tumor growth in suitable animal hosts such as nude mice, and the like, in vitro, in vivo, and ex vivo.

[0110] The numbering of amino acid residues in the antibody constant region throughout the specification is according to the EU index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991), unless otherwise explicitly stated. Antibody constant chain numbering can be found, for example at ImMunoGeneTics website, at IMGT Web resources at IMGT Scientific charts.

[0111] Conventional one and three-letter amino acid codes are used herein as shown in Table 1.Table 1.Anti-CD38 antibodies for the treatment of High-Risk Smoldering Multiple Myeloma (HR-SMM)

[0112] Although the last decade has seen the development of effective target therapies for participants with multiple myeloma (MM), the clinical utility of targeted therapies has been hampered by the development of drug resistance, clonal evolution and disease progression making the quest for cure ever more elusive for MM. Even with the best combinations of agents that are currently available; cure is not achieved for most participants with MM. Smoldering multiple myeloma (SMM) is associated with an overall risk of progression to multiple myeloma of 10% per year for the first 5 years after diagnosis. Risk-stratification models have been implemented to identify patients at the highest risk of progression to active multiple myeloma. Approximately 40% of patients with SMM were classified as high risk across real-world populations regardless of the risk-stratification model used.

[0113] The previous approach for patients with SMM was to observe without treatment until criteria for active multiple myeloma was met. This approach is termed ‘Watch and Wait’ and entails hematology check-ups, typically several times a year. Treatment of the precursor states of MM may result in delay and / or prevention of progression to active MM. Without being bound by theory, it is believed that early intervention in high-risk SMM provides an opportunity to delay or prevent progression by aggressively targeting the tumor cells before clonal heterogeneity occurs and before immune dysfunction and microenvironmental dysregulation occurs.

[0114] The goal of therapy in high-risk SMM should be to deliver as highly effective therapy as possible to ultimately prevent or significantly delay the progression of MM without compromising safety. The present inventors have developed novel methods for treating high-risk SMM using anti-CD38 antibodies.

[0115] Daratumumab is a human IgGlK mAh that binds with high affinity to a unique epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy that attacks tumor cells that overexpress CD38, a transmembrane glycoprotein, in a variety of hematological malignancies including MM. Daratumumab induces lysis of CD38- expressing tumor cells, including MM tumor cells that were freshly isolated from patients, by a wide spectrum of mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibodydependent cellular phagocytosis, through activation of complement proteins, natural killer (NK) cells, and macrophages, respectively as described in de Weers et al, J Immunol. (2011); 186: 1840-1848 and Overdijk et al, Monoclonal Antibodies.(2015);7:311-321.

[0116] Daratumumab (marketed as DARZALEX®, DARZALEX FASPRO®, or DARZALEX® SC) is approved for the treatment of patients with newly diagnosed and relapsed or refractory multiple myeloma. Compelling clinical activity has been demonstrated with daratumumab treatment in subjects with pretreated MM, as monotherapy and in combination with bortezomib / dexamethasone, lenalidomide / dexamethasone or pomalidomide / dexamethasone. Importantly, daratumumab is well-tolerated as demonstrated by a low rate of treatment discontinuation across clinical studies. Daratumumab was seen in MM treatment to have had a favorable safety profile. It is now shown herein that daratumumab is safe and effective for use in treating patients with high-risk SMM.Antibodies

[0117] Any suitable Anti-CD38 antibody known to those skilled in the art in view of the present disclosure can be used.

[0118] In some embodiments, the anti-CD38 antibody comprises any one of the CD38 binding domains described in W02017 / 079150, the entire content of which is incorporated herein by reference. In some embodiments, the anti-CD38 antibody comprises any one of the anti-CD38 antibodies described in W02017 / 079150.

[0119] In some embodiments, the antibody is an IgGl, an IgG2, an IgG3 or an IgG4 isotype. In preferred embodiments, the antibody is an IgGl isotype.

[0120] 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.

[0121] The antibody can be of any allotype. It is expected that allotype has no influence on properties of the bispecific antibodies, such as binding or Fc-mediated effector functions. Immunogenicity of therapeutic antibodies is associated with increased risk of infusion reactions and decreased duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which therapeutic antibodies induce an immune response in the host can be determined in part by the allotype of the antibody (Stickler et al., (2011) Genes and Immunity 12:213-21). Antibody allotype is related to amino acid sequence variations at specific locations in the constant region sequences of the antibody.

[0122] Table 2 provides sequences of an exemplary embodiment of an anti-CD38 antibody, according to the Kabat numbering system.Table 2. Exemplary sequences of a CD38 binding arm

[0123] In preferred embodiments, the anti-CD38 antibody is daratumumab, which has the sequences described in Table 2. In a specific embodiment, the anti-CD38 antibody is daratumumab, which has the amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11.

[0124] According to particular embodiments, the anti-CD38 antibody has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the amino acid sequence of daratumumab. In particular embodiments, the anti-CD38 antibody is a daratumumab biosimilar that has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the amino acid sequence of daratumumab.Pharmaceutical Compositions

[0125] In some embodiments, the anti-CD38 antibody is administered in a pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises about 1,800 mg of the anti-CD38 antibody. In some embodiments, the anti- CD38 antibody is administered in a pharmaceutical composition comprising the anti- CD38 antibody and a hyaluronidase. In certain embodiments, the pharmaceutical composition comprises about 1,800 mg of the anti-CD38 antibody and about 30,000 U hyaluronidase. In further embodiments, the pharmaceutical composition comprises about 120 mg / mL of the anti-CD38 antibody. In further embodiments, the pharmaceutical composition comprises about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL hyaluronidase. In certain embodiments, the pharmaceutical composition comprises about 1,800 mg of the anti-CD38 antibody. In certain embodiments, the pharmaceutical composition comprises about 1,800 mg of the anti-CD38 antibody. In further embodiments, the pharmaceutical composition comprises about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL rHuPH20.

[0126] In some embodiments, the pharmaceutical composition comprises the anti-CD38 antibody daratumumab. In some embodiments, the pharmaceutical composition comprises a daratumumab biosimilar. In some embodiments, the daratumumab, or daratumumab biosimilar, is administered in a pharmaceutical composition comprising daratumumab, or daratumumab biosimilar, and a hyaluronidase. In certain embodiments, the pharmaceutical composition comprises about 1,800 mg daratumumab and about 30,000 U hyaluronidase. In certain embodiments, the pharmaceutical composition comprises about 1,800 mg of a daratumumab biosimilar and about 30,000 U hyaluronidase. In further embodiments, the pharmaceutical composition comprises about 120 mg / mL of daratumumab and about 2,000 U / mL hyaluronidase. In further embodiments, the pharmaceutical composition comprises about 120 mg / mL of a daratumumab biosimilar and about 2,000 U / mL hyaluronidase. In certain embodiments, the pharmaceutical composition comprises about 1,800 mg daratumumab and about 30,000 U rHuPH20. In certain embodiments, the pharmaceutical composition comprises about 1,800 mg of a daratumumab biosimilar and about 30,000 U rHuPH20 recombinant human hyaluronidase. In further embodiments, the pharmaceutical composition comprises about 120 mg / mL daratumumab and about 2,000 U / mL rHuPH20. In further embodiments, the pharmaceutical composition comprises about 120 mg / mL of a daratumumab biosimilar and about 2,000 U / mL rHuPH20 recombinant human hyaluronidase.

[0127] In a specific embodiment, the pharmaceutical composition comprises daratumumab, or a daratumumab biosimilar, and a hyaluronidase. A number of suitable hyaluronidase enzymes in accordance with the present disclosure are known. The preferred enzyme is a human hyaluronidase enzyme, such as a soluble human PH20 hyaluronidase, preferably the recombinant human hyaluronidase enzyme product known as rHuPH20. 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, solublehyaluronidases include those whose sequence are set forth in any of SEQ ID NOs: 12-16. Soluble PH20 hyaluronidase, when expressed in a cell, include a signal sequence for trafficking in the cell. In some embodiments, the amino acid sequence of sequence of a soluble PH20 hyaluronidase SEQ ID NO: 13, 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: 14. In some embodiments, the amino acid sequence of a soluble PH20 hyaluronidase comprises SEQ ID NO: 15. In some embodiments, the amino acid sequence a soluble PH20 hyaluronidase rHuPH20 comprises SEQ ID NO: 16. In some embodiments, the amino acid sequence of a soluble PH20 hyaluronidase comprises SEQ ID NO: 12. 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: 12 to SEQ ID NO: 16 in various abundance. The average molecular weight is 61 kDa.

[0128] Recombinant human hyaluronidase 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 recombinant human hyaluronidase, includes a mixture of species that can include any one or more of the polypeptides of SEQ ID NO: 12-16, and some shorter polypeptides, in various abundances. Typically, recombinant human hyaluronidase is produced in cells, such as CHO cells, (for example DG44 CHO cells) that facilitate correct N-glycosylation to retain activity.

[0129] 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 the anti- CD38 antibody; about 30,000 U of recombinant human hyaluronidase; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine. In a specific embodiment, the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of daratumumab, or a daratumumab biosimilar; about 30,000 U of recombinant human hyaluronidase; 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 the anti-CD38 antibody; about 2,000 U / mL ofrecombinant human hyaluronidase; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.

[0130] In some embodiments, the pharmaceutical composition comprises one or more excipients.

[0131] In some embodiments, the one or more excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0132] In some embodiments, the pharmaceutical composition comprises a) between about 5 mM and about 15 mM histidine; between about 100 mM and about 300 mM sorbitol; c) between about 0.01% w / v and about 0.04 % w / v PS-20; and d) between about 1 mg / mL and about 2 mg / mL methionine, at a pH of about 5.5-5.6.

[0133] In some embodiments, the pharmaceutical composition comprises about 10 mM histidine.

[0134] In some embodiments, the pharmaceutical composition comprises about 300 mM sorbitol.

[0135] In some embodiments, the pharmaceutical composition comprises about 0.04% (w / v) PS -20.

[0136] In some embodiments, the pharmaceutical composition comprises about 1 mg / mL methionine.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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).

[0142] 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.

[0143] 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.

[0144] 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, phenyl-substituted 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.Patient populations with high-risk smoldering multiple myeloma

[0145] The inventors have developed novel methods diagnosing and characterizing HR- SMM in patients. SMM is a heterogeneous disease with varying risks of progression and efforts have been made to better define the characteristics of patients with SMM. Examination of this patient population led to the identification of risk factors associated with a high risk of progression to active myeloma. For this disclosure, HR-SMM was determined based on a novel compilation of risk factors.

[0146] In certain embodiments; diagnosis of HR-SMM is based on the demonstration of clonal bone marrow plasma cells (BMPCs) >10% and at least one risk factor including Serum M protein >30 g / L, IgA SMM, immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes, serum involved: uninvolved free light chain ratio >8 and <100, and / or clonal BMPCs >50% to <60% with measurable disease. Patients with HR- SMM generally have an annual risk of progression of 10% for the first 5 years. As such, HR-SMM is thought to comprise a mixture of high-risk patients, who may benefit from early therapeutic intervention before irreversible organ damage and symptoms appear. These high-risk SMM patients are defined as having a 50% progression rate within 2 years. The rationale is that early therapeutic interception of disease progression in these high-risk individuals will prevent / delay end-organ damage and associated morbidities. In addition, early intervention before clonal evolution with secondary acquisition of mutations along with immune-suppressive deregulation of the microenvironment may lead to a significant improvement in disease response, progression-free survival, and overall survival.

[0147] It is recognized in the art that a patient with high-risk smoldering multiple myeloma generally meets either the Mayo 2018 Criteria (“20-2-20” criteria) or the IMWG Scoring System for SMM (see, e.g., Lakshman A, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J 2018;8:59; and Mateos MV, et al. IMWG risk stratification model for smoldering multiple myeloma. Blood Cancer J 2020; 10: 102, which are incorporated by reference herein). Thus, a patient with high-risk smoldering multiple myeloma generally meets the following diagnostic criteria as shown in Table 3:TABLE 3 - HR-SMM Diagnostic CriteriaBMPC% bone marrow plasma cell percentage, IMWG International Myeloma Working Group,FLCr serum free light chain ratio, SMM smoldering multiple myeloma.X: component required; +: at least 1,2,3 component(s) required; component not part of risk criteria.For the Mayo Clinic criteria, low-risk patients had no components; for IMWG criteria, low-risk patients had 1 or no components; and for the AQUILA trial criteria, low-risk patients did not satisfy the criteria. For the Mayo Clinic criteria, intermediate risk patients had 1 of the + components, and for the IMWG 2020 criteria, intermediate risk patients had 2 of the + components.

[0148] Embodiments provide methods of treating high-risk smoldering multiple myeloma (HR-SMM) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-CD38 antibody (e.g., daratumumab or a daratumumab biosimilar). In certain embodiments, the method comprises subcutaneously administering to the subject a therapeutically effective amount of an anti- CD38 antibody. In a specific embodiment, the method comprises subcutaneously administering to the subject a therapeutically effective amount of daratumumab, or a daratumumab biosimilar. In preferred embodiments, the subject has not received prior SMM directed therapy. In preferred embodiments, the anti-CD38 antibody (e.g., daratumumab or a daratumumab biosimilar) is administered as a monotherapy (i.e., without another concurrent SMM directed therapy).

[0149] In certain embodiments, there are provided methods of preventing or inhibiting development of HR-SMM into active multiple myeloma (MM) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-CD38 antibody (e.g., daratumumab or a daratumumab biosimilar). In certain embodiments, there are provided methods of improving progression-free survival (PFS) in a subject diagnosed with HR-SMM, comprising administering to the subject a therapeutically effective amount of an anti-CD38 antibody (e.g., daratumumab or a daratumumab biosimilar).Dosing regimens for the treatment of HR-SMM

[0150] The inventors have developed novel dosing regimens for the treatment of HR- SMM that achieve meaningful and statistically significant clinical responses.

[0151] Unless otherwise specified herein, an anti-CD38 antibody, such as daratumumab, or a daratumumab biosimilar, is administered on a dosing schedule based on sequential 28-day cycles, for example, Cycle 1 starts on Day 1 of Cycle 1 and ends on Day 28 of Cycle 1, and then Day 1 of Cycle 2 starts the day after Day 28 of Cycle 1 and ends on Day 28 of Cycle 2, and then Day 1 of Cycle 3 starts the day after Day 28 of Cycle 2 and ends on Day 28 of Cycle 3, and so on. As used herein with respect to treatment cycles, “Cl” refers to Cycle 1, “C2” refers to Cycle 2, “C3” refers to Cycle 3, and so on. Multiple cycles may also be described, e.g., “C3-6” refers to Cycles 3-6 (Cycles 3, 4, 5 and 6). A cycle number with a “+” symbol refers to that cycle and all subsequent cycles,e.g., “C3+” refers to from Cycle 3 and all subsequent cycles (i.e., C3, C4, C5, C6, C7, and so on).

[0152] As used herein “Q4W” means once every four weeks, “Q2W” (also referred to as “bi-weekly” or “biweekly”) means once every two weeks, and “QW” (also referred to as “weekly”) means once weekly. Q4W is sometimes referred to herein as “monthly” but technically refers to once every 4 weeks or once every 28 days (e.g., in 28-day cycles, a first treatment dose occurs on Day 1 of Cycle 1, a second treatment dose occurs on Day 1 of Cycle 2, etc.). Administration of a treatment dose once weekly (QW) is also referred to herein as a weekly dosing schedule; for example, a 28-day treatment cycle may have a weekly dosing schedule that comprises four doses one week apart from each other (e.g., on Days 1, 8, 15 and 22), or three doses one week apart from each other (e.g., on Days 8, 15 and 22), or two doses one week apart from each other (e.g., on Days 8 and 15). Administration of a treatment dose once every two weeks (Q2W) is also referred to herein as a bi-weekly dosing schedule. Administration of a treatment dose once every four weeks (Q4W) is also referred to herein as a monthly dosing schedule. Dosing regimens may be described herein in terms of the dose amount and frequency; for example, “Cl: 1800 mg QW” refers to administration of 1800 mg once per week in Cycle 1 of a therapeutically effective regimen, “C3-6: 1800 mg Q2W” refers to administration of 1800 mg once every two weeks from Cycle 3 through Cycle 6, “C7+: 1800 mg Q4W” refers to administration of 1800 mg once every four weeks starting in Cycle 7, etc.

[0153] Additional abbreviations used herein include the following: CR, complete response; PR, partial response; Q2W, once every 2 weeks; Q4W, once every 4 weeks; QW, once weekly.

[0154] According to embodiments, methods of treating HR-SMM are effective in eliciting a clinical response in a subject as determined by IMWG response criteria for MM, utilized for SMM (Table 4)(see, e.g., Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467- 1473.; Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4691-4695.; Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimalresidual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-46., which are incorporated by reference herein). According to particular embodiments, the methods of treatment are effective in eliciting a partial response (PR), a very good partial response (VGPR), a complete response (CR) or a stringent complete response (sCR), as determined by IMWG response criteria for MM, utilized for SMM (Table 4). As used herein, overall response rate (ORR) refers to the percentage of patients in a population that achieve a partial response (PR) or better, i.e., a partial response, very good partial response, complete response or stringent complete response. Unless indicated otherwise herein, PR, VGPR, CR and sCR are as defined by IMWG response criteria for MM, utilized for SMM (Table 4).TABLE 4IM WG= In ternational Myeloma Working Group; FLC=free light chain; MM=multiple myeloma; PC=plasma cell.All response categories (CR, sCR, VGPR, PR) require 2 consecutive assessments made at any time before the institution of any new therapy and no known evidence of progressive or new bone lesions if radiographic studies were performed. VGPR and CR categories require serum and urine studies regardless of whether disease at baseline was measurable on serum, urine, both, or neither.Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be confirmed. a Subjects will continue in the last confirmed response category until there is confirmation of progression or improvement to a higher response status; subjects cannot move to a lower response category. b Presence / absence of clonal cells is based upon the kappa / lambda ratio. An abnormal kappa / lambda ratio by immunohistochemistry or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is kappa / lambda of >4:1 or <1:2. c Clarifications to IMWG criteria for coding CR and VGPR in subjects in whom the only measurable disease is by serum FLC levels: CR in such subjects indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR in such subjects requires a >90% decrease in the difference between involved and uninvolved FLC levels.

[0155] IMWG response criteria are also described, for example, in Durie et al., Kumar et al. and Rajkumar et al., which are incorporated by reference herein: Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9): 1467-1473; Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-346; Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical Trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011 ; 117(18):4691-4695.

[0156] According to certain embodiments, one or more predose medications are administered to the subject prior to administration of a dose of the anti-CD38 antibody (e.g., daratumumab or a daratumumab biosimilar). According to certain embodiments, one or more predose medications are administered to the subject 1 to 3 hours prior to each daratumumab, or daratumumab biosimilar, administration. According to certain embodiments, one or more pretreatment medications are selected from the group consisting of antipyretic, antihistamine, corticosteroid, or any combination thereof. According to certain embodiments, one or more pretreatment medications are selected from the group consisting of methylprednisolone, diphenhydramine, acetaminophen, and any combination thereof. According to an exemplary embodiment, pretreatment medications are administered to the subject as shown in Table 5.TABLE 5: Predose medications

[0157] In certain embodiments, the methods achieve a clinical response in the subject that is a partial response (PR), a very good partial response (VGPR), a complete response (CR) or a stringent complete response (sCR), as defined by IMWG response criteria for MM, utilized for SMM (Table 4).

[0158] In certain embodiments, after the subject has received at least 39 28-day cycles of treatment with the anti-CD38 antibody (e.g., daratumumab or a daratumumab biosimilar), the subject’s HR-SMM does not progress. In certain embodiments, administration of the anti-CD38 antibody to the subject for a maximum of 39 28-day treatment cycles prevents the subject from developing multiple myeloma.

[0159] In certain embodiments, administration of the anti-CD38 antibody (e.g., daratumumab or a daratumumab biosimilar) to the subject for a maximum of 39 28-day treatment cycles prevents the subject from developing multiple myeloma.

[0160] In certain embodiments, the method achieves a rate of progression free survival in a population of subjects with HR-SMM that is greater than a rate PFS achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody (e.g., daratumumab or a daratumumab biosimilar).

[0161] In certain embodiments, the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM that is greater than an ORR achieved in a reference population of subjects with HR-SMM, said reference population having notbeen administered the anti-CD38 antibody (e.g., daratumumab or a daratumumab biosimilar).

[0162] In certain embodiments, the method achieves a percentage of overall survival (OS) in a population of subjects with HR-SMM that is greater than a percentage of OS achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody (e.g., daratumumab or a daratumumab biosimilar).

[0163] For each of the methods of treatment described herein, it will be understood that the methods of treatment may also be framed as methods of manufacturing a medicament for the treatment of the described indications or as a pharmaceutical composition in combination for use in the treatment of the described indications.EXEMPLARY EMBODIMENTS

[0164] Provided below are enumerated embodiments. These embodiments are illustrative only and do not limit the scope of the present disclosure or of the claims attached hereto.Embodiments Section 11. A method of treating high-risk smoldering multiple myeloma (HR-SMM) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-CD38 antibody.2. The method of embodiment 1, wherein the method provides an improvement in progression free survival (PFS), overall response rate (ORR), rate of partial response (PR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), progression-free survival on first-line treatment for multiple myeloma (PFS 2), or overall survival (OS).3. The method of embodiment 1 or 2, wherein the anti-CD38 antibody comprises a CD38 binding domain 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: 6.4. The method of any of embodiments 1-3, wherein the CD38 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 8.5. The method of any of embodiments 1-4, wherein the anti-CD38 antibody is an IgGl, an IgG2, an IgG3 or an IgG4 isotype.6. The method of any of embodiments 1-5, wherein the anti-CD38 antibody is an IgGl isotype.7. The method of any of embodiments 1-6, wherein the anti-CD38 antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10.8. The method of any of embodiments 1-7, wherein the anti-CD38 antibody is daratumumab or a daratumumab biosimilar.9. The method of any of embodiments 1-8, wherein the anti-CD38 antibody is administered as a monotherapy.10. The method of any of embodiments 1-9, comprising subcutaneously administering the anti-CD38 antibody.11. The method of any of embodiments 1-10, wherein the anti-CD38 antibody is administered in a pharmaceutical composition comprising about 1,800 mg of the anti- CD38 antibody.12. The method of embodiment 11, wherein the anti-CD38 antibody is administered in a pharmaceutical composition comprising the anti-CD38 antibody and a hyaluronidase.13. The method of embodiment 12, wherein the hyaluronidase comprises a recombinant human hyaluronidase.14. The method of any of embodiments 1-13, wherein the recombinant human hyaluronidase has an amino acid sequence of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 16.15. The method of any of embodiments 1-14, wherein the pharmaceutical composition comprises a mixture of recombinant human hyaluronidase with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.16. The method of any of embodiments 1-15, wherein the pharmaceutical composition comprises about 1,800 mg of the anti-CD38 antibody and about 30,000 U of hyaluronidase.17. The method of embodiment 15, wherein the pharmaceutical composition comprises about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of hyaluronidase.18. The method of any of embodiments 1-17, wherein the pharmaceutical composition comprises one or more excipients.19. The method of embodiment 18, wherein at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.20. The method of any of embodiments 1-19, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of the anti-CD38 antibody; about 30,000 U of hyaluronidase; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.21. The method of embodiment 20, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL of the anti-CD38 antibody; about 2,000 U / mL of hyaluronidase; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.22. The method of any of embodiments 1-21, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of daratumumab, or a daratumumab biosimilar; about 30,000 U of recombinant human hyaluronidase; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.23. The method of any of embodiments 1-22, wherein the anti-CD38 antibody is administered at a dose of about 1,800 mg once a week, about 1,800 mg once in two weeks, or about 1,800 mg once in four weeks.24. The method of any of embodiments 1-23, comprising treating the subject according to a therapeutically effective regimen that comprises sequential 28 -day treatment cycles.25. The method of any of embodiments 1-24, comprising administering the anti- CD38 antibody once a week for two treatment cycles.26. The method of any of embodiments 1-25, comprising administering the anti- CD38 antibody once every two weeks for four treatment cycles.27. The method of any of embodiments 1-26, comprising administering the anti- CD38 antibody once every four weeks until 39 cycles or up to 36 months, or confirmed disease progression, whichever occurs first.28. The method of any of embodiments 1-27, comprising administering the anti- CD38 antibody according to a regimen comprising 28-day cycles wherein the regimen comprises: in Cycles 1 to 2, administering the anti-CD38 antibody once a week, in Cycles 3 to 6, administering the anti-CD38 antibody once every two weeks, and then administering the anti-CD38 antibody once every 4 weeks.29. The method of any of embodiments 1-28, wherein the subject has not received prior SMM directed therapy.30. The method of any of embodiments 1-29, wherein the subject does not have active multiple myeloma.31. The method of embodiment 30, wherein the method achieves a clinical response in the subject that is a progression free survival (PFS) as defined by IRC assessment.32. The method of embodiment 31, wherein the method achieves a clinical response in the subject that is a partial response (PR), a very good partial response (VGPR), a complete response (CR) or a stringent complete response (sCR), as defined by IMWG response criteria for MM, utilized for SMM (Table 4).33. The method of any of claims 1-32, wherein the method achieves PFS in a population of subjects with HR-SMM of 60% or higher.34. The method of any of embodiments 1-33, wherein the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM of 60% or higher.35. The method of any of embodiments 1-34, wherein the method achieves a PFS2 rate in a population of subjects with HR-SMM of 85% or higher.36. The method of any of embodiments 1-35, wherein the method achieves an OS rate in a population of subjects with HR-SMM of 90% or higher.37. The method of any of embodiments 1-36, wherein, after the subject has received at least 38 28-day cycles of treatment with the anti-CD38 antibody, the subject’s HR- SMM does not progress.38. The method of any of embodiments 1-37, wherein administration of the anti- CD38 antibody to the subject for a maximum of 39 28-day treatment cycles prevents the subject from developing multiple myeloma.39. The method of any of embodiments 1-38, wherein the method prevents the subject from developing MM.40. The method of any of embodiments 1-39, wherein the method achieves a rate of progression free survival in a population of subjects with HR-SMM that is greater than a rate PFS achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.41. The method of any of embodiments 1-40, wherein, the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM that is greater than an ORR achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.42. The method of any of embodiments 1-41, wherein the method achieves a percentage of overall survival (OS) in a population of subjects with HR-SMM that is greater than a percentage of OS achieved in a reference population of subjects with HR- SMM, said reference population having not been administered the anti-CD38 antibody.43. A method of treating HR-SMM in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of daratumumab.44. A method of treating HR-SMM in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a daratumumab biosimilar.45. A method of treating HR-SMM in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of daratumumab, or a daratumumab biosimilar, and a hyaluronidase.46. A method of treating HR-SMM in a subject in need thereof, comprising administering subcutaneously to the subject a therapeutically effective and safe amount of daratumumab, or a daratumumab biosimilar.47. A method of treating HR-SMM in a subject in need thereof, comprising administering subcutaneously to the subject a therapeutically effective and safe amount of daratumumab, or a daratumumab biosimilar, and a hyaluronidase.48. A method of treating HR-SMM in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of daratumumab, or a daratumumab biosimilar, wherein the method provides an improvement in progression free survival (PFS), overall response rate (ORR), rate of partial response (PR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), progression-free survival on first-line treatment for multiple myeloma (PFS 2), or overall survival (OS) compared to a reference population.49. A method of treating HR-SMM in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of daratumumab, or a daratumumab biosimilar, and a hyaluronidase, wherein the method provides an improvement in progression free survival (PFS), overall response rate (ORR), rate of partial response (PR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), progression-free survival on first-line treatment for multiple myeloma (PFS2), or overall survival (OS) compared to a reference population.50. A use of a pharmaceutical composition for the treatment of HR-SMM in a subject in need thereof, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of an anti-CD38 antibody.51. A use of a pharmaceutical composition for the treatment of HR-SMM in a subject in need thereof, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of daratumumab, or a daratumumab biosimilar.52. A use of a pharmaceutical composition for the treatment of HR-SMM in a subject in need thereof, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of daratumumab, or a daratumumab biosimilar, and a hyaluronidase.53. A use of a pharmaceutical composition for the manufacture of a medicament for the treatment of HR-SMM in a subject in need thereof, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of an anti-CD38 antibody.54. A use of a pharmaceutical composition for the manufacture of a medicament for the treatment of HR-SMM in a subject in need thereof, wherein the pharmaceuticalcomposition comprises a therapeutically safe and effective amount of daratumumab, or a daratumumab biosimilar.55. A use of a pharmaceutical composition for the treatment of HR-SMM in a subject in need thereof, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of daratumumab, or a daratumumab biosimilar, and a hyaluronidase.56. A use of a pharmaceutical composition for the manufacture of a medicament for the treatment of HR-SMM in a subject in need thereof, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of daratumumab, or a daratumumab biosimilar, and a hyaluronidase.57. A use of a pharmaceutical composition for improving a clinical endpoint in a subject or population of subjects with HR-SMM, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of an anti-CD38 antibody.58. A use of a pharmaceutical composition for improving a clinical endpoint in a subject or population of subjects with HR-SMM, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of daratumumab, or a daratumumab biosimilar.59. A use of a pharmaceutical composition for improving a clinical endpoint in a subject or population of subjects with HR-SMM, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of daratumumab, or a daratumumab biosimilar, and a hyaluronidase.60. A use of a pharmaceutical composition for the manufacture of a medicament for improving a clinical endpoint in a subject or population of subjects with HR-SMM, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of an anti-CD38 antibody.61. A use of a pharmaceutical composition for the manufacture of a medicament for improving a clinical endpoint in a subject or population of subjects with HR-SMM, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of daratumumab, or a daratumumab biosimilar.62. A use of a pharmaceutical composition for the manufacture of a medicament for improving a clinical endpoint in a subject or population of subjects with HR-SMM,wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of daratumumab, , or a daratumumab biosimilar, and a hyaluronidase.63. The use of any of embodiments 57-62, wherein clinical endpoint is progression free survival (PFS), overall response rate (ORR), rate of partial response (PR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), progression-free survival on first-line treatment for multiple myeloma (PFS 2), or overall survival (OS).Embodiments Section 21. Use of a pharmaceutical composition for the manufacture of a medicament for treating high-risk smoldering multiple myeloma (HR-SMM) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti- CD38 antibody.2. The use of embodiment 1 , wherein the use provides an improvement in progression free survival (PFS), overall response rate (ORR), rate of partial response (PR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), progression-free survival on first-line treatment for multiple myeloma (PFS 2), or overall survival (OS).3. The use of embodiment 1 or 2, wherein the anti-CD38 antibody comprises a CD38 binding domain 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: 6.4. The use of any of embodiments 1-3, wherein the CD38 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 8.5. The use of any of embodiments 1-4, wherein the anti-CD38 antibody is an IgGl, an IgG2, an IgG3 or an IgG4 isotype.6. The use of any of embodiments 1-5, wherein the anti-CD38 antibody is an IgGl isotype.7. The use of any of embodiments 1-6, wherein the anti-CD38 antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10.8. The use of any of embodiments 1-7, wherein the anti-CD38 antibody is daratumumab or a daratumumab biosimilar.9. The use of any of embodiments 1-8, wherein the anti-CD38 antibody is administered as a monotherapy.10. The use of any of embodiments 1-9, comprising subcutaneously administering the anti-CD38 antibody.11. The use of any of embodiments 1-10, wherein the anti-CD38 antibody is administered in a pharmaceutical composition comprising about 1,800 mg of the anti- CD38 antibody.12. The use of embodiment 11, wherein the anti-CD38 antibody is administered in a pharmaceutical composition comprising the anti-CD38 antibody and a hyaluronidase.13. The use of embodiment 12, wherein the hyaluronidase comprises a recombinant human hyaluronidase.14. The use of any of embodiments 1-13, wherein the recombinant human hyaluronidase has an amino acid sequence of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 16.15. The use of any of embodiments 1-14, wherein the pharmaceutical composition comprises a mixture of recombinant human hyaluronidase with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO:16.16. The use of any of embodiments 1-15, wherein the pharmaceutical composition comprises about 1,800 mg of the anti-CD38 antibody and about 30,000 U of hyaluronidase.17. The use of embodiment 15, wherein the pharmaceutical composition comprises about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of hyaluronidase.18. The use of any of embodiments 1-17, wherein the pharmaceutical composition comprises one or more excipients.19. The use of embodiment 18, wherein at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.20. The use of any of embodiments 1-19, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of the anti-CD38 antibody; about 30,000 U of hyaluronidase; about 10 mMhistidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.21. The use of embodiment 20, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL of the anti-CD38 antibody; about 2,000 U / mL of hyaluronidase; about 10 mM histidine; about 300 m sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.22. The use of any of embodiments 1-21, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of daratumumab, or a daratumumab biosimilar; about 30,000 U of recombinant human hyaluronidase; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.23. The use of any of embodiments 1-22, wherein the anti-CD38 antibody is administered at a dose of about 1,800 mg once a week, about 1,800 mg once in two weeks, or about 1,800 mg once in four weeks.24. The use of any of embodiments 1-23, comprising treating the subject according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles.25. The use of any of embodiments 1-24, comprising administering the anti-CD38 antibody once a week for two treatment cycles.26. The use of any of embodiments 1-25, comprising administering the anti-CD38 antibody once every two weeks for four treatment cycles.27. The use of any of embodiments 1-26, comprising administering the anti-CD38 antibody once every four weeks until 39 cycles or up to 36 months, or confirmed disease progression, whichever occurs first.28. The use of any of embodiments 1-27, comprising administering the anti-CD38 antibody according to a regimen comprising 28-day cycles wherein the regimen comprises: in Cycles 1 to 2, administering the anti-CD38 antibody once a week, in Cycles 3 to 6, administering the anti-CD38 antibody once every two weeks, and then administering the anti-CD38 antibody once every 4 weeks.29. The use of any of embodiments 1-28, wherein the subject has not received prior SMM directed therapy.30. The use of any of embodiments 1-29, wherein the subject does not have active multiple myeloma.31. The use of embodiment 30, wherein the use achieves a clinical response in the subject that is a progression free survival (PFS) as defined by IRC assessment.32. The use of embodiment 31, wherein the use achieves a clinical response in the subject that is a partial response (PR), a very good partial response (VGPR), a complete response (CR) or a stringent complete response (sCR), as defined by IMWG response criteria for MM, utilized for SMM (Table 4).33. The use of any of claims 1-32, wherein the use achieves PFS in a population of subjects with HR-SMM of 60% or higher.34. The use of any of embodiments 1-33, wherein the use achieves an overall response rate (ORR) in a population of subjects with HR-SMM of 60% or higher.35. The use of any of embodiments 1-34, wherein the use achieves a PFS2 rate in a population of subjects with HR-SMM of 85% or higher.36. The use of any of embodiments 1-35, wherein the use achieves an OS rate in a population of subjects with HR-SMM of 90% or higher.37. The use of any of embodiments 1-36, wherein, after the subject has received at least 38 28-day cycles of treatment with the anti-CD38 antibody, the subject’s HR-SMM does not progress.38. The use of any of embodiments 1-37, wherein administration of the anti-CD38 antibody to the subject for a maximum of 39 28-day treatment cycles prevents the subject from developing multiple myeloma.39. The use of any of embodiments 1-38, wherein the use prevents the subject from developing MM.40. The use of any of embodiments 1-39, wherein the use achieves a rate of progression free survival in a population of subjects with HR-SMM that is greater than a rate PFS achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.41. The use of any of embodiments 1-40, wherein, the use achieves an overall response rate (ORR) in a population of subjects with HR-SMM that is greater than an ORR achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.42. The use of any of embodiments 1-41, wherein the use achieves a percentage of overall survival (OS) in a population of subjects with HR-SMM that is greater than a percentage of OS achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.Embodiments Section 31. A pharmaceutical composition for use in the treating high-risk smoldering multiple myeloma (HR-SMM) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-CD38 antibody.2. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition provides an improvement in progression free survival (PFS), overall response rate (ORR), rate of partial response (PR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), progression-free survival on first-line treatment for multiple myeloma (PFS2), or overall survival (OS).3. The pharmaceutical composition of embodiment 1 or 2, wherein the anti-CD38 antibody comprises a CD38 binding domain 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: 6.4. The pharmaceutical composition of any of embodiments 1-3, wherein the CD38 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 8.5. The pharmaceutical composition of any of embodiments 1-4, wherein the anti- CD38 antibody is an IgGl, an IgG2, an IgG3 or an IgG4 isotype.6. The pharmaceutical composition of any of embodiments 1-5, wherein the anti- CD38 antibody is an IgGl isotype.7. The pharmaceutical composition of any of embodiments 1-6, wherein the anti- CD38 antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10.8. The pharmaceutical composition of any of embodiments 1-7, wherein the anti- CD38 antibody is daratumumab or a daratumumab biosimilar.9. The pharmaceutical composition of any of embodiments 1-8, wherein the anti- CD38 antibody is administered as a monotherapy.10. The pharmaceutical composition of any of embodiments 1-9, comprising subcutaneously administering the anti-CD38 antibody.11. The pharmaceutical composition of any of embodiments 1-10, wherein the anti- CD38 antibody is administered in a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody.12. The pharmaceutical composition of embodiment 11, wherein the anti-CD38 antibody is administered in a pharmaceutical composition comprising the anti-CD38 antibody and a hyaluronidase.13. The pharmaceutical composition of embodiment 12, wherein the hyaluronidase comprises a recombinant human hyaluronidase.14. The pharmaceutical composition of any of embodiments 1-13, wherein the recombinant human hyaluronidase has an amino acid sequence of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 16.15. The pharmaceutical composition of any of embodiments 1-14, wherein the pharmaceutical composition comprises a mixture of recombinant human hyaluronidase with the amino acid sequences of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.16. The pharmaceutical composition of any of embodiments 1-15, wherein the pharmaceutical composition comprises about 1,800 mg of the anti-CD38 antibody and about 30,000 U of hyaluronidase.17. The pharmaceutical composition of embodiment 15, wherein the pharmaceutical composition comprises about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of hyaluronidase.18. The pharmaceutical composition of any of embodiments 1-17, wherein the pharmaceutical composition comprises one or more excipients.19. The pharmaceutical composition of embodiment 18, wherein at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.20. The pharmaceutical composition of any of embodiments 1-19, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceuticalcomposition comprises: about 1,800 mg of the anti-CD38 antibody; about 30,000 U of hyaluronidase; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS- 20; and about 1 mg / mL methionine.21. The pharmaceutical composition of embodiment 20, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 120 mg / mL of the anti-CD38 antibody; about 2,000 U / mL of hyaluronidase; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS- 20; and about 1 mg / mL methionine.22. The pharmaceutical composition of any of embodiments 1-21, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of daratumumab, or a daratumumab biosimilar; about 30,000 U of recombinant human hyaluronidase; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.23. The pharmaceutical composition of any of embodiments 1-22, wherein the anti- CD38 antibody is administered at a dose of about 1,800 mg once a week, about 1,800 mg once in two weeks, or about 1,800 mg once in four weeks.24. The pharmaceutical composition of any of embodiments 1-23, comprising treating the subject according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles.25. The pharmaceutical composition of any of embodiments 1-24, comprising administering the anti-CD38 antibody once a week for two treatment cycles.26. The pharmaceutical composition of any of embodiments 1-25, comprising administering the anti-CD38 antibody once every two weeks for four treatment cycles.27. The pharmaceutical composition of any of embodiments 1-26, comprising administering the anti-CD38 antibody once every four weeks until 39 cycles or up to 36 months, or confirmed disease progression, whichever occurs first.28. The pharmaceutical composition of any of embodiments 1-27, comprising administering the anti-CD38 antibody according to a regimen comprising 28-day cycles wherein the regimen comprises: in Cycles 1 to 2, administering the anti-CD38 antibody once a week, in Cycles 3 to 6, administering the anti-CD38 antibody once every two weeks, and then administering the anti-CD38 antibody once every 4 weeks.29. The pharmaceutical composition of any of embodiments 1-28, wherein the subject has not received prior SMM directed therapy.30. The pharmaceutical composition of any of embodiments 1-29, wherein the subject does not have active multiple myeloma.31. The pharmaceutical composition of embodiment 30, wherein the method achieves a clinical response in the subject that is a progression free survival (PFS) as defined by IRC assessment.32. The pharmaceutical composition of embodiment 31, wherein the method achieves a clinical response in the subject that is a partial response (PR), a very good partial response (VGPR), a complete response (CR) or a stringent complete response (sCR), as defined by IMWG response criteria for MM, utilized for SMM (Table 4).33. The pharmaceutical composition of any of claims 1-32, wherein the method achieves PFS in a population of subjects with HR-SMM of 60% or higher.34. The pharmaceutical composition of any of embodiments 1-33, wherein the method achieves an overall response rate (ORR) in a population of subjects with HR- SMM of 60% or higher.35. The pharmaceutical composition of any of embodiments 1-34, wherein the method achieves a PFS2 rate in a population of subjects with HR-SMM of 85% or higher.36. The pharmaceutical composition of any of embodiments 1-35, wherein the method achieves an OS rate in a population of subjects with HR-SMM of 90% or higher.37. The pharmaceutical composition of any of embodiments 1-36, wherein, after the subject has received at least 38 28-day cycles of treatment with the anti-CD38 antibody, the subject’s HR-SMM does not progress.38. The pharmaceutical composition of any of embodiments 1-37, wherein administration of the anti-CD38 antibody to the subject for a maximum of 39 28-day treatment cycles prevents the subject from developing multiple myeloma.39. The pharmaceutical composition of any of embodiments 1-38, wherein the pharmaceutical composition prevents the subject from developing MM.40. The pharmaceutical composition of any of embodiments 1-39, wherein the pharmaceutical composition achieves a rate of progression free survival in a population of subjects with HR-SMM that is greater than a rate PFS achieved in a referencepopulation of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.41. The pharmaceutical composition of any of embodiments 1-40, wherein, the pharmaceutical composition achieves an overall response rate (ORR) in a population of subjects with HR-SMM that is greater than an ORR achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.42. The pharmaceutical composition of any of embodiments 1-41, wherein the pharmaceutical composition achieves a percentage of overall survival (OS) in a population of subjects with HR-SMM that is greater than a percentage of OS achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.

[0165] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations.

[0166] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, in its entirety.EXAMPLES

[0167] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments.Example 1: A Phase 3 Randomized, Multicenter Study of Subcutaneous Daratumumab Versus Active Monitoring in Subjects with High-risk Smoldering Multiple Myeloma (Aquila SMM3001)Objectives:

[0168] The primary objective is to determine whether treatment with daratumumab administered SC prolongs PFS compared with active monitoring in subjects with high- risk SMM. The secondary objectives are to demonstrate additional clinical benefit (ORR, PFS2, OS, etc.) for subjects with high-risk SMM treated with daratumumab comparedwith active monitoring and to assess the safety profile of daratumumab in subjects with high-risk SMM.Methods:

[0169] This is a two arm, randomized, phase III, multicenter study evaluating daratumumab vs active monitoring in HR-SMM. Eligibility criteria included HR-SMM per clonal bone marrow plasma cells (BMPCs) >10% and one or more risk factors selected from (1) involvedmninvolved FLC ratio >8 and <100, (2) serum M-protein >30 g / L, (3) IgASMM , (4) immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes, and (5) clonal bone marrow plasma cells (BMPCs) >50% to <60%.

[0170] Subject participation included a Screening Phase, an Active Monitoring Phase (Arm A) or a Treatment Phase (Arm B), and a Follow-up Phase. The Screening Phase was within 35 days before randomization. The Active Monitoring Phase (Arm A) and Treatment Phase (Arm B) were 36 months in duration, to balance efficacy with subject convenience and expected side effects. Cycles were 4 weeks in length. For all subjects, disease evaluations were performed every 12 weeks until confirmed disease progression.

[0171] Daratumumab SC (daratumumab 1800 mg + rHuPH20 [2000 U / mE]) was administered by SC injection through a syringe by a manual push over approximately 5 minutes. For subjects randomized to daratumumab, daratumumab was administered weekly in Cycle 1 and 2, then every 2 weeks for Cycle 3 to Cycle 6, and thereafter every 4 weeks until 39 cycles or up to 36 months or until confirmed PD, Subjects randomized to active monitoring received no study medication but underwent the same disease evaluations and at the same frequency as the subjects randomized to daratumumab.

[0172] The primary endpoint was progression-free survival (PFS), defined as progression to active MM as assessed by an independent review committee and according to IMWG diagnostic criteria for MM (SEiM-CRAB) or death, whichever occurred first. Key secondary endpoints included overall response rate (ORR), PFS on first-line MM treatment (PFS2), and overall survival (OS). Other secondary endpoints included time to first line subsequent treatment of MM Time to biochemical or diagnostic (SLiM-CRAB) progression defined as the earlier of time to the earlier of biochemical progression or diagnostic (SLiM-CRAB) progression. Overall response rate (ORR), defined as, the proportion of subjects with a PR or better as defined by IMWG response criteria for MM, utilized for SMM (Table 4). Progression-free survival on first-line treatment for MM (PFS2), defined as, the time from the date of randomization to the date of documented progressive disease (PD) on the first-line treatment for MM or death, whichever comes first. Overall survival (OS), defined as, the time from the date of randomization to the date of death.Eligibility Criteria:Inclusion CriteriaAge > 18 years.Diagnosis of SMM (per IMWG criteria) for <5 years with measurable disease at the time of randomization, defined as serum M protein >10 g / L or urine M protein >200 mg / 24 hours or involved serum FLC >100 mg / L and abnormal serum FLC ratio.High risk SMM defined as:• Clonal BMPCs >10% ; and• At least 1 of the following risk factors; o Serum M protein >30 g / L, o IgA SMM, o Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes (only IgA, IgM, and IgG should be considered in determination for immunoparesis; IgD and IgE are not considered in this assessment), o Serum involved: uninvolved FLC ratio >8 and <100, or o Clonal BMPCs >50% to <60% with measurable disease.ECOG Performance Status (PS) 0 or 1Pretreatment clinical laboratory values meet the following criteria during the Screening Phase:• ANC >1.0 x 109 / L• PLT >50 x 109 / L (not permissible to transfuse a subject within 2 weeks prior to the Screening platelet count to reach this level)• Total bilirubin < 2.0 xULN• AST <2.5 x institutional upper limit of normal (ULN)• ALT <2.5 x institutional upper limit of normal (ULN)All female participants of child-bearing potential must have a negative pregnancy test before enrollment.Exclusion CriteriaMultiple myeloma, requiring treatment, defined by any of the following: Bone lesions (one or more osteolytic lesions on low-dose whole body computed tomography [LDCT], positron-emission tomography with computed tomography [PET- CT] or CT). Hypercalcemia (serum calcium >0.25 mmol / L [>1 mg / dL] higher than ULN or >2.75 mmol / L [>11 mg / dL]). Renal insufficiency, preferably determined by creatinine clearance <40 mL / min measured or estimated using the MDRD, or serum creatinine >177 pmol / L. Anemia, defined as hemoglobin <10 g / dL or >2 g / dL below lower limit of normal or both; transfusion support or concurrent treatment with erythropoietin stimulating agents is not permitted. Clonal BMPC percentage >60% Serum FLC ratio (involvedmninvolved) >100 More than 1 focal lesion >5 mm in diameter by MRIPrimary systemic AL (immunoglobulin light chain) amyloidosis.Exposure to any of the following: Prior exposure to daratumumab or prior exposure to other anti-CD38 therapies Prior exposure to approved or investigational treatments for SMM or MM (including but not limited to conventional chemotherapies, IMiDs, or Pls). Exposure to investigational drug (including investigational vaccines) or invasive investigational medical device for any indication within 4 weeks or 5 half-lives, whichever is longer, before Cycle 1, Day 1 Ongoing treatment with corticosteroids with a dose >10 mg prednisone or equivalent per day at the time of randomization; or >280 mg cumulative prednisone dose or equivalent for any 4-week period in the year prior to randomization Ongoing treatment with other monoclonal antibodies (e.g., infliximab, rituximab), immunomodulators (eg, abatacept, methotrexate, azathioprine, cyclosporine) or other treatments that are likely to interfere with the study procedures or results Received treatment (chemotherapy, surgery, etc) for a malignancy (other than SMM) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion), which is considered cured with minimal risk of recurrence within 3 years.Either of the following: Known or suspected chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal Moderate or severe persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification. Known to be seropositive for human immunodeficiency virus (HIV) Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as a viremia at least 12 weeks after completion of antiviral therapy)Medical or psychiatric condition or disease (eg, active systemic disease [including presence of auto-antibodies] , uncontrolled diabetes) 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.Clinically significant cardiac disease, including: myocardial infarction within 6 months with left ventricular dysfunction or uncontrolled ischemic cardiac disease before Cycle 1 Day 1 , or unstable or uncontrolled disease / condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV) Uncontrolled cardiac arrhythmia (Grade 2 or higher by National Cancer Institute- Common Terminology Criteria for Adverse Events [NCI-CTCAE] Version 4.03) or clinically significant ECG abnormalities Screening 12-lead ECG showing a baseline QT interval as corrected QT interval corrected for heart rate >470 msec.Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies, hyaluronidase, or other human proteins, or their excipients or known sensitivity to mammalian-derived products (including dairy allergy).Vaccination with live attenuated vaccines within 4 weeks of first study agent administrationPregnant, breast-feeding, or planning to become pregnant while receiving study treatment or within 3 months after the last dose of daratumumab.Plans to father a child while receiving study treatment or within 3 months after the last dose of daratumumab.Major surgery (requiring general anesthesia or presence of other factors that determines surgery to be considered major) within 2 weeks before randomization or who have not fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of daratumumab. Known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder).Results:

[0173] A total of 390 patients (DARA, n = 194; active monitoring, n = 196) were randomized (FIG. 1). Median (range) age (64 [31-86] years) and time from initial SMM diagnosis to randomization (0.72 [0-5.0] years) were balanced between treatment groups. Median treatment duration in the DARA group was 38 cycles (35.0 months).

[0174] At a median (range) follow-up of 65.2 (0-76.6) months, Treatment with daratumumab SC resulted in a clinically meaningful and statistically significant improvement in PFS, with a 51% reduction in the risk of progression or death compared with active monitoring (hazard ratio | HR|=0.49; 95% confidence interval [CI]: 0.36, 0.67; 2-sided p<0.0001). Prespecified analyses showed generally consistent PFS improvement with DARA versus active monitoring across subgroups (FIG. 3). Median PFS was not reached in the Daratumumab arm and was 41.5 months (95% CI: 26.4, 53.3) in the Active Monitoring arm (60-month PFS rate: Daratumumab 63.1%; Active Monitoring 40.8% (FIG. 2).

[0175] A pronounced benefit was observed in patients who were retrospectively identified as high risk per the Mayo 2018 criteria (FIG. 3 and FIG. 10); however, a benefit was also observed in the lower-risk groups per the Mayo 2018 criteria. ORR was 63.4% with DARA versus 2.0% with active monitoring (P <0.0001) (FIG. 4). In patients retrospectively identified as high risk per the Mayo 2018, ORR was 62.5% with DARA versus 0% with active monitoring (FIG. 13). As of the clinical cutoff, 64 (33.0%) patients in the DARA group and 102 (52.0%) patients in the active monitoring group had started first-line MM treatment (defined as time from randomization to date of first-line treatment for MM). Median time from randomization to first-line MM treatment was not reached with DARA versus 50.2 months with active monitoring (HR, 0.46; 95% CI,0.33-0.62; nominal P <0.0001) (FIG. 7). PFS2 showed a positive trend in favor of DARA (HR, 0.58; 95% CI, 0.35-0.96), therefore, early treatment with DARA did not appear to impair later treatment for MM (FIG. 5). Although OS requires further follow up for maturity, there was also a positive trend in favor of DARA (60-month OS rates: DARA, 93.0%; active monitoring, 86.9%; HR, 0.52; 95% CI, 0.27-0.98) (FIG.6). A total of 41 deaths were observed, 15 for the DARA group and 26 for the active monitoring group.

[0176] Overall, no new safety concerns were identified in patients receiving DARA (FIG. 9 and Table 22). Grade 3 / 4 treatment-emergent adverse events (TEAEs) occurred in 40.4% and 30.1% of patients in the DARA and active monitoring groups, respectively (FIG. 8). The most common (>5% in either group) grade 3 / 4 TEAE was hypertension (DARA, 5.7%; active monitoring, 4.6%) (FIG. 9A). The frequency of TEAEs leading to DARA discontinuation was low (5.7%), as was the incidence of fatal TEAEs in both groups (DARA, 1.0%; active monitoring, 2.0%). Grade 3 / 4 infections were typically of short duration, and the majority recovered or resolved. The frequency of second primary malignancies was similar for the DARA (n = 18 [9.3%]) and active monitoring (n = 20 [10.2%]) groups. Systemic infusion-related reactions were reported in 32 (16.6%) patients in the DARA group, including 2 (1.0%) with grade 3 / 4 reactions; local injectionsite reactions were reported in 53 (27.5%) patients, all of which were grade Vi in severity.

[0177] In an expanded assessment of patient-reported outcomes, health-related quality of life was maintained with DARA across multiple measures and domains, with similar mean changes from baseline reported at Week 112 for both groups (FIGs. 11 and 12) Conclusions:

[0178] DARA monotherapy was well tolerated and demonstrated a clinically meaningful and significant benefit in preventing or delaying progression to active MM compared with active monitoring in patients with high-risk SMM. ORR was significantly higher and time to first-line MM treatment was prolonged with DARA compared with active monitoring. This was accompanied by strong trends for PFS2 and OS in favor of DARA. These results strongly support the benefit of early intervention with DARA monotherapy versus active monitoring, the current standard of care, in patients with high-risk SMM.

[0179] Results from the phase 3 study strongly support early intervention with subcutaneous DARA monotherapy for a fixed duration in patients with high-risk SMM,representing an opportunity to delay or avoid end-organ damage and progression to MM, while preserving quality of life and extending survival. Once patients progress to active multiple myeloma, multi-drug (i.e., 3- to 4-drug) treatment regimens, possibly including autologous stem cell transplant (ASCT), are used. Various treatment regimens are utilized as the disease progresses, since there is no cure for multiple myeloma. In addition, many of the regimens carry significant side effects. Therefore, patients and clinicians need an approved treatment for high-risk SMM with a tolerable safety profile that can delay disease progression to active myeloma and the need for continuous multidrug systemic therapy. Results from the Phase 3 AQUILA study establish that daratumumab monotherapy can provide this proactive therapy and meet this unmet need.

[0180] Treatment with DARA monotherapy for 36 months led to a statistically significant 51 % reduction in the risk of disease progression or death compared with active monitoring (HR, 0.49). The most notable PFS benefit was seen in patients retrospectively identified as high risk per the Mayo 2018 criteria (HR, 0.36), although a benefit was also observed among low- and intermediate-risk patients per the Mayo 2018 criteria. DARA also extended OS (HR, 0.52) and PFS on first-line treatment for MM (HR, 0.58). DARA demonstrated a favorable safety profile, with a low rate (5.7%) of treatment discontinuation due to TEAEs. Patients maintained their health-related quality of life during DARA treatment.Example 2. Full Prescribing InformationINDICATIONS AND USAGEMultiple Myeloma

[0181] DARZALEX FASPRO® is indicated for the treatment of adult patients with multiple myeloma: in combination with bortezomib, lenalidomide, and dexamethasone for induction and consolidation in newly diagnosed patients who are eligible for autologous stem cell transplant. in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant.in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy. in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant. in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy. in combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor. in combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy. as monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.High-Risk Smoldering Multiple Myeloma

[0182] DARZALEX FASPRO® as monotherapy is indicated for the treatment of adult patients with high-risk smoldering multiple myeloma.Light Chain Amyloidosis

[0183] DARZALEX FASPRO® in combination with bortezomib, cyclophosphamide and dexamethasone is indicated for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis.

[0184] This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).Limitations of Use

[0185] DARZALEX FASPRO® is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials.DOSAGE AND ADMINISTRATIONImportant Dosing Information

[0186] DARZALEX FAS PRO® is for subcutaneous use only. Administer medications before and after administration of DARZALEX FASPRO® to minimize administration- related reactions. Type and screen patients prior to starting DARZALEX FASPRO®. Recommended Dosage for Multiple Myeloma

[0187] The recommended dose of DARZALEX FASPRO® is 1,800 mg / 30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3-5 minutes. Tables 6-10 provide the recommended dosing schedule when DARZALEX FASPRO® is administered as monotherapy or as part of a combination therapy.Monotherapy and In Combination with Lenalidomide and Dexamethasone (DARZALEX FASPRO®-Rd), Pomalidomide and Dexamethasone (DARZALEX FASPRO®-Pd) or Carfilzomib and Dexamethasone (DARZALEX FASPRO®-Kd)

[0188] Use the dosing schedule provided in Table 6 when DARZALEX FASPRO® is administered: in combination with lenalidomide and dexamethasone (4-week cycle) OR in combination with pomalidomide and dexamethasone (4-week cycle) OR in combination with carfilzomib and dexamethasone (4-week cycle) OR as monotherapy.Table 6: DARZALEX FASPRO® dosing schedule in combination with lenalidomide, pomalidomide or carfilzomib and dexamethasone (4-week cycle) and for monotherapya. First dose of the every-2-week dosing schedule is given at Week 9 b. First dose of the every-4-week dosing schedule is given at Week 25

[0189] When DARZALEX FASPRO® is administered as part of a combination therapy, and the prescribing information for dosage recommendations for the other drugs.In Combination with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO®- VMP)

[0190] Use the dosing schedule provided in Table 7 when DARZALEX FASPRO® is administered in combination with bortezomib, melphalan and prednisone (6-week cycle).Table 7: DARZALEX FASPRO® dosing schedule in combination with bortezomib, melphalan and prednisone (6-week cycle)a. First dose of the every-3-week dosing schedule is given at Week 7 b. First dose of the every-4-week dosing schedule is given at Week 55

[0191] When DARZALEX FASPRO® is administered as part of a combination therapy, and the prescribing information for dosage recommendations for the other drugs.In Combination with Bortezomib, Thalidomide, and Dexamethasone (DARZALEX FASPRO®-VTd)

[0192] Use the dosing schedule in Table 8 when DARZALEX FASPRO® is administered in combination with bortezomib, thalidomide, and dexamethasone (4-week cycle).Table 8: DARZALEX FASPRO® dosing schedule in combination with bortezomib, thalidomide and dexamethasone (4-week cycle)a. First dose of the every-2-week dosing schedule is given at Week 9 b. First dose of the every-2-week dosing schedule is given at Week 1 upon reinitiation of treatment following ASCT

[0193] When DARZALEX FASPRO® is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs.In Combination with Bortezomib and Dexamethasone (DARZALEX FASPRO®-Vd)

[0194] Use the dosing schedule in Table 9 when DARZALEX FASPRO® is administered in combination with bortezomib and dexamethasone (3-week cycle).Table 9: DARZALEX FASPRO® dosing schedule in combination with bortezomib and dexamethasone (3-week cycle)a. First dose of the every-3-week dosing schedule is given at Week 10 b. First dose of the every-4-week dosing schedule is given at Week 25

[0195] When DARZALEX FASPRO® is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs. Recommended Dosage for High-Risk Smoldering Multiple Myeloma

[0196] The recommended dose of DARZALEX FASPRO® is 1,800 mg / 30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3 to 5 minutes.

[0197] Use the dosing schedule provided in Table 10 when DARZALEX FASPRO® is administered as monotherapy in high-risk smoldering multiple myeloma patients (4- week cycle).Table 10: DARZALEX FASPRO® dosing schedule for monotherapy (4-week cycle)First dose of the every-2-week dosing schedule is given at Week 9First dose of the every-4-week dosing schedule is given at Week 25Recommended Dosage for Light Chain AmyloidosisIn Combination with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO®-VCd)

[0198] Use the dosing schedule provided in Table 11 when DARZALEX FASPRO® is administered in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle).Table 11: DARZALEX FASPRO® dosing schedule in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle)a. First dose of the every-2-week dosing schedule is given at Week 9 b. First dose of the every-4-week dosing schedule is given at Week 25

[0199] When DARZALEX FAS PRO® is administered as part of a combination therapy, and the prescribing information for dosage recommendations for the other drugs.Administration

[0200] If a dose of DARZALEX FASPRO® is missed, administer the dose as soon as possible and adjust the dosing schedule to maintain the dosing interval.Recommended Concomitant MedicationsPre-medication

[0201] Administer the following pre-medications 1-3 hours before each dose of DARZALEX FASPRO®:• Acetaminophen 650 to 1,000 mg orally• Diphenhydramine 25 to 50 mg (or equivalent) orally or intravenously• Corticosteroid (long- or intermediate- acting) Monotherapy

[0202] Administer methylprednisolone 100 mg (or equivalent) orally or intravenously. Consider reducing the dose of methylprednisolone to 60 mg (or equivalent) following the second dose of DARZALEX FASPRO®.In Combination

[0203] Administer dexamethasone 20 mg (or equivalent) orally or intravenously prior to every DARZALEX FASPRO® administration.

[0204] When dexamethasone is the background regimen-specific corticosteroid, the dexamethasone dose that is part of the background regimen will serve as pre-medication on DARZALEX FASPRO® administration days.

[0205] Do not administer background regimen-specific corticosteroids (e.g. prednisone) on DARZALEX FASPRO® administration days when patients have received dexamethasone (or equivalent) as a pre-medication.Post-medication

[0206] Administer the following post-medications:Monotherapy

[0207] Administer methylprednisolone 20 mg (or an equivalent dose of an intermediate- or long- acting corticosteroid) orally for 2 days starting the day after the administration of DARZALEX FASPRO®.In Combination

[0208] Consider administering oral methylprednisolone at a dose of less than or equal to 20 mg (or an equivalent dose of an intermediate- or long-acting corticosteroid) beginning the day after administration of DARZALEX FASPRO®.

[0209] If a background regimen- specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the administration of DARZALEX FASPRO®, additional corticosteroids may not be needed.

[0210] If the patient does not experience a major systemic administration-related reaction after the first 3 doses of DARZALEX FASPRO®, consider discontinuing the administration of corticosteroids (excluding any background regimen-specific corticosteroid).

[0211] For patients with a history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 doses of DARZALEX FASPRO®, consider discontinuing these additional post-medications, if the patient does not experience a major systemic administration- related reaction.Prophylaxis for Herpes Zoster Reactivation

[0212] Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX FASPRO® and continue for 3 months following the end of treatment.Dosage Modifications for Adverse Reactions

[0213] No dose reductions of DARZALEX FASPRO® are recommended. Consider withholding DARZALEX FASPRO® to allow recovery of blood cell counts in the event of myelosuppression.Preparation and Administration

[0214] DARZALEX FASPRO® should be administered by a healthcare provider.

[0215] To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is DARZALEX FASPRO® for subcutaneous use. Do not administer DARZALEX FASPRO® intravenously. DARZALEX FASPRO® is ready to use.Preparation

[0216] Remove the DARZALEX FASPRO® vial from refrigerated storage [2°C to 8°C (36°F to 46°F)] and equilibrate to ambient temperature [15°C to 30°C (59°F to 86°F)]. Store the unpunctured vial at ambient temperature and ambient light for a maximum of 24 hours. Keep out of direct sunlight. Do not shake.

[0217] Withdraw 15 mL from the vial into a syringe.

[0218] DARZALEX FASPRO® is compatible with polypropylene or polyethylene syringe material; polypropylene, polyethylene, or polyvinyl chloride (PVC) subcutaneous infusion sets; and stainless steel transfer and injection needles. Use the product immediately.

[0219] After the solution of DARZALEX FASPRO® is withdrawn into the syringe, replace the transfer needle with a syringe closing cap. Label the syringe appropriately to include the route of administration per institutional standards. Label the syringe with the peel-off label.

[0220] To avoid needle clogging, attach the hypodermic injection needle or subcutaneous infusion set to the syringe immediately prior to injection.

[0221] Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if opaque particles, discoloration or other foreign particles are present.Storage

[0222] If the syringe containing DARZALEX FASPRO® is not used immediately, store refrigerated at 2 °C to 8 °C (36 °F to 46 °F) for up to 24 hours and / or at room temperature at 15°C to 25°C (59°F to 77°F) for up to 12 hours under ambient light.

[0223] Discard if storage time exceeds these limits.

[0224] If stored in the refrigerator, allow the solution to come to room temperature before administration.Administration

[0225] Inject 15 mL of DARZALEX FASPRO® into the subcutaneous tissue of the abdomen approximately 3 inches [7.5 cm] to the right or left of the navel overapproximately 3-5 minutes. No data are available on performing the injection at other sites of the body.

[0226] Rotate injection sites for successive injections.

[0227] Never inject DARZALEX FASPRO® into areas where the skin is red, bruised, tender, hard or areas where there are scars.

[0228] Pause or slow down delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.

[0229] During treatment with DARZALEX FASPRO®, do not administer other medications for subcutaneous use at the same site as DARZALEX FASPRO®.DOSAGE FORMS AND STRENGTHS

[0230] Injection: 1,800 mg daratumumab and 30,000 units hyaluronidase per 15 mL (120 mg and 2,000 units / mL) colorless to yellow and clear to opalescent solution in a single-dose vial.CONTRAINDICATIONS

[0231] DARZALEX FASPRO® is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation.WARNINGS AND PRECAUTIONSHypersensitivity and Other Administration Reactions

[0232] Both systemic administration-related reactions, including severe or lifethreatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO®. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO®.Systemic Reactions

[0233] In a pooled safety population of 1446 patients with multiple myeloma (N=1253) or light chain (AL) amyloidosis (N= 193) who received DARZALEX FASPRO® as monotherapy or as part of a combination therapy, 7% of patients experienced a systemic administration-related reaction (Grade 2: 3%, Grade 3: 0.8%, Grade 4: 0.1%). In patients with high-risk smoldering multiple myeloma (N=l 93), systemic administration-related reactions occurred in 17% of patients in AQUILA (Grade 2: 7%, Grade 3: 1%).

[0234] In all patients (N=l 639), systemic administration-related reactions occurred in 7% of patients with the first injection, 0.5% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range:4 minutes to 3.5 days). Of the 283 systemic administration-related reactions that occurred in 135 patients, 240 (85%) occurred on the day of DARZALEX FASPRO® administration. Delayed systemic administration-related reactions have occurred in 1% of the patients.

[0235] Severe reactions include hypoxia, dyspnea, hypertension, and tachycardia, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and blurred vision.

[0236] Pre-medicate patients with histamine- 1 receptor antagonist, acetaminophen and corticosteroids. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life- threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZAEEX FASPRO®. Consider administering corticosteroids and other medications after the administration of DARZAEEX FASPRO® depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions.

[0237] Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with daratumumab-containing products. If ocular symptoms occur, interrupt DARZALEX FASPRO® and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO®.Local Reactions

[0238] In this pooled safety population of 1446 patients with multiple myeloma (N=1253) or light chain (AL) amyloidosis (N= 193), injection-site reactions occurred in 8% of patients, including Grade 2 reactions in 1.1%. The most frequent (>1%) injectionsite reactions were injection site erythema and injection site rash. In patients with high- risk smoldering multiple myeloma (N=l 93), injection-site reactions occurred in 28% ofpatients, including Grade 2 reactions in 3%. These local reactions occurred a median of 6 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO®. Monitor for local reactions and consider symptomatic management.Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis

[0239] Serious or fatal cardiac adverse reactions occurred in patients with light chain (AL) amyloidosis who received DARZALEX FASPRO® in combination with bortezomib, cyclophosphamide and dexamethasone. Serious cardiac disorders occurred in 16% and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with NYHA Class IIIB or IV disease were not studied.

[0240] Monitor patients with cardiac involvement of light chain (AL) amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate.Infections

[0241] DARZALEX FASPRO® can cause serious, life-threatening, or fatal infections. In patients who received DARZALEX FASPRO® in a pooled safety population including patients with smoldering multiple myeloma and light chain (AL) amyloidosis (N=l 639), serious infections, including opportunistic infections, occurred in 24% of patients, Grade 3 or 4 infections occurred in 22%, and fatal infections occurred in 2.5%. The most common type of serious infection reported was pneumonia (8.5%).

[0242] Monitor patients for signs and symptoms of infection prior to and during treatment with DARZALEX FASPRO® and treat appropriately. Administer prophylactic antimicrobials according to guidelines Neutropenia

[0243] Daratumumab may increase neutropenia induced by background therapy.

[0244] Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO® until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO®, higher rates of Grade 3-4 neutropenia were observed.Thrombocytopenia

[0245] Daratumumab may increase thrombocytopenia induced by background therapy.

[0246] Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Consider withholding DARZALEX FASPRO® until recovery of platelets.Embryo-Fetal Toxicity

[0247] Based on the mechanism of action, DARZALEX FASPRO® can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO® may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO® and for 3 months after the last dose.

[0248] The combination of DARZALEX FASPRO® with lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide or pomalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, thalidomide or pomalidomide prescribing information on use during pregnancy.Interference with Serological Testing

[0249] Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted.

[0250] Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO®. Type and screen patients prior to starting DARZALEX FASPRO®.Interference with Determination of Complete Response

[0251] Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO®- treated patients with IgG kappa myeloma protein.ADVERSE REACTIONS

[0252] The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity and Other Administration Reactions, Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis, Neutropenia, and ThrombocytopeniaClinical Trials Experience

[0253] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Newly Diagnosed Multiple MyelomaIn Combination with Bortezomib, Melphalan and Prednisone

[0254] The safety of DARZALEX FASPRO® with bortezomib, melphalan and prednisone was evaluated in a single-arm cohort of PLEIADES. Patients received DARZALEX FASPRO® 1,800 mg / 30,000 units administered subcutaneously once weekly from weeks 1 to 6, once every 3 weeks from weeks 7 to 54 and once every 4 weeks starting with week 55 until disease progression or unacceptable toxicity (N=67) in combination with bortezomib, melphalan and prednisone. Among these patients, 93% were exposed for 6 months or longer and 19% were exposed for greater than one year.

[0255] Serious adverse reactions occurred in 39% of patients who received DARZALEX FASPRO®. Serious adverse reactions in >5% of patients included pneumonia and pyrexia. Fatal adverse reactions occurred in 3% of patients.

[0256] Permanent discontinuation of DARZALEX FASPRO® due to an adverse reaction occurred in 4.5% of patients. The adverse reaction resulting in permanent discontinuation of DARZALEX FASPRO® in more than 1 patient was neutropenic sepsis.

[0257] Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 51% of patients who received DARZALEX FASPRO®. Adverse reactions requiring dosage interruptions in >5% of patients included thrombocytopenia, neutropenia, anemia, and pneumonia.

[0258] The most common adverse reactions (>20%) were upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain.

[0259] Table 12 summarizes the adverse reactions in patients who received DARZALEXFASPRO® in PLEIADES.Table 12: Adverse Reactions (>10%) in Patients Who Received DARZALEX FASPRO® with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO®- VMP) in PLEIADESaUpper respiratory tract infection includes nasopharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, tonsillitis, upper respiratory tract infection, and viral pharyngitis. b Pneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, pneumonia, and pneumonia bacterial.Abdominal pain includes abdominal pain, and abdominal pain upper.^Fatigue includes asthenia, and fatigue. cEdema peripheral includes edema, edema peripheral, and peripheral swelling. fCough includes cough, and productive cough.#Only Grade 3 adverse reactions occurred.

[0260] Clinically relevant adverse reactions in <10% of patients who receivedDARZALEX FASPRO® with bortezomib, melphalan and prednisone included:General disorders and administration site conditions: infusion reaction, injection site reaction, chillsInfections: herpes zoster, urinary tract infection, influenza, sepsisMusculoskeletal and connective tissue disorders: arthralgia, muscle spasmsNervous system disorders: headache, paresthesiaMetabolism and nutrition disorders: hypocalcemia, hyperglycemiaRespiratory, thoracic and mediastinal disorders: dyspnea, pulmonary edemaCardiac disorders: atrial fibrillation

[0261] Table 13 summarizes the laboratory abnormalities in patients who receivedDARZALEX FASPRO® in PLEIADES.Table 13: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO® with Bortezomib, Melphalan and Prednisone (DARZALEX FASPRO®-VMP) in PLEIADES‘Denominator is based on the safety population treated with DARZALEX FASPRO®-VMP (N=67).Relapsed / Refractory Multiple MyelomaIn Combination with Lenalidomide and Dexamethasone

[0262] The safety of DARZALEX FASPRO® with lenalidomide and dexamethasone was evaluated in a single-arm cohort of PLEIADES. Patients received DARZALEX FASPRO® 1,800 mg / 30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity (N=65) in combination with lenalidomide and dexamethasone. Among these patients, 92% were exposed for 6 months or longer and 20% were exposed for greater than one year.

[0263] Serious adverse reactions occurred in 48% of patients who received DARZALEX FASPRO®. Serious adverse reactions in >5% of patients included pneumonia, influenza and diarrhea. Fatal adverse reactions occurred in 3.1% of patients.

[0264] Permanent discontinuation of DARZAEEX FASPRO® due to an adverse reaction occurred in 11% of patients who received DARZAEEX FASPRO®. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO® in more than 1 patient were pneumonia and anemia.

[0265] Dosage interruptions due to an adverse reaction occurred in 63% of patients who received DARZALEX FASPRO®. Adverse reactions requiring dosage interruptions in >5% of patients included neutropenia, pneumonia, upper respiratory tract infection, influenza, dyspnea, and blood creatinine increased.

[0266] The most common adverse reactions (>20%) were fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea.

[0267] Table 14 summarizes the adverse reactions in patients who received DARZALEX FASPRO® in PLEIADES.Table 14: Adverse Reactions (>10%) in Patients Who Received DARZALEX FASPRO® with Lenalidomide and Dexamethasone (DARZALEX FASPRO®-Rd) in PLEIADESaFatigue includes asthenia, and fatigue. b Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection viral, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract infection bacterial.cPneumonia includes lower respiratory tract infection, lung infection, and pneumonia. Bronchitis includes bronchitis, and bronchitis viral.eDyspnea includes dyspnea, and dyspnea exertional. Cough includes cough, and productive cough.#Only Grade 3 adverse reactions occurred.

[0268] Clinically relevant adverse reactions in <10% of patients who receivedDARZALEX FASPRO® with lenalidomide and dexamethasone included:Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest painNervous system disorders: dizziness, headache, paresthesiaSkin and subcutaneous tissue disorders: rash, pruritusGastrointestinal disorders: abdominal painInfections: influenza, sepsis, herpes zosterMetabolism and nutrition disorders: decreased appetiteCardiac disorders: atrial fibrillationGeneral disorders and administration site conditions: chills, infusion reaction, injection site reactionVascular disorders: hypotension, hypertension

[0269] Table 15 summarizes the laboratory abnormalities in patients who receivedDARZALEX FASPRO® in PLEIADES.Table 15: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO® with Lenalidomide and Dexamethasone (DARZALEX FASPRO®-Rd) in PLEIADES^Denominator is based on the safety population treated with DARZALEX FASPRO®-Rd (N=65).In Combination with Pomalidomide and Dexamethasone

[0270] The safety of DARZALEX FASPRO® with pomalidomide and dexamethasone compared to pomalidomide and dexamethasone (Pd) in patients who had received at least one prior line of therapy with lenalidomide and a proteasome inhibitor (PI) was evaluated in APOLLO. Patients received DARZALEX FASPRO® 1,800 mg / 30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity in combination with pomalidomide and dexamethasone (n= 149) or pomalidomide and dexamethasone (n= 150). Among patients receiving DARZALEX FASPRO®-Pd, 71% were exposed for 6 months or longer and 50% were exposed for greater than one year.

[0271] Serious adverse reactions occurred in 50% of patients who received DARZALEX FASPRO®-Pd. The most frequent serious adverse reactions in >5% of patients who received DARZALEX FASPRO®-Pd were pneumonia (15%) and lower respiratory tract infection (12%). Fatal adverse reactions occurred in 7% of patients who received DARZALEX FASPRO®-Pd.

[0272] Permanent treatment discontinuation due to an adverse reaction occurred in 2% of patients who received DARZALEX FASPRO®-Pd.

[0273] The most common adverse reactions (>20%) were fatigue, pneumonia, upper respiratory tract infection, and diarrhea.

[0274] Table 16 summarizes the adverse reactions in patients who received DARZALEX FASPRO® in APOLLO.Table 16: Adverse Reactions Reported in >10% of Patients and With at Least a 5% Greater Frequency in the DARZALEX FASPRO®-Pd Arm in APOLLOKey : Pd=pomalidomide-dexamethasoneaFatigue includes asthenia, and fatigue. b Edema peripheral includes edema, edema peripheral and peripheral swelling.cPneumonia includes atypical pneumonia, lower respiratory tract infection, pneumonia, pneumonia aspiration, pneumonia bacterial, and pneumonia respiratory syncytial viral. Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, and viral upper respiratory tract infection.eCough includes cough, and productive cough.#Only Grade 3 adverse reactions occurred.® Grade 5 adverse reactions occurred, n=3 (2.0%) in the DARZALEX FASPRO®-Pd arm and n=2 (1.3%) in the Pd arm.

[0275] Clinically relevant adverse reactions in <10% of patients who receivedDARZALEX FASPRO® with pomalidomide and dexamethasone include:Metabolism and nutrition disorders: hypocalcemia, hypokalemia, decreased appetite, dehydrationNervous system disorders: peripheral sensory neuropathy, syncope, headache, paresthesia, dizzinessMusculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgiaPsychiatric disorders: insomniaGastrointestinal disorders: nausea, abdominal pain, vomitingSkin and subcutaneous tissue disorders: rash, pruritusCardiac disorders: atrial fibrillationGeneral disorders and administration site conditions: infusion reactions, chills, injection site reactionInfections: urinary tract infection, influenza, hepatitis B reactivation, herpes zoster, sepsisVascular disorders: hypertension, hypotension

[0276] Table 17 summarizes the laboratory abnormalities in patients who receivedDARZALEX FASPRO® in APOLLO.Table 17: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO®-Pd or Pd in APOLLOKey : Pd=pomalidomide-dexamethasoneaDenominator is based on number of subjects with a baseline and post-baseline laboratory value for each laboratory test: N=148 for DARZALEX FASPRO®-Pd and N=149 for Pd.In Combination with Carfilzomib and Dexamethasone

[0277] The safety of DARZALEX FASPRO® with carfilzomib and dexamethasone was evaluated in a single-arm cohort of PLEIADES. Patients received DARZALEX FASPRO® 1,800 mg / 30,000 units administered subcutaneously once weekly from Weeks 1 to 8, once every 2 weeks from Weeks 9 to 24 and once every 4 weeks starting with Week 25 until disease progression or unacceptable toxicity (N=66) in combination with carfilzomib and dexamethasone. Among these patients, 77% were exposed for 6 months or longer and 27% were exposed for greater than one year.

[0278] Serious adverse reactions occurred in 27% of patients who received DARZALEX FASPRO® in combination with carfilzomib and dexamethasone. Fatal adverse reactions occurred in 3% of patients who received DARZALEX FASPRO® in combination with carfilzomib and dexamethasone.

[0279] Permanent discontinuation of DARZALEX FASPRO® due to an adverse reaction occurred in 6% of patients who received DARZALEX FASPRO®.

[0280] Dosage interruptions due to an adverse reaction occurred in 46% of patients who received DARZALEX FASPRO®.

[0281] The most common adverse reactions (>20%) were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.

[0282] Table 18 summarizes the adverse reactions in patients who received DARZALEX FASPRO® with carfilzomib and dexamethasone (DARZALEX FASPRO®-Kd) in PLEIADES.Table 18: Adverse Reactions (>10%) in Patients Who Received DARZALEX FASPRO® with Carfilzomib and Dexamethasone (DARZALEX FASPRO®-Kd) in PLEIADESaUpper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, viral pharyngitis, and viral upper respiratory tract infection. b Bronchitis includes bronchitis, and bronchitis viral.cFatigue includes asthenia, and fatigue. Edema peripheral includes generalized edema, edema peripheral, and peripheral swelling.eHypertension includes blood pressure increased, and hypertension. Cough includes cough, and productive cough.& Dyspnea includes dyspnea, and dyspnea exertional.#Only Grade 3 adverse reactions occurred.

[0283] Clinically relevant adverse reactions in <10% of patients who receivedDARZALEX FASPRO® with carfilzomib and dexamethasone include:Gastrointestinal disorders: abdominal pain, constipation, pancreatitisInfection and infestations: pneumonia, influenza, urinary tract infection, herpes zoster, sepsisMetabolism and nutrition disorders: hyperglycemia, decreased appetite, hypocalcemiaMusculoskeletal and connective tissue disorders: muscle spasms, arthralgiaNervous system disorders: paresthesia, dizziness, syncopeGeneral disorders and administration site conditions: injection site reaction, infusion reactions, chillsSkin and subcutaneous tissue disorders: rash, pruritusCardiac disorders: cardiac failureVascular disorders: hypotension

[0284] Table 19 summarizes the laboratory abnormalities in patients who receivedDARZALEX FASPRO® with carfilzomib and dexamethasone in PLEIADES.Table 19: Select Laboratory Abnormalities (>30%) Worsening from Baseline in Patients Who Received DARZALEX FASPRO®-Kd in PLEIADESdenominator is based on the safety population treated with DARZALEX FASPRO®-Kd (N=66).Monotherapy

[0285] The safety of DARZALEX FASPRO® as monotherapy was evaluated in COLUMBA. Patients received DARZALEX FASPRO® 1,800 mg / 30,000 units administered subcutaneously or daratumumab 16 mg / kg administered intravenously; each administered once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity. Among patients receiving DARZALEX FASPRO®, 37% were exposed for 6 months or longer and 1 % were exposed for greater than one year.

[0286] Serious adverse reactions occurred in 26% of patients who received DARZALEX FASPRO®. Fatal adverse reactions occurred in 5% of patients. Fatal adverse reactions occurring in more than 1 patient were general physical health deterioration, septic shock, and respiratory failure.

[0287] Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received DARZAEEX FASPRO®. Adverse reactions resulting in permanent discontinuation of DARZAEEX FASPRO® in more than 2 patients were thrombocytopenia and hypercalcemia.

[0288] Dosage interruptions due to an adverse reaction occurred in 26% of patients who received DARZALEX FASPRO®. Adverse reactions requiring dosage interruption in >5% of patients included thrombocytopenia.

[0289] The most common adverse reaction (>20%) was upper respiratory tract infection. Table 20 summarizes the adverse reactions in COLUMBA.Table 20: Adverse Reactions (>10%) in Patients Who Received DARZALEX FASPRO® or Intravenous Daratumumab in COLUMBAaUpper respiratory tract infection includes acute sinusitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, rhinovirus infection, sinusitis, andupper respiratory tract infection. b Pneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, and pneumonia. c Fatigue includes asthenia, and fatigue. d Infusion reactions includes terms determined by investigators to be related to infusion. e Cough includes cough, and productive cough. f Dyspnea includes dyspnea, and dyspnea exertional.#Only Grade 3 adverse reactions occurred.® Grade 5 adverse reactions occurred.

[0290] Clinically relevant adverse reactions in <10% of patients who receivedDARZALEX FASPRO® included:General disorders and administration site conditions: injection site reaction, peripheral edemaMusculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, muscle spasmsGastrointestinal disorders: constipation, vomiting, abdominal painMetabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydrationPsychiatric disorders: insomniaVascular disorders: hypertension, hypotensionNervous system disorders: dizziness, peripheral sensory neuropathy, paresthesiaInfections: bronchitis, influenza, urinary tract infection, herpes zoster, sepsis, hepatitis B virus reactivationSkin and subcutaneous tissue disorders: pruritus, rashCardiac disorders: atrial fibrillationRespiratory, thoracic and mediastinal disorders: pulmonary edema

[0291] Table 21 summarizes the laboratory abnormalities in COLUMBA.Table 21: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Receiving DARZALEX FASPRO® or Intravenous Daratumumab in COLUMBAaDenominator is based on the safety population treated with DARZALEX FASPRO®(N=260) and Intravenous Daratumumab (N=258).High-Risk Smoldering Multiple Myeloma

[0292] The safety of DARZALEX FASPRO® as monotherapy in patients with high-risk smouldering multiple myeloma was evaluated in AQUILA. Patients received DARZALEX FASPRO® 1,800 mg / 30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until 39 cycles or up to 36 months or until diagnosis of multiple myeloma or unacceptable toxicity.

[0293] The median duration of treatment for patients receiving DARZALEX FASPRO® was 35 months (0 to 36 months).

[0294] Serious adverse reactions occurred in 29% of patients who received DARZALEX FASPRO®. The most frequent serious adverse reactions in >2% of patients who received DARZALEX FASPRO® were pneumonia (7%), fracture (3%), sepsis (2%), and upper respiratory tract infection (2%). Fatal adverse reactions occurred in 1% of patients who received DARZALEX FASPRO®, including COVID-19 (0.5%) and pneumonia (0.5%).

[0295] Permanent treatment discontinuation due to an adverse reaction occurred in 6% of patients who received DARZALEX FASPRO®. Adverse reactions which resulted in permanent discontinuation of DARZALEX FASPRO® in more than 1 patient included fatigue, anxiety, and dyspnea.

[0296] Dosage interruptions of DARZALEX FASPRO® due to an adverse reaction occurred in 47% of patients. Adverse reactions which required dosage interruption in >5% of patients included upper respiratory infection, pneumonia, and COVID-19.

[0297] The most common adverse reactions (>20%) were upper respiratory tract infection, musculoskeletal pain, fatigue, diarrhea, rash, sleep disorder, sensory neuropathy, and injection site reactions.

[0298] Table 22 summarizes the adverse reactions in patients who received DARZALEX FASPRO® in AQUILA.Table 22: Adverse Reactions Reported in >10% of Patients with High-Risk Smoldering Multiple Myeloma and with at Least a 5% Greater Frequency in the DARZALEX FASPRO® Arm in AQUILAKey: ACTM=activc monitoring a Upper respiratory tract infection includes acute sinusitis, adenoviral upper respiratory infection, catarrh, influenza, influenza like illness, laryngitis, metapneumovirus infection, nasal congestion, nasopharyngitis, parainfluenzae virus infection, pharyngitis, respiratory tract congestion, respiratory tract infection, respiratory tract infection viral, sinus congestion, sinusitis, throat irritation, tonsillitis, tracheitis, upper respiratory tract congestion, upper respiratory tract infection, upper respiratory tract infection bacterial, upper-airway cough syndrome, and viral upper respiratory tract infection.bPneumonia includes covid- 19 pneumonia, lower respiratory tract infection, organizing pneumonia, pneumonia, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, and pneumonia viral.cRhinitis includes rhinitis, rhinitis atrophic, rhinorrhea, rhinovirus infection, and viral rhinitis.dMusculoskeletal pain includes arthralgia, axillary pain, back pain, breast pain, chest pain, facial spasm, fibromyalgia, flank pain, groin pain, muscle fatigue, muscle rupture, muscle spasms, muscle strain, muscle tightness, muscular weakness, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain, pain in extremity, pain in jaw, periarthritis, radicular pain, rotator cuff syndrome, spinal pain, spinal stenosis, and tendon pain.eFatigue includes asthenia, fatigue, and malaise.fInjection site reaction includes injection site discoloration, injection site erythema, injection site hemorrhage, injection site induration, injection site edema, injection site pain, injection site pruritus, injection site rash, injection site swelling, injection site urticaria, injection site vesicles, and injection site warmth.8Infusion-related reactions includes terms determined by investigators to be related to infusion.hEdema includes brain edema, eye swelling, eyelid edema, generalized edema, joint swelling, laryngeal edema, localized edema, edema, edema peripheral, peripheral swelling, post procedural edema, post procedural swelling, swelling face, and swelling of eyelid.1Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain. j Rash includes acne, dermatitis, dermatitis allergic, dermatitis bullous, dermatitis contact, drug eruption, drug hypersensitivity, eczema, eczema asteatotic, eczema infected, erysipelas, erythema, erythema multiforme, rash, rash erythematous, rash maculo-papular, rash papular, rash pruritic, seborrheic dermatitis, seborrheic keratosis, skin lesion, skin reaction, skin ulcer, and urticaria.kSleep disorder includes insomnia, restless legs syndrome, sleep apnea syndrome, sleep deficit, and sleep disorder.1Sensory neuropathy includes allodynia, anosmia, burning sensation, carpal tunnel syndrome, cervical radiculopathy, cervicobrachial syndrome, dysesthesia, hypoesthesia, hypoesthesia oral, paresthesia, paresthesia oral, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, pharyngeal paresthesia, polyneuropathy, and sensory disturbance.mHeadache includes headache, migraine, and vascular headache.nDizziness includes dizziness, and dizziness postural.0Cough includes cough, and productive cough.pDyspnea includes dyspnea, and dyspnea exertional.#Only Grade 3 adverse reactions occurred.cFatal adverse reactions occurred for Pneumonia: n= l (1%) in the DARZALEX FASPRO® arm.

[0299] Clinically relevant adverse reactions in <10% of patients who receivedDARZALEX FASPRO® included:Gastrointestinal disorders: constipation, vomitingSkin and subcutaneous tissue disorders: pruritusInfections: bronchitis, urinary tract infection, herpes zoster, sepsisGeneral disorders and administration site conditions: chillsMetabolism and nutrition disorders: decreased appetite, hyperglycemia, dehydrationNervous system disorders: syncopeVascular disorders: hypotension

[0300] Table 23 summarizes the laboratory abnormalities in patients who receivedDARZALEX FASPRO® in AQUILA.Table 23: Select Laboratory Abnormalities (>20%) that Worsened from Baseline in Patients with High-Risk Smoldering Multiple Myeloma Who Received DARZALEX FASPRO® in AQUILAKey: ACTM=activc monitoringaDenominator is based on number of subjects with a baseline and post-baseline laboratory value for each laboratory test: N= I 9 I for DARZALEX FASPRO® and N=191 for ACTM.Light Chain AmyloidosisIn Combination with Bortezomib, Cyclophosphamide and Dexamethasone

[0301] The safety of DARZALEX FASPRO® with bortezomib, cyclophosphamide and dexamethasone (DARZALEX FASPRO®-VCd) was evaluated in ANDROMEDA. Patients received DARZALEX FASPRO® 1,800 mg / 30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity or a maximum of 2 years. Among patients who received DARZALEX FASPRO®-VCd, 74% were exposed for 6 months or longer and 32% were exposed for greater than one year.

[0302] Serious adverse reactions occurred in 43% of patients who received DARZALEX FASPRO® in combination with VCd. Serious adverse reactions that occurred in at least 5% of patients in the DARZALEX FASPRO®-VCd arm were pneumonia (9%), cardiac failure (8%), and sepsis (5%). Fatal adverse reactions occurred in 11% of patients. Fatal adverse reactions that occurred in more than one patient included cardiac arrest (4%), sudden death (3%), cardiac failure (3%), and sepsis (1%).

[0303] Permanent discontinuation of DARZALEX FASPRO® due to an adverse reaction occurred in 5% of patients. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO® in more than one patient were pneumonia, sepsis, and cardiac failure.

[0304] Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 36% of patients who received DARZALEX FASPRO®. Adverse reactions which required a dosage interruption in >3% of patients included upper respiratory tract infection (9%), pneumonia (6%), cardiac failure (4%), fatigue (3%), herpes zoster (3%), dyspnea (3%), and neutropenia (3%).

[0305] The most common adverse reactions (>20%) were upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough.

[0306] Table 24 below summarizes the adverse reactions in patients who receivedDARZALEX FASPRO® in ANDROMEDA.Table 24: Adverse Reactions (>10%) in Patients with AL Amyloidosis Who Received DARZALEX FASPRO® with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO®-VCd) with a Difference Between Arms of >5% Compared to VCd in ANDROMEDA#Only Grade 3 adverse reactions occurred. a- Upper respiratory tract infection includes laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection, upper respiratory tract infection bacterial, and viral upper respiratory tract infection. b- Pneumonia includes lower respiratory tract infection, pneumonia, pneumonia aspiration, and pneumonia pneumococcal. c- Dyspnea includes dyspnea, and dyspnea exertional. - Cough includes cough, and productive cough. e- Arrhythmia includes atrial flutter, atrial fibrillation, supraventricular tachycardia, bradycardia, arrhythmia, bradyarrhythmia, cardiac flutter, extrasystoles, supraventricular extrasystoles, ventricular arrhythmia, ventricular extrasystoles, atrial tachycardia, ventricular tachycardia f- Injection site reactions includes terms determined by investigators to be related to daratumumab injection.

[0307] Clinically relevant adverse reactions not included in Table 21 and occurred in patients who received DARZALEX FASPRO® with bortezomib, cyclophosphamide and dexamethasone included:Skin and subcutaneous tissue disorders: rash, pruritusNervous system disorders: paresthesiaGeneral disorders and administration site conditions: infusion reaction, chillsCardiac disorders: cardiac failurea, cardiac arrestMetabolism and nutrition disorders: hyperglycemia, hypocalcemia, dehydrationInfections: bronchitis, herpes zoster, sepsis, urinary tract infection, influenzaVascular disorders: hypertensionMusculoskeletal and connective tissue disorders: musculoskeletal chest painGastrointestinal disorders: pancreatitisRespiratory, thoracic and mediastinal disorders: pulmonary edema a Cardiac failure includes cardiac dysfunction, cardiac failure, cardiac failure congestive, cardiovascular insufficiency, diastolic dysfunction, pulmonary edema, and left ventricular dysfunction occurred in 11 % of patients.

[0308] Table 25 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO® in ANDROMEDA.Table 25: Select Hematology Laboratory Abnormalities Worsening from Baseline in Patients Who Received DARZALEX FASPRO® with Bortezomib, Cyclophosphamide and Dexamethasone (DARZALEX FASPRO®-VCd) in ANDROMEDADenominator is based on the number of patients with a baseline and post-baseline laboratory value for each laboratory test, N=188 for DARZALEX FASPRO®-VCd and N= 186 for VCd.Cardiac Adverse Reactions in Light Chain (AL) Amyloidosis

[0309] Among patients who received DARZALEX FASPRO® in combination withVCd, 72% of patients had baseline cardiac involvement with Mayo Cardiac Stage I (3%), Stage II (46%) and Stage III (51%). Serious cardiac disorders occurred in 16% of patients (8% of patients with Mayo Cardiac Stage I and II and 28% of patients with Stage III). Serious cardiac disorders in >2% of patients included cardiac failure (8%), cardiac arrest (4%) and arrhythmia (4%). Fatal cardiac disorders occurred in 10% of patients (5% of patients with Mayo Cardiac Stage I and II and 19% of patients with StageIII) who received DARZALEX FASPRO® in combination with VCd. Fatal cardiac disorders that occurred in more than one patient in the DARZAEEX FASPRO®-VCd arm included cardiac arrest (4%), sudden death (3%), and cardiac failure (3%).Immunogenicity

[0310] As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other daratumumab products or other hyaluronidase products may be misleading.

[0311] With the median DARZAEEX FASPRO® treatment ranging from 6.5 to 56.6 months across 9 clinical trials of patients with smoldering multiple myeloma, multiple myeloma and light chain (AL) amyloidosis treated with DARZALEX® as monotherapy or as combination therapies, the incidence of anti-daratumumab antibody development was 0.6% (9 / 1,563) and 8 patients tested positive for neutralizing antibodies. Because of the low occurrence of anti-daratumumab antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and / or effectiveness of daratumumab products is unknown.With the median DARZALEX FASPRO® treatment ranging from 6.5 to 56.5 months across 9 clinical trials of patients with smoldering multiple myeloma, multiple myeloma and light chain (AL) amyloidosis treated with DARZALEX® as monotherapy or as combination therapies, the incidence of anti-rHuPH20 antibody development was 8.7% (136 / 1,555) and 1 patient tested positive for neutralizing antibodies. There was no identified clinically significant effect of anti-rHuPH20 antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of daratumumab products.Postmarketing Experience

[0312] The following adverse reactions have been identified with post-approval use of daratumumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Immune System: Anaphylactic reaction, Systemic administration reactions (including death)Gastrointestinal: PancreatitisInfections: Cytomegalovirus, ListeriosisDRUG INTERACTIONSEffects of Daratumumab on Laboratory TestsInterference with Indirect Antiglobulin Tests (Indirect Coombs Test)

[0313] Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, supply K-negative units after ruling out or identifying alloantibodies using DTT-treated RBCs.

[0314] If an emergency transfusion is required, administer non-cross-matched ABO / RhD-compatible RBCs per local blood bank practices.Interference with Serum Protein Electrophoresis and Immunofixation Tests

[0315] Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). False positive SPE and IFE assay results may occur for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In DARZALEX FASPRO®- treated patients with persistent very good partial response, where daratumumab interference is suspected, consider using a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient’s serum, to facilitate determination of a complete response.USE IN SPECIFIC POPULATIONSPregnancyRisk Summary

[0316] DARZALEX FASPRO® can cause fetal harm when administered to a pregnant woman. The assessment of associated risks with daratumumab products is based on themechanism of action and data from target antigen CD38 knockout animal models (see Data). There are no available data on the use of DARZALEX FASPRO® in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted.

[0317] The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

[0318] The combination of DARZALEX FASPRO® and lenalidomide, thalidomide or pomalidomide is contraindicated in pregnant women, because lenalidomide, thalidomide and pomalidomide may cause birth defects and death of the unborn child. Lenalidomide, thalidomide and pomalidomide are only available through a REMS program. Refer to the lenalidomide, thalidomide or pomalidomide prescribing information on use during pregnancy.Clinical ConsiderationsFetal / Neonatal Adverse Reactions

[0319] Immunoglobulin G1 (IgGl) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, DARZALEX FASPRO® may cause depletion of fetal CD38 positive immune cells and decreased bone density. Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed.DataAnimal Data

[0320] DARZALEX FASPRO® for subcutaneous injection contains daratumumab and hyaluronidase. Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. Data from studies using CD38 knockout animal models also suggest the involvement of CD38 in the regulation of humoral immune responses (mice), feto- maternal immune tolerance (mice), and early embryonic development (frogs).

[0321] No systemic exposure of hyaluronidase was detected in monkeys given 22,000U / kg subcutaneously (12 times higher than the human dose) and there were no effects onembryo-fetal development in pregnant mice given 330,000 U / kg hyaluronidase subcutaneously daily during organogenesis, which is 45 times higher than the human dose.

[0322] There were no effects on pre- and post-natal development through sexual maturity in offspring of mice treated daily from implantation through lactation with 990,000 U / kg hyaluronidase subcutaneously, which is 134 times higher than the human doses.LactationRisk Summary

[0323] There is no data on the presence of daratumumab and hyaluronidase in human milk, the effects on the breastfed child, or the effects on milk production. Maternal immunoglobulin G is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. Because of the potential for serious adverse reactions in the breastfed child when DARZALEX FASPRO® is administered with lenalidomide, thalidomide or pomalidomide, advise women not to breastfeed during treatment with DARZALEX FASPRO®. Refer to lenalidomide, thalidomide or pomalidomide prescribing information for additional information.DataAnimal Data

[0324] No systemic exposure of hyaluronidase was detected in monkeys given 22,000 U / kg subcutaneously (12 times higher than the human dose) and there were no effects on post-natal development through sexual maturity in offspring of mice treated daily during lactation with 990,000 U / kg hyaluronidase subcutaneously, which is 134 times higher than the human doses.Females and Males of Reproductive PotentialDARZALEX FASPRO® can cause fetal harm when administered to a pregnant woman.Pregnancy Testing

[0325] With the combination of DARZALEX FASPRO® with lenalidomide, thalidomide or pomalidomide, refer to the lenalidomide, thalidomide or pomalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential.Contraception

[0326] Advise females of reproductive potential to use effective contraception during treatment with DARZALEX FASPRO® and for 3 months after the last dose. Additionally, refer to the lenalidomide, thalidomide or pomalidomide labeling for additional recommendations for contraception.Pediatric Use

[0327] Safety and effectiveness of DARZALEX FASPRO® in pediatric patients have not been established.Geriatric Use

[0328] Of the 291 patients who received DARZALEX FASPRO® as monotherapy for relapsed and refractory multiple myeloma, 37% were 65 to <75 years of age, and 19% were 75 years of age or older. No overall differences in effectiveness of DARZALEX FASPRO® have been observed between patients >65 years of age and younger patients. Adverse reactions that occurred at a higher frequency (>5% difference) in patients >65 years of age included upper respiratory tract infection, urinary tract infection, dizziness, cough, dyspnea, diarrhea, nausea, fatigue, and peripheral edema. Serious adverse reactions that occurred at a higher frequency (>2% difference) in patients >65 years of age included pneumonia.

[0329] Of the 214 patients who received DARZALEX FASPRO® as combination therapy with pomalidomide and dexamethasone or DARZALEX FASPRO® as combination therapy with lenalidomide and low-dose dexamethasone for relapsed and refractory multiple myeloma, 43% were 65 to <75 years of age, and 18% were 75 years of age or older. No overall differences in effectiveness were observed between patients >65 years (n= 131 ) and <65 years (n=85). Adverse reactions occurring at a higher frequency (>5% difference) in patients >65 years of age included fatigue, pyrexia, peripheral edema, urinary tract infection, diarrhea, constipation, vomiting, dyspnea, cough, and hyperglycemia. Serious adverse reactions occurring at a higher frequency (>2% difference) in patients >65 years of age included neutropenia, thrombocytopenia, diarrhea, anemia, COVID- 19, ischemic colitis, deep vein thrombosis, general physical health deterioration, pulmonary embolism, and urinary tract infection.

[0330] Of the 355 patients who were newly diagnosed with multiple myeloma and eligible for ASCT who received DARZALEX FASPRO® as combination therapy withbortezomib, lenalidomide and dexamethasone during induction and consolidation in the clinical trial, 74% were <65 years of age, and 26% were 65 to 70 years of age. The clinical trial did not enroll patients older than 70 years of age. No overall differences in effectiveness of DARZALEX FASPRO® in combination with bortezomib, lenalidomide and dexamethasone were observed between patients <65 years of age compared to patients 65 to 70 years of age. Adverse reactions that occurred at a higher frequency (>5% difference) in patients 65 to 70 years of age included constipation, hemorrhoids, nausea, injection site erythema, bronchitis, nasopharyngitis, back pain, myalgia, pain in extremity, dysgeusia, peripheral motor neuropathy, and insomnia. Serious adverse reactions that occurred at a higher frequency (>2% difference) in patients 65 to 70 years of age included febrile bone marrow aplasia, atrial fibrillation, pyrexia, and orthostatic hypotension.

[0331] Of the 193 patients who received DARZALEX FASPRO® as monotherapy for high-risk smoldering multiple myeloma, 35% 01=67) were 65 to <75 years of age, and 11% (n=21) were 75 years of age and older. No overall difference in effectiveness were observed between patients 65 to 75 years (n=67) and <65 years (n=105); there were too few patients 75 years of age and older to assess for a difference in effectiveness. Adverse reactions that occurred at a higher frequency (>5% difference) in patients >65 years of age were pneumonia, dizziness, arrhythmia, hemorrhage, arthritis, and cataract. Serious adverse reactions occurring at a higher frequency (>5% difference) in patients >65 years of age included pneumonia and fracture.

[0332] Of the 193 patients who received DARZALEX FASPRO® as part of a combination therapy for light chain (AL) amyloidosis, 35% were 65 to <75 years of age, and 10% were 75 years of age or older. Clinical studies of DARZALEX FASPRO® as part of a combination therapy for patients with light chain (AL) amyloidosis did not include sufficient numbers of patients aged 65 and older to determine whether effectiveness differs from that of younger patients. Adverse reactions that occurred at a higher frequency in patients >65 years of age were peripheral edema, asthenia, pneumonia and hypotension.

[0333] No clinically meaningful differences in the pharmacokinetics of daratumumab were observed in geriatric patients compared to younger adult patients.CLINICAL STUDIESNewly Diagnosed Multiple MyelomaIn Combination with Bortezomib. Lenalidomide and Dexamethasone in Patients Eligible for Autologous Stem Cell Transplant

[0334] The efficacy of DARZALEX FASPRO® with bortezomib, lenalidomide and dexamethasone (DARZALEX FASPRO®-VRd) during induction and consolidation was evaluated in PERSEUS (NCT03710603), an open-label, randomized, active-controlled trial in patients with newly diagnosed multiple myeloma eligible for ASCT. Enrollment was limited to patients 70 years of age and younger.

[0335] Patients received DARZALEX FASPRO® 1,800 mg / 30,000 units administered subcutaneously once weekly from weeks 1 to 8 and once every 2 weeks from weeks 9 to 16 during induction. After week 16, patients underwent stem cell mobilization, high dose chemotherapy, and ASCT. Within 12 weeks of ASCT, and when engraftment was complete, patients received DARZALEX FASPRO® once every 2 weeks from weeks 1 to 8 during consolidation. Bortezomib was administered by subcutaneous injection at a dose of 1.3 mg / m2body surface area twice weekly for two weeks (days 1, 4, 8, and 11) of each 28-day cycle for weeks 1-16 during induction and weeks 1-8 during consolidation. Lenalidomide was administered orally at 25 mg daily (days 1-21) during weeks 1-16 during induction and weeks 1-8 during consolidation. Dexamethasone (oral or intravenous) was administered at 40 mg on Days 1-4 and Days 9-12 during weeks 1-16 during induction and weeks 1-8 during consolidation. On the days of DARZALEX FASPRO® injection, the dexamethasone dose was administered orally or intravenously as a pre-injection medication. Following consolidation, patients received an investigational treatment regimen for maintenance that included DARZALEX FASPRO® in combination with lenalidomide or lenalidomide alone. The trial was not designed to isolate the effect of DARZALEX FASPRO® in the maintenance phase of treatment. The efficacy of DARZALEX FASPRO® in combination with lenalidomide for maintenance has not been established.

[0336] The major efficacy outcome measure was progression-free survival (PFS) by independent review committee (IRC) based on IMWG response criteria.

[0337] A total of 709 patients were randomized: 355 to the DARZALEX FASPRO®-VRd arm and 354 to the VRd arm. The median age was 60 years (range: 31 to 70); 59% were male, 92% were White, 1 % were Black or African American, and 1 % were Asian. Fifty-one percent had ISS Stage I, 34% had ISS Stage II, 15% had ISS Stage III disease. High- risk cytogenetics (presence of del(17p), t(4; 14), t(14, 16)) were present in 22% of patients.

[0338] PERSEUS demonstrated an improvement in PFS in the DARZALEX 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).Table 26: Efficacy Results through End of Consolidation from PERSEUSCI=confidcncc interval a Based on intent-to-treat population b Exact 95% confidence interval c Based on threshold of 10"5using a next-generation sequencing assay (clonoSEQ) d Patients achieved both MRD negativity (threshold of 10"5) and response of CR or better e Based on patients with CR or better response by the end of consolidationIn Combination with Bortezomib, Melphalan and Prednisone

[0339] The efficacy of DARZALEX FASPRO® with bortezomib, melphalan and prednisone was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multicohort, open-label trial. Eligible patients were required to have newly diagnosed multiple myeloma who are ineligible for transplant. Patients received DARZALEX FASPRO®1,800 mg / 30,000 units administered subcutaneously once weekly from weeks 1 to 6, once every 3 weeks from weeks 7 to 54 and once every 4 weeks starting with week 55 until disease progression or unacceptable toxicity; bortezomib

[0340] 1.3 mg / m2subcutaneously twice weekly on Weeks 1, 2, 4 and 5 for the first 6-week cycle (Cycle 1 ; 8 doses), followed by once weekly on Weeks 1, 2, 4 and 5 for eight more 6-week cycles (Cycles 2- 9; 4 doses per cycle); and melphalan 9 mg / m2and prednisone 60 mg / m2orally on Days 1 to 4 of the nine 6-week cycles (Cycles 1-9). The major efficacy outcome measure was overall response rate (ORR).

[0341] A total of 67 patients received DARZALEX FASPRO® with VMP. The median age was 75 years (range: 66 to 86 years); 46% were male; 69% were White, 8% Asian, and 2% Black or African American; and 33% had ISS Stage I, 45% had ISS Stage II, and 22% had ISS Stage III disease.

[0342] Efficacy results are summarized in Table 27. The median duration of follow-up for patients was 6.9 months.Table 27: Efficacy Results from PLEIADES in Patients Who Received DARZALEX FASPRO®- VMPCl=conf idcncc interval a Based on treated patientsRelapsed / Refractory Multiple MyelomaIn Combination with Lenalidomide and Dexamethasone

[0343] The efficacy of DARZALEX FASPRO® with lenalidomide and dexamethasone(DARZALEX FASPRO®-Rd) was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multi- cohort, open-label trial. Patients received DARZALEX FASPRO® 1,800 mg / 30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity with lenalidomide 25 mgonce daily orally on Days 1-21 of each 28-day cycle; and dexamethasone 40 mg per week (or a reduced dose of 20 mg per week for patients >75 years or BMI <18.5). The major efficacy outcome measure was ORR.

[0344] A total of 65 patients received DARZALEX FASPRO® with Rd. The median age was 69 years (range: 33 to 82 years); 69% were male; 69% were White, and 3% Black or African American; and 42% had ISS Stage I, 30% had ISS Stage II, and 28% had ISS Stage III disease. Patients had received a median of 1 prior line of therapy. A total of 52% of patients had a prior ASCT; 95% of patients received a prior PI; 59% received a prior immunomodulatory agent, including 22% who received prior lenalidomide; and 54% of patients received both a prior PI and immunomodulatory agent.

[0345] Efficacy results are summarized in Table 28. The median duration of follow-up for patients was 7.1 months.Table 28: Efficacy Results from PLEIADES in Patients Who ReceivedDARZALEX FASPRO®-RdCl=confidence interval a Based on treated patientsIn Combination with Pomalidomide and Dexamethasone

[0346] The efficacy of DARZALEX FASPRO® with pomalidomide and dexamethasone (DARZALEX FASPRO®-Pd) versus pomalidomide and dexamethasone (Pd) alone was evaluated in APOLLO (NCT03180736), an open-label, randomized, active-controlled trial. Patients received DARZALEX FASPRO® 1,800 mg / 30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity with pomalidomide 4 mg once daily orally on Days 1-21 of each 28-day cycle;and dexamethasone 40 mg per week (or a reduced dose of 20 mg per week for patients >75 years). The major efficacy outcome measure was progression-free survival (PFS).

[0347] A total of 304 patients were randomized: 151 to the DARZALEX FASPRO®-Pd arm and 153 to the Pd arm. The median age was 67 years (range: 35 to 90); 53% were male and 89% were White, <1% were Black or African American, and <1% were Asian, and 45% had ISS Stage I, 33% had ISS Stage II, and 22% had ISS Stage III disease. Patients had received a median of 2 prior lines of therapy (range 1-5), with 11% of patients having received 1 prior line of therapy and 75% of patients having received 2-3 prior lines of therapy. All patients received a prior treatment with a PI and lenalidomide, and 56% of patients received prior AS CT. The majority of patients were refractory to lenalidomide (80%), a PI (48%), or both an immunomodulatory agent and a PI (42%). APOLLO demonstrated an improvement in PFS in the DARZALEX FASPRO®-Pd treatment group as compared to the Pd treatment group; the median PFS was 12.4 months in the DARZALEX FASPRO®-Pd treatment group and 6.9 months in the Pd treatment group (HR [95% CI]: 0.63 [0.47, 0.85]; p-value = 0.0018), representing a 37% reduction in the risk of disease progression or death for patients treated with DARZALEX FASPRO®-Pd versus Pd.

[0348] Additional efficacy results from APOLLO are presented in Table 29.Table 29: Efficacy results from APOLLOaPd=pomalidomide-dexamethasone; MRD=minimal residual disease; CI=confidence interval a. Based on intent- to-treat population b. p-value from Cochran Mantel-Haenszel Chi-Squared test adjusted for stratification factors c. Based on the intent- to-treat population d. p-value from Fisher’ s exact test. e. Based on threshold of 10'5using a next-generation sequencing assay (clonoSEQ).

[0349] In responders, the median time to response was 1 month (range: 0.9 to 9.1 months) in the DARZALEX FASPRO®-Pd group and 1.9 months (range: 0.9 to 17.3 months) in the Pd group. The median duration of response had not been reached in the DARZALEX FASPRO®-Pd group (range: 1 to 34.9+ months) and was 15.9 months (range: 1+ to 24.8 months) in the Pd group.

[0350] With a median follow-up of 16.9 months, 99 deaths were observed; 48 in the DARZALEX FASPRO®-Pd group and 51 in the Pd group. Median OS was not reached for either treatment group.In Combination with Carfilzomib and Dexamethasone

[0351] The efficacy of DARZALEX FASPRO® with carfilzomib and dexamethasone (DARZALEX FASPRO®-Kd) was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multi- cohort, open-label trial. This cohort enrolled patients with relapsed or refractory multiple myeloma excluding patients with left ventricular ejection fraction (LVEF) less than 40%, myocardial infarction within 6 months, uncontrolled cardiac arrhythmia, or uncontrolled hypertension (systolic blood pressure >159 mmHg or diastolic >99 mmHg despite optimal treatment). Patients received DARZALEX FASPRO® 1,800 mg / 30,000 units administered subcutaneously once weekly from Weeks 1 to 8, once every 2 weeks from Weeks 9 to 24 and once every 4 weeks starting with Week 25 until disease progression or unacceptable toxicity with carfilzomib administered by IV infusion at a dose of 20 mg / m2on Cycle 1 Day 1 and if a dose of 20 mg / m2was tolerated, carfilzomib was administered at a dose of 70 mg / m2as a 30-minute IV infusion, on Cycle 1 Day 8 and Day 15, and then Day 1, 8 and 15 of each cycle and dexamethasone 40 mg per week (or a reduced dose of 20 mg per week for patients >75 years or BMI < 18.5). The major efficacy outcome measure was ORR.

[0352] A total of 66 patients received DARZALEX FASPRO® with Kd. The median age was 61 years (range: 42 to 84); 52% were male; 73% were White and 3% Black orAfrican American; and 68% had ISS Stage I, 18% had ISS Stage II, and 14% had ISS Stage III disease. A total of 79% of patients had a prior ASCT; 91% of patients received a prior PI. All patients received 1 prior line of therapy with exposure to lenalidomide and 62% of patients were refractory to lenalidomide.

[0353] Efficacy results are summarized in Table 30. At a median follow-up of 9.2 months, the median duration of response had not been reached and an estimated 85.2% (95% CI: 72.5, 92.3) maintained response for at least 6 months and 82.5% (95% CI: 68.9, 90.6) maintained response for at least 9 months.Table 30: Efficacy Results from PLEIADES in Patients Who Received DARZALEX FASPROO-KdCl=confidence interval a Based on treated patientsMonotherapy

[0354] The efficacy of DARZALEX FASPRO® as monotherapy was evaluated in COLUMBA (NCT03277105), an open-label, randomized, non-inferiority study. Eligible patients were required to have relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who were double -refractory to a proteasome inhibitor and an immunomodulatory agent. Patients were randomized to receive DARZALEX FASPRO® 1,800 mg / 30, 000 units administered subcutaneously or daratumumab 16 mg / kg administered intravenously; each administered once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until unacceptable toxicity or disease progression. The major efficacy outcome measures were ORR by the IMWG response criteria for SMM and maximum Ctrough at pre-doseCycle 3 Day. Randomization was stratified by body weight, myeloma type, and number of prior lines of therapy.

[0355] A total of 522 patients were randomized: 263 to the DARZALEX FASPRO® arm and 259 to the intravenous daratumumab arm. The median age was 67 years (range: 33 to 92 years); 55% were male; and 78% were White, 14% Asian, and 3% Black or African American. The median weight was 73 kg (range: 29 to 138). Patients had received a median of 4 prior lines of therapy. A total of 51 % of patients had a prior ASCT ; 100% of patients received both a PI and an immunomodulatory agent. Forty-nine percent of patients were refractory both a PI and an immunomodulatory agent. Eighty-two percent of patients were refractory to their last line of prior systemic therapy.

[0356] The results show that DARZAEEX FASPRO® 1 ,800 mg / 30,000 units administered subcutaneously is non-inferior to daratumumab 16 mg / kg administered intravenously in terms of ORR and maximum trough concentration. Median progression- free survival was 5.6 months in the DARZAEEX FASPRO® arm and 6.1 months in the intravenous daratumumab arm. ORR results are provided in Table 31.Table 31: Efficacy Results from COLUMBAaBased on intent-to-treat population.High-Risk Smoldering Multiple Myeloma

[0357] The efficacy of DARZALEX FASPRO® as monotherapy versus active monitoring was evaluated in AQUILA (NCT03301220), an open-label, randomized trial in patients with high-risk smoldering multiple myeloma.

[0358] Patients randomized to the treatment arm received DARZALEX FASPRO® 1,800 mg / 30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25until 39 cycles or up to 36 months or until diagnosis to multiple myeloma or unacceptable toxicity.

[0359] The major efficacy outcome measure was progression-free survival (PFS) by independent review committee (IRC) as defined as the diagnosis of multiple myeloma based on the IMWG diagnostic criteria for multiple myeloma or death.

[0360] A total of 390 patients were randomized: 194 to the DARZALEX FASPRO® arm and 196 to the active monitoring arm. The median age was 64 years (range: 31 to 86); 12% were >75 years; 48% were male; 83% White, 8% Asian, and 3% were Black or African American. Forty-one percent of patients had 2 or more of the following criteria for high-risk smoldering multiple myeloma: serum monoclonal protein level >2 g / dE, involved- to-uninvolved serum-free light chain ratio >20, and bone marrow plasma cells >20%. DARZALEX FASPRO® is only indicated for patients with high-risk smoldering multiple myeloma. It is not indicated for other risk categories.

[0361] PFS results are shown in FIG. 2. Additional efficacy results from AQUILA are presented in Table 32.Table 32: Efficacy Results from AQUILAaBased on intent-to-treat population per investigator assessmentLight Chain AmyloidosisIn Combination with Bortezomib, Cyclophosphamide and Dexamethasone

[0362] The efficacy of DARZALEX FASPRO® with VCd was evaluated in ANDROMEDA (NCT03201965), an open-label, randomized, active-controlled trial. Eligible patients were required to have newly diagnosed light chain (AL) amyloidosis with at least one affected organ, measurable hematologic disease, Cardiac Stage I-IIIA (based on European Modification of Mayo 2004 Cardiac Stage), and NYHA Class I- IIIA. Patients with NYHA Class IIIB and IV were excluded. Patients were randomized toreceive bortezomib 1.3 mg / m2administered subcutaneously, cyclophosphamide 300 mg / m2(max dose 500 mg) administered orally or intravenously, and dexamethasone 40 mg (or a reduced dose of 20 mg for patients >70 years or body mass index <18.5 or who have hypervolemia, poorly controlled diabetes mellitus or prior intolerance to steroid therapy) administered orally or intravenously on Days 1, 8, 15, and 22 of each 28-day cycle with or without DARZALEX FASPRO® 1,800 mg / 30,000 units subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or a maximum of two years.When DARZALEX FASPRO® and dexamethasone were administered on the same day, dexamethasone 20 mg was administered before DARZALEX FASPRO® with the remaining dose of dexamethasone administered after DARZALEX FASPRO® if applicable. The major efficacy outcome measure was confirmed hematologic complete response (HemCR) rate based on Consensus Criteria as determined by the Independent Review Committee (negative serum and urine immunofixation, involved free light chain level decrease to less than the upper limit of normal, and normal free light chain ratio). Randomization was stratified by Cardiac Stage (European Modification of Mayo 2004 Cardiac Stage) countries that typically offer autologous stem cell transplant (ASCT) for patients with light chain (AL) amyloidosis, and renal function.

[0363] A total of 388 patients were randomized: 195 to DARZALEX FASPRO®-VCd and 193 to VCd. The median patient age was 64 years (range: 34 to 87 years); 58% were male; 76% White, 17% Asian, and 3% Black or African American; 23% had light chain (AL) amyloidosis Cardiac Stage 1, 40% had Stage II, and 37% had Stage IIIA. The median number of organs involved was 2 (range: 1-6) and 66% of patients had 2 or more organs involved. Vital organ involvement was: cardiac 71%, renal 59% and hepatic 8%. The majority (79%) of patients had lambda free light chain disease.

[0364] Efficacy results are summarized in Table 33.Table 33: Efficacy results from ANDROMEDA3VCd=bortezomib-cyclophosphamide-dexamethasone a. Based on intent- to-treat population b. p-value from Cochran Mantel-Haenszel Chi-Squared test. c. Major organ deterioration-PFS defined as hematologic progression, major organ (cardiac or renal) deterioration or death

[0365] The median time to HemCR was 59 days (range: 8 to 299 days) in the DARZALEX FASPRO®- VCd arm and 59 days (range: 16 to 340 days) in the VCd arm. The median time to VGPR or better was 17 days (range: 5 to 336 days) in the DARZALEX FASPRO®-VCd arm and 25 days (range: 8 to 171 days) in the VCd arm. The median duration of HemCR had not been reached in either arm.

[0366] The median follow-up for the study is 11.4 months. Overall survival (OS) data were not mature. A total of 56 deaths were observed |N=27 (13.8%) DARZALEX FASPRO®-VCd vs. N=29 (15%) VCd group], HOW SUPPLIED / STORAGE AND HANDLING

[0367] DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) injection is a sterile, preservative- free, colorless to yellow, and clear to opalescent solution for subcutaneous use supplied as individually packaged single-dose vials providing 1,800 mg of daratumumab and 30,000 units of hyaluronidase per 15 mL (NDC 57894-503-01).

[0368] Store DARZALEX FASPRO® vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

[0369] Do not freeze or shake.SEQUENCE LISTING

Claims

CLAIMSWhat is claimed is:

1. A method of treating high-risk smoldering multiple myeloma (HR-SMM) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-CD38 antibody.

2. The method of claim 1, wherein the method provides an improvement in progression free survival (PFS), overall response rate (ORR), rate of partial response (PR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of stringent CR (sCR), progression-free survival on first-line treatment for multiple myeloma (PFS 2), or overall survival (OS).

3. The method of claim 1 or 2, wherein the anti-CD38 antibody comprises a CD38 binding domain 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.

4. The method of any of claims 1-3, wherein the CD38 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 8.

5. The method of any of claims 1-4, wherein the anti-CD38 antibody is an IgGl, an IgG2, an IgG3 or an IgG4 isotype.

6. The method of any of claims 1-5, wherein the anti-CD38 antibody is an IgGl isotype.

7. The method of any of claims 1-6, wherein the anti-CD38 antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10.

8. The method of any of claims 1-7, wherein the anti-CD38 antibody is daratumumab, or a daratumumab biosimilar.

9. The method of any of claims 1-8, wherein the anti-CD38 antibody is administered as a monotherapy.

10. The method of any of claims 1-9, comprising subcutaneously administering the anti-CD38 antibody.

11. The method of any of claims 1-10, wherein the anti-CD38 antibody is administered in a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody.

12. The method of claim 11, wherein the anti-CD38 antibody is administered in a pharmaceutical composition comprising the anti-CD38 antibody and a hyaluronidase.

13. The method of claim 12, wherein the hyaluronidase comprises a recombinant human hyaluronidase.

14. The method of any of claims 1-13, wherein the recombinant human hyaluronidase has an amino acid sequence of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 16.

15. The method of any of claims 1-14, wherein the pharmaceutical composition comprises a mixture of recombinant human hyaluronidases with the amino acid sequences of one or more of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

16. The method of any of claim 1-15, wherein the pharmaceutical composition comprises about 1,800 mg of the anti-CD38 antibody and about 30,000 U of hyaluronidase.

17. The method of claim 16, wherein the pharmaceutical composition comprises about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of hyaluronidase.

18. The method of any of claims 1-17, wherein the pharmaceutical composition comprises one or more excipients.

19. The method of claim 18, wherein at least one of said excipients is histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

20. The method of any of claims 1-19, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of the anti-CD38 antibody; about 30,000 U of hyaluronidase; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.

21. The method of claim 20, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises:about 120 mg / mL of the anti-CD38 antibody; about 2,000 U / mL of hyaluronidase; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.

22. The method of any of claims 1-21, wherein the pharmaceutical composition is at a pH of about 5.6, and wherein the pharmaceutical composition comprises: about 1,800 mg of daratumumab or a daratumumab biosimilar; about 30,000 U of recombinant human hyaluronidase; about 10 mM histidine; about 300 mM sorbitol; about 0.04 % (w / v) PS-20; and about 1 mg / mL methionine.

23. The method of any of claims 1-22, wherein the anti-CD38 antibody is administered at a dose of about 1,800 mg once a week, about 1,800 mg once in two weeks, or about 1,800 mg once in four weeks.

24. The method of any of claims 1-23, comprising treating the subject according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles.

25. The method of any of claims 1-24, comprising administering the anti-CD38 antibody once a week for two treatment cycles.

26. The method of any of claims 1-25, comprising administering the anti-CD38 antibody once every two weeks for four treatment cycles.

27. The method of any of claims 1-26, comprising administering the anti-CD38 antibody once every four weeks until 39 cycles or up to 36 months, or confirmed disease progression, whichever occurs first.

28. The method of any of claims 1-27, comprising administering the anti-CD38 antibody according to a regimen comprising 28-day cycles wherein the regimen comprises: in Cycles 1 to 2, administering the anti-CD38 antibody once a week, in Cycles 3 to 6, administering the anti-CD38 antibody once every two weeks, and then administering the anti-CD38 antibody once every 4 weeks.

29. The method of any of claims 1-28, wherein the subject has not received prior SMM directed therapy.

30. The method of any of claims 1-29, wherein the subject does not have active multiple myeloma.

31. The method of claim 30, wherein the method achieves a clinical response in the subject that is progression free survival (PFS).

32. The method of claim 31, wherein the method achieves a clinical response in the subject that is a partial response (PR), a very good partial response (VGPR), a complete response (CR) or a stringent complete response (sCR).

33. The method of any of claims 1-32, wherein the method achieves PFS in a population of subjects with HR-SMM of 60% or higher.

34. The method of any of claims 1-33, wherein the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM of 60% or higher.

35. The method of any of claims 1-34, wherein the method achieves a PFS2 rate in a population of subjects with HR-SMM of 85% or higher.

36. The method of any of claims 1-35, wherein the method achieves an OS rate in a population of subjects with HR-SMM of 90% or higher.

37. The method of any of claims 1-36, wherein, after the subject has received at least 38 28-day cycles of treatment with the anti-CD38 antibody, the subject’s HR-SMM does not progress.

38. The method of any of claims 1-37, wherein administration of the anti-CD38 antibody to the subject for a maximum of 39 28-day treatment cycles prevents the subject from developing multiple myeloma.

39. The method of any of claims 1-38, wherein the method prevents the subject from developing MM.

40. The method of any of claims 1-39, wherein the method achieves a rate of progression free survival in a population of subjects with HR-SMM that is greater than a rate PFS achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.

41. The method of any of claims 1-40, wherein, the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM that is greater than anORR achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.

42. The method of any of claims 1-41, wherein the method achieves a percentage of overall survival (OS) in a population of subjects with HR-SMM that is greater than a percentage of OS achieved in a reference population of subjects with HR-SMM, said reference population having not been administered the anti-CD38 antibody.

43. A method of treating HR-SMM in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of daratumumab.

44. A method of treating HR-SMM in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a daratumumab biosimilar.

45. A pharmaceutical composition for use in treating HR-SMM in a subject in need thereof, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of an anti-CD38 antibody.

46. The use of claim 45, wherein the anti-CD38 antibody is daratumumab.

47. The use of claim 45, wherein the anti-CD38 antibody is a daratumumab biosimilar.

48. A use of a pharmaceutical composition for the manufacture of a medicament for the treatment of HR-SMM in a subject in need thereof, wherein the pharmaceutical composition comprises a therapeutically safe and effective amount of an anti-CD38 antibody.

49. The use of claim 48, wherein the anti-CD38 antibody is daratumumab.

50. The use of claim 48, wherein the anti-CD38 antibody is a daratumumab biosimilar.

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