Methods of treating newly diagnosed multiple myeloma with a combination of an antibody that specifically binds to CD38, lenalidomide, and dexamethasone

Abstract

Disclosed herein are methods of treating multiple myeloma using an antibody that specifically binds to CD38 in combination with lenalidomide and dexamethasone.

Description

[Technical Field]

[0001] Disclosed herein are methods of treating multiple myeloma using an antibody that specifically binds to CD38 in combination with lenalidomide and dexamethasone.

[0002] (Sequence Listing) This application contains a Sequence Listing submitted via EFS-Web, which is incorporated herein by reference in its entirety. The ASCII text file, created on February 20, 2020, has the file name JBI6048WOPCT1ST25.txt and is 13 kilobytes in size. [Background technology]

[0003] Multiple myeloma is a malignant disease of plasma cells characterized by the uncontrolled and progressive proliferation of plasma cell clones, which leads to progressive morbidity and eventual mortality by reducing resistance to infection and causing significant skeletal destruction (with bone pain, pathological fractures, and hypercalcemia), anemia, renal failure, neurological complications, and hypercalcemia syndrome.

[0004] Despite the availability of multiagent therapies, multiple myeloma remains incurable with standard chemotherapy. Summary of the Invention [Problem to be solved by the invention]

[0005] There remains a need for new treatment options in a cutting-edge setting that can better control disease and provide deeper, more durable responses and better long-term outcomes, including preservation of health-related quality of life. [Means for solving the problem]

[0006] The present disclosure provides methods of treating a subject newly diagnosed with multiple myeloma, comprising administering to the subject a combination therapy comprising daratumumab, lenalidomide, and dexamethasone, wherein the method achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is administered a combination of lenalidomide and dexamethasone.

[0007] The present disclosure also provides a method of treating a subject with newly diagnosed multiple myeloma who is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT), comprising administering or providing for the administration of daratumumab to the subject, wherein the daratumumab is administered in combination with lenalidomide and dexamethasone, and the method achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is administered a combination of lenalidomide and dexamethasone.

[0008] The present disclosure also provides a method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy that has been demonstrated to increase the likelihood of achieving a very good partial response (VGPR) or better in subjects with multiple myeloma, the combination therapy comprising daratumumab, lenalidomide, and dexamethasone.

[0009] The present disclosure also provides a method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy that has been demonstrated to increase the likelihood of achieving minimal residual disease (MRD) negativity in subjects with newly diagnosed multiple myeloma, the combination therapy comprising daratumumab, lenalidomide, and dexamethasone.

[0010] The present disclosure also provides a method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy that has been demonstrated to increase the likelihood of achieving a complete response (CR) or better in subjects with newly diagnosed multiple myeloma, the combination therapy comprising daratumumab, lenalidomide, and dexamethasone.

[0011] The present disclosure also provides a method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy demonstrated to reduce the risk of multiple myeloma progression or death in subjects with newly diagnosed multiple myeloma, the combination therapy comprising daratumumab, lenalidomide, and dexamethasone.

[0012] The present disclosure also includes a method of treating a subject with newly diagnosed multiple myeloma, comprising: Providing daratumumab to healthcare professionals (HCPs) and providing information to an HCP that treating the subject with the combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject was treated with a combination of lenalidomide and dexamethasone, wherein performing steps a) and b) results in the subject with newly diagnosed multiple myeloma receiving, by an HCP or by self-administration as directed by an HCP, the combination therapy comprising daratumumab, lenalidomide, and dexamethasone, thereby treating the subject with newly diagnosed multiple myeloma.

[0013] The disclosure also provides a method of providing daratumumab to an HCP for treating a subject with newly diagnosed multiple myeloma with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone, wherein the treatment with the combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is treated with a combination of lenalidomide and dexamethasone; manufacturing daratumumab; providing the HCP with information that treatment with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint; and transporting the daratumumab to the HCP or an authorized distributor of daratumumab for the HCP to purchase the daratumumab, thereby providing the HCP with daratumumab.

[0014] The disclosure also provides a method for an HCP to provide a treatment option for treating a subject with newly diagnosed multiple myeloma with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone, wherein treatment with the combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is treated with a combination of lenalidomide and dexamethasone; manufacturing daratumumab; providing the HCP with information that a combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint; and transporting daratumumab to the HCP or an authorized distributor of daratumumab for the HCP to purchase the daratumumab, thereby providing a treatment option for the HCP. [Brief explanation of the drawings]

[0015] The Summary of the Invention, as well as the Detailed Description that follows, will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the disclosed method, there are shown in the drawings exemplary embodiments of the method. However, the method is not limited to the particular embodiments disclosed therein. The drawings are as follows: [Figure 1] Kaplan-Meier estimates of progression-free survival among patients in the intention-to-treat population are shown. The daratumumab (DARZALEX®) group received treatment with daratumumab (DARZALEX®), lenalidomide, and dexamethasone. The control group received treatment with lenalidomide and dexamethasone. An interim analysis of progression-free survival was performed after 240 events of disease progression or death had occurred (62% of the 390 events planned for the final analysis). [Figure 2]Results of an analysis of progression-free survival in prespecified subgroups within the intent-to-treat population are shown. The daratumumab (DARZALEX®) group received treatment with daratumumab (DARZALEX®), lenalidomide, and dexamethasone. The control group received treatment with lenalidomide and dexamethasone. International Staging System (ISS) stages were derived based on a combination of serum beta-2-microglobulin and albumin levels, with higher stages indicating more advanced disease. Baseline liver dysfunction included mild impairment (total bilirubin levels below the upper limit of the normal range (ULN) and aspartate aminotransferase levels above the ULN, or total bilirubin levels above the ULN and ≤1.5x the ULN), moderate impairment (total bilirubin levels above 1.5x the ULN and ≤3x the ULN), and severe impairment (total bilirubin levels above 3x the ULN). Subgroup analysis by myeloma type was performed on data from patients with measurable disease in serum or urine. A high-risk cytogenetic profile was defined by the detection of del17p, t(14;16), and / or t(4;14) cytogenetic abnormalities on fluorescent in situ hybridization or karyotype. Eastern Cooperative Oncology Group (ECOG) performance status was scored on a scale of 0 to 5, with 0 indicating no symptoms and higher scores indicating worsening disability. NE indicates probable disability. DETAILED DESCRIPTION OF THE INVENTION

[0016] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if fully set forth.

[0017] It is understood that certain features of the invention that are described herein for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. That is, unless expressly incompatible or specifically excluded, each individual embodiment is considered combinable with any other embodiment, and such combinations are considered to be separate embodiments. Conversely, different features of the invention that are described for simplicity in the context of a single embodiment may also be provided separately or in any subcombination. Finally, while embodiments may be described as part of a series of steps or as part of a more general structure, each step may be considered an independent embodiment in itself and may be combined with others.

[0018] When lists are presented, it is to be understood that each individual element of that list and every combination of that list is a separate embodiment, unless otherwise specified. For example, a list of embodiments presented as "A, B, or C" should be interpreted to include the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0019] "About" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on the limitations of the method, i.e., measurement system, by which the value is measured or determined. Unless expressly stated otherwise in the examples or elsewhere in the specification in the context of a particular assay, result, or embodiment, "about" means within one standard deviation or a range of up to 5%, whichever is greater, according to practice in the art.

[0020] "About once a week" refers to an approximate number and can include every 7 days ± 2 days, i.e., every 5 days to every 9 days. Thus, the administration frequency of "once a week" can be every 5 days, every 6 days, every 7 days, every 8 days, or every 9 days.

[0021] "About once every two weeks" refers to an approximate number and can include every 14 days ±2 days, ie, every 12 days to every 16 days.

[0022] "About once every three weeks" refers to an approximate number and can include every 21 days ±2 days, i.e., every 19 days to every 23 days.

[0023] "About once every four weeks" refers to an approximate number and can include every 28 days ±2 days, i.e., every 26 days to every 30 days.

[0024] "About once every 5 weeks" refers to an approximate number and can include every 35 days ± 2 days, i.e., every 33 days to every 37 days.

[0025] "About once every six weeks" refers to an approximate number and can include every 42 days ± 2 days, ie, every 40 days to every 38 days.

[0026] "About twice a week" refers to an approximate number and can include twice a week, for example, a first administration on day 1 and a second administration on day 2, 3, 4, 5, 6, or 7 of the week; a first administration on day 2 and a second administration on day 3, 4, 5, 6, or 7 of the week; a first administration on day 3 and a second administration on day 4, 5, 6, or 7 of the week; a first administration on day 4 and a second administration on day 5, 6, or 7 of the week; a first administration on day 5 and a second administration on day 6 or 7 of the week; or a first administration on day 6 and a second administration on day 7 of the week.

[0027] An "adverse event" (AE) refers to any untoward medical occurrence in a clinical study subject administered an antibody that specifically binds CD38, such as daratumumab. An AE does not necessarily have a causal relationship to treatment. Thus, an AE can be any untoward and unintended sign (including an abnormal finding), symptom, or disease that is temporally associated with the use of a medicinal product (investigational or non-investigational), whether or not related to an antibody that specifically binds CD38, such as daratumumab.

[0028] The connective term "and / or" between multiple listed elements is understood to encompass both individual and combined alternatives. For example, when two elements are connected by "and / or," the first alternative refers to the first element being applicable without the second element. The second alternative refers to the second element being applicable without the first element. The third alternative refers to the first and second elements being applicable together. Any one of these alternatives is understood to be within the meaning and therefore meets the requirements of the term "and / or" as used herein. The simultaneous applicability of two or more of the alternatives is also understood to be within the meaning and therefore meets the requirements of the term "and / or."

[0029] "Antibody" includes immunoglobulin molecules belonging to any class, IgA, IgD, IgE, IgG, and IgM, or subclasses, IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4, and containing either kappa (κ) or lambda (λ) light chains. Antibodies include monoclonal antibodies, including human, humanized, and chimeric monoclonal antibodies. A full-length antibody molecule is composed of two heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (consisting of domains CH1, hinge, CH2, and CH3). Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs), interspersed with framework regions (FRs). Each VH and VL is composed of three CDR and four FR segments, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0030] "Biosimilar" (of an approved reference product / biological product) refers to a biological product that is closely similar to the reference product, with minor differences in clinically inactive ingredients, but with no clinically meaningful differences between the biosimilar and the reference product in terms of safety, purity, and potency, based on data obtained from the following: (a) analytical studies that demonstrate that the biological product is closely similar to the reference product, with minor differences in clinically inactive ingredients, (b) animal studies (including evaluation of toxicity), and / or (c) clinical study(s) (including evaluation of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate safety, purity, and potency under one or more appropriate conditions of use, such as the conditions for which the reference product is licensed and the conditions for which the reference product is intended to be used, and the conditions for granting licensure to the biosimilar. A biosimilar may be an interchangeable product that can be substituted for the reference product in pharmacies without the intervention of a prescribing healthcare professional. To comply with additional standards of "interchangeability," a biosimilar is required to produce the same clinical results as the reference product in any given patient, and when a biosimilar is administered multiple times to an individual, the risks of reduced safety or efficacy resulting from alternating or switching between the use of the biosimilar and the reference product do not outweigh the risks associated with using the reference product without such alternation or switching. To the extent the mechanism of action of the reference product is known, the biosimilar utilizes the same mechanism of action for the proposed conditions of use. The conditions of use specified, recommended, or suggested in the proposed labeling for the biosimilar are already approved for the reference product. The route of administration, dosage form, and / or strength of the biosimilar are the same as those of the reference product, and the biosimilar is manufactured, processed, packaged, or held in facilities meeting standards designed to ensure the continued maintenance of safety, purity, and strength of the biosimilar. Biosimilars may contain minor modifications of the amino acid sequence (e.g., N- or C-terminal truncations) that are not expected to alter the performance of the biosimilar when compared to the reference product.

[0031] "Cancer" refers to an abnormal growth of cells that tends to grow uncontrolled and, in some cases, metastasize (spread) to other areas of the patient's body.

[0032] "CD38" refers to the 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.

[0033] A "clinical efficacy endpoint" or "clinical endpoint" refers to an outcome that represents clinical benefit, such as progression-free survival (PFS), time to disease progression (TTP), time to next treatment, overall response rate (ORR), proportion of subjects achieving a partial response (PR), proportion of subjects achieving a very good partial response (VGPR), proportion of subjects achieving a complete response (CR), proportion of subjects achieving a stringent complete response (sCR), proportion of subjects achieving minimal residual disease (MRD), or proportion of subjects achieving both sCR and MRD negativity.

[0034] "Clinically proven" refers to clinical efficacy results sufficient to meet the approval standards of the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or a corresponding national regulatory agency. For example, a clinical study may be an appropriately sized randomized, double-blind, controlled trial used to clinically prove the effectiveness of a drug.

[0035] "Co-administration," "administration with," "administration in combination with," "in combination with," and the like are intended to encompass administration of selected therapeutic agents or drugs to a single patient, and include therapeutic regimens in which the therapeutic agents or drugs are administered by the same or different routes of administration or at the same or different times.

[0036] "Combination" refers to a combination of two or more therapeutic agents or drugs that can be administered either together or separately.

[0037] "Complementarity-determining regions (CDRs)" are the "antigen-binding sites" of antibodies. CDRs can be defined based on sequence variability (Wu and Kabat, J Exp Med 132:211-250, 1970; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991) or alternative delineations (see Lefranc et al., Dev Comparat Immunol 27:55-77, 2003). The International ImMunoGeneTics (IMGT) database (http: / / www_imgt_org) provides standardized numbering and definitions of antigen-binding sites.

[0038] "Complete response rate or better" (CR rate or better) refers to the proportion of subjects who achieve a CR or stringent complete response (sCR) during or after treatment.

[0039] "Comprising," "consisting essentially of," and "consisting of" are intended to connote their generally accepted meanings in patent terminology, i.e., (i) "comprising" is synonymous with "comprising," "containing," or "characterized by" and is inclusive or open-ended and does not exclude other 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 the claim to the specified materials or steps and those that do not materially affect the "basic and novel characteristic(s)" of the claimed invention. Embodiments described with the phrase "comprising" (or its equivalents) also provide, as embodiments, those described independently with the terms "consisting of" and "consisting essentially of."

[0040] "Corticosteroids" refers to a class of steroid hormones produced in the adrenal cortex or synthetically, including dexamethasone, methylprednisolone, prednisolone, and prednisone. Dexamethasone is commercially available under the trade name DECARON®.

[0041] "Cycle" refers to the administration schedule of one or more therapeutic agents or drugs and refers to the period during which one or more therapeutic agents or drugs are administered to a subject. A cycle may include the number of days on which the drug is administered and a rest period during which the drug is not administered. The length of a cycle may vary, for example, 2 weeks, 3 weeks, 28 days (or 4 weeks), 5 weeks, or 6 weeks.

[0042] "Daily" in the context of administration refers to the total dose of a drug, such as lenalidomide, administered to a subject in one day. The dose may be divided into two or more administrations during the day, or may be given as a single administration per day. For example, the total dose may be 25 mg per day administered as a single dose.

[0043] "Daratumumab" refers to an antibody that specifically binds to CD38, comprising a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, an 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 commercially available under the trade name DARZALEX®. "Daratumumab" refers to any drug containing daratumumab as the active ingredient, including biosimilars of DARZALEX®.

[0044] "Daratumumab-containing drug product" refers to any drug product in which daratumumab is the active ingredient.

[0045] "Dexamethasone" is chemically designated as 9-fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione. The structure of dexamethasone is shown in Formula 1.

[0046] [ka]

[0047] "Dose" refers to the amount or quantity of a therapeutic agent or drug taken at each time.

[0048] "Dosage" refers to information regarding the amount of a therapeutic agent or drug taken by a subject and the frequency of times the therapeutic agent is taken by a subject.

[0049] "Drug product" (DP) generally, but not necessarily, refers to a finished dosage form, e.g., a tablet, capsule, or solution, that contains an active pharmaceutical ingredient (e.g., a drug substance) along with inactive ingredients.

[0050] "Drug substance" (DS) means any substance or mixture of substances intended for use in the manufacture of a drug (pharmaceutical) product that, when used in the production of a drug, becomes the active ingredient of that drug product. Such substances are intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body.

[0051] "Duration of response" refers to the time between the date of first confirmed response (partial response (PR) or better) and the date of first confirmed evidence of progressive disease.

[0052] "Effective" refers to a dose or administration of a therapeutic agent or drug (such as an antibody that specifically binds CD38, such as daratumumab) or combination of therapeutic agents or drugs that provides a therapeutic effect for a given condition and administration regimen in a subject receiving or having received the therapeutic agent or drug or combination of therapeutic agents or drugs. "Effective" is intended to mean an amount sufficient to reduce and / or prevent a clinically significant impairment in the subject's activity, function, and response, or to cause a clinically significant improvement in a condition in a subject.

[0053] "Frontline" or "first line" therapy refers to the first treatment for a disease, such as multiple myeloma, administered to a subject.

[0054] "Glutamic acid derivatives" refers to immunomodulatory agents that are derivatives of glutamic acid, such as lenalidomide, thalidomide, and pomalidomide. Lenalidomide is commercially available under the trade name REVLIMID®. Thalidomide is commercially available under the trade name THALOMID®. Pomalidomide is commercially available under the trade name POMALYST®.

[0055] "Health care practitioner" (HCP) means a physician, nurse, nurse's assistant, or any person working under the direct direction of a physician or nurse, or working in a hospital or other place where treatment may be provided to a subject.

[0056] "High-dose chemotherapy" (HDC) and "autologous stem cell transplant" (ASCT) refer to treatment of subjects with newly diagnosed multiple myeloma who are deemed appropriate. Subjects under 65 years of age or over 65 years of age who have one or more comorbidities likely to adversely affect the tolerability of HDC and ASCT are generally considered ineligible for HDC and ASCT (e.g., the subject is "ineligible") due to frail physical conditions that increase the risk of death and transplant-related complications. An exemplary comorbidity is renal insufficiency. An exemplary HDC regimen is 200 mg / m 2 These include melphalan at a dose of 100 mg / kg (with dose reductions based on age and renal function), cyclophosphamide and melphalan, carmustine, etoposide, cytarabine, and melphalan (BEAM), high-dose idarubicin, cyclophosphamide, thiotepa, busulfan, and cyclophosphamide, busulfan and melphalan, and high-dose lenalidomide (Mahajan et al., Ther Adv Hematol 9:123-133, 2018).

[0057] "High-risk multiple myeloma" refers to multiple myeloma characterized by one or more cytogenetic abnormalities, del17p, t(4;14), t(14;20), t(14;16), or del13, or any combination thereof.

[0058] "Information" refers to the reported results from a clinical trial and may be provided in written or electronic form, orally, or may be available on the internet.

[0059] "Infusion-related reaction" (IRR) refers to any sign or symptom experienced by a subject during administration of a drug or therapeutic agent, or any event occurring within 24 hours of administration. IRRs are typically classified as Grade 1, 2, 3, or 4.

[0060] "Label" and "labeling" are used interchangeably herein and refer to all labels and indications of written, printed, or graphic information that are on, in, or attached to a container or package that contains a drug, such as daratumumab, or that are otherwise available electronically or over the internet. "Label" and "labeling" include package inserts and prescribing information.

[0061] "Lenalidomide," a thalidomide analog, is an immunomodulatory agent with antiangiogenic and antitumor properties. Its chemical name is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione and has the structure shown in Formula 2. Lenalidomide is commercially available under the trade name REVLIMID®.

[0062] [ka]

[0063] "Minimal residual disease" (MRD) refers to small numbers of clonal multiple myeloma cells that remain in a patient after treatment and / or during remission.

[0064] "MRD negative" or "negative status for MRD" means a 1:10 x 10 5 It refers to the proportion of clonal multiple myeloma cells that are at or below the normal range.

[0065] "MRD-negativity rate" refers to the proportion of subjects assessed as MRD-negative at any time after the date of randomization.

[0066] "Multiple myeloma" refers to a malignant disease of plasma cells characterized by the uncontrolled and progressive proliferation of one or more malignant plasma cells. The abnormal proliferation of plasma (myeloma) cells causes displacement of normal bone marrow, resulting in dysfunction of hematopoietic tissues and destruction of bone marrow architecture, leading to progressive morbidity and eventual mortality.

[0067] "Newly diagnosed" refers to a human subject who has been diagnosed with multiple myeloma but has not yet received treatment for it.

[0068] "Overall response rate" (ORR) refers to the proportion of subjects who achieve a partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) during or after treatment.

[0069] "Overall survival" (OS) is defined as the time from the start of treatment to the date of death from any cause. For the purposes of the clinical trial described in this example, OS is defined as the time from randomization of the study population to the date of death of the patient.

[0070] "W / v percent" (w / v%) refers to weight in grams per 100 ml.

[0071] "Per week" refers to the total dose of a drug, such as dexamethasone, administered to a subject in a week. The dose may be divided into two or more doses administered on the same or different days. For example, the total dose may be 40 mg, with 20 mg administered on the first day of the week and 20 mg administered on the third day of the week.

[0072] A "pharmaceutically acceptable carrier" or "excipient" refers to an ingredient in a pharmaceutical composition other than an active ingredient that is not toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, stabilizers, or preservatives.

[0073] "Progression-free survival" (PFS) means the time from initiation of treatment to the first evidence of disease progression or death from any cause (whichever occurs first). For purposes of the clinical trial described in this example, PFS is defined as the time from the date of randomization of the study population to the first confirmed progressive disease or death from any cause (whichever occurs first).

[0074] "Progression-free survival with the first subsequent therapy" (PFS2) is defined as the time from the start of treatment to progression on the next treatment or death, whichever occurs first.

[0075] "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 have their conventional meanings as understood by those skilled in the art of designing, conducting, or reviewing clinical trials. Response to treatment may be assessed using the International Myeloma Working Group (IMWG) International Uniform Response Criteria Consensus Recommendations, as shown in Table 1.

[0076] "Refractory" refers to a disease that does not respond to treatment. A refractory disease may be resistant to treatment before or at the start of treatment, or a refractory disease may become resistant during treatment.

[0077] "Relapse" refers to the return of a disease or signs and symptoms of a disease after a period of improvement following previous treatment with a therapeutic agent.

[0078] "Reference product" refers to an approved biological product, such as the DARZALEX® brand of daratumumab, to which a biosimilar is compared. The reference product is approved in the United States based on, among other things, a full complement of safety and efficacy data.

[0079] "Safety," in the context of a composition, dose, dosing regimen, treatment, or method using a therapeutic agent or drug (such as an antibody that specifically binds to CD38, e.g., daratumumab), refers to a benefit:risk ratio with an acceptable frequency and / or acceptable severity of adverse events (AEs) and / or treatment-emergent adverse events (TEAEs) compared to a standard of care (e.g., a combination of lenalidomide and dexamethasone) or another comparator drug.

[0080] "Safe and effective" refers to the amount and / or dosage of a drug (such as an antibody that specifically binds to CD38, e.g., daratumumab) or drug combination that elicits a desired biological or drug response in a subject's biological system without the risks outweighing the benefits of such a 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 trials to determine the maximum tolerated dose or optimal dose of the drug or drug combination necessary to achieve the desired effect. Efficacy is evaluated in human clinical trials to determine whether the drug or drug combination demonstrates a health benefit relative to placebo or other interventions. A safe and effective drug or drug combination is granted marketing approval by the FDA for its indicated use.

[0081] An antibody that "specifically binds to CD38" refers to an antibody that binds to CD38 with higher affinity than other antigens. Typically, the antibody binds to CD38 with a concentration of about 1 x 10 -8 M or less, for example, about 1 × 10 -9M or less, approximately 1×10 -10 M or less, approximately 1×10 -11 M or less, or about 1 x 10 -12 The equilibrium dissociation constant (K D ), typically K for binding to nonspecific antigens (e.g., BSA, casein) D At least 100 times lower than D Binds to CD38 at K D can be measured using standard procedures. However, antibodies that specifically bind to CD38 may have cross-reactivity to other related antigens, for example, the same antigen (homologues) from other species, such as monkeys, e.g., Macaca fascicularis (cynomolgus, cyno), Pan troglodytes (chimpanzee, chimp), or Callithrix jacchus (common marmoset, marmoset).

[0082] "Subject" refers to a human patient. The terms "subject" and "patient" may be used interchangeably herein.

[0083] A "therapeutically effective amount" refers to an amount effective, at the dosage and for the duration required, to achieve the desired therapeutic result. A therapeutically effective amount may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. Examples of indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, an improvement in the patient's health, a decrease in tumor burden, a halt or slowing of tumor growth, and / or the absence of metastasis of cancer cells to other locations in the body.

[0084] "Time to progression" (TTP) means the time from the date of randomization to the date of first documented evidence of progressive disease.

[0085] "Time to next treatment" refers to the time from randomization to the start of next treatment.

[0086] "Time to response" refers to the time between randomization and the first efficacy assessment in which a subject met all criteria for PR or better.

[0087] "Time to subsequent anti-myeloma therapy" refers to the time from initiation of treatment to confirmation of administration of a new anti-myeloma therapy to a subject.

[0088] "Treate," "treating," or "treatment" refers to therapeutic treatment. Individuals in need of treatment include subjects diagnosed with a disorder or symptoms of a disorder. Subjects who may be treated also include those prone to or susceptible to having a disorder, or those in whom the disorder may be prevented. Beneficial or desired clinical results include alleviation of symptoms, lessening of the extent of the disease, a stabilized (i.e., not worsening) disease state, delaying or slowing of disease progression, improvement or palliation of the disease state, remission of the disease (whether partial or complete), and prolonging survival as compared to expected survival if the subject were not treated or if they were receiving another treatment.

[0089] "Treatment-emergent adverse event" (TEAE), as used herein, has its conventional meaning as understood by those skilled in the art of designing, conducting, or reviewing clinical trials, and refers to an AE that is considered to be associated with the use of an antibody that specifically binds CD38, e.g., daratumumab, if attributable, likely attributable, or likely attributable.

[0090] "Unacceptable adverse event" and "unacceptable adverse reaction" refer to any adverse or undesirable outcome associated with or caused by the administration of a pharmaceutical composition or therapeutic agent, which adverse or undesirable outcome reaches a level of severity such that a regulatory authority considers the pharmaceutical composition or therapeutic agent to be unacceptable for its proposed use.

[0091] "Very good partial response or better" (VGPR rate or better) refers to the proportion of subjects who achieve a VGPR, complete response (CR), or stringent complete response (sCR) during or after treatment.

[0092] Multiple myeloma Multiple myeloma causes significant morbidity and mortality. It accounts for approximately 1% and 13% of all malignancies and hematological cancers worldwide. Approximately 50,000 patients are diagnosed with multiple myeloma in the EU and US each year, and 30,000 patients die from the disease each year.

[0093] Most patients with multiple myeloma produce functionally impaired immunoglobulins (Ig) or their fragments, known as monoclonal proteins (paraproteins, M-proteins, or M-components) (Kyle and Rajkumar, Leukemia 23:3-9, 2009; Palumbo and Anderson, N Engl J Med 364:1046-1060, 2011). Normal immunoglobulin levels are impaired in patients, resulting in susceptibility to infection. Proliferating multiple myeloma cells displace normal bone marrow, leading to dysfunction of normal hematopoietic tissues and destruction of normal bone marrow architecture, reflected by clinical findings such as anemia, abnormal proteins in serum or urine, and bone resorption, seen as diffuse osteoporosis or lytic lesions on radiographs (Kyle et al., Mayo Clin Proc 78:21-33, 2003). In addition, hypercalcemia, renal insufficiency or failure, and neurological complications are common. A small minority of patients with multiple myeloma are non-secretory.

[0094] Treatment options for multiple myeloma vary depending on age, comorbidities, disease aggressiveness, and associated prognostic factors (Palumbo and Anderson, N Engl J Med 364:1046-1060, 2011). Newly diagnosed patients with multiple myeloma are typically divided into two subpopulations, usually defined by age and suitability for subsequent approaches to treatment. Younger patients typically undergo an induction regimen, followed by consolidation therapy with high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). For patients not considered suitable for HDC and ASCT, longer-term treatment with multidrug combinations including alkylating agents, high-dose steroids, and novel agents is currently considered the standard of care. In general, patients over 65 years of age or with significant comorbidities are usually not considered eligible for HDC and ASCT. For many years, oral combination melphalan-prednisone (MP) was considered the standard of care for patients with multiple myeloma who were ineligible for ASCT (Gay and Palumbo, Blood Reviews 25:65-73, 2011). The advent of immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) has led to numerous new treatment options for newly diagnosed patients who are ineligible for transplant-based therapy.

[0095] Diagnosis of Multiple Myeloma Subjects with multiple myeloma meet the CRAB (calcium elevation, renal insufficiency, anemia, and bone abnormalities) criteria, have ≥10% clonal bone marrow plasma cells, or biopsy-confirmed bone or extramedullary plasmacytoma, and have measurable disease. Measurable disease is defined by any of the following: - IgG myeloma: serum monoclonal abnormality (M-protein) level of 1.0 g / dL or greater, or urine M-protein level of 200 mg / 24 hours or greater, or IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level of 0.5 g / dL or greater, or urine M-protein level of 200 mg / 24 hours or greater, or -Light chain multiple myeloma without measurable disease in serum or urine: serum immunoglobulin free light chains ≥ 10 mg / dL and an abnormal serum immunoglobulin kappa lambda free light chain ratio.

[0096] CRAB Standards Hypercalcemia: Serum calcium greater than 0.25 mM / L (greater than 1 mg / dL) above the upper limit of normal [ULN] or greater than 2.75 mM / L (greater than 11 mg / dL) Decreased renal function: Creatinine clearance less than 40 mL / min or serum creatinine greater than 177 μM / L (greater than 2 mg / dL) Anemia: Hemoglobin levels more than 2 g / dL below the lower limit of normal, or less than 10 g / dL Bone lesions: one or more osteolytic lesions on bone radiography, CT, or PET-CT

[0097] Response to treatment can be assessed using the International Myeloma Working Group (IMWG) International Uniform Response Criteria Consensus Recommendations, as shown in Table 1.

[0098] [Table 1]

[0099] Methods of the present disclosure The present disclosure provides methods of treating a subject with multiple myeloma, comprising administering to the subject a combination therapy comprising daratumumab and one or more immunomodulatory agents or bortezomib.

[0100] In some embodiments, one or more immunomodulatory agents are glutamic acid derivatives.

[0101] In some embodiments, the glutamic acid derivative is lenalidomide or pomalidomide.

[0102] In some embodiments, the multiple myeloma is relapsed multiple myeloma.

[0103] In some embodiments, the multiple myeloma is refractory multiple myeloma.

[0104] In some embodiments, the multiple myeloma is newly diagnosed multiple myeloma.

[0105] The present disclosure also provides a method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy comprising daratumumab, lenalidomide, and dexamethasone.

[0106] The present disclosure also provides a method of treating a subject newly diagnosed with multiple myeloma, comprising administering to the subject a combination therapy comprising daratumumab, lenalidomide, and dexamethasone, wherein the method achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is administered a combination of lenalidomide and dexamethasone.

[0107] The present disclosure also provides a method of treating a subject newly diagnosed with multiple myeloma who is ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT), comprising administering or providing for the administration of daratumumab to the subject, wherein the daratumumab is administered in combination with lenalidomide and dexamethasone, and the method achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is administered a combination of lenalidomide and dexamethasone.

[0108] In some embodiments, the improved clinical efficacy endpoint is an increased likelihood of achieving a complete response (CR) or better, an increased likelihood of achieving a very good partial response (VGPR) or better, an increased likelihood of achieving minimal residual disease (MRD) negativity, a reduced risk of multiple myeloma progression or death, an increased progression-free survival (PFS), or an increased likelihood of achieving 30-month progression-free survival.

[0109] The present disclosure also provides a method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy demonstrated to increase the likelihood of achieving VGPR or better in subjects with multiple myeloma, the combination therapy comprising daratumumab, lenalidomide, and dexamethasone.

[0110] In some embodiments, the likelihood of achieving VGPR or better is about 79% or greater.

[0111] The present disclosure also provides a method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy that has been demonstrated to increase the likelihood of achieving MRD-negative status in subjects with newly diagnosed multiple myeloma, the combination therapy comprising daratumumab, lenalidomide, and dexamethasone.

[0112] In some embodiments, the chance of achieving a negative status for MRD is about 24% or greater.

[0113] MRD status can be assessed from bone marrow aspirate samples, for example, using next-generation sequencing (NGS) of immunoglobulin heavy and light chains. An updated and analytically validated version (version 2) of the clonoSEQ® assay by Adaptive Biotechnologies can be used to detect, quantitate, and analyze MRD.

[0114] The present disclosure also provides a method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy that has been demonstrated to increase the likelihood of achieving CR or better in subjects with newly diagnosed multiple myeloma, the combination therapy comprising daratumumab, lenalidomide, and dexamethasone.

[0115] In some embodiments, the likelihood of achieving a CR or better is about 47% or greater.

[0116] The present disclosure also provides a method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy demonstrated to reduce the risk of multiple myeloma progression or death in subjects with newly diagnosed multiple myeloma, the combination therapy comprising daratumumab, lenalidomide, and dexamethasone.

[0117] In some embodiments, the risk of progression or death from multiple myeloma is reduced by about 44%.

[0118] In some embodiments, the subject with newly diagnosed multiple myeloma is ineligible for autologous stem cell transplantation (ASCT).

[0119] In eligible subjects, ASCT is provided in conjunction with high-dose chemotherapy (HDC) as described herein.

[0120] In some embodiments, the combination therapy comprises about 16 mg / kg daratumumab, about 25 mg lenalidomide, and about 20 mg to about 40 mg dexamethasone.

[0121] In some embodiments, the combination therapy comprises administering about 16 mg / kg of daratumumab once weekly for weeks 1-8, once every two weeks for weeks 9-24, and once every four weeks thereafter, administering about 25 mg of lenalidomide per day on days 1-21 of repeated four-week cycles, and administering about 20 mg to about 40 mg of dexamethasone per week.

[0122] In some embodiments, dexamethasone is administered as a premedication on the day of daratumumab administration.

[0123] Dexamethasone may be administered at approximately 20 mg on the day of daratumumab administration and 20 mg one day after daratumumab administration.

[0124] In some embodiments, daratumumab is administered intravenously, lenalidomide is administered orally, and dexamethasone is administered intravenously or orally.

[0125] In some embodiments, lenalidomide, dexamethasone, or both lenalidomide and dexamethasone are self-administered.

[0126] In some embodiments, daratumumab is provided for administration by the manufacturer of daratumumab in a single-dose vial containing 100 mg of daratumumab in 5 mL of solution or in a single-dose vial containing 400 mg of daratumumab in 20 mL of solution.

[0127] In some embodiments, each single-dose vial containing 100 mg of daratumumab in 5 mL of solution and each single-dose vial containing 400 mg of daratumumab in 20 mL of solution further contains glacial acetic acid, mannitol, polysorbate 20, sodium acetate trihydrate, and sodium chloride.

[0128] In some embodiments, each single-dose vial containing 100 mg of daratumumab in 5 mL of solution contains 0.9 mg of glacial acetic acid, 127.5 mg of mannitol, 2 mg of polysorbate 20, 14.8 mg of sodium acetate trihydrate, 17.5 mg of sodium chloride, and water for injection, and each single-dose vial containing 400 mg of daratumumab in 20 mL of solution contains 400 mg of daratumumab, 3.7 mg of glacial acetic acid, 510 mg of mannitol, 8 mg of polysorbate 20, 59.3 mg of sodium acetate trihydrate, 70.1 mg of sodium chloride, and water for injection.

[0129] In some embodiments, daratumumab is diluted in 0.9% sodium chloride prior to administration.

[0130] In some embodiments, information is provided on the daratumumab-containing drug product label or package insert that the combination therapy including daratumumab, lenalidomide, and dexamethasone is safe and effective.

[0131] Exemplary information is clinical trial results from the open-label, randomized, active-controlled Phase 3 study MAIA, listed in the ClinicalTrials_gov database as study NCT02252172.

[0132] In some embodiments, the daratumumab-containing drug product label includes the information that the recommended dose of daratumumab is 16 mg / kg administered as an intravenous infusion.

[0133] In some embodiments, the daratumumab-containing drug product labeling includes the information that the recommended dosing schedule for daratumumab in combination with lenalidomide is once weekly from weeks 1 to 8, once every two weeks from weeks 9 to 24, and once every four weeks thereafter.

[0134] In some embodiments, the daratumumab-containing drug product labeling includes the information that the recommended dosing schedule for lenalidomide is 25 mg per day on days 1-21 of repeated 4-week cycles.

[0135] In some embodiments, the daratumumab-containing drug product label includes information that the recommended dosing schedule for dexamethasone is about 20 mg or about 40 mg per week.

[0136] In some embodiments, the daratumumab, lenalidomide, and dexamethasone are administered according to a recommended dosing schedule.

[0137] In some embodiments, the daratumumab-containing drug product label includes data from an open-label, randomized, active-controlled Phase 3 study comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in subjects with newly diagnosed multiple myeloma who are ineligible for ASCT.

[0138] In some embodiments, the open-label, randomized, active-controlled Phase 3 trial is known as MAIA, which is listed in the ClinicalTrials_gov database as study NCT02252172.

[0139] In some embodiments, the daratumumab-containing drug product label includes data that treatment with DRd resulted in about a 44% reduction in the risk of multiple myeloma progression or death compared to treatment with Rd.

[0140] In some embodiments, the daratumumab-containing drug product label includes data that treatment with DRd resulted in about 79.3% of subjects achieving VGPR or better, about 24% of subjects achieving negativity for MRD, or about 47.6% of subjects achieving CR or better, or any combination thereof.

[0141] In some embodiments, the daratumumab-containing drug product label includes a Kaplan-Meier curve of progression-free survival (PFS) comparing subjects with newly diagnosed multiple myeloma treated with DRd to subjects with newly diagnosed multiple myeloma treated with Rd.

[0142] In some embodiments, the daratumumab-containing drug product label includes data from a Phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, melphalan, and prednisone (D-VMP) with treatment with bortezomib, melphalan, and prednisone (VMP) in subjects with newly diagnosed multiple myeloma.

[0143] In some embodiments, the Phase 3 active-controlled trial is known as ALCYONE, which is listed in the ClinicalTrials_gov database as study NCT02195479.

[0144] In some embodiments, the daratumumab-containing drug product label includes data from a Phase 3 active-controlled trial comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in relapsed, refractory, or relapsed-refractory multiple myeloma.

[0145] In some embodiments, the Phase 3 active-controlled trial is known as POLLUX, which is listed in the ClinicalTrials_gov database as study NCT02076009.

[0146] In some embodiments, the daratumumab-containing drug product label includes data from a Phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, and dexamethasone (DVd) with treatment with bortezomid and dexamethasone (Vd) in relapsed, refractory, or relapsed-refractory multiple myeloma.

[0147] In some embodiments, the Phase 3 active-controlled trial is known as CASTOR, which is listed in the ClinicalTrials_gov database as study NCT02136134.

[0148] In some embodiments, the daratumumab-containing drug product labeling includes drug interaction data reporting that clinical pharmacokinetic evaluation of daratumumab in combination with lenalidomide, pomalidomide, bortezomib, and dexamethasone showed no clinically relevant drug-drug interactions between daratumumab and lenalidomide, pomalidomide, bortezomib, and dexamethasone.

[0149] In some embodiments, the daratumumab-containing drug product label includes information that side effects of daratumumab include weakness, loss of appetite, bronchitis, and lung infection.

[0150] In some embodiments, the daratumumab-containing drug product labeling includes information regarding daratumumab's approved indications, dosage and administration, adverse reactions, drug interactions, use in specific populations, clinical pharmacology, nonclinical toxicology, clinical studies, and storage and handling, or any combination thereof.

[0151] In some embodiments, the daratumumab is the DARZALEX® brand of daratumumab.

[0152] In some embodiments, the daratumumab is a biosimilar to the DARZALEX® brand of daratumumab.

[0153] In some embodiments, daratumumab comprises a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6.

[0154] In some embodiments, daratumumab comprises a heavy chain variable region (VH) of SEQ ID NO:7 and a light chain variable region (VL) of SEQ ID NO:8.

[0155] In some embodiments, daratumumab is an immunoglobulin IgG1 kappa (IgG1κ).

[0156] An exemplary IgG1 constant domain sequence comprises the amino acid sequence of SEQ ID NO: 11. Within the IgG1 constant domain, there are several mutations (e.g., known allotypes) including mutations at positions 214, 356, 358, 422, 431, 435, or 436 (residue numbering according to EU numbering) (see, e.g., IMGT Web Resource; IMGT Repertoire (IG and TR); Proteins and Alleles; Allotypes). Antibodies that specifically bind to CD38 may be any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28.

[0157] In some embodiments, daratumumab comprises a heavy chain (HC) of SEQ ID NO:9 and a light chain (LC) of SEQ ID NO:10.

[0158] In some embodiments, daratumumab is produced in a mammalian cell line.

[0159] In some embodiments, the mammalian cell line is a Chinese hamster ovary (CHO) cell line. In some embodiments, the mammalian cell line is a Hek cell line.

[0160] In some embodiments, the molecular weight of daratumumab is about 148 kDa.

[0161] In some embodiments, dexamethasone can be substituted for a dexamethasone equivalent, where the dexamethasone equivalent is methylprednisolone, prednisolone, prednisone, or betamethasone, or any combination thereof.

[0162] The present disclosure also includes a method of treating a subject with newly diagnosed multiple myeloma, comprising: providing daratumumab to healthcare professionals (HCPs); providing information to an HCP that treating the subject with the combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject was treated with a combination of lenalidomide and dexamethasone, wherein performing steps a) and b) results in the subject with newly diagnosed multiple myeloma receiving, by an HCP or by self-administration as directed by an HCP, the combination therapy comprising daratumumab, lenalidomide, and dexamethasone, thereby treating the subject with newly diagnosed multiple myeloma.

[0163] The disclosure also provides a method of providing daratumumab to an HCP for treating a subject with newly diagnosed multiple myeloma with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone, wherein the treatment with the combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is treated with a combination of lenalidomide and dexamethasone; manufacturing daratumumab; Providing information to HCPs that treatment with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves improved clinical efficacy endpoints; and and transporting the daratumumab to the HCP or an authorized distributor of daratumumab for the HCP to purchase the daratumumab, thereby providing the daratumumab to the HCP.

[0164] The disclosure also provides a method for an HCP to provide a treatment option for treating a subject with newly diagnosed multiple myeloma with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone, wherein treatment with the combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is treated with a combination of lenalidomide and dexamethasone; manufacturing daratumumab; Providing information to HCPs that combination therapy including daratumumab, lenalidomide, and dexamethasone achieves improved clinical efficacy endpoints; and and transporting the daratumumab to the HCP or an authorized distributor of daratumumab for the HCP to purchase the daratumumab, thereby providing a treatment option for the HCP.

[0165] Exemplary information is clinical trial results from an open-label, randomized, active-controlled phase 3 trial known as MAIA, listed in the ClinicalTrials_gov database as study NCT02252172.

[0166] In some embodiments, the subject is ineligible for autologous stem cell transplantation (ASCT).

[0167] In eligible subjects, ASCT is provided in conjunction with high-dose chemotherapy (HDC) as described herein.

[0168] In some embodiments, combination therapy comprising daratumumab, lenalidomide, and dexamethasone is demonstrated to increase the likelihood of achieving VGPR or better in subjects with newly diagnosed multiple myeloma.

[0169] In some embodiments, the likelihood of achieving VGPR or better is about 79% or greater.

[0170] In some embodiments, combination therapy comprising daratumumab, lenalidomide, and dexamethasone is demonstrated to increase the likelihood of achieving MRD-negativity in subjects with newly diagnosed multiple myeloma.

[0171] In some embodiments, the chance of achieving a negative status for MRD is about 24% or greater.

[0172] In some embodiments, combination therapy comprising daratumumab, lenalidomide, and dexamethasone is demonstrated to increase the likelihood of achieving CR or better in subjects with newly diagnosed multiple myeloma.

[0173] In some embodiments, the likelihood of achieving a CR or better is about 47% or greater.

[0174] In some embodiments, combination therapy comprising daratumumab, lenalidomide, and dexamethasone is demonstrated to reduce the risk of multiple myeloma progression or death in subjects with newly diagnosed multiple myeloma.

[0175] In some embodiments, the risk of progression or death from multiple myeloma is reduced by about 44%.

[0176] In some embodiments, the combination therapy comprises about 16 mg / kg daratumumab, about 25 mg lenalidomide, and about 20 mg to about 40 mg dexamethasone.

[0177] In some embodiments, the combination therapy comprises administering about 16 mg / kg of daratumumab once weekly for weeks 1-8, once every two weeks for weeks 9-24, and once every four weeks thereafter, administering about 25 mg of lenalidomide per day on days 1-21 of repeated four-week cycles, and administering about 20 mg to about 40 mg of dexamethasone per week.

[0178] In some embodiments, the combination therapy includes administering dexamethasone as a premedication on the day of daratumumab administration.

[0179] Dexamethasone may be administered at approximately 20 mg on the day of daratumumab administration and 20 mg one day after daratumumab administration.

[0180] In some embodiments, the combination therapy comprises intravenously administered daratumumab, orally administered lenalidomide, and intravenously or orally administered dexamethasone.

[0181] In some embodiments, daratumumab is shipped or provided by the manufacturer of daratumumab in a single-dose vial containing 100 mg of daratumumab in 5 mL of solution or in a single-dose vial containing 400 mg of daratumumab in 20 mL of solution.

[0182] In some embodiments, each single-dose vial containing 100 mg of daratumumab in 5 mL of solution and each single-dose vial containing 400 mg of daratumumab in 20 mL of solution further contains glacial acetic acid, mannitol, polysorbate 20, sodium acetate trihydrate, and sodium chloride.

[0183] In some embodiments, each single-dose vial containing 100 mg of daratumumab in 5 mL of solution contains 0.9 mg of glacial acetic acid, 127.5 mg of mannitol, 2 mg of polysorbate 20, 14.8 mg of sodium acetate trihydrate, 17.5 mg of sodium chloride, and water for injection, and each single-dose vial containing 400 mg of daratumumab in 20 mL of solution contains 400 mg of daratumumab, 3.7 mg of glacial acetic acid, 510 mg of mannitol, 8 mg of polysorbate 20, 59.3 mg of sodium acetate trihydrate, 70.1 mg of sodium chloride, and water for injection.

[0184] In some embodiments, daratumumab is diluted in 0.9% sodium chloride prior to administration.

[0185] In some embodiments, information is provided on the daratumumab-containing drug product label that the combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint.

[0186] In some embodiments, the daratumumab-containing drug product label includes the information that the recommended dose of daratumumab is 16 mg / kg administered as an intravenous infusion.

[0187] In some embodiments, the daratumumab-containing drug product labeling includes the information that the recommended dosing schedule for daratumumab in combination with lenalidomide is once weekly from weeks 1 to 8, once every two weeks from weeks 9 to 24, and once every four weeks thereafter.

[0188] In some embodiments, the daratumumab-containing drug product labeling includes the information that the recommended dosing schedule for lenalidomide is 25 mg once daily on days 1-21 of repeated 4-week cycles.

[0189] In some embodiments, the daratumumab-containing drug product label includes information that the recommended dosing schedule for dexamethasone is about 20 mg or about 40 mg per week.

[0190] In some embodiments, the daratumumab, lenalidomide, and dexamethasone are administered according to a recommended dosing schedule.

[0191] In some embodiments, the daratumumab-containing drug product label includes data from an open-label, randomized, active-controlled Phase 3 study comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in subjects with newly diagnosed multiple myeloma who are ineligible for ASCT.

[0192] In some embodiments, the open-label, randomized, active-controlled Phase 3 trial is known as MAIA, which is listed in the ClinicalTrials_gov database as study NCT02252172.

[0193] In some embodiments, the daratumumab-containing drug product label includes data that treatment with DRd resulted in about a 44% reduction in the risk of multiple myeloma progression or death compared to treatment with Rd.

[0194] In some embodiments, the daratumumab-containing drug product label includes data that treatment with DRd resulted in about 79.3% of subjects achieving VGPR or better, about 24% of subjects achieving negativity for MRD, or about 47.6% of subjects achieving CR or better, or any combination thereof.

[0195] In some embodiments, the daratumumab-containing drug product label includes a Kaplan-Meier curve of progression-free survival (PFS) comparing subjects with newly diagnosed multiple myeloma treated with DRd to subjects with newly diagnosed multiple myeloma treated with Rd.

[0196] In some embodiments, the daratumumab-containing drug product label includes data from a Phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, melphalan, and prednisone (D-VMP) with treatment with bortezomib, melphalan, and prednisone (VMP) in subjects with newly diagnosed multiple myeloma.

[0197] In some embodiments, the Phase 3 active-controlled trial is known as ALCYONE, which is listed in the ClinicalTrials_gov database as study NCT02195479.

[0198] In some embodiments, the daratumumab-containing drug product label includes data from a Phase 3 active-controlled trial comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in relapsed, refractory, or relapsed-refractory multiple myeloma.

[0199] In some embodiments, the Phase 3 active-controlled trial is known as POLLUX, which is listed in the ClinicalTrials_gov database as study NCT02076009.

[0200] In some embodiments, the daratumumab-containing drug product label includes data from a Phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, and dexamethasone (DVd) with treatment with bortezomid and dexamethasone (Vd) in relapsed, refractory, or relapsed-refractory multiple myeloma.

[0201] In some embodiments, the Phase 3 active-controlled trial is known as CASTOR, which is listed in the ClinicalTrials_gov database as study NCT02136134.

[0202] In some embodiments, the daratumumab-containing drug product labeling includes drug interaction data reporting that clinical pharmacokinetic evaluation of daratumumab in combination with lenalidomide, pomalidomide, bortezomib, and dexamethasone showed no clinically relevant drug-drug interactions between daratumumab and lenalidomide, pomalidomide, bortezomib, and dexamethasone.

[0203] In some embodiments, the daratumumab-containing drug product label includes information that side effects of daratumumab include weakness, loss of appetite, bronchitis, and lung infection.

[0204] In some embodiments, the daratumumab-containing drug product labeling includes information regarding daratumumab's approved indications, dosage and administration, adverse reactions, drug interactions, use in specific populations, clinical pharmacology, nonclinical toxicology, clinical studies, and storage and handling, or any combination thereof.

[0205] In some embodiments, the daratumumab is the DARZALEX® brand of daratumumab.

[0206] In some embodiments, the daratumumab is a biosimilar to the DARZALEX® brand of daratumumab.

[0207] In some embodiments, daratumumab comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6.

[0208] In some embodiments, the daratumumab comprises a VH of SEQ ID NO:7 and a VL of SEQ ID NO:8.

[0209] In some embodiments, daratumumab is an immunoglobulin IgG1 kappa (IgG1κ).

[0210] An exemplary IgG1 constant domain sequence comprises the amino acid sequence of SEQ ID NO: 11. Within the IgG1 constant domain, there are several mutations (e.g., known allotypes) including mutations at positions 214, 356, 358, 422, 431, 435, or 436 (residue numbering according to EU numbering) (see, e.g., IMGT Web Resource; IMGT Repertoire (IG and TR); Proteins and Alleles; Allotypes). Antibodies that specifically bind to CD38 may be any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28.

[0211] In some embodiments, daratumumab comprises an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10.

[0212] In some embodiments, daratumumab is produced in a mammalian cell line.

[0213] In some embodiments, the mammalian cell line is a Chinese hamster ovary (CHO) cell line.

[0214] In some embodiments, the molecular weight of daratumumab is about 148 kDa.

[0215] In some embodiments, dexamethasone can be substituted for a dexamethasone equivalent, where the dexamethasone equivalent is methylprednisolone, prednisolone, prednisone, or betamethasone, or any combination thereof.

[0216] Combination Therapies and Drug Products of the Disclosure The present disclosure also provides a combination therapy comprising daratumumab, lenalidomide, and dexamethasone for providing treatment of a subject with newly diagnosed multiple myeloma, wherein the treatment achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is treated with a combination of lenalidomide and dexamethasone.

[0217] In some embodiments, the combination therapy of the present disclosure comprises about 16 mg / kg daratumumab, about 25 mg lenalidomide, and about 20 mg to about 40 mg dexamethasone.

[0218] In some embodiments, treatment of a subject with newly diagnosed multiple myeloma comprises administering to the subject about 16 mg / kg of daratumumab once per week, once every two weeks, or once every four weeks, about 25 mg of lenalidomide per day, and about 20 mg to about 40 mg of dexamethasone per week.

[0219] In some embodiments, treatment of a subject with newly diagnosed multiple myeloma comprises administering to the subject about 16 mg / kg of daratumumab once weekly for weeks 1-8, once every two weeks for weeks 9-24, and once every four weeks thereafter, about 25 mg of lenalidomide once daily on days 1-21 of repeated four-week cycles, and about 20 mg or about 40 mg of dexamethasone per week.

[0220] In some embodiments, combination therapy is demonstrated to increase the likelihood of achieving VGPR or better in subjects with newly diagnosed multiple myeloma.

[0221] In some embodiments, the likelihood of achieving VGPR or better is about 79% or greater.

[0222] In some embodiments, combination therapy is demonstrated to increase the likelihood of achieving MRD-negative status in subjects with newly diagnosed multiple myeloma.

[0223] In some embodiments, the chance of achieving a negative status for MRD is about 24% or greater.

[0224] In some embodiments, combination therapy is demonstrated to increase the likelihood of achieving a CR or better in subjects with newly diagnosed multiple myeloma.

[0225] In some embodiments, the likelihood of achieving a CR or better is about 47% or greater.

[0226] In some embodiments, the combination therapy is demonstrated to reduce the risk of multiple myeloma progression or death in subjects with newly diagnosed multiple myeloma.

[0227] In some embodiments, the risk of progression or death from multiple myeloma is reduced by about 44%.

[0228] In some embodiments, the subject with multiple myeloma is ineligible for autologous stem cell transplantation (ASCT).

[0229] In some embodiments, the combination therapy is promoted by the manufacturer of daratumumab for the treatment of newly diagnosed multiple myeloma. Promotion may be in the form of any publicly documented document demonstrating that the treatment is safe and effective and approved by the FDA, such as product claim advertising, either print or broadcast, promotional labeling, including brochures and materials mailed or provided to consumers, and other types of materials distributed by the manufacturer of daratumumab-containing drug products, including drug product labels and prescribing information.

[0230] In some embodiments, the combination therapy is promoted on the daratumumab-containing drug product labeling and by the manufacturer of the daratumumab-containing drug product for the treatment of newly diagnosed multiple myeloma.

[0231] In some embodiments, the daratumumab-containing drug product label includes data from an open-label, randomized, active-controlled Phase 3 study comparing treatment with daratumumab in combination with lenalidomide and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma.

[0232] In some embodiments, the open-label, randomized, active-controlled Phase 3 trial is known as MAIA, which is listed in the ClinicalTrials_gov database as study NCT02252172.

[0233] In some embodiments, the daratumumab-containing drug product label includes data that treatment with DRd resulted in about a 44% reduction in the risk of multiple myeloma progression or death compared to treatment with Rd.

[0234] In some embodiments, the daratumumab-containing drug product label includes data that treatment with DRd resulted in about 79.3% of subjects achieving VGPR or better, about 24% of subjects achieving negativity for MRD, or about 47.6% of subjects achieving CR or better, or any combination thereof.

[0235] In some embodiments, the daratumumab-containing drug product label includes a Kaplan-Meier curve of progression-free survival (PFS) comparing subjects with newly diagnosed multiple myeloma treated with DRd to subjects with newly diagnosed multiple myeloma treated with Rd.

[0236] In some embodiments, the daratumumab-containing drug product label includes data from a Phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, melphalan, and prednisone (D-VMP) with treatment with bortezomib, melphalan, and prednisone (VMP) in subjects with newly diagnosed multiple myeloma.

[0237] In some embodiments, the Phase 3 active-controlled trial is known as ALCYONE, which is listed in the ClinicalTrials_gov database as study NCT02195479.

[0238] In some embodiments, the daratumumab-containing drug product label includes data from a Phase 3 active-controlled trial comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in relapsed, refractory, or relapsed-refractory multiple myeloma.

[0239] In some embodiments, the Phase 3 active-controlled trial is known as POLLUX, which is listed in the ClinicalTrials_gov database as study NCT02076009.

[0240] In some embodiments, the daratumumab-containing drug product label includes data from a Phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, and dexamethasone (DVd) with treatment with bortezomid and dexamethasone (Vd) in relapsed, refractory, or relapsed-refractory multiple myeloma.

[0241] In some embodiments, the Phase 3 active-controlled trial is known as CASTOR, which is listed in the ClinicalTrials_gov database as study NCT02136134.

[0242] In some embodiments, the daratumumab-containing drug product labeling includes drug interaction data reporting that clinical pharmacokinetic evaluation of daratumumab in combination with lenalidomide, pomalidomide, bortezomib, and dexamethasone showed no clinically relevant drug-drug interactions between daratumumab and lenalidomide, pomalidomide, bortezomib, and dexamethasone.

[0243] In some embodiments, the daratumumab-containing drug product label includes information that side effects of daratumumab include weakness, loss of appetite, bronchitis, and lung infection.

[0244] In some embodiments, the daratumumab-containing drug product labeling includes information regarding daratumumab's approved indications, dosage and administration, adverse reactions, drug interactions, use in specific populations, clinical pharmacology, nonclinical toxicology, clinical studies, and storage and handling, or any combination thereof.

[0245] In some embodiments, the daratumumab is the DARZALEX® brand of daratumumab.

[0246] In some embodiments, the daratumumab is a biosimilar to the DARZALEX® brand of daratumumab.

[0247] In some embodiments, daratumumab comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6.

[0248] In some embodiments, the daratumumab comprises a VH of SEQ ID NO:7 and a VL of SEQ ID NO:8.

[0249] In some embodiments, daratumumab is an immunoglobulin IgG1 kappa (IgG1κ).

[0250] An exemplary IgG1 constant domain sequence comprises the amino acid sequence of SEQ ID NO: 11. Within the IgG1 constant domain, there are several mutations (e.g., known allotypes) including mutations at positions 214, 356, 358, 422, 431, 435, or 436 (residue numbering according to EU numbering) (see, e.g., IMGT Web Resource; IMGT Repertoire (IG and TR); Proteins and Alleles; Allotypes). Antibodies that specifically bind to CD38 may be any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28.

[0251] In some embodiments, daratumumab comprises an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10.

[0252] In some embodiments, daratumumab is produced in a mammalian cell line.

[0253] In some embodiments, the mammalian cell line is a Chinese hamster ovary (CHO) cell line.

[0254] In some embodiments, the molecular weight of daratumumab is about 148 kDa.

[0255] In some embodiments, dexamethasone can be substituted for a dexamethasone equivalent, where the dexamethasone equivalent is methylprednisolone, prednisolone, prednisone, or betamethasone, or any combination thereof.

[0256] The disclosure also provides a drug product comprising daratumumab provided in a package containing one or more single-dose vials comprising daratumumab, and a drug product label comprising the information that treatment of subjects with newly diagnosed multiple myeloma with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subjects are administered a combination of lenalidomide and dexamethasone.

[0257] In some embodiments, one or more single-dose vials contain 100 mg of daratumumab in 5 mL of solution or 400 mg of daratumumab in 20 mL of solution.

[0258] In some embodiments, the one or more single dose vials containing 100 mg of daratumumab in 5 mL of solution and the one or more single dose vials containing 400 mg of daratumumab in 20 mL of solution further contain glacial acetic acid, mannitol, polysorbate 20, sodium acetate trihydrate, and sodium chloride.

[0259] In some embodiments, one or more single-dose vials containing 100 mg of daratumumab in 5 mL of solution contain 0.9 mg of glacial acetic acid, 127.5 mg of mannitol, 2 mg of polysorbate 20, 14.8 mg of sodium acetate trihydrate, 17.5 mg of sodium chloride, and water for injection, and one or more single-dose vials containing 400 mg of daratumumab in 20 mL of solution contain 400 mg of daratumumab, 3.7 mg of glacial acetic acid, 510 mg of mannitol, 8 mg of polysorbate 20, 59.3 mg of sodium acetate trihydrate, 70.1 mg of sodium chloride, and water for injection.

[0260] In some embodiments, the drug product labeling includes the information that the recommended dosing schedule for dexamethasone is about 16 mg / kg weekly for weeks 1-8, once every two weeks for weeks 9-24, and once every four weeks thereafter; the recommended dosing schedule for lenalidomide is about 25 mg per day on days 1-21 of repeated four-week cycles; and the recommended dosing schedule for dexamethasone is about 20 mg per week or about 40 mg per week.

[0261] In some embodiments, the drug product label includes data from an open-label, randomized, active-controlled Phase 3 study comparing treatment with daratumumab in combination with lenalidomide and dexamethasone (DRd) to treatment with lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma.

[0262] In some embodiments, the open-label, randomized, active-controlled Phase 3 trial is known as MAIA, which is listed in the ClinicalTrials_gov database as study NCT02252172.

[0263] In some embodiments, the drug product label includes data that treatment with DRd resulted in about a 44% reduction in the risk of progression or death from multiple myeloma compared to treatment with Rd.

[0264] In some embodiments, the drug product label includes data that treatment with DRd resulted in about 79.3% of subjects achieving VGPR or better, about 24% of subjects achieving negativity for MRD, or about 47.6% of subjects achieving CR or better, or any combination thereof.

[0265] In some embodiments, the drug product label includes a Kaplan-Meier curve of progression-free survival (PFS) comparing subjects with newly diagnosed multiple myeloma treated with DRd to subjects with newly diagnosed multiple myeloma treated with Rd.

[0266] In some embodiments, the drug product label includes data from a Phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, melphalan, and prednisone (VMP) to treatment with bortezomib, melphalan, and prednisone (VMP).

[0267] In some embodiments, the Phase 3 active-controlled trial is known as ALCYONE, which is listed in the ClinicalTrials_gov database as study NCT02195479.

[0268] In some embodiments, the drug product label includes data from a Phase 3 active-controlled trial comparing treatment with daratumumab in combination with lenalidomide and dexamethasone (DRd) to treatment with lenalidomide and dexamethasone (Rd) in relapsed, refractory, or relapsed-refractory multiple myeloma.

[0269] In some embodiments, the Phase 3 active-controlled trial is known as POLLUX, which is listed in the ClinicalTrials_gov database as study NCT02076009.

[0270] In some embodiments, the drug product label includes data from a Phase 3 active-controlled trial comparing treatment with daratumumab in combination with bortezomib and dexamethasone (DVd) to treatment with bortezomid and dexamethasone (Vd) in relapsed, refractory, or relapsed-refractory multiple myeloma.

[0271] In some embodiments, the Phase 3 active-controlled trial is known as CASTOR, which is listed in the ClinicalTrials_gov database as study NCT02136134.

[0272] In some embodiments, the drug product labeling includes drug product interaction data reporting that a clinical pharmacokinetic evaluation of daratumumab in combination with lenalidomide, pomalidomide, bortezomib, and dexamethasone showed no clinically relevant drug-drug interactions between daratumumab and lenalidomide, pomalidomide, bortezomib, and dexamethasone.

[0273] In some embodiments, the drug product label includes information that side effects of daratumumab include weakness, loss of appetite, bronchitis, and lung infection.

[0274] In some embodiments, the drug product labeling includes information regarding daratumumab's approved indications, dosage and administration, adverse reactions, drug interactions, use in specific populations, clinical pharmacology, nonclinical toxicology, clinical studies, and storage and handling, or any combination thereof.

[0275] In some embodiments, the daratumumab is the DARZALEX® brand of daratumumab.

[0276] In some embodiments, the daratumumab is a biosimilar to the DARZALEX® brand of daratumumab.

[0277] In some embodiments, daratumumab comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6.

[0278] In some embodiments, the daratumumab comprises a VH of SEQ ID NO:7 and a VL of SEQ ID NO:8.

[0279] In some embodiments, daratumumab is an immunoglobulin IgG1 kappa (IgG1κ).

[0280] An exemplary IgG1 constant domain sequence comprises the amino acid sequence of SEQ ID NO: 11. Within the IgG1 constant domain, there are several mutations (e.g., known allotypes) including mutations at positions 214, 356, 358, 422, 431, 435, or 436 (residue numbering according to EU numbering) (see, e.g., IMGT Web Resource; IMGT Repertoire (IG and TR); Proteins and Alleles; Allotypes). Antibodies that specifically bind to CD38 may be any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28.

[0281] In some embodiments, daratumumab comprises an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10.

[0282] In some embodiments, daratumumab is produced in a mammalian cell line.

[0283] In some embodiments, the mammalian cell line is a Chinese hamster ovary (CHO) cell line.

[0284] In some embodiments, the molecular weight of daratumumab is about 148 kDa.

[0285] The present disclosure also provides a method of selling a drug product comprising daratumumab, manufacturing daratumumab; and promoting, when the combination therapy comprising daratumumab, lenalidomide, and dexamethasone is administered to a subject with newly diagnosed multiple myeloma, achievement of an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is administered the combination of lenalidomide and dexamethasone, wherein performing steps a) and b) results in an HCP purchasing the drug product, thereby selling the drug product.

[0286] Promotion may be in the form of any public record demonstrating that the treatment is safe and effective and approved by FDA, such as product claim advertising, either print or broadcast, promotional labeling, including brochures and materials mailed or provided to consumers, and other types of materials distributed by the manufacturer of daratumumab, including drug product labeling and prescribing information.

[0287] In some embodiments, the promotion includes including on the drug product label data from an open-label, randomized, active-controlled Phase 3 trial comparing treatment with daratumumab in combination with lenalidomide and dexamethasone (DRd) to treatment with lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma.

[0288] In some embodiments, the drug product label further includes data that treatment with DRd resulted in about a 44% reduction in the risk of progression or death from multiple myeloma compared to treatment with Rd.

[0289] In some embodiments, the drug product label further comprises a Kaplan-Meier curve of progression-free survival (PFS) comparing subjects with newly diagnosed multiple myeloma treated with DRd to subjects with newly diagnosed multiple myeloma treated with Rd.

[0290] The present invention also provides a method of marketing a drug product comprising daratumumab, manufacturing daratumumab; and selling a drug product, wherein the drug product label includes instructions for treating a subject with newly diagnosed multiple myeloma with a combination of daratumumab, lenalidomide, and dexamethasone.

[0291] In some embodiments, the daratumumab is the DARZALEX® brand of daratumumab.

[0292] In some embodiments, the daratumumab is a biosimilar to the DARZALEX® brand of daratumumab.

[0293] In some embodiments, daratumumab comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6.

[0294] In some embodiments, the daratumumab comprises a VH of SEQ ID NO:7 and a VL of SEQ ID NO:8.

[0295] In some embodiments, daratumumab is an immunoglobulin IgG1 kappa (IgG1κ).

[0296] An exemplary IgG1 constant domain sequence comprises the amino acid sequence of SEQ ID NO: 11. Within the IgG1 constant domain, there are several mutations (e.g., known allotypes) including mutations at positions 214, 356, 358, 422, 431, 435, or 436 (residue numbering according to EU numbering) (see, e.g., IMGT Web Resource; IMGT Repertoire (IG and TR); Proteins and Alleles; Allotypes). Antibodies that specifically bind to CD38 may be any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28.

[0297] In some embodiments, daratumumab comprises a heavy chain (HC) of SEQ ID NO:9 and a light chain (LC) of SEQ ID NO:10.

[0298] In some embodiments, daratumumab is produced in a mammalian cell line.

[0299] In some embodiments, the mammalian cell line is a Chinese hamster ovary (CHO) cell line.

[0300] In some embodiments, the molecular weight of daratumumab is about 148 kDa.

[0301] Methods for producing antibodies Methods for producing antibodies on a large scale are known. Antibodies can be produced, for example, in cultured CHO cells using known methods. Antibodies can be isolated and / or purified from the culture medium by removing solids by centrifugation or filtration as a first step in the purification process. Antibodies can be further purified by standard methods, including chromatography (e.g., ion exchange, affinity, size exclusion, and hydroxyapatite chromatography), gel filtration, centrifugation, or differential solubility, ethanol precipitation, or any other available technique for purifying antibodies. To reduce or eliminate antibody degradation during the purification process, protease inhibitors such as phenylmethylsulfonyl fluoride (PMSF), leupeptin, pepstatin, or aprotinin may be added at any or all stages. Those skilled in the art will understand that the exact purification technique will vary depending on the characteristics of the polypeptide or protein being purified, the characteristics of the cells in which the polypeptide or protein is expressed, and the composition of the medium in which the cells are grown.

[0302] The purified antibody may be formulated into a pharmaceutical composition containing one or more excipients and packaged in a container such as a sealed bottle or vessel such as a glass vial, with a label affixed to the container or included in the packaging. Alternatively, the purified antibody may be lyophilized and provided as a lyophilized powder in a container.

[0303] Having generally described the invention, embodiments of the invention are further disclosed in the following examples, which should not be construed as limiting the scope of the claims.

[0304] Example 1: A Phase 3 Study Comparing DARZALEX® (daratumumab), Lenalidomide, and Dexamethasone (DRd) to Lenalidomide and Dexamethasone (Rd) in Subjects with Previously Untreated Multiple Myeloma Who Are Ineligible for High-Dose Chemotherapy (HDC) and Autologous Stem Cell Transplant (ASCT) Objectives and Hypothesis Main purpose The primary objective is to compare the efficacy of daratumumab (DARZALEX®) (DRd) in combination with lenalidomide and dexamethasone with that of lenalidomide and dexamethasone (Rd) in terms of progression-free survival (PFS) in subjects with newly diagnosed myeloma who are not candidates for high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT).

[0305] Secondary Objectives Secondary objectives are to: To assess clinical outcomes, including: -Time to progression (TTP) -CR rate -MRD negative rate - PFS2 (defined as the time from randomization to progression or death on subsequent treatment, whichever occurs first) -Overall survival -Time until next treatment -Strict CR (sCR) rate - Overall response rate (partial response [PR] or better) - Proportion of subjects achieving very good partial response (VGPR) or better -Time to response -Duration of response To evaluate the safety and tolerability of daratumumab (DARZALEX®) when administered in combination with Rd To evaluate the pharmacokinetics of daratumumab (DARZALEX®) in combination with Rd To evaluate the immunogenicity of daratumumab (DARZALEX®) Evaluate the effect of treatment on patient-reported outcomes and health economics / resource utilization To evaluate the clinical efficacy of daratumumab (DARZALEX®) in combination with Rd in high-risk molecular subgroups

[0306] Experimental Purpose Investigating biomarkers that predict response or resistance to therapy -To assess persistence of MRD negativity

[0307] Study design overview This is a randomized, open-label, active-controlled, parallel-group, multicenter trial in subjects at least 18 years of age with newly diagnosed multiple myeloma who are not candidates for HDC and ASCT. Approximately 730 subjects will be enrolled in the trial, with 365 subjects planned per treatment group.

[0308] Subject participation includes a screening phase, a treatment phase, and a follow-up phase. The screening phase is for up to 21 days prior to Cycle 1, Day 1. The treatment phase continues from Cycle 1, Day 1 until discontinuation of all study treatment. For subjects assigned to DRd, daratumumab (DARZALEX®) will be administered weekly for the first 8 weeks of treatment (Cycles 1-2), then every 2 weeks for 16 weeks (Cycles 3-6), and then every 4 weeks (Cycles 7 and beyond) until disease progression or unacceptable toxicity. This equates to 9 consecutive weeks of administration at the start of the study and a total of 23 administrations during the first year. Lenalidomide will be administered orally (PO) at a dose of 25 mg on Days 1-21 of each 28-day cycle, and dexamethasone will be administered once weekly at a dose of 40 mg. Subjects in both treatment groups will continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group will continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomization will be stratified by International Stage Classification (I vs. II vs. III), region (North America vs. Other), and age (<75 vs. ≥75 years) using a 1:1 equal allocation ratio.

[0309] Measures to prevent infusion-related reactions include pre-infusion medication with dexamethasone, acetaminophen (paracetamol), and an antihistamine before each daratumumab (DARZALEX®) infusion.

[0310] The follow-up phase begins when a subject discontinues all study treatment. Subjects who discontinue for reasons other than disease progression must continue to undergo disease assessment according to the time and event schedule. The follow-up phase continues until death, loss to follow-up, withdrawal of consent, or end of study (whichever occurs first). After the clinical cut-off, data collection will be reduced.

[0311] An Independent Data Monitoring Committee (IDMC) will be commissioned to this trial to review efficacy and safety results at a planned interim analysis. After the interim review, the IDMC will make a recommendation regarding continuation of the trial.

[0312] Tumor response and disease progression assessments will be performed according to the International Myeloma Working Group (IMWG) response criteria. MRD assessments will be performed on bone marrow samples. Safety assessments will include adverse event monitoring, physical examinations, electrocardiogram (ECG) monitoring, clinical laboratory parameters (hematology and chemistry), vital sign measurements, and Eastern Cooperative Oncology Group (ECOG) performance status. Blood samples will be collected for evaluation of pharmacokinetic parameters.

[0313] Target population Key eligibility criteria include: subjects must be ≥ 18 years of age, have a definitive diagnosis of symptomatic multiple myeloma and measurable secretory disease, an ECOG performance status score of 0, 1, or 2, be newly diagnosed, and not be considered candidates for high-dose chemotherapy (HDC) with autologous stem cell transplant (ASCT).

[0314] Dosage and Administration Daratumumab (DARZALEX®) (16 mg / kg) will be administered by IV infusion to subjects in Arm B initially once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks until confirmed progression, unacceptable toxicity, or end of study.

[0315] Lenalidomide will be self-administered at a dose of 25 mg PO on days 1-21 of each 28-day cycle.

[0316] Dexamethasone (or industry standard equivalent) is administered at a total dose of 40 mg weekly.

[0317] Efficacy assessment / endpoint Disease assessments should be performed every 28 days for the first 2 years, then every 8 weeks until disease progression. A time window of ±7 days is allowed. If treatment is delayed for any reason, disease assessments should be performed according to the schedule, regardless of any changes to the dosing regimen.

[0318] The primary endpoint is PFS, defined as the time from the date of randomization to either progressive disease or death, whichever occurs first. Disease progression will be determined according to IMWG criteria.

[0319] Secondary efficacy endpoints include: Time to progression (TTP) is defined as the time from randomization to the date of first documented evidence of PD, as defined by IMWG criteria. For subjects who have not progressed, data will be censored at the date of disease assessment, prior to the initiation of any subsequent anti-myeloma therapy. CR rate, defined as the proportion of subjects achieving CR, as defined below: - negative immunofixation of serum and urine, and -Disappearance of soft tissue plasmacytomas, and - Less than 5% plasma cells (PC) in bone marrow For subjects with negative serum M-protein quantification by electrophoresis (SPEP) and suspected daratumumab (DARZALEX®) interference with immunofixation, a reflex assay using anti-idiotypic antibodies will be utilized to confirm daratumumab (DARZALEX®) interference and rule out false-positive immunofixation. Patients with confirmed daratumumab (DARZALEX®) interference but who meet all other clinical criteria for CR or sCR will be considered in CR / sCR. MRD negativity rate, defined as the proportion of subjects assessed as MRD negative at any time point after the randomization date. Progression-free survival on subsequent treatment (PFS2), defined as the time from randomization to progression on subsequent treatment or death (whichever occurs first). Disease progression is based on investigator judgment. Subjects who are still alive and have not progressed on subsequent treatment will be censored at the last day of follow-up. Overall survival (OS), measured from the date of randomization to the date of the subject's death. If the subject is alive or their vital status is unknown, the subject's data will be censored at the date the subject was last known to be alive. Time to next treatment, defined as the time from randomization to the start of next treatment. · sCR rate, defined as the percentage of subjects achieving CR in addition to having a normal free light chain (FLC) ratio and the absence of clonal cells in the bone marrow by immunohistochemistry, immunofluorescence, and 2- to 4-color flow cytometry. Overall response rate (ORR), defined as the proportion of subjects achieving PR or better according to IMWG criteria during or after study treatment. Proportion of subjects achieving VGPR or better, defined as the proportion of subjects achieving VGPR and CR (including sCR) according to IMWG criteria during or after study treatment at the time of data cutoff. Time to response, defined as the time between randomization and the first efficacy assessment in which the subject met all criteria for PR or better. For non-responding subjects, data are censored at either the date of progressive disease or the absence of progressive disease at the last disease assessment before the start of subsequent anti-myeloma therapy. Duration of response, calculated from the date of first confirmed response (PR or better) to the date of first confirmed evidence of progressive disease, as defined by IMWG criteria. For subjects who have not progressed, data are censored at the last disease assessment, prior to the initiation of any subsequent anti-myeloma therapy. To evaluate the clinical efficacy of DRd in high-risk molecular subgroups compared with Rd alone. To assess the impact of DRd compared with Rd on patient-reported perception of overall health.

[0320] Pharmacokinetic and immunogenicity evaluation Pharmacokinetic samples for determining serum concentrations of daratumumab (DARZALEX®) will be obtained for all subjects in Group B. Venous blood samples (5 mL per sample) will be collected to determine serum concentrations of daratumumab (DARZALEX®), and the serum will be divided into three aliquots: one aliquot for pharmacokinetic analysis, one aliquot for daratumumab (DARZALEX®) analysis, if appropriate, and one aliquot for reserve.

[0321] Biomarker evaluation Bone marrow aspirates are collected at screening and post-treatment. Baseline bone marrow aspirate samples are subjected to DNA and RNA sequencing to stratify subjects into high-risk molecular subgroups and establish myeloma clones for MRD monitoring. In addition to scheduled bone marrow aspirate evaluations, whole blood samples are collected from subjects for processing into plasma and PBMCs.

[0322] Safety evaluation Safety will be measured by assessment of adverse events, laboratory test results, ECG, vital sign measurements, physical examination findings, and ECOG performance status score.

[0323] statistical methods The sample size calculation is based on the following assumptions: Based on published data, the median PFS of the Rd group is assumed to be approximately 24 months. Assuming that DRd can reduce the risk of disease progression or death by 25%, i.e., assuming a hazard ratio (DRd vs. Rd) of 0.75, a total of 390 PFS events are required to achieve 80% power to detect this hazard ratio with a log-rank test (two-sided alpha is 0.05). With a 21-month enrollment period and an additional 24 months of follow-up, the total sample size required for the study is approximately 730 subjects (365 per group). The sample size calculation takes into account a 5% annual discontinuation rate.

[0324] Long-term survival follow-up will continue until 330 deaths have been observed, or 7 years after the last subject was randomized. Thus, the study will achieve approximately 80% power to detect a 27% reduction in risk of death (hazard ratio = 0.73) using the log-rank test (two-sided alpha = 0.05).

[0325] Response to study treatment and progressive disease will be assessed by computer algorithms. For the primary endpoint of PFS, the primary analysis will consist of a stratified log-rank test for comparison of PFS distributions between the two treatment groups. The Kaplan-Meier method will be used to estimate the overall PFS distribution for each treatment. Treatment effects (hazard ratios) and their two-sided 95% confidence intervals will be estimated using stratified Cox regression models with treatment as the only explanatory variable.

[0326] Rationale for DNA and biomarker collection Biomarker samples are collected to assess the depth of clinical response to daratumumab (DARZALEX®) using DNA sequencing of immunoglobulin genes to assess MRD, to determine response rates in specific molecular subgroups of multiple myeloma, and to enable evaluation of high-risk genomics, deletion 17p, t(4;14), t(14;20), t(14;16), deletion 13, GEP signatures such as UAMS-70, and mutations in p53, BRAF, FGFR, IGH, PI3K, or other molecular subtypes associated with disease progression. Other biomarker targets include assessing potential mechanisms of resistance, inter-individual variability in clinical outcome, or identifying population subgroups that respond differently to treatment.

[0327] Inclusion criteria Each potential subject must meet all of the following criteria to be enrolled in this study.

[0328] 1. Subjects must be at least 18 years of age (or the legal age of consent in the jurisdiction where the study is being conducted).

[0329] 2.2.1 Subjects must have confirmed multiple myeloma meeting the CRAB (elevated calcium, decreased renal function, anemia, and bone abnormalities) criteria, 10% or more monoclonal bone marrow plasma cells, or the presence of plasmacytoma on biopsy diagnosis, and measurable disease. · Measurable disease, as assessed by a central laboratory, defined by any of the following: - IgG myeloma: serum monoclonal abnormality (M-protein) level of 1.0 g / dL or greater, or urine M-protein level of 200 mg / 24 hours or greater, or IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level of 0.5 g / dL or greater, or urine M-protein level of 200 mg / 24 hours or greater, or -Light chain multiple myeloma without measurable disease in serum or urine: serum immunoglobulin free light chains ≥ 10 mg / dL and an abnormal serum immunoglobulin kappa lambda free light chain ratio.

[0330] 3. Newly diagnosed and not considered a candidate for high-dose chemotherapy with SCT for the following reasons: Are 65 years of age or older, or In subjects under 65 years of age, the presence of significant comorbid condition(s) is likely to adversely affect the tolerability of high-dose chemotherapy with stem cell transplant. Sponsor review and approval is required for subjects under 65 years of age prior to randomization.

[0331] 4. Subjects must have an ECOG performance status score of 0, 1, or 2.

[0332] 5. Subjects must have pre-treatment clinical laboratory values that meet the following criteria during the screening phase: a) hemoglobin ≥ 7.5 g / dL (≥ 5 mM / L, conventional red blood cell (RBC) transfusion or recombinant human erythropoietin use is permitted); b) 1.0 × 10 9 Absolute neutrophil count ≥ 1 / L (granulocyte colony stimulating factor (GCSF) use permitted), c) For subjects in which less than 50% of bone marrow nucleated cells are plasma cells, ≥ 70 x 10 9 / L platelet count, otherwise 50 × 10 9 platelet count > / L (transfusions are not permitted to achieve this minimum platelet count), d) aspartate aminotransferase (AST) less than 2.5 times the upper limit of normal (ULN); e) alanine aminotransferase (ALT) less than 2.5 times the ULN; f) Total bilirubin ≤ 2.0 times the ULN, except for subjects with congenital bilirubinemia (direct bilirubin ≤ 2.0 times the ULN), such as Gilbert syndrome; g1) Creatinine clearance of 30 mL / min or greater (for lenalidomide dose adjustment in subjects with a creatinine clearance of 30-50 mL / min). Creatinine clearance can be calculated using the Cockcroft-Gault formula, or for overweight or underweight subjects, creatinine clearance can be measured from a 24-hour urine collection. h1) Corrected serum calcium of 14 mg / dL or less (3.5 mM / L or less) or free ionized calcium of 6.5 mg / dL or less (1.6 mM / L or less)

[0333] 6. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical research. Women of childbearing potential must agree to either continuously abstain from heterosexual intercourse or simultaneously use two reliable methods of birth control. This includes one highly effective form of contraception (tubal ligation, intrauterine device (IUD), hormonal (progesterone-only birth control pills or injections), or partner's vasectomy) and one additional effective method of contraception (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must be initiated 4 weeks prior to administration and continued for 3 months after the last dose of daratumumab (DARZALEX®). Reliable contraception is indicated even in women with a history of infertility, unless it is due to a hysterectomy or bilateral oophorectomy.

[0334] 7. Men who are sexually active with women of childbearing potential must agree to use latex or synthetic condoms, even if they have had a successful vasectomy. All men must also donate sperm during the study, for 4 weeks after their last dose of lenalidomide, and for 3 months after their last dose of daratumumab (DARZALEX®).

[0335] 8. Women of childbearing potential must have two negative serum or urine pregnancy tests at screening, one within 10-14 days prior to infusion and one within 24 hours prior to infusion.

[0336] 9. Each subject (or the subject's legal representative) must sign an informed consent form (ICF), indicating that he or she understands the purpose of the study and the procedures it will entail, and is willing to participate in the study. Subjects must be willing and able to abide by the prohibitions and restrictions specified in this protocol, as referenced in the ICF.

[0337] Exclusion criteria Any potential subject who meets any of the following criteria will be excluded from participation in this study.

[0338] 1. Subjects have a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined significance is defined by the presence of serum M-protein less than 3 g / dL; M-protein-associated lytic bone lesions, anemia, hypercalcemia, and decreased renal function; and (if determined) a bone marrow plasma cell percentage of 10% or less (Kyle et al., Mayo Clin Proc 78:21-33, 2003). Smoldering multiple myeloma is characterized by associated organ or tissue dysfunction, end-organ damage, or both. It is defined as asymptomatic multiple myeloma without any clinical features (Kyle et al., Mayo Clin Proc 78:21-33, 2003; Kyle et al., N Engl J Med 356:2582-2590, 2007).

[0339] 2. Subject has Waldenstrom's disease or other condition with lytic bone lesions in which IgM M-proteins are present in the absence of a clonal plasma cell infiltrate.

[0340] 3. Subjects must have a short-term (equivalent to 4 days of dexamethasone 40 mg / day) Previous or current systemic therapy or SCT for multiple myeloma, excluding emergency use of corticosteroids.

[0341] 4. Subject has a history of malignancy (other than multiple myeloma) within 5 years prior to the date of randomization (with the exception of squamous cell and basal cell carcinoma of the skin and carcinoma in situ of the cervix, or a malignancy that, in the opinion of the investigator and in agreement with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 5 years).

[0342] 5. Subject has received radiation therapy within 14 days of randomization.

[0343] 6. Subject has undergone plasma exchange within 28 days of randomization.

[0344] 7. Subject exhibits clinical signs of meningeal involvement of multiple myeloma.

[0345] 8.8.1a) Subject has known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) less than 50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD, and subjects must be excluded if their FEV1 is less than 50% of predicted normal. 8.1b) Subjects have known moderate or severe persistent asthma within the past two years or currently have any classification of uncontrolled asthma. (Please note that subjects with currently controlled intermittent asthma or controlled mild persistent asthma are allowed in the study.)

[0346] 9. Subject is known to be seropositive for human immunodeficiency virus (HIV), or hepatitis B (defined by a positive test for hepatitis B surface antigen (HBsAg) or antibodies to hepatitis B surface antigen and core antigen (anti-HBs and anti-HBc, respectively)), or hepatitis C (positive anti-HCV antibodies or positive HCV RNA quantification).

[0347] 10. Subject has any concurrent medical or psychiatric condition or illness (e.g., active systemic infection, poorly controlled diabetes, acute diffuse infiltrative pulmonary disease) that may interfere with the study procedures or results or that, in the opinion of the investigator, would pose a risk to participation in this study.

[0348] 11. Subject has clinically significant cardiac disease, including: Myocardial infarction within 1 year prior to randomization, or any unstable or poorly controlled disease / condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association class III-IV) Uncontrolled arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4, grade 3 or higher) or clinically significant ECG abnormalities A screening 12-lead ECG showing a baseline QT interval corrected by the Fridericia formula (QTcF) of greater than 470 milliseconds

[0349] 12. Subject has a known allergy, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies, or human proteins, or their excipients (see respective package inserts or Investigator Brochure), or a known sensitivity to products of mammalian origin.

[0350] 13. Subject has plasma cell leukemia (according to World Health Organization [WHO] criteria: 2 × 10 9 ≥20% of cells in peripheral blood with an absolute plasma cell count >1 / L) or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).

[0351] 14. The subject is known or suspected to be unable to comply with the study protocol (e.g., due to alcoholism, drug dependence, or psychiatric disorder). The subject has any condition where, in the opinion of the investigator, participation would not be in the subject's best interest (e.g., would jeopardize their well-being) or could interfere with, limit, or confound protocol-specified assessments. The subject is taking any prohibited medication.

[0352] 15. The subject is a woman who is pregnant, breastfeeding, or planning to become pregnant within 4 weeks after the last dose of lenalidomide or within 3 months after the last dose of daratumumab (DARZALEX®) while enrolled in this study. Alternatively, the subject is a man who plans to father a child within 4 weeks after the last dose of lenalidomide or within 3 months after the last dose of daratumumab (DARZALEX®) while enrolled in this study.

[0353] 16. Subject has undergone major surgery within 2 weeks prior to randomization, or has not fully recovered from surgery, or has surgery planned during the period in which the subject is expected to participate in this study. Vertebroplasty or kyphoplasty is not considered major surgery.

[0354] 17. Subject has received an investigational drug (including an investigational vaccine) or used an invasive investigational medical device within 4 weeks prior to randomization, or is currently enrolled in an interventional clinical trial.

[0355] 18. Subject has contraindications to required prophylaxis for deep vein thrombosis and pulmonary embolism.

[0356] 19. Occurrence of gastrointestinal disease that may significantly alter oral drug absorption.

[0357] Prevention of infusion reactions Pre-infusion medications for subjects receiving daratumumab (DARZALEX®) will be administered as follows: On the day of daratumumab (DARZALEX®) infusion, subjects will receive the following medications prior to the infusion: Acetaminophen (paracetamol) 650 to 1000 mg IV or orally (PO) within approximately 1 hour before daratumumab (DARZALEX®) infusion Antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent, but avoid IV promethazine) within approximately 1 hour prior to the infusion after Cycle 6. Modifications are permitted at the investigator's discretion if the subject is not experiencing an infusion-related reaction and is intolerant to the antihistamine. Dexamethasone 40 mg IV (preferred) or PO within approximately 1 hour prior to daratumumab (DARZALEX®) infusion. For subjects over 75 years of age or underweight (body mass index [BMI] less than 18.5), dexamethasone 20 mg may be administered as appropriate. An equivalent intermediate- or long-acting corticosteroid may be substituted. On days when subjects receive this dose of dexamethasone in the clinic, dexamethasone will not be self-administered at home. If the weekly dexamethasone dose is reduced to less than 10 mg due to adverse events during the study, subjects should continue to receive a minimum of 10 mg IV dexamethasone prior to daratumumab (DARZALEX®) infusion.

[0358] If desired, all PO pre-infusion medications may be administered outside the clinic on the day of infusion, provided they are administered within 3 hours prior to the infusion.

[0359] Pre-infusion medications For subjects at higher risk of respiratory complications (i.e., subjects with mild asthma or subjects with COPD with an FEV1 less than 80%), the following post-infusion medications should be considered: Antihistamines (diphenhydramine or equivalent) Short-acting beta-2 adrenergic receptor agonists, e.g., salbutamol aerosol Controller medications for pulmonary disease (e.g., inhaled corticosteroids ± long-acting beta-2 adrenergic receptor agonists for subjects with asthma, long-acting bronchodilators, e.g., tiotropium or salmeterol ± inhaled corticosteroids for subjects with COPD)

[0360] Lenalidomide dose reduction Lenalidomide dose adjustments will follow approved labeling as follows: ·Starting dose: 25mg Dose level 1: 15mg Dose level 2: 10mg Dose level 3: 5mg

[0361] Dose adjustments should be based on the highest grade toxicity attributable to lenalidomide. After initiation of lenalidomide, subsequent lenalidomide dose adjustments will be based on the individual subject's tolerance to treatment. If the investigator determines that an adverse event may be related to lenalidomide, a dose adjustment may be made even if not specified in this protocol.

[0362] Response category Disease assessments should be performed every 28 days for the first 2 years, then every 8 weeks until disease progression. A time window of ±7 days is allowed. If treatment is delayed for any reason, disease assessments should be performed according to the schedule, regardless of any changes to the dosing regimen.

[0363] Disease assessment will be performed by a central laboratory (unless otherwise specified). This study will use the IMWG consensus recommendations for multiple myeloma treatment response criteria (Durie et al., Leukemia, 20:1467-7143, 2006; Rajkumar et al., Blood, 117:4691-4695, 2011), presented in Table 1. For quantitative immunoglobulin, M-protein, and immunofixation measurements in serum and 24-hour urine, the investigator will use the results provided by the central laboratory. Subjects with positive serum IFE, confirmed daratumumab (DARZALEX) IFE interference, and who meet all other clinical criteria for complete response or stringent complete response will be considered in CR / sCR.

[0364] Disease progression must be confirmed consistently across clinical study sites using the criteria in Table 1. For patients with measurable disease by SPEP or UPEP at baseline, serum free light chain (FLC) or FLC ratio alone does not meet the criteria for progressive disease.

[0365] Example 2: A Phase 3 Study Comparing Daratumumab (DARZALEX®), Lenalidomide, and Dexamethasone (DRd) to Lenalidomide and Dexamethasone (Rd) in Subjects with Previously Untreated Multiple Myeloma Who Are Ineligible for High-Dose Chemotherapy (HDC) and Autologous Stem Cell Transplant (ASCT) - Interim Analysis at a Median Follow-Up of 28 Months 737 patients with newly diagnosed myeloma who were ineligible for HDC and ASCT were randomly assigned to receive lenalidomide and dexamethasone alone (control group) or with daratumumab (DARZALEX®) (daratumumab (DARZALEX® group)), and treatment continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival. The study protocol is described in Example 1.

[0366] After a median follow-up of 28 months, median progression-free survival was not reached in the daratumumab (DARZALEX®) group compared with 31.9 months in the control group (hazard ratio, 0.56; 95% confidence interval, 0.43-0.73; P<0.0001). The rates of complete response or better were 47.6% vs. 24.9% in the daratumumab (DARZALEX®) and control groups, respectively (P<0.0001). 24.2% of patients in the daratumumab (DARZALEX®) group were minimal residual disease-negative compared with 7.3% of patients in the control group (10 5(P<0.0001). The most common (>10%) grade 3 / 4 adverse events in the daratumumab (DARZALEX®) vs. control groups were neutropenia (50.0% vs. 35.3%), lymphopenia (15.1% vs. 10.7%), pneumonia (13.7% vs. 7.9%), anemia (11.8% vs. 19.7%), and leukopenia (11.0% vs. 4.9%).

[0367] Daratumumab (DARZALEX®) plus lenalidomide and dexamethasone significantly reduced the risk of disease progression or death compared with lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma who were ineligible for autologous stem cell transplant. Higher rates of neutropenia and pneumonitis were observed in the daratumumab (DARZALEX®) group.

[0368] In this randomized, open-label, active-controlled, multicenter, phase 3 trial, patients were enrolled between March 2015 and January 2017 at sites located in 14 countries across North America, Europe, the Middle East, and the Asia-Pacific region. An independent ethics committee or institutional review board at each site approved the protocol. The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation-Good Clinical Practice guidelines. All patients provided written informed consent. Janssen Research & Development, LLC, sponsored this study and compiled / maintained the data.

[0369] patient Eligible patients had newly diagnosed myeloma (Rajkumar et al., Lancet Oncol 15:e538-e548, 2014), confirmed Eastern Cooperative Oncology Group performance status 2 or less, and were ineligible for high-dose chemotherapy with stem cell transplant due to age (≥65 years) or comorbidities. Patients had a hemoglobin level of ≥7.5 g / dL, a serum creatinine level of ≥1.0 × 10 9 Absolute neutrophil count of 70 × 10 / L or more 9 / L or higher (50 × 10 if less than 50% of bone marrow nucleated cells are plasma cells) 9 / L), aspartate aminotransferase and alanine aminotransferase less than 2.5 times the upper limit of normal, total bilirubin less than 2.0 times the upper limit of normal, creatinine clearance greater than 30 mL / min, and corrected serum calcium less than 14 mg / dL.

[0370] Test treatment Patients were randomized using an interactive web response system (1:1 ratio) to receive daratumumab (DARZALEX®) in combination with lenalidomide and dexamethasone (daratumumab (DARZALEX®) group), or lenalidomide and dexamethasone alone (control group). Patients were stratified by International Stage Classification System (ISS; I vs. II vs. III), region (North America vs. others), and age (<75 vs. ≥75 years).

[0371] During each 28-day cycle, all patients received oral lenalidomide (25 mg, days 1–21) and oral dexamethasone (40 mg, days 1, 8, 15, and 22) until disease progression or unacceptable toxicity. 2 For patients with a body mass index less than 18.0, dexamethasone was administered at a dose of 20 mg once weekly. Patients in the daratumumab (DARZALEX®) group also received intravenous daratumumab (DARZALEX®) 16 mg / kg once weekly during cycles 1-2, every 2 weeks during cycles 3-6, and every 4 weeks thereafter. Pre-infusion medications were administered to manage infusion reactions.

[0372] Endpoints and Evaluation The primary endpoint was progression-free survival (time from the date of randomization to either disease progression or death). Secondary efficacy endpoints were time to progression, complete response rate, stringent complete response rate, and minimal residual disease-negative rate (10 5 The endpoints were progression-free survival (PFS), overall survival, overall response rate, proportion of patients achieving a very good partial response or better, time to response and duration of response, efficacy in high-risk molecular subgroups, and safety. Progressive disease was determined according to the International Myeloma Working Group criteria (Rajkumar et al., Blood 117:4691-4695, 2011; Durie et al., Leukemia 20:1467-1473, 2006).

[0373] A central laboratory performed disease assessments (serum and 24-hour urine samples) every 28 days for 2 years, then every 8 weeks until disease progression. Complete responses were confirmed using a reflex assay for patients with positive serum immunofixation and daratumumab (DARZALEX®) interference (McCudden et al., Clin Chem Lab Med 54:1095-1104, 2016). Minimal residual disease was assessed by next-generation sequencing (clonoSEQ®) version 2.0; Adaptive Biotechnologies) on bone marrow aspirates collected at baseline, at the time of suspected complete response or stringent complete response (undetectable M-protein on two consecutive serum and urine electrophoresis tests), and at 12, 18, 24, and 30 months after the first dose in patients who achieved a complete response or better.

[0374] Safety analyses included adverse event assessment graded in severity according to NCI-CTCAE version 4, electrocardiogram, clinical laboratory tests, physical examination, and vital signs.

[0375] statistical analysis The primary analysis population included all patients randomized to the intention-to-treat population. The safety population included patients who received any dose of study treatment. For the primary endpoint of progression-free survival, a stratified log-rank test was used. Treatment effects and 95% confidence intervals (CIs) were estimated using a stratified Cox regression model with treatment as the only explanatory variable. Other time-to-event efficacy endpoints were analyzed similarly. Response to study treatment and progressive disease were assessed using previously described validated computer algorithms (Dimopoulos et al., N Engl J Med 375:1319-1331 2016; Palumbo et al., N Engl J Med 375:754-766, 2016). Continuous, categorical, and time-to-event variables were summarized using descriptive statistics, frequency tables, and the Kaplan-Meier method, respectively. Binary endpoints were analyzed using the stratified Cochran-Mantel-Haenszel test. If the primary endpoint was statistically significant, the following secondary endpoints were tested sequentially as ordered here (each had an overall two-sided alpha of 0.05): complete response rate or better, very good partial response or better, and minimal residual disease negativity, overall response rate, and overall survival.

[0376] Two planned interim analyses were performed. The first interim analysis evaluated safety after 100 patients had received at least 8 weeks of treatment or had discontinued treatment. The second interim analysis, reported here, evaluated safety and efficacy after 240 progression-free survival events (62% of the 390 planned progression-free survival events for the primary analysis). The trial will end when 330 deaths have been reported.

[0377] A sample size of 730 patients was estimated to provide 80% power to detect a 25% reduction in the risk of progression or death in the daratumumab (DARZALEX®) group compared with the control group using the log-rank test at a two-sided alpha level of 0.05.

[0378] result Patients and Treatment Of 737 enrolled patients, 368 and 369 were randomized to the daratumumab (DARZALEX®) and control groups, respectively. Baseline demographic and clinical characteristics were well balanced (Table 2). Median age was 73.0 years (range, 45-90), and 14.3% of patients had a high-risk cytogenetic profile. Median time since diagnosis was 0.9 months (range, 0-14.5).

[0379] Among randomized patients, 729 patients (364 in the daratumumab (DARZALEX®) group and 365 in the control group) received at least one dose of study treatment (364 in the daratumumab (DARZALEX®) group and 365 in the control group) received at least a single dose of study treatment. At the clinical cutoff date (September 24, 2018), 118 patients (32.4%) in the daratumumab (DARZALEX®) group and 207 patients (56.7%) in the control group had discontinued treatment, most commonly due to progressive disease (14.6% vs. 23.8%) and adverse events (7.4% vs. 16.2%).

[0380] [Table 2]

[0381] The median treatment duration was 25.3 months (range: 0.1-40.4) in the daratumumab (DARZALEX®) group and 21.3 months (range: 0.03-40.6) in the control group, with a median number of cycles received of 27 (range: 1-44) versus 22 (range: 1-43). The median relative dose intensity (ratio of administered dose to planned dose) of daratumumab (DARZALEX®) was 98.4%. The median relative dose intensity of lenalidomide was 76.2% in the daratumumab (DARZALEX®) group and 91.4% in the control group. A higher rate of lenalidomide dose modifications due to treatment-emergent adverse events was reported in the daratumumab (DARZALEX®) group versus the control group, including dose discontinuation (20.9% vs. 17.0%, respectively), or dose delays, reductions, re-escalations, or skips (combined: 77.5% vs. 64.7%, respectively). The median relative dose intensity of dexamethasone was 84.2% in the daratumumab (DARZALEX®) group and 90.7% in the control group.

[0382] Effectiveness During a median follow-up of 28.0 months (range, 0-41.4), a total of 240 events of disease progression or death occurred (97 patients [26.4%] in the daratumumab (DARZALEX®) group vs. 143 patients [38.8%] in the control group). The hazard ratio for disease progression or death in the daratumumab (DARZALEX®) group vs. the control group was 0.56 (95% CI, 0.43-0.73; P<0.0001) (Figure 1). The Kaplan-Meier estimates of 30-month progression-free survival were 70.6% (95% CI, 65.0-75.4) in the (DARZALEX®) group and 55.6% (95% CI, 49.5-61.3) in the control group. Median progression-free survival was not reached in the daratumumab (DARZALEX®) group (95% CI, not estimable) compared with 31.9 months in the control group (95% CI, 28.9 to not estimable) (P<0.0001). In a time-to-event analysis of disease progression, 179 events were observed (66 patients [17.9%] in the daratumumab (DARZALEX®) group vs. 113 patients [30.6%] in the control group), and the median progression-free period was not reached in the daratumumab (DARZALEX®) group compared with 35.8 months in the control group (95% CI, 31.4 to not estimable) (hazard ratio, 0.47; 95% CI, 0.35 to 0.64; P<0.0001).

[0383] Prespecified subgroup analyses of progression-free survival confirmed the superiority of the daratumumab (DARZALEX®) arm over the control arm across all subgroups, except for patients with hepatic impairment (Figure 2). The progression-free survival benefit was maintained in patients aged 75 years or older (hazard ratio, 0.63; 95% CI, 0.44-0.92) and among patients with a historically poor prognosis, including those with high-risk cytogenetic profiles (hazard ratio, 0.85; 95% CI, 0.44-1.65) and ISS stage III disease (hazard ratio, 0.72; 95% CI, 0.48-1.09). The hazard ratio for disease progression or death was lower for patients with a standard-risk cytogenetic profile (hazard ratio, 0.49) than for patients with a high-risk cytogenetic profile, but the results favored the daratumumab (DARZALEX®) arm in both subpopulations. The small number of patients with a high-risk cytogenetic profile limits the interpretation of these findings.

[0384] In the intent-to-treat population (e.g., all subjects enrolled and randomized to treatment), patients in the daratumumab (DARZALEX®) group achieved significantly higher rates of complete response or better (47.6% vs. 24.9%, P<0.0001) and very good partial response or better (79.3% vs. 53.1%, P<0.0001) compared with the control group (Table 3). The overall response rate was 92.9% in the daratumumab (DARZALEX®) group and 81.3% in the control group (p<0.0001).

[0385] The higher rate of deeper responses in the daratumumab (DARZALEX®) group was more than three times higher in the daratumumab (DARZALEX®) group versus the control group (24.2% vs. 7.3%, P<0.0001), with minimal residual disease negative status (10 5The progression-free survival was revealed by RT-PCR (at a threshold of one tumor cell per 100 white blood cells) (Table 3). Patients with negative status for minimal residual disease demonstrated longer progression-free survival compared with patients with positive status, regardless of study treatment. All patients who achieved negative status for minimal residual disease achieved a complete response or better.

[0386] A total of 138 deaths occurred (62 in the daratumumab (DARZALEX®) group vs. 76 in the control group). Median overall survival was not reached in either treatment group (hazard ratio, 0.78; 95% CI, 0.56 to 1.10; P=0.1528), and long-term follow-up is ongoing.

[0387] The median duration of response was not achieved in the daratumumab (DARZALEX®) group (95% CI, not estimable) compared with 34.7 months in the control group (95% CI, 30.8–not estimable). The median time to first response among responders was 1.05 months in both groups, and the median time to complete response or better was 10.4 months in the daratumumab (DARZALEX®) group and 11.2 months in the control group. Minimal residual disease-negative events accumulated more rapidly in the daratumumab (DARZALEX®) group.

[0388] The progression-free survival benefit observed with daratumumab (DARZALEX®) was maintained with subsequent therapy, as demonstrated by longer progression-free survival in the daratumumab (DARZALEX®) group than in the control group (median progression-free survival was not reached in either treatment group; hazard ratio, 0.70; 95% CI, 0.51-0.96; P=0.0278). The 36-month progression-free survival rates were 77.1% (95% CI, 70.6-82.3) in the DARZALEX® group and 65.2% (95% CI, 54.2-74.1) in the control group. A total of 155 events of progression or death were observed while patients were receiving subsequent therapy (68 patients in the daratumumab (DARZALEX®) group and 87 patients in the control group).

[0389] [Table 3]

[0390] safety Table 4 summarizes the most common adverse events of any grade (in >30% of patients in either group) or grade 3 or 4 adverse events (in >10% of patients in either group) during treatment for the safety population; the most common grade 3 or 4 adverse events were neutropenia (50.0% vs. 35.3%, respectively), lymphopenia (15.1% vs. 10.7%, respectively), pneumonia (13.7% vs. 7.9%, respectively), anemia (11.8% vs. 19.7%, respectively), and leukopenia (11.0% vs. 4.9%, respectively). The infection rate of any grade was 86.3% in the daratumumab (DARZALEX®) group and 73.4% in the control group, with grade 3 or 4 infection rates of 32.1% and 23.3%, respectively.

[0391] Serious adverse events were reported in 62.9% of patients in the daratumumab (DARZALEX®) group and 62.7% of patients, of which pneumonia was the most common, occurring in 13.2% and 7.4% of patients, respectively. The proportion of patients with adverse events leading to discontinuation of study treatment was 7.1% in the daratumumab (DARZALEX®) group and 15.9% in the control group. Discontinuation of study treatment due to infection occurred in 0.5% of the daratumumab (DARZALEX®) group and 1.4% of the control group, and no patients in the daratumumab (DARZALEX®) group discontinued treatment due to neutropenia, compared with one patient (0.3%) in the control group.

[0392] Adverse events leading to death were observed in 25 patients (6.9%) in the daratumumab (DARZALEX®) group and 23 patients (6.3%) in the control group, the most common of which was pneumonia, occurring in 0.5% and 0.8% of patients, respectively. Invasive second primary malignancies were reported in 12 (3.3%) patients in the daratumumab (DARZALEX®) group (2.7% solid tumors; 0.5% hematologic malignancies) and 13 (3.6%) patients in the control group (3.0% solid tumors; 0.5% hematologic malignancies).

[0393] Infusion-related reactions associated with daratumumab (DARZALEX®) were reported in 40.9% of patients, with 2.7% being grade 3 or 4 events (one patient reported grade 4 hypertension), and no grade 5 events. Infusion-related reactions usually occurred during the first dose (in 98.0% of patients with infusion reactions), and only one patient discontinued daratumumab (DARZALEX®) treatment due to an infusion-related reaction (grade 4 hypertension).

[0394] [Table 4]

[0395] Example 3: Effect of Age on the Efficacy and Safety of Daratumumab (DARZALEX®) (DRd) in Combination with Lenalidomide and Dexamethasone in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma (NDMM): MAIA DRd significantly reduced the risk of progression or death by 44% compared with Rd in transplant-ineligible NDMM patients in the primary analysis of the phase 3 MAIA trial (Example 2). To examine the effect of age on the efficacy and safety of D-Rd versus Rd in this patient population, subgroup analyses were performed within patients under 75 years of age and ≥ 75 years of age.

[0396] Methods: Transplant-ineligible NDMM patients were randomized 1:1 to Rd ± DARA. Stratification was based on age (<75 vs. ≥75 years), ISS (I, II, III), and region (North America vs. others). For standard Rd dosing, patients received 28-day cycles of lenalidomide 25 mg PO QD on days 1-21 and dexamethasone 40 mg PO on days 1, 8, 15, and 22 until progression. A subset of patients received 10 mg lenalidomide and 20 mg dexamethasone at treatment initiation. In the DRd group, patients received daratumumab (DARZALEX) 16 mg / kg IV QW in cycles 1-2, Q2W in cycles 3-6, and Q4W thereafter until progression. PFS was the primary endpoint.

[0397] Results: Of 737 randomized patients (D-Rd, n=368; Rd, n=369), 321 (44%) were aged 75 years or older. A higher proportion of patients in the D-Rd group received a lower starting dose of lenalidomide (10 mg) compared with the Rd group (30.8% vs. 22.7%) and a lower relative median dose intensity for lenalidomide (<75 years: 79% vs. 93%; ≥75 years: 66% vs. 89%). After a median follow-up of 28 months, the significant PFS benefit of D-Rd versus Rd remained in both subgroups of patients under 75 years of age (<75 years: median not reached [NR] vs. 33.7 months; HR 0.50; 95% CI 0.35-0.71; ≥75 years: median NR vs. 31.9 months; HR 0.63; 95% CI 0.44-0.92). Overall response rate (<75 years: 95% vs. 82%; ≥75 years: 90% vs. 81%), complete response rate or better (<75 years: 52% vs. 25%; ≥75 years: 41% vs. 25%), very good partial response rate or better (<75 years: 81% vs. 53%; ≥75 years: 77% vs. 53%), and minimal residual disease-negative rate (10 -5The thresholds (<75 years: 28% vs. 7%; ≥75 years: 19% vs. 8%) remained higher for D-Rd vs. Rd in both age subgroups. The most common (≥10%; D-Rd / Rd) grade 3 / 4 TEAEs in patients <75 years were neutropenia (43% / 31%), pneumonia (13% / 6%), lymphopenia (12% / 10%), leukopenia (10% / 4%), and anemia (9% / 18%). The most common (≥10%; D-Rd / Rd) grade 3 / 4 TEAEs in patients ≥75 years were neutropenia (60% / 41%), lymphopenia (19% / 12%), anemia (16% / 22%), pneumonia (15% / 10%), leukopenia (12% / 6%), and thrombocytopenia (8% / 11%). Fewer patients receiving D-Rd vs. Rd discontinued treatment due to TEAEs (<75 years: 5% vs. 12%; ≥75 years: 10% vs. 21%), and the rate of discontinuation due to infection was lower in both age groups for D-Rd vs. Rd (<75 years: 1% vs. 1%; ≥75 years: 0% vs. 2%). A higher proportion of patients ≥75 years discontinued lenalidomide due to TEAEs compared with patients <75 years (≥75 years: 29% vs. 22%; <75 years: 15% vs. 13%).

[0398] Conclusions: Patients with DRd received less lenalidomide than those in the Rd group, regardless of age. The efficacy of DRd in patients under and over 75 years of age was consistent with the ITT population, and DRd demonstrated acceptable tolerability regardless of age. Together with the Phase 3 ALCYONE trial, these studies confirm the clinical efficacy of daratumumab (DARZALEX®) added to standard of care in transplant-ineligible NDMM patients 75 years of age and older.

[0399] [Table 5]

[0400] [Table 6]

[0401] [Table A]

[0402] Full prescribing information 1. Indications and usage DARZALEX is indicated for the treatment of patients with multiple myeloma: In combination with immunomodulatory agents or bortezomib-containing regimens [see Dosage and Administration (2) and Clinical Studies (14)] 1 As monotherapy in patients who have received at least three prior therapies, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are dually refractory to a PI and an immunomodulatory agent

[0403] 2. Dosage and Administration 2.1 Recommended Dosage and Schedule Administer pre- and post-infusion medications [see Dosage and Administration (2.2)] Administer only as an intravenous infusion after dilution with 0.9% sodium chloride injection [see Dosage and Administration (2.4, 2.5)] DARZALEX should be administered by healthcare professionals who have ready access to emergency equipment and appropriate medical assistance to manage any infusion reactions that may occur [see Warnings and Precautions (5.1)].

[0404] The DARZALEX dosing schedules in Table 1 are for combination therapy (4-week cycle regimen) and monotherapy as follows: -Lenalidomide in combination with low-dose dexamethasone for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) 2 -Lenalidomide or pomalidomide in combination with low-dose dexamethasone for patients with relapsed / refractory multiple myeloma -As a monotherapy for patients with relapsed / refractory multiple myeloma.

[0405] The recommended dose of DARZALEX is 16 mg / kg actual body weight administered as an intravenous infusion according to the following dosing schedule:

[0406] [Table 7] a The first dose of the every 2 weeks dosing schedule is given at week 9. b The first dose of the every 4 weeks dosing schedule is given at week 25.

[0407] For dosing instructions for combination medications administered with DARZALEX, please refer to clinical studies (14) and the manufacturer's prescribing information.

[0408] The DARZALEX dosing schedule in Table 2 is for combination therapy with bortezomib, melphalan, and prednisone (6-week cycle regimen) for patients with newly diagnosed multiple myeloma who are ineligible for ASCT.

[0409] The recommended dose of DARZALEX is 15 mg / kg actual body weight administered as an intravenous infusion according to the following dosing schedule:

[0410] [Table 8] a The first dose of the every 3 weeks dosing schedule is given at week 7. b The first dose of the every 4 weeks dosing schedule is given at week 55.

[0411] For dosing instructions for combination medications administered with DARZALEX, see Clinical Studies (14.1).

[0412] Table 3 shows the DARZALEX dosing schedule for patients with relapsed / refractory multiple myeloma in combination with bortezomib and dexamethasone (3-week cycle regimen).

[0413] The recommended dose of DARZALEX is 16 mg / kg actual body weight administered as an intravenous infusion according to the following dosing schedule in Table 3:

[0414] [Table 9] a The first dose of the every 3 weeks dosing schedule is given at week 10. b The first dose of the every 4 weeks dosing schedule is given at week 25.

[0415] For dosing instructions for combination medications administered with DARZALEX, please refer to Clinical Studies (14.2) and the manufacturer's prescribing information.

[0416] Missed DARZALEX dose If a scheduled dose of DARZALEX is missed, administer that dose as soon as possible and adjust the dosing schedule accordingly to maintain the treatment interval.

[0417] Management of infusion rate and infusion reactions DARZALEX infusion will be administered intravenously at the infusion rates set forth below in Table 4. Escalation of the infusion rate will be considered only in the absence of infusion reactions.

[0418] For ease of administration, the initially prescribed dose of 16 mg / kg in week 1 may be split into 8 mg / kg on two consecutive days, i.e., days 1 and 2, respectively, see Table 4 below.

[0419] [Table 10] aConsider incremental increases in infusion rate only in the absence of an infusion reaction. b Use a dilution volume of 500 mL for the 16 mg / kg dose only if there has been no infusion reaction in the previous week. Otherwise, use a dilution volume of 1000 mL. c Use the modified initial rate (100 mL / hr) for subsequent infusions (i.e., week 3 onwards) only if there was no infusion reaction during the previous infusion. Otherwise, continue to use the instructions shown in the table for the infusion rate for week 2.

[0420] For infusion reactions of any grade / severity, immediately interrupt the DARZALEX infusion and manage symptoms. Management of infusion reactions may further require reduction of the infusion rate or discontinuation of DARZALEX therapy, as outlined below [see Warnings and Precautions (5.1)]. Grade 1-2 (mild to moderate): Once the reaction symptoms have resolved, resume the infusion at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, the infusion rate escalation may be resumed at clinically appropriate increments and intervals up to a maximum rate of 200 mL / hour (Table 4). Grade 3 (severe): Once reaction symptoms have resolved, consider resuming the infusion at no more than half the rate at which the reaction occurred. If the patient experiences no further symptoms, resume escalating the infusion rate at the increments and intervals outlined in Table 4. In the event of recurrence of Grade 3 symptoms, repeat the above procedure. At the third occurrence of a Grade 3 or higher infusion reaction, permanently discontinue DARZALEX. Grade 4 (life-threatening): Permanently discontinue DARZALEX treatment.

[0421] 2.2 Recommended concomitant medications Pre-infusion medications Administer the following pre-infusion medications 1 to 3 hours before each infusion of DARZALEX to reduce the risk of infusion reactions in all patients: Corticosteroids (long-acting or intermediate-acting) Monotherapy: Methylprednisolone 100 mg, or equivalent administered intravenously. After the second infusion, the corticosteroid dose may be reduced (oral or intravenous methylprednisolone 60 mg). Combination therapy: Administer 20 mg of dexamethasone (or equivalent) prior to each DARZALEX infusion. If dexamethasone is the corticosteroid of the background regimen, the therapeutic dose of dexamethasone will instead serve as premedication on the day of DARZALEX infusion [clinical study (14)]. 3 Dexamethasone is administered intravenously prior to the first DARZALEX infusion, and oral administration is considered prior to subsequent infusions. Additional background regimen-specific corticosteroids (e.g., prednisone) should not be taken on the day of a DARZALEX infusion in which patients receive dexamethasone (or equivalent) as premedication. Antipyretic (oral acetaminophen 650-1000mg) ·Antihistamines (oral or intravenous diphenhydramine 25-50 mg or equivalent).

[0422] Post-infusion medication Administer post-infusion medications to reduce the risk of delayed infusion reactions to all patients as follows: Monotherapy: Oral corticosteroids (20 mg methylprednisolone, or an equivalent dose of intermediate- or long-acting corticosteroid according to local standards) will be administered on each of the two days following all DARZALEX infusions (starting the day after the infusion). Combination therapy: Consider administering low-dose oral methylprednisolone (<20 mg) or equivalent on the day following a DARZALEX infusion. However, if a background regimen-specified corticosteroid (e.g., dexamethasone, prednisone) is administered the day following a DARZALEX infusion, additional post-infusion medications may not be required [see Clinical Study (14)].

[0423] Additionally, for any patient with a history of chronic obstructive pulmonary disease, consider prescribing post-infusion medications such as short- and long-acting bronchodilators and inhaled corticosteroids. If the patient does not experience a significant infusion reaction after the first four infusions, these additional post-infusion inhaled medications can be discontinued.

[0424] Shingles reactivation prophylaxis Antiviral prophylaxis should be initiated within 1 week of starting DARZALEX to prevent herpes zoster reactivation and continued for 3 months after treatment [see Adverse Reactions (6.1)].

[0425] 2.3 Dose modification Dose reduction of DARZALEX is not recommended. Dose delays may be necessary to allow for recovery of blood counts in the event of hematologic toxicity [see Warnings and Precautions (5.3, 5.4)]. Refer to the manufacturer's prescribing information for information regarding drugs administered in combination with DARZALEX.

[0426] 2.4 Preparation for administration DARZALEX is for single use only.

[0427] Prepare injectable solutions using sterile technique as follows: Calculate the number of DARZALEX vials needed based on the dose (mg), the total volume (mL) of DARZALEX solution needed, and the patient's actual weight. Ensure DARZALEX solution is colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign matter are present. Remove a volume of 0.9% Sodium Chloride Injection, USP from the infusion bag / container equal to the required volume of DARZALEX Solution. Withdraw the required amount of DARZALEX solution and dilute to the appropriate volume by adding it to an infusion bag / container containing 0.9% Sodium Chloride Injection, USP, as specified in Table 4 [see Dosage and Administration (2.1)]. The infusion bag / container should be made of either polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blends (PP+PE). Dilute under appropriate sterile conditions. Discard any unused portion remaining in the vial. Mix the solution by gently inverting the bag / container. Do not shake. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever the solution and container permit. Diluted solutions may produce very small, translucent to white proteinaceous particles because daratumumab is a protein. Do not use if visually opaque particles, discoloration, or foreign matter are observed. Because DARZALEX does not contain preservatives, administer the diluted solution immediately at room temperature (15°C to 25°C, 59°F to 77°F) and room lighting. The diluted solution may be kept at room temperature for up to 15 hours (including the infusion time). If not used immediately, the diluted solution may be stored under refrigerated conditions, 2°C to 8°C (36°F to 46°F), protected from light, for up to 24 hours before administration. Do not freeze.

[0428] 2.5 Administration If stored in a refrigerator, allow the solution to come to room temperature. Administer the diluted solution by intravenous infusion using an infusion set equipped with a flow regulator and an in-line, sterile, non-pyrogenic, low-protein binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometers). The administration set should be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE. Do not store any unused portion of the injection solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements. Do not infuse DARZALEX with other medications through the same intravenous line.

[0429] 3. Dosage form and strength DARZALEX is a colorless to pale yellow, preservative-free solution available as: injection: · 100 mg / 5 mL (20 mg / mL) in a single-dose vial. · 400 mg / 20 mL (20 mg / mL) in a single-dose vial.

[0430] 4 Contraindications DARZALEX is contraindicated in patients with a history of severe hypersensitivity (e.g., anaphylactic reaction) to daratumumab or any of the components of the formulation [see Warnings and Precautions (5.1) and Adverse Reactions (6,3)].

[0431] 5. Warnings and Precautions 5.1 Infusion reactions DARZALEX may cause severe and / or critical infusion reactions, including anaphylactic reactions. In clinical trials, approximately half of all patients experienced infusion reactions. Most infusion reactions occurred during the first infusion and were Grade 1-2 [see Adverse Reactions (6.1)].

[0432] Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during the infusion or within 4 hours of completion of DARZALEX. Prior to the introduction of post-infusion medications in clinical trials, infusion reactions occurred up to 48 hours after infusion.

[0433] Severe reactions have occurred, including bronchospasm, hypoxia, hypertension, laryngeal edema, and pulmonary edema. Signs and symptoms may include nasal congestion, cough, throat irritation, and respiratory symptoms such as chills, vomiting, and nausea. Less common symptoms were wheezing, allergic rhinitis, fever, chest discomfort, pruritus, and hypotension [see Adverse Reactions (6.1)].

[0434] Premedicate patients with antihistamines, antipyretics, and corticosteroids. Monitor patients frequently during the entire infusion. Interrupt the DARZALEX infusion for any reaction of any severity and initiate medical management as needed. If an anaphylactic or life-threatening (Grade 4) reaction occurs, permanently discontinue DARZALEX therapy and initiate appropriate emergency treatment. For patients with a Grade 1, 2, or 3 reaction, reduce the infusion rate when the infusion is restarted [see Dosage and Administration (2.1)].

[0435] Administer oral corticosteroids to all patients after DARZALEX infusion to reduce the risk of delayed infusion reactions [see Dosage and Administration (2.2)]. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

[0436] 5.2 Interference with serological tests Daratumumab binds to CD38 on red blood cells (RBCs) and produces a positive indirect antiglobulin test (indirect Coombs test). A positive daratumumab-mediated indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab binding to RBCs masks the detection of antibodies to minor antigens in the patient's serum [see Reference (15)]. The patient's ABO and Rh blood typing are not affected [see Drug Interactions (7.1)].

[0437] Notify the transfusion center of this interference with serology and notify the blood bank that the patient received DARZALEX. Classify and screen patients prior to initiating DARZALEX.

[0438] 5.3 Neutropenia DARZALEX may increase neutropenia induced by background therapy [see Adverse Reactions (6.1)].

[0439] For background therapy, monitor complete blood counts periodically during treatment according to the manufacturer's prescribing information. Monitor neutropenic patients for signs of infection. A DARZALEX dose delay may be required to allow for neutrophil recovery. DARZALEX dose reduction is not recommended. Consider supportive care with growth factors.

[0440] 5.4 Thrombocytopenia DARZALEX may increase thrombocytopenia induced by background therapy [see Adverse Reactions (6.1)].

[0441] For background therapy, monitor complete blood counts periodically during treatment according to the manufacturer's prescribing information. A DARZALEX dose delay may be required to allow for platelet recovery. DARZALEX dose reduction is not recommended. Consider supportive care with transfusions.

[0442] 5.5 Interference with the determination of complete response Daratumumab is a human IgG kappa monoclonal antibody that can be detected by both serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for clinical monitoring of endogenous M-protein [see Drug Interactions (7.1)]. This interference may affect determination of complete response and disease progression in some patients with IgG kappa myeloma protein.

[0443] 6 Adverse Reactions The following clinically significant adverse reactions are also listed elsewhere in the labeling: Infusion reactions [see Warnings and Precautions (5.1)]. Neutropenia [see Warnings and Precautions (5.3)]. Thrombocytopenia [see Warnings and Precautions (5.4)].

[0444] 6.1 Adverse Reactions in Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect rates actually observed.

[0445] The safety data described below reflect exposure to DARZALEX (16 mg / kg) in 1,530 patients with multiple myeloma, including 1,374 patients who received DARZALEX in combination with a background regimen and 156 patients who received DARZALEX as monotherapy. 4

[0446] Newly diagnosed multiple myeloma Combination therapy with lenalidomide and dexamethasone (DRd) The adverse reactions described in the table below reflect exposure to DARZALEX in the Phase 3 active-controlled study MAIA, with a median treatment duration of 25.3 months (range: 0.1 to 40.44 months) for the daratumumab-lenalidomide-dexamethasone (DRd) arm and 213 months (range: 0.03 to 40.64 months) for the lenalidomide-dexamethasone (Rd) arm. 5The most frequent (≥20%) adverse reactions were infusion reaction, diarrhea, constipation, nausea, peripheral edema, fatigue, back pain, asthenia, fever, upper respiratory tract infection, bronchitis, pneumonia, decreased appetite, muscle spasms, peripheral sensory neuropathy, dyspnea, and cough. Serious adverse reactions with an incidence higher than 2% in the DRd group compared with the Rd group were dehydration (DRd 2% vs. Rd <1%), bronchitis (DRd 4% vs. Rd 2%), and pneumonia (DRd 15% vs. Rd 8%). 6

[0447] [Table 11] List of abbreviations: D = daratumumab, Rd = lenalidomide-dexamethasone. a Infusion reactions include terms determined by the investigator to be infusion-related; see the Infusion Reactions section below. b Peripheral edema, generalized edema, peripheral swelling c Acute sinusitis, bacterial rhinitis, laryngitis, metapneumovirus infection, nasopharyngitis, oropharyngeal candidiasis, pharyngitis, respiratory syncytial virus infection, respiratory infection, viral respiratory infection, rhinitis, rhinovirus infection, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection d Bronchiolitis, bronchitis, viral bronchitis, respiratory syncytial virus bronchiolitis, tracheobronchitis e atypical pneumonia, bronchopulmonary aspergillosis, lung infection, Pneumocystis jirovecii infection, Pneumocystis jirovecii pneumonia, pneumonia, aspiration pneumonia, pneumococcal pneumonia, viral pneumonia, pulmonary mycosis f Dyspnea, exertional dyspnea g Cough, wet cough h Increased blood pressure, hypertension

[0448] Laboratory abnormalities worsening during treatment from baseline are listed in Table 6 .

[0449] [Table 12] List of abbreviations: D = daratumumab, Rd = lenalidomide-dexamethasone.

[0450] Combination treatment with bortezomib, melphalan, and prednisone The adverse reactions listed in Table 7 reflect exposure to DARZALEX in the phase 3 active-controlled ALCYONE study, with a median treatment duration of 14.7 months (range: 0-25.8 months) for the daratumumab, bortezomib, melphalan, and prednisone (D-VMP) arm and 12 months (range: 0.1-14.9 months) for the VMP arm. The most frequent adverse reactions (≥20% with a frequency of at least 5% higher in the D-VMP arm) were infusion reactions, upper respiratory tract infections, and peripheral edema. Serious adverse reactions with an incidence of at least 2% higher in the D-VMP arm compared with the VMP arm were pneumonia (11% D-VMP vs. 4% VMP), upper respiratory tract infections (5% D-VMP vs. 1% VMP), and pulmonary edema (2% D-VMP vs. 0% VMP).

[0451] [Table 13] List of abbreviations: D = daratumumab, VMP = bortezomib-melphalan-prednisone a Infusion reactions include terms determined by the investigator to be infusion-related; see the Infusion Reactions section below. b Peripheral edema, generalized edema, peripheral swelling c Upper respiratory tract infection, bronchitis, bacterial bronchitis, epiglottitis, laryngitis, bacterial laryngitis, metapneumovirus infection, nasopharyngitis, oropharyngeal candidiasis, pharyngitis, streptococcal pharyngitis, respiratory syncytial virus infection, respiratory infection, viral respiratory infection, rhinitis, sinusitis, tonsillitis, tracheitis, tracheobronchitis, viral rhinitis, viral upper respiratory tract infection. d Pneumonia, lung infection, aspiration pneumonia, bacterial pneumonia, pneumococcal pneumonia, staphylococcal pneumonia, viral pneumonia, and septic pneumonia e Cough, wet cough f Dyspnea, exertional dyspnea g High blood pressure, elevated blood pressure

[0452] Laboratory abnormalities worsening during treatment from baseline listed in Table 8.

[0453] [Table 14] List of abbreviations: D = daratumumab, VMP = bortezomib-melphalan-prednisone

[0454] Relapsed / refractory multiple myeloma Combination therapy with lenalidomide and dexamethasone The adverse reactions described in Table 9 reflect exposure to DARZALEX in the phase 3 active-controlled trial POLLUX, with a median treatment duration of 13.1 months (range: 0-20.7 months) for the daratumumab-lenalidomide-dexamethasone (DRd) arm and 12.3 months (range: 0.2-20.1 months) for the lenalidomide-dexamethasone (Rd) arm. The most frequent adverse reactions (≥20%) were infusion reaction, diarrhea, nausea, fatigue, fever, upper respiratory tract infection, muscle cramps, cough, and dyspnea. The overall incidence of serious adverse reactions was 49% in the DRd arm compared with 42% in the Rd arm. Serious adverse reactions with an incidence of at least 2% higher in the DRd group compared with the Rd group were pneumonia (DRd 12% vs. Rd 10%), upper respiratory tract infection (DRd 7% vs. Rd 4%), influenza, and fever (DRd 3% vs. Rd 1% for each).

[0455] Adverse reactions led to discontinuation in 7% (n = 19) of patients in the DRd group vs. 8% (n = 22) in the Rd group.

[0456] [Table 15] List of abbreviations: D = daratumumab, Rd = lenalidomide-dexamethasone. a Infusion reactions include terms determined by the investigator to be infusion-related; see the Infusion Reactions section below. b Upper respiratory tract infection, bronchitis, sinusitis, viral respiratory infection, rhinitis, pharyngitis, respiratory infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, viral bronchitis, streptococcal pharyngitis, tracheitis, bacterial upper respiratory tract infection, bacterial bronchitis, epiglottitis, viral laryngitis, oropharyngeal candidiasis, pneumonia, viral rhinitis, acute tonsillitis, rhinovirus infection c Cough, wet cough, allergic cough d Dyspnea, exertional dyspnea

[0457] Laboratory abnormalities worsening during treatment from baseline listed in Table 10.

[0458] [Table 16] List of abbreviations: D = daratumumab, Rd = lenalidomide-dexamethasone.

[0459] Combination treatment with bortezomib and dexamethasone The adverse reactions described in Table 11 reflect exposure to DARZALEX in the phase 3, active-controlled, CASTOR trial, with a median treatment duration of 6.5 months (range: 0-14.8 months) for the daratumumab-bortezomib-dexamethasone (DVd) arm and 5.2 months (range: 0.2-8.0 months) for the bortezomib-dexamethasone (Vd) arm. The most frequent adverse reactions (>20%) were infusion reaction, diarrhea, peripheral edema, upper respiratory tract infection, peripheral sensory neuropathy, cough, and dyspnea. The overall incidence of serious adverse reactions was 42% in the DVd arm compared with 34% in the Vd arm. Serious adverse reactions with an incidence of at least 2% higher in the DVd group compared to the Vd group were upper respiratory tract infections (DVd 5% vs. Vd 2%), diarrhea, and atrial fibrillation (DVd 2% vs. Vd 0% for each).

[0460] Adverse reactions led to discontinuation in 7% (n = 18) of patients in the DVd group vs. 9% (n = 22) in the Vd group.

[0461] [Table 17] List of abbreviations: D = daratumumab, Vd = bortezomib-dexamethasone. a Infusion reactions include terms determined by the investigator to be infusion-related; see the Infusion Reactions section below. b Peripheral edema, edema, generalized edema, peripheral swelling c Upper respiratory tract infection, bronchitis, sinusitis, viral respiratory infection, rhinitis, pharyngitis, respiratory infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, viral bronchitis, streptococcal pharyngitis, tracheitis, bacterial upper respiratory tract infection, bacterial bronchitis, epiglottitis, viral laryngitis, oropharyngeal candidiasis, pneumonia, viral rhinitis, acute tonsillitis, rhinovirus infection dCough, wet cough, allergic cough e Dyspnea, exertional dyspnea

[0462] Laboratory abnormalities that worsen during treatment are listed in Table 12.

[0463] [Table 18] List of abbreviations: D = daratumumab, Vd = bortezomib-dexamethasone.

[0464] Combination treatment with pomalidomide and dexamethasone The adverse reactions described in Table 13 reflect exposure to DARZALEX, pomalidomide, and dexamethasone (DPd) in EQUULEUS over a median treatment duration of 6 months (range: 0.03 to 16.9 months). The most frequent adverse reactions (>20%) were infusion reaction, diarrhea, constipation, nausea, vomiting, fatigue, fever, upper respiratory tract infection, muscle cramps, back pain, arthralgia, dizziness, insomnia, cough, and dyspnea. The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% of patients included pneumonia (7%). Adverse reactions led to discontinuation in 13% of patients.

[0465] [Table 19] List of abbreviations: D = daratumumab, Pd = pomalidomide-dexamethasone. a Infusion reactions include terms determined by the investigator to be infusion-related; see the Infusion Reactions section below. b Edema, peripheral edema, peripheral swelling. c Acute tonsillitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection d Lung infection, pneumonia, aspiration pneumonia e Cough, wet cough, allergic cough f Dyspnea, exertional dyspnea

[0466] Laboratory abnormalities that worsen during treatment are listed in Table 14.

[0467] [Table 20] List of abbreviations: D = daratumumab, Pd = pomalidomide-dexamethasone.

[0468] Monotherapy Safety data reflect exposure to DARZALEX in 156 adult patients with relapsed and refractory multiple myeloma treated with DARZALEX at 16 mg / kg in three open-label clinical trials. The median treatment duration was 3.3 months (range: 0.03 to 20.04 months). Serious adverse reactions were reported in 51 patients (33%). The most frequent serious adverse reactions were pneumonia (6%), decreased general physical health (3%), and fever (3%).

[0469] Adverse reactions, most frequently infections, led to treatment delays in 24 (15%) patients. Adverse reactions led to discontinuation in 6 (4%) patients.

[0470] Adverse reactions occurring in at least 10% of patients are shown in Table 15. Table 16 lists grade 3-4 laboratory abnormalities reported at a rate of 10% or greater.

[0471] [Table 21] a Infusion reactions include terms determined by the investigator to be infusion-related; see the Infusion Reactions section below. b Pneumonia also includes the terms streptococcal pneumonia and lobar pneumonia.

[0472] [Table 22]

[0473] infusion reaction 9 In clinical trials (monotherapy and combination therapy, N=1530), the incidence of any grade infusion reactions was 40% for the first (16 mg / kg, Week 1) DARZALEX infusion, 2% for the Week 2 infusion, and cumulatively 4% for subsequent infusions. Fewer than 1% of patients had a Grade 3 / 4 infusion reaction at Week 2 or any subsequent infusion.

[0474] The median time to onset of reaction was 1.5 hours (range: 0-72.8 hours). The incidence of infusion modification due to reaction was 37%. The median infusion durations for 16 mg / kg at week 1, week 2, and subsequent infusions were approximately 7, 4, and 3 hours, respectively.

[0475] Serious infusion reactions included bronchospasm, dyspnea, laryngeal edema, pulmonary edema, hypoxia, and hypertension. Other adverse infusion reactions included nasal congestion, cough, chills, throat irritation, vomiting, and nausea.

[0476] In EQUULEUS, patients receiving daratumumab combination therapy (n=97) received an initial 16 mg / kg daratumumab dose in Week 1, divided into 2 doses: 8 mg / kg on Days 1 and 2, respectively. The incidence of infusion-related reactions of any grade was 42%, with 36% of patients experiencing an infusion reaction on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% on subsequent infusions. The median time to onset of reaction was 1.8 hours (range: 0.1-5.4 hours). The incidence of infusion interruptions due to reactions was 30%. The median infusion durations were 4.2 hours for Day 1 of Week 1, 4.2 hours for Day 2 of Week 1, and 3.4 hours for subsequent infusions.

[0477] varicella-zoster virus reactivation Herpes zoster virus reactivation prophylaxis was recommended for patients in some clinical trials of DARZALEX. In monotherapy trials, shingles was reported in 3% of patients. In monotherapy trials, shingles was reported in 2% to 5% of patients receiving DARZALEX.

[0478] infectious disease In patients receiving DARZALEX combination therapy, the following grade 3 or 4 infections were reported: Trials in relapsed / refractory patients: DVd: 21%, Vd: 19%, DRd: 27%, Rd: 23%, DPd: 28% Trials in newly diagnosed patients: D-VMP: 23%, VMP: 15%, DRd: 32%, Rd: 23%. 10 Pneumonia was the most commonly reported severe (grade 3 or 4) infection across studies. In the active-controlled trials, infections (1-4%) and treatment discontinuations due to fatal infections were generally rare and balanced between DARZALEX-containing regimens and the active control group. Fatal infections were primarily due to pneumonia and sepsis. 11

[0479] 6.2 Immunogenicity 12 As with all therapeutic proteins, there is a potential for immunogenicity. Detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the positive incidence of antibodies (including neutralizing antibodies) observed in an assay can be affected 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 to daratumumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In clinical trials of multiple myeloma patients treated with DARZALEX as monotherapy or in combination therapy, 0 of 111 evaluable monotherapy patients and 2 of 749 combination therapy patients tested positive for anti-daratumumab antibodies. One patient receiving DARZALEX as combination therapy developed primary neutralizing antibodies to daratumumab. However, this assay has limitations in detecting anti-daratumumab antibodies in the presence of high concentrations of daratumumab. Therefore, the incidence of antibody development may not be reliably determined.

[0480] 6.3 Post-marketing experience The following adverse reactions have been identified during post-approval use of DARZALEX.

[0481] Immune System Disorders: Anaphylactic Reactions 7. Drug Interactions 7.1 Effect of daratumumab on laboratory tests Interference with the indirect antiglobulin test (indirect Coombs test) Daratumumab binds to CD38 on RBCs, interfering with antibody screening and compatibility testing, including cross-reactivity testing. Methods to mitigate daratumumab interference include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding [see Reference (15)] or genotyping. Because the Kell blood group is also sensitive to DTT treatment, K-negative units should be delivered after alloantibodies have been ruled out or identified using DTT-treated RBCs.

[0482] If an emergency transfusion is required, uncrosslinked ABO / RhD compatible RBCs can be given according to local blood bank practices.

[0483] Interference with serum protein electrophoresis and immunofixation tests Daratumumab can be detected by serum protein electrophoresis (SPE) and immunofixation (IFE) assays used to monitor disease monoclonal immunoglobulins (M-proteins). This can lead to false-positive SPE and IFE assay results in patients with IgG kappa myeloma proteins, affecting the initial assessment of complete response according to the International Myeloma Working Group (IMWG) criteria. If daratumumab interference is suspected in patients with a sustained very good partial response, consider using an FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M-proteins in the patient's serum to facilitate the determination of complete response.

[0484] 8 Use in specific populations 8.1 Pregnancy Risk Overview There are no human data to inform the risks associated with the use of DARZALEX during pregnancy. No animal studies have been conducted. However, clinical considerations exist [see Clinical Considerations]. The estimated background risks of major birth defects and miscarriage in the indicated population are unknown. All pregnancies carry a background risk of birth defects, death, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

[0485] Clinical considerations Fetal / neonatal adverse reactions Immunoglobulin G1 (IgG1) monoclonal antibodies cross the placenta. Based on its mechanism of action, DARZALEX may cause fetal myeloid or lymphoid cell depletion and reduced bone mineral density. Administration of live vaccines to neonates and infants exposed to DARZALEX in utero should be postponed until a hematologic evaluation is complete.

[0486] data Animal Data Mice genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone mineral density at birth that recovered by 5 months of age. In cynomolgus monkeys exposed during pregnancy to other monoclonal antibodies that affect white blood cell populations, infant monkeys had reversible reductions in white blood cells.

[0487] 8.2 Breastfeeding Risk Overview No information exists regarding the presence of daratumumab in human breast milk, its effects on breast-fed infants, or its effects on breast milk production. Human IgG is known to be present in human breast milk. Published data suggest that antibodies in breast milk do not enter the circulation of newborns and infants in substantial amounts.

[0488] The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DARZALEX and any potential adverse effects on the breastfed infant from DARZALEX or the underlying maternal condition.

[0489] 8.3 Women and men of reproductive potential contraception To avoid fetal exposure, females of reproductive potential should use effective contraception during treatment and for 3 months after discontinuing DARZALEX treatment.

[0490] 8.4 Pediatric Use The safety and effectiveness of DARZALEX in patients have not been established.

[0491] 8.5 Elderly Use Of 1,530 patients who received DARZALEX at the recommended dose, 48% were 65 to 75 years of age and 22% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients [see Clinical Study (14)]. 13、14

[0492] 11 Properties Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human monoclonal antibody against the CD38 antigen, produced in a mammalian cell line (Chinese hamster ovary [CHO]) using recombinant DNA technology. Daratumumab has a molecular weight of approximately 148 kDa.

[0493] DARZALEX is supplied in single-dose vials as a colorless to pale yellow, preservative-free solution for intravenous infusion. The pH is 5.5. DARZALEX should be diluted with 0.9% Sodium Chloride Injection, USP [see Dosage and Administration (2.4)].

[0494] Each DARZALEX single-dose 20 mL vial contains 400 mg of daratumumab, glacial acetic acid (3.7 mg), mannitol (510 mg), polysorbate 20 (8 mg), sodium acetate trihydrate (59.3 mg), sodium chloride (70.1 mg), and water for injection.

[0495] Each DARZALEX single-dose 5 mL vial contains 100 mg of daratumumab, glacial acetic acid (0.9 mg), mannitol (127.5 mg), polysorbate 20 (2 mg), sodium acetate trihydrate (14.8 mg), sodium chloride (17.5 mg), and water for injection.

[0496] 12 Clinical Pharmacology 12.1 Mechanism of Action CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues, and has multiple functions, including receptor-mediated adhesion, signal transduction, and regulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the proliferation of CD38-expressing cells by directly inducing apoptosis through Fc-mediated cross-linking, as well as by immune-mediated cytolysis via complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). It also inhibits the proliferation of CD38-expressing cells, including myeloid-derived suppressor cells (CD38+ MDSCs), regulatory T cells (CD38+ T cells), and inflammatory cytokines. reg ), and B cells (CD38+B regs ) subset is reduced by daratumumab.

[0497] 12.2 Pharmacodynamics NK cells express CD38 and are susceptible to daratumumab-mediated cytolysis. Total (CD16+CD56+) and activated (CD16+CD56) NK cells in peripheral whole blood and bone marrow were dim ) A decrease in the absolute number and percentage of NK cells was observed with DARZALEX treatment.

[0498] Cardiac Electrophysiology As a large protein, DARZALEX is unlikely to interact directly with ion channels. There is no evidence from preclinical or clinical data to suggest that DARZALEX has the potential to delay ventricular repolarization.

[0499] 12.3 Pharmacokinetics Over the dose range of 1 to 24 mg / kg of DARZALEX as monotherapy or 1 to 16 mg / kg in combination with other therapies, the increase in area under the concentration-time curve (AUC) was greater than dose-proportional.

[0500] Following the recommended dose of 16 mg / kg when administered as monotherapy or in combination with DARZALEX, the mean maximum serum concentration (C max ) values are the mean serum C max The mean ± standard deviation (SD) trough serum concentrations (C min ) was 573±332 μg / mL when DARZALEX was administered as monotherapy and 502±196 to 607±231 μg / mL when DARZALEX was administered as combination therapy. Split administration of the first dose resulted in a different PK profile on Day 1 compared to single administration. However, similar C max and C min Concentrations were predicted and observed after administration of the second divided dose on day 2 of week 1.

[0501] When DARZALEX was administered as monotherapy, daratumumab steady state was achieved approximately 5 months into the every 4-week dosing period (up to the 21st infusion), with steady-state C max vs. C after first dose max The mean ± SD ratio of was 1.6 ± 0.5.

[0502] distribution At the recommended dose of 16 mg / kg, the mean ± SD central volume of distribution was 4.7 ± 13 L when DARZALEX was administered as monotherapy and 4.4 ± 1.5 L when DARZALEX was administered as combination therapy.

[0503] Detachment Daratumumab clearance decreased with increasing dose and multiple dosing. At the recommended dose of 16 mg / kg of Darzalex as monotherapy, the mean ± SD linear clearance was estimated to be 171.4 ± 95.3 mL / day. The mean ± SD estimated elimination half-life associated with linear clearance was 18 ± 9 days when Darzalex was administered as monotherapy and ranged from a mean of 15 to 23 days when administered as combination therapy. 15

[0504] Specific populations The following population characteristics have no clinically significant effect on the pharmacokinetics of daratumumab in patients receiving DARZALEX as monotherapy or combination therapy: gender, age (31-93 years), mild (total bilirubin 1-1.5 times the upper limit of normal (ULN) or aspartate aminotransaminase (AST) above the ULN), and moderate (total bilirubin 1.5-3 times the ULN and any AST) hepatic impairment or renal impairment (creatinine clearance (CLcr) 15-89 mL / min). The effect of severe (total bilirubin >3 times the ULN and any AST) hepatic impairment is unknown. Increased body weight increases the central volume of distribution and clearance of daratumumab, supporting a weight-based dosing regimen.

[0505] Drug interactions Clinical pharmacokinetic evaluation of daratumumab in combination with lenalidomide, pomalidomide, bortezomib, and dexamethasone showed no clinically relevant drug-drug interactions between daratumumab and these small molecule drugs. 16

[0506] 13 Non-clinical toxicity 13.1 Carcinogenesis, Mutagenesis, and Reproductive Impairment No carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been conducted to evaluate the potential effects of daratumumab on reproduction or development or to determine its potential effects on fertility in males or females.

[0507] 14 Clinical research 14.1 Newly diagnosed multiple myeloma Combination therapy with lenalidomide and dexamethasone in patients ineligible for autologous stem cell transplantation MAIA (NCT02252172), an open-label, randomized, active-controlled phase 3 trial, compared treatment with DARZALEX 16 mg / kg (DRd) in combination with lenalidomide and low-dose dexamethasone to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple myeloma. Lenalidomide (25 mg orally once daily on days 1-21 of repeated 28-day [4-week] cycles) was given with low-dose oral or intravenous dexamethasone 40 mg / week (or a reduced dose of 20 mg / week for patients over 75 years of age or with a body mass index [BMI] less than 18.5). On the day of DARZALEX infusion, a dexamethasone dose was given as pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to the manufacturer's prescribing information. Treatment continued in both groups until disease progression or unacceptable toxicity. 17

[0508] A total of 737 patients were randomized: 368 to the DRd group and 369 to the Rd group. Baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 73 years (range: 45-90 years), and 44% of patients were 75 years or older. The majority were white (92%) and male (52%). 34% had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1, and 17% had an ECOG performance score of 2 or higher. 27% had International Staging System (ISS) stage I disease, 43% had ISS stage II disease, and 29% had ISS stage III disease. Efficacy was assessed by progression-free survival (PFS) based on the International Myeloma Working Group (IMWG) criteria. 18、19

[0509] The MAIA demonstrated improved progression-free survival (PFS) in the DRd arm compared with the Rd arm. Median PFS was not reached in the DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR] = 0.56; 95% CI: 0.43, 0.73; p < 0.0001), representing a 44% reduction in the risk of disease progression or death in patients treated with DRd. 20

[0510] [Table B]

[0511] Additional efficacy results from the MAIA are shown in Table 17 below. 21、22

[0512] [Table 23] DRd = daratumumab-lenalidomide-dexamethasone, Rd = lenalidomide-dexamethasone, MRD = minimal residual disease, CI = confidence interval a Based on the intention-to-treat population b P values from Cochran-Mantel-Haenszel chi-square test. c 10 -5 Based on the threshold of d We use the Mantel-Haenszel estimate of odds ratios for unstratified tables. Odds ratios greater than 1 indicate a benefit of DRd. e p-values from Fisher's exact test.

[0513] Among responders, the median time to response was 1.05 months (range: 0.2–12.1 months) in the DRd group and 1.05 months (range: 0.3–15.3 months) in the Rd group. 23The median duration of response was not achieved in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rd group. 24

[0514] Combination treatment with bortezomib, melphalan, and prednisone (VMP) in patients ineligible for autologous stem cell transplantation ALCYONE (NCT02195479), an open-label, randomized, active-controlled phase 3 trial, compared treatment with DARZALEX 16 mg / kg in combination with bortezomib, melphalan, and prednisone (D-VMP) with treatment with VMP in patients with newly diagnosed multiple myeloma. 2 It was administered by subcutaneous (SC) injection at a dose of 9 mg / m body surface area twice weekly during weeks 1, 2, 4, and 5 of an initial 6-week cycle (Cycle 1; 8 doses), followed by once weekly during weeks 1, 2, 4, and 5 of eight subsequent 6-week cycles (Cycles 2-9; 4 doses per cycle). 2 of melphalan and 60 mg / m 2 of prednisone was administered orally on days 1-4 of nine 6-week cycles (Cycles 1-9). DARZALEX treatment was continued until disease progression or unacceptable toxicity.

[0515] A total of 706 patients were randomized: 350 to the D-VMP group and 356 to the VMP group. Baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 71 years (range: 40-93 years), and 30% of patients were 75 years or older. The majority were white (85%) and female (54%). 25% had an ECOG performance score of 0, 50% had an ECOG performance score of 1, and 25% had an ECOG performance score of 2. 19% of patients had ISS stage I disease, 42% had ISS stage II disease, and 38% had ISS stage III disease. Efficacy was assessed by progression-free survival (PFS) based on the International Medical Group Working Group criteria.

[0516] ALCYONE demonstrated improved PFS in the D-VMP arm compared with the VMP arm. Median PFS was not reached in the D-VMP arm and was 18.1 months (95% CI: 16.53, 19.91) in the VMP arm (HR=0.5; 95% CI: 0.38, 0.65; p<0.0001), representing a 50% reduction in the risk of disease progression or death in patients treated with D-VMP.

[0517] [Table C]

[0518] Additional efficacy results from ALCYONE are shown in Table 18 below.

[0519] [Table 24] D-VMP = daratumumab-bortezomib-melphalan-prednisone, VMP = bortezomib-melphalan-prednisone, MRD = minimal residual disease, CI = confidence interval a Based on the intention-to-treat population b P values from Cochran-Mantel-Haenszel chi-square test. c 10 -5 Based on the threshold of d p-values from Fisher's exact test.

[0520] Among responders, the median time to response was 0.79 months (range: 0.4-15.5 months) in the D-VMP group and 0.82 months (range: 0.7-12.6 months) in the VMP group. The median duration of response was not achieved in the D-VMP group and 21.3 months (range: 0.5+, 23.7+) in the VMP group.

[0521] 14.2 Relapsed / Refractory Multiple Myeloma Combination therapy with lenalidomide and dexamethasone POLLUX (NCT02076009), an open-label, randomized, active-controlled phase 3 trial, compared treatment with DARZALEX 16 mg / kg (DRd) in combination with lenalidomide and low-dose dexamethasone to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg orally once daily on days 1-21 of repeated 28-day [4-week] cycles) was given with low-dose oral or intravenous dexamethasone 40 mg / week (or a reduced dose of 20 mg / week for patients over 75 years of age or with a BMI less than 18.5). A 20 mg dexamethasone dose was given as pre-infusion medication on the day of DARZALEX infusion, and the remainder was given the day following the infusion. For patients whose dexamethasone dose was reduced, the full 20 mg dose was given as DARZALEX pre-infusion medication. Dose adjustments of lenalidomide and dexamethasone were applied according to the manufacturer's prescribing information. Treatment continued in both groups until disease progression or unacceptable toxicity.

[0522] A total of 569 patients were randomized: 286 to the DRd group and 283 to the Rd group. Baseline demographic and disease characteristics were similar between the DARZALEX and control groups. The median patient age was 65 years (range, 34-89 years), 11% were 75 years or older, 59% were male, 69% were Caucasian, 18% were Asian, and 3% were African American. Patients had received a median of one prior therapy. Sixty-three percent (63%) of patients had received a prior autologous stem cell transplant (ASCT). The majority (86%) of patients had received a prior PI, 55% had received a prior immunomodulatory agent (including 18% who had received prior lenalidomide), and 44% had received both a prior PI and an immunomodulatory agent. At baseline, 27% of patients were refractory to their last therapy. Eighteen percent (18%) of patients were refractory to PIs alone and 21% were refractory to bortezomib. Efficacy was assessed by PFS according to IMWG criteria.

[0523] POLLUX demonstrated improved PFS in the DRd arm compared with the Rd arm. Median PFS was not reached in the DRd arm and was 18.4 months in the Rd arm (hazard ratio [HR] = 0.37; 95% CI: 0.27, 0.52; p < 0.0001), representing a 63% reduction in the risk of disease progression or death in patients treated with DRd.

[0524] [Table D]

[0525] Additional efficacy results from POLLUX are shown in Table 19 below.

[0526] [Table 25] DRd = daratumumab-lenalidomide-dexamethasone, Rd = lenalidomide-dexamethasone a Based on the intention-to-treat population b P values from Cochran-Mantel-Haenszel chi-square test.

[0527] Among responders, the median time to response was 1 month (range: 0.9-13 months) in the DRd group and 1.1 months (range: 0.9-10 months) in the Rd group. The median duration of response was not achieved in the D-VMP group (range: 1+-19.8+ months) and 17.4 months (range: 1.4+-18.5+ months) in the Rd group.

[0528] At a median follow-up of 13.5 months, 75 deaths occurred: 30 in the DRd group and 45 in the Rd group.

[0529] Combination treatment with bortezomib and dexamethasone CASTOR (NCT02136134), an open-label, randomized, active-controlled phase 3 trial, compared treatment with DARZALEX 16 mg / kg (DVd) in combination with bortezomib and dexamethasone to treatment with bortezomib and dexamethasone (Vd) in patients with multiple myeloma who had received at least one prior therapy. Bortezomib was administered at 1.3 mg / m twice weekly for 2 weeks (days 1, 4, 8, and 11) of repeated 21-day (3-week) treatment cycles for a total of 8 cycles. 2 Dexamethasone was administered orally at a dose of 20 mg per body surface area (body surface area) via SC injection or IV infusion on days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the eight bortezomib cycles (80 mg / week for two out of three weeks of the bortezomib cycle), or at a reduced dose of 20 mg for patients over 75 years of age, with a BMI below 18.5, poorly controlled diabetes, or previous intolerance to steroid therapy. On the day of DARZALEX infusion, a 20 mg dose of dexamethasone was administered as a pre-infusion medication. For patients whose dexamethasone dose was reduced, the full 20 mg dose was given as a pre-infusion medication. DARZALEX was administered until disease progression, while bortezomib and dexamethasone were given for eight 3-week cycles in both treatment groups. However, in the DVd group, dexamethasone 20 mg was continued as a pre-infusion medication for DARZALEX. Dose adjustments of bortezomib and dexamethasone were applied according to the manufacturer's prescribing information.

[0530] A total of 498 patients were randomized: 251 to the DVd group and 247 to the Vd group. Baseline demographic and disease characteristics were similar between the DARZALEX and control groups. The median patient age was 64 years (range, 30-88 years), 12% were 75 years or older, 57% were male, 87% were Caucasian, 5% were Asian, and 4% were African American. Patients had received a median of two prior therapies, with 61% of patients having received a prior autologous stem cell transplant (ASCT). Sixty-nine percent (69%) of patients had received a prior PI (66% had received bortezomib), and 76% had received an immunomodulatory agent (42% had received lenalidomide). At baseline, 32% of patients were refractory to their last therapy, and the proportion of patients refractory to any particular prior therapy was generally well balanced between treatment groups. Thirty-three percent (33%) of patients were refractory to immunomodulatory agents alone, and 24% of patients in the DVd group and 33% of patients in the Vd group were refractory to lenalidomide. Efficacy was assessed by PFS according to IMWG criteria.

[0531] CASTOR demonstrated improved PFS in the DVd arm compared with the Vd arm: median PFS was not reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% CI]: 0.39 [0.28, 0.53]; p-value <0.0001), representing a 61% reduction in the risk of disease progression or death for patients treated with DVd versus Vd.

[0532] [Table E]

[0533] Additional efficacy results from CASTOR are shown in Table 20 below.

[0534] [Table 26] DVd = daratumumab-bortezomib-dexamethasone, Vd = bortezomib-dexamethasone aBased on the intention-to-treat population b P values from Cochran-Mantel-Haenszel chi-square test.

[0535] Among responders, the median time to response was 0.8 months (range: 0.7-4 months) in the DVd group and 1.5 months (range: 0.7-5 months) in the Vd group. The median duration of response was not achieved in the DVd group (range: 1.4+-14.1+ months) and 7.9 months (1.4+-12+ months) in the Vd group.

[0536] At a median follow-up of 7.4 months, 65 deaths occurred: 29 in the DVd group and 36 in the Vd group.

[0537] Combination treatment with pomalidomide and dexamethasone In EQUULEUS (NCT01998971), 103 patients with multiple myeloma who had received a previous PI and immunomodulatory agent received 16 mg / kg of DARZALEX in combination with pomalidomide and low-dose dexamethasone until disease progression. Pomalidomide (4 mg orally once daily on days 1–21 of repeated 28-day (4-week) cycles) was administered with low-dose oral or intravenous dexamethasone 40 mg / week (a reduced dose of 20 mg / week for patients over 75 years of age or with a BMI less than 18.5). On the day of DARZALEX infusion, a 20 mg dose of dexamethasone was administered as pre-infusion medication, and the remainder was administered the day after the infusion. For patients whose dexamethasone dose was reduced, the full 20 mg dose of DARZALEX was administered as pre-infusion medication.

[0538] The median patient age was 64 years (range: 35-86 years), and 8% of patients were 75 years or older. Patients in the study had received a median of four prior therapies. Seventy-four percent (74%) of patients had received a prior ASCT. Ninety-eight percent (98%) of patients had received prior bortezomib, and 33% had received prior carfilzomib. All patients had received prior lenalidomide, and 98% of patients had been previously treated with a combination of bortezomib and lenalidomide. Eighty-nine percent (89%) of patients were refractory to lenalidomide, 71% were refractory to bortezomib, and 64% were refractory to both bortezomib and lenalidomide.

[0539] Efficacy outcomes were based on overall response rate as determined by an Independent Review Committee using IMWG criteria (see Table 21).

[0540] [Table 27] ORR=sCR+CR+VGPR+PR CI = confidence interval

[0541] The median time to response was 1 month (range: 0.9-2.8 months), and the median duration of response was 13.6 months (range: 0.9+-14.6+ months).

[0542] Monotherapy SIRIUS (NCT01985126) was an open-label study evaluating DARZALEX monotherapy in patients with relapsed or refractory multiple myeloma who had received at least three prior therapies, including a proteasome inhibitor and an immunomodulatory agent, or who were dually refractory to a proteasome inhibitor and an immunomodulatory agent. DARZALEX 16 mg / kg was administered with pre- and post-infusion medications in 106 patients. Treatment continued until unacceptable toxicity or disease progression.

[0543] The median patient age was 63.5 years (range: 31-84 years), 49% were male, and 79% were white. Patients had received a median of five prior therapies. Eighty percent of patients had received a prior autologous stem cell transplant (ASCT). Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%), and carfilzomib (50%). At baseline, 97% of patients were refractory to their last therapy, 95% were refractory to both proteasome inhibitors (PIs) and immunomodulatory agents, and 77% were refractory to alkylating agents.

[0544] Efficacy outcomes were based on overall response rate as determined by Independent Review Committee assessment using IMWG criteria (see Table 22).

[0545] [Table 28] ORR=sCR+CR+VGPR+PR CI = confidence interval

[0546] The median time to response was 1 month (range: 0.9-5.6 months), and the median duration of response was 7.4 months (range: 1.2+-13.1+ months).

[0547] Study GEN501 (NCT00574288) was an open-label, dose-escalation study evaluating DARZALEX monotherapy in patients with relapsed or refractory multiple myeloma who had received at least two different cytoreductive therapies. Forty-two patients received DARZALEX 16 mg / kg with pre- and post-infusion medications. Treatment continued until unacceptable toxicity or disease progression.

[0548] The median patient age was 64 years (range: 44-76 years), 64% were male, and 76% were white. Patients in the study had received a median of four prior therapies. Seventy-four percent of patients had received a prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%), and carfilzomib (19%). At baseline, 76% of patients were refractory to their last therapy, 64% were refractory to both PIs and immunomodulatory agents, and 60% were refractory to alkylating agents.

[0549] The overall response rate was 36% (95% CI: 21.6, 52.0%) with one complete response and three very large partial responses. The median time to response was 1 month (range: 0.5-3.2 months). The median duration of response was not estimable (range: 2.2+ to 13.1+ months).

[0550] 15 References 1. Chapuy, CI, RT Nicholson, MD Aguad, et al., 2015, Resolving the daratumumab interference with blood compatibility testing, Transfusion, 55:1545-1554 (accessible at http: / / onliselibrary.wiley.com / doi / 10.1111 / trf.13069 / epdf).

[0551] 16. Supply Form / Storage and Handling 16.1 Supply form DARZALEX is a colorless to pale yellow, preservative-free solution for intravenous infusion supplied as follows: NDC 57894-502-05 contains one 100 mg / 5 mL single-dose vial NDC 57894-502-20 contains one 400 mg / 20 mL single dose vial.

[0552] 16.2 Storage and Stability Store refrigerated at 2°C to 8°C (36°F to 46°F).

[0553] Do not freeze or shake. Protect from light. This product contains no preservatives.

[0554] 17 Patient Counseling Information Advise patients to read the FDA-approved package insert (Patient Information).

[0555] infusion reaction Advise patients to seek immediate medical attention for any of the following signs and symptoms of an infusion reaction: Itchy, runny, or stuffy nose; chills, nausea, throat irritation, cough, headache, shortness of breath, or difficulty breathing [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

[0556] Neutropenia Advise patients to contact their healthcare provider if they have a fever [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

[0557] Thrombocytopenia Advise patients to notify their healthcare provider if they notice any signs of bruising or bleeding [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

[0558] Interference with laboratory tests Advise patients to notify their healthcare providers, including transfusion centers / personnel, that they are receiving DARZALEX in the event of a planned transfusion [see Warnings and Precautions (5.2) and Adverse Reactions (7.1)].

[0559] Advise patients that DARZALEX may affect the results of some studies used to determine complete response in some patients and that additional studies may be needed to evaluate response [see Warnings and Precautions (5.5) and Adverse Reactions (7.1)].

[0560] manufacturer: Janssen Biotech, Inc. Horsham,PA 19044 US License No. 1864 (Copyright) 2015 Janssen Pharmaceutical Companies

[0561] [Table F] The inventions described in the original claims of this application are listed below. [Invention 1] 1. A method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy comprising daratumumab, lenalidomide, and dexamethasone, wherein the method achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is administered a combination of lenalidomide and dexamethasone. [Invention 2] 1. A method of treating a subject with newly diagnosed multiple myeloma who is ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT), comprising administering or providing for the administration of daratumumab to the subject, wherein daratumumab is administered in combination with lenalidomide and dexamethasone, and wherein the method achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is administered a combination of lenalidomide and dexamethasone. [Invention 3] The method of invention 1 or 2, wherein the improved clinical efficacy endpoint is an increased likelihood of achieving a complete response (CR) or better, an increased likelihood of achieving a very good partial response (VGPR) or better, an increased likelihood of achieving negativity for minimal residual disease (MRD), a reduced risk of multiple myeloma progression or death, an increased progression-free survival (PFS), or an increased likelihood of achieving a 30-month progression-free survival rate. [Invention 4] 4. The method of claim 3, wherein the likelihood of achieving CR or better is about 47% or higher. [Invention 5] 4. The method of claim 3, wherein the likelihood of achieving VGPR or higher is about 79% or higher. [Invention 6] 4. The method of claim 3, wherein the likelihood of achieving a negative status for MRD is about 24% or greater. [Invention 7] The method of invention 3, wherein the risk of progression or death from multiple myeloma is reduced by about 44%. [Invention 8] A method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy demonstrated to increase the likelihood of achieving VGPR or better in subjects with multiple myeloma, wherein the combination therapy comprises daratumumab, lenalidomide, and dexamethasone. [Invention 9] 9. The method of claim 8, wherein the likelihood of achieving VGPR or better is about 79% or better. [Invention 10] A method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy demonstrated to increase the likelihood of achieving MRD-negative status in subjects with newly diagnosed multiple myeloma, wherein the combination therapy comprises daratumumab, lenalidomide, and dexamethasone. [Invention 11] 11. The method of claim 10, wherein said likelihood of achieving said negative status for MRD is about 24% or greater. [Invention 12] A method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy demonstrated to increase the likelihood of achieving CR or better in subjects with newly diagnosed multiple myeloma, wherein the combination therapy comprises daratumumab, lenalidomide, and dexamethasone. [Invention 13] 13. The method of claim 12, wherein the likelihood of achieving CR or better is about 47% or higher. [Invention 14] A method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject a combination therapy demonstrated to reduce the risk of multiple myeloma progression or death in subjects with newly diagnosed multiple myeloma, wherein the combination therapy comprises daratumumab, lenalidomide, and dexamethasone. [Invention 15] 15. The method of claim 14, wherein the risk of progression or death from multiple myeloma is reduced by about 44%. [Invention 16] 16. The method according to any one of inventions 8 to 15, wherein said subject with newly diagnosed multiple myeloma is ineligible for HDC and ASCT. [Invention 17] 17. The method according to any one of Inventions 1 to 16, wherein the combination therapy comprises about 16 mg / kg of daratumumab, about 25 mg of lenalidomide, and about 20 mg to about 40 mg of dexamethasone. [Invention 18] 18. The method of any one of Inventions 1 to 17, wherein the combination therapy comprises administration of about 16 mg / kg of daratumumab once weekly from weeks 1 to 8, once every two weeks from weeks 9 to 24, and once every four weeks thereafter, administration of about 25 mg of lenalidomide per day on days 1 to 21 of repeated four-week cycles, and administration of about 20 mg to about 40 mg of dexamethasone per week. [Invention 19] 19. The method according to claim 18, wherein dexamethasone is administered as premedication on the day of administration of daratumumab. [Invention 20] 20. The method according to claim 19, wherein daratumumab is administered intravenously, lenalidomide is administered orally, and dexamethasone is administered intravenously or orally. [Invention 21] 21. The method of claim 20, wherein lenalidomide, dexamethasone, or both lenalidomide and dexamethasone are self-administered. [Invention 22] 22. The method of any one of claims 1 to 21, wherein daratumumab is provided for administration by the manufacturer of daratumumab in a single dose vial containing 100 mg daratumumab in 5 mL of solution, or in a single dose vial containing 400 mg daratumumab in 20 mL of solution. [Invention 23] 23. The method of claim 22, wherein each single-dose vial containing 100 mg of daratumumab in 5 mL of solution and each single-dose vial containing 400 mg of daratumumab in 20 mL of solution further comprises glacial acetic acid, mannitol, polysorbate 20, sodium acetate trihydrate, and sodium chloride. [Invention 24] 24. The method of claim 23, wherein each single-dose vial containing 100 mg of daratumumab in 5 mL of solution contains 0.9 mg of glacial acetic acid, 127.5 mg of mannitol, 2 mg of polysorbate 20, 14.8 mg of sodium acetate trihydrate, 17.5 mg of sodium chloride, and water for injection, and wherein each single-dose vial containing 400 mg of daratumumab in 20 mL of solution contains 400 mg of daratumumab, 3.7 mg of glacial acetic acid, 510 mg of mannitol, 8 mg of polysorbate 20, 59.3 mg of sodium acetate trihydrate, 70.1 mg of sodium chloride, and water for injection. [Invention 25] 25. The method according to any one of claims 22 to 24, wherein daratumumab is diluted in 0.9% sodium chloride prior to administration. [Invention 26] 26. The method according to any one of claims 1 to 25, wherein information that the combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves the improved clinical efficacy endpoint is provided on a daratumumab-containing drug product label. [Invention 27] 27. The method of claim 26, wherein the daratumumab-containing drug product label includes the information that the recommended dose of daratumumab is 16 mg / kg administered as an intravenous injection. [Invention 28] 28. The method of claim 27, wherein the daratumumab-containing drug product label comprises the information that the recommended dosing schedule for daratumumab in combination with lenalidomide is once weekly from weeks 1 to 8, once every two weeks from weeks 9 to 24, and once every four weeks thereafter. [Invention 29] 29. The method of claim 28, wherein the daratumumab-containing drug product label comprises the information that the recommended dosing schedule for lenalidomide is 25 mg per day on days 1 to 21 of repeated 4-week cycles. [Invention 30] 30. The method of claim 29, wherein the daratumumab-containing drug product label includes the information that the recommended dosing schedule for dexamethasone is about 20 mg or about 40 mg per week. [Invention 31] 31. The method according to any one of Inventions 27 to 30, wherein daratumumab, lenalidomide, and dexamethasone are administered according to the recommended administration schedule. [Invention 32] 32. The method of any one of inventions 26 to 31, wherein the daratumumab-containing drug product label comprises data from an open-label, randomized, active-controlled phase 3 study comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in subjects with newly diagnosed multiple myeloma who are ineligible for HDC and ASCT. [Invention 33] 33. The method of claim 32, wherein the daratumumab-containing drug product label includes data that treatment with DRd resulted in about a 44% reduction in the risk of multiple myeloma progression or death compared to treatment with Rd. [Invention 34] 34. The method of claim 32 or 33, wherein said daratumumab-containing drug product label comprises data that treatment with DRd resulted in about 79.3% of subjects achieving VGPR or better, about 24% of subjects achieving negativity for MRD, or about 47.6% of subjects achieving CR or better, or any combination thereof. [Invention 35] 35. The method of any one of inventions 32 to 34, wherein the daratumumab-containing drug product label comprises a Kaplan-Meier curve of progression-free survival (PFS) comparing subjects with newly diagnosed multiple myeloma treated with DRd to subjects with newly diagnosed multiple myeloma treated with Rd. [Invention 36] 36. The method of any one of inventions 32 to 35, wherein the daratumumab-containing drug product label comprises data from a Phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, melphalan, and prednisone (D-VMP) with treatment with bortezomib, melphalan, and prednisone (VMP) in subjects with newly diagnosed multiple myeloma. [Invention 37] 37. The method of any one of inventions 32 to 36, wherein the daratumumab-containing drug product label comprises data from a Phase 3 active-controlled trial comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in relapsed, refractory, or relapsed-refractory multiple myeloma. [Invention 38] 38. The method of any one of inventions 32 to 37, wherein the daratumumab-containing drug product label comprises data from a phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, and dexamethasone (DVd) with treatment with bortezomib and dexamethasone (Vd) in relapsed, refractory, or relapsed-refractory multiple myeloma. [Invention 39] 39. The method of any one of inventions 32 to 38, wherein the daratumumab-containing drug product label comprises drug interaction data reporting that a clinical pharmacokinetic evaluation of daratumumab in combination with lenalidomide, pomalidomide, bortezomib, and dexamethasone showed no clinically relevant drug-drug interactions between daratumumab and lenalidomide, pomalidomide, bortezomib, and dexamethasone. [Invention 40] 40. The method of any one of claims 32 to 39, wherein the daratumumab-containing drug product label includes information that side effects of daratumumab include weakness, loss of appetite, bronchitis, and lung infection. [Invention 41] 41. The method of any one of inventions 32 to 40, wherein the daratumumab-containing drug product label includes information regarding daratumumab's approved indications, dosage and administration, adverse reactions, drug-product interactions, use in specific populations, clinical pharmacology, nonclinical toxicology, clinical studies, and storage and handling, or any combination thereof. [Invention 42] 42. The method according to any one of Inventions 1 to 41, wherein daratumumab comprises heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6. [Invention 43] 43. The method according to any one of Inventions 1 to 42, wherein daratumumab comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8. [Invention 44] 44. The method according to any one of Inventions 1 to 43, wherein daratumumab is immunoglobulin IgG1 kappa (IgG1κ). [Invention 45] 45. The method according to any one of Inventions 1 to 44, wherein daratumumab comprises a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO: 10. [Invention 46] 46. The method according to any one of claims 1 to 45, wherein daratumumab is produced in a mammalian cell line. [Invention 47] 47. The method of claim 46, wherein the mammalian cell line is a Chinese hamster ovary (CHO) cell line. [Invention 48] 48. The method according to claim 47, wherein the molecular weight of daratumumab is about 148 kDa. [Invention 49] 49. The method according to any one of claims 1 to 48, wherein dexamethasone can be substituted for a dexamethasone equivalent, said dexamethasone equivalent being methylprednisolone, prednisolone, prednisone, or betamethasone, or any combination thereof. [Invention 50] 1. A method of treating a subject with newly diagnosed multiple myeloma, comprising: a) Providing daratumumab to healthcare professionals (HCPs); and b) providing the HCP with information that treating the subject with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject was treated with a combination of lenalidomide and dexamethasone; performing steps a) and b) results in the subject with newly diagnosed multiple myeloma receiving the combination therapy comprising daratumumab, lenalidomide, and dexamethasone by the HCP or by self-administration as directed by the HCP, thereby treating the subject with newly diagnosed multiple myeloma; The method. [Invention 51] 1. A method of providing daratumumab to a HCP for treating a subject with newly diagnosed multiple myeloma with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone, the method comprising: wherein said treatment with said combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when said subject is treated with a combination of lenalidomide and dexamethasone; a) manufacturing daratumumab; and b) providing information to the HCP that treatment with the combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves the improved clinical efficacy endpoint; and c) transporting the daratumumab to the HCP or an authorized distributor of daratumumab for the HCP to purchase the daratumumab, thereby providing the daratumumab to the HCP; The method. [Invention 52] 1. A method in which an HCP provides a treatment option for treating a subject with newly diagnosed multiple myeloma with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone, the method comprising: wherein said treatment with said combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when said subject is treated with a combination of lenalidomide and dexamethasone; a) manufacturing daratumumab; and b) providing information to the HCP that the combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves the improved clinical efficacy endpoint; and c) transporting daratumumab to the HCP or an authorized distributor of daratumumab for the HCP to purchase, thereby providing the treatment option for the HCP. The method. [Invention 53] 53. The method according to any one of claims 50 to 52, wherein the subject is ineligible for HDC and ASCT. [Invention 54] 54. The method according to any one of Inventions 50 to 53, wherein the combination therapy comprising daratumumab, lenalidomide, and dexamethasone is demonstrated to increase the likelihood of achieving VGPR or better in subjects with newly diagnosed multiple myeloma. [Invention 55] 55. The method of claim 54, wherein the likelihood of achieving VGPR or better is about 79% or better. [Invention 56] 56. The method according to any one of inventions 50 to 55, wherein said combination therapy comprising daratumumab, lenalidomide, and dexamethasone is demonstrated to increase the likelihood of achieving a negative status for MRD in subjects with newly diagnosed multiple myeloma. [Invention 57] 57. The method of claim 56, wherein said likelihood of achieving said negative status for MRD is about 24% or greater. [Invention 58] 58. The method according to any one of Inventions 50 to 57, wherein the combination therapy comprising daratumumab, lenalidomide, and dexamethasone is demonstrated to increase the likelihood of achieving CR or better in subjects with newly diagnosed multiple myeloma. [Invention 59] 59. The method of claim 58, wherein the likelihood of achieving CR or better is about 47% or higher. [Invention 60] 59. The method according to any one of Inventions 50 to 58, wherein the combination therapy comprising daratumumab, lenalidomide, and dexamethasone is demonstrated to reduce the risk of multiple myeloma progression or death in subjects with newly diagnosed multiple myeloma. [Invention 61] 61. The method of claim 60, wherein said risk of progression or death from multiple myeloma is reduced by about 44%. [Invention 62] 62. The method according to any one of Inventions 50 to 61, wherein the combination therapy comprises about 16 mg / kg of daratumumab, about 25 mg of lenalidomide, and about 20 mg to about 40 mg of dexamethasone. [Invention 63] 63. The method of any one of Inventions 60 to 62, wherein said combination therapy comprises administration of about 16 mg / kg of daratumumab once weekly from weeks 1 to 8, once every two weeks from weeks 9 to 24, and once every four weeks thereafter, administration of about 25 mg of lenalidomide per day on days 1 to 21 of repeated four-week cycles, and administration of about 20 mg to about 40 mg of dexamethasone per week. [Invention 64] 64. The method according to any one of Inventions 50 to 63, wherein the combination therapy comprises administering dexamethasone as a premedication on the day of administration of daratumumab. [Invention 65] 65. The method according to any one of Inventions 50 to 64, wherein the combination therapy comprises administering daratumumab intravenously, lenalidomide orally, and dexamethasone intravenously or orally. [Invention 66] 66. The method of any one of inventions 50 to 65, wherein the daratumumab is shipped or provided by the manufacturer of daratumumab in a single dose vial containing 100 mg of daratumumab in 5 mL of solution, or in a single dose vial containing 400 mg of daratumumab in 20 mL of solution. [Invention 67] 67. The method of claim 66, wherein each single-dose vial containing 100 mg of daratumumab in 5 mL of solution and each single-dose vial containing 400 mg of daratumumab in 20 mL of solution further comprises glacial acetic acid, mannitol, polysorbate 20, sodium acetate trihydrate, and sodium chloride. [Invention 68] 68. The method of invention 67, wherein each single-dose vial containing 100 mg of daratumumab in 5 mL of solution contains 0.9 mg of glacial acetic acid, 127.5 mg of mannitol, 2 mg of polysorbate 20, 14.8 mg of sodium acetate trihydrate, 17.5 mg of sodium chloride, and water for injection, and wherein each single-dose vial containing 400 mg of daratumumab in 20 mL of solution contains 400 mg of daratumumab, 3.7 mg of glacial acetic acid, 510 mg of mannitol, 8 mg of polysorbate 20, 59.3 mg of sodium acetate trihydrate, 70.1 mg of sodium chloride, and water for injection. [Invention 69] 69. The method according to any one of claims 66 to 68, wherein daratumumab is diluted in 0.9% sodium chloride prior to administration. [Invention 70] 70. The method of any one of claims 50 to 69, wherein information that the combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves the improved clinical efficacy endpoint is provided on a daratumumab-containing drug product label. [Invention 71] 71. The method of claim 70, wherein the daratumumab-containing drug product label includes the information that the recommended dose of daratumumab is 16 mg / kg administered as an intravenous injection. [Invention 72] 72. The method of claim 71, wherein the daratumumab-containing drug product label comprises the information that the recommended dosing schedule for daratumumab in combination with lenalidomide is once weekly from weeks 1 to 8, once every two weeks from weeks 9 to 24, and once every four weeks thereafter. [Invention 73] 73. The method of claim 72, wherein the daratumumab-containing drug product label comprises the information that the recommended dosing schedule for lenalidomide is 25 mg once daily on days 1 to 21 of repeated 4-week cycles. [Invention 74] 74. The method of claim 73, wherein the daratumumab-containing drug product label includes the information that the recommended dosing schedule for dexamethasone is about 20 mg or about 40 mg per week. [Invention 75] 75. The method according to any one of Inventions 70 to 74, wherein daratumumab, lenalidomide, and dexamethasone are administered according to the recommended administration schedule. [Invention 76] 76. The method of any one of inventions 70 to 75, wherein the daratumumab-containing drug product label comprises data from an open-label, randomized, active-controlled phase 3 study comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in subjects with newly diagnosed multiple myeloma who are ineligible for ASCT. [Invention 77] 77. The method of claim 76, wherein the daratumumab-containing drug product label includes data that treatment with DRd resulted in about a 44% reduction in the risk of multiple myeloma progression or death compared to treatment with Rd. [Invention 78] 78. The method of claim 76 or 77, wherein said daratumumab-containing drug product label comprises data that treatment with DRd resulted in about 79.3% of subjects achieving VGPR or better, about 24% of subjects achieving negativity for MRD, or about 47.6% of subjects achieving CR or better, or any combination thereof. [Invention 79] 79. The method of any one of inventions 76 to 78, wherein the daratumumab-containing drug product label comprises a Kaplan-Meier curve of progression-free survival (PFS) comparing subjects with newly diagnosed multiple myeloma treated with DRd to subjects with newly diagnosed multiple myeloma treated with Rd. [Invention 80] 80. The method of any one of inventions 70 to 79, wherein the daratumumab-containing drug product label comprises data from a Phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, melphalan, and prednisone (D-VMP) with treatment with bortezomib, melphalan, and prednisone (VMP) in subjects with newly diagnosed multiple myeloma. [Invention 81] 81. The method of any one of inventions 70 to 80, wherein the daratumumab-containing drug product label comprises data from a phase 3 active-controlled trial comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in relapsed, refractory, or relapsed-refractory multiple myeloma. [Invention 82] 82. The method of any one of inventions 70 to 81, wherein the daratumumab-containing drug product label comprises data from a phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, and dexamethasone (DVd) with treatment with bortezomib and dexamethasone (Vd) in relapsed, refractory, or relapsed-refractory multiple myeloma. [Invention 83] 83. The method of any one of inventions 70 to 82, wherein the daratumumab-containing drug product label comprises drug interaction data reporting that a clinical pharmacokinetic evaluation of daratumumab in combination with lenalidomide, pomalidomide, bortezomib, and dexamethasone showed no clinically relevant drug-drug interactions between daratumumab and lenalidomide, pomalidomide, bortezomib, and dexamethasone. [Invention 84] 84. The method of any one of inventions 70 to 83, wherein the daratumumab-containing drug product label includes information that side effects of daratumumab include weakness, loss of appetite, bronchitis, and lung infection. [Invention 85] 85. The method of any one of inventions 70 to 84, wherein the daratumumab-containing drug product labeling includes information regarding daratumumab's approved indications, dosage and administration, adverse reactions, drug interactions, use in specific populations, clinical pharmacology, nonclinical toxicology, clinical studies, and storage and handling, or any combination thereof. [Invention 86] The method of any one of Inventions 50 to 85, wherein daratumumab comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6. [Invention 87] The method according to any one of Inventions 50 to 86, wherein daratumumab comprises VH of SEQ ID NO: 7 and VL of SEQ ID NO: 8. [Invention 88] 88. The method according to any one of Inventions 50 to 87, wherein daratumumab is immunoglobulin IgG1 kappa (IgG1κ). [Invention 89] The method according to any one of Inventions 50 to 88, wherein daratumumab comprises HC of SEQ ID NO: 9 and LC of SEQ ID NO: 10. [Invention 90] 90. The method according to any one of claims 50 to 89, wherein daratumumab is produced in a mammalian cell line. [Invention 91] 91. The method of claim 90, wherein said mammalian cell line is a Chinese hamster ovary (CHO) cell line. [Invention 92] The method of Invention 91, wherein the molecular weight of daratumumab is about 148 kDa. [Invention 93] 93. The method of any one of claims 50 to 92, wherein dexamethasone can be substituted for a dexamethasone equivalent, said dexamethasone equivalent being methylprednisolone, prednisolone, prednisone, or betamethasone, or any combination thereof. [Invention 94] 1. A combination therapy comprising daratumumab, lenalidomide, and dexamethasone for providing treatment of a subject with newly diagnosed multiple myeloma, the treatment achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subject is treated with a combination of lenalidomide and dexamethasone. The combination therapy. [Invention 95] 95. The combination therapy according to invention 94, comprising about 16 mg / kg daratumumab, about 25 mg lenalidomide, and about 20 mg to about 40 mg dexamethasone. [Invention 96] 96. The combination therapy of claim 94 or 95, wherein said treating said subject with newly diagnosed multiple myeloma comprises administering to said subject about 16 mg / kg of daratumumab, about 25 mg of lenalidomide per day, and about 20 mg to about 40 mg of dexamethasone per week once per week, once every two weeks, or once every four weeks. [Invention 97] 97. The combination therapy of claim 96, wherein said treating of said subject with newly diagnosed multiple myeloma comprises administering to said subject about 16 mg / kg of daratumumab once weekly from weeks 1 to 8, once every two weeks from weeks 9 to 24, and once every four weeks thereafter, about 25 mg of lenalidomide once daily on days 1 to 21 of repeated four-week cycles, and about 20 mg or about 40 mg of dexamethasone per week. [Invention 98] 98. The combination therapy of invention 97, which is demonstrated to increase the likelihood of achieving VGPR or better in subjects with newly diagnosed multiple myeloma. [Invention 99] 99. The combination therapy of claim 98, wherein said likelihood of achieving said VGPR or better is about 79% or greater. [Invention 100] 98. The combination therapy of invention 97, which is demonstrated to increase the likelihood of achieving a negative status for MRD in subjects with newly diagnosed multiple myeloma. [Invention 101] 101. The combination therapy of claim 100, wherein said likelihood of achieving said negative status for MRD is about 24% or greater. [Invention 102] 98. The combination therapy of invention 97, which is demonstrated to increase the likelihood of achieving CR or better in subjects with newly diagnosed multiple myeloma. [Invention 103] 103. The combination therapy of claim 102, wherein said likelihood of achieving CR or better is about 47% or greater. [Invention 104] 98. The combination therapy of invention 97, which is demonstrated to reduce the risk of multiple myeloma progression or death in subjects with newly diagnosed multiple myeloma. [Invention 105] 105. The combination therapy of claim 104, wherein said risk of progression or death from multiple myeloma is reduced by about 44%. [Invention 106] The combination therapy according to any one of inventions 94 to 105, wherein said subject with multiple myeloma is ineligible for HDC and ASCT. [Invention 107] 107. The combination therapy according to any one of inventions 94 to 106, wherein said combination therapy is promoted by the manufacturer of daratumumab for the treatment of newly diagnosed multiple myeloma on the daratumumab-containing drug product label. [Invention 108] 108. The combination therapy of invention 107, wherein said daratumumab-containing drug product label comprises data from an open-label, randomized, active-controlled phase 3 study comparing treatment with daratumumab in combination with lenalidomide and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma. [Invention 109] The combination therapy of invention 108, wherein said daratumumab-containing drug product label comprises data that treatment with DRd resulted in about a 44% reduction in said risk of multiple myeloma progression or death compared to treatment with Rd. [Invention 110] 109. The combination therapy of claim 108 or 109, wherein said daratumumab-containing drug product label comprises data that treatment with DRd resulted in about 79.3% of subjects achieving VGPR or better, about 24% of subjects achieving negativity for MRD, or about 47.6% of subjects achieving CR or better, or any combination thereof. [Invention 111] 111. The combination therapy according to any one of inventions 107 to 110, wherein said daratumumab-containing drug product label comprises a Kaplan-Meier curve of progression-free survival (PFS) comparing subjects with newly diagnosed multiple myeloma treated with DRd to subjects with newly diagnosed multiple myeloma treated with Rd. [Invention 112] 112. The combination therapy according to any one of inventions 107 to 111, wherein said daratumumab-containing drug product label comprises data from a Phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, melphalan, and prednisone (D-VMP) in subjects with newly diagnosed multiple myeloma with treatment with bortezomib, melphalan, and prednisone (VMP) in subjects with newly diagnosed multiple myeloma. [Invention 113] 113. The combination therapy according to any one of inventions 107 to 112, wherein said daratumumab-containing drug product label comprises data from a phase 3 active-controlled trial comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in relapsed, refractory, or relapsed-refractory multiple myeloma. [Invention 114] 114. The combination therapy according to any one of inventions 107 to 113, wherein the daratumumab-containing drug product label comprises data from a phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, and dexamethasone (DVd) with treatment with bortezomib and dexamethasone (Vd) in relapsed, refractory, or relapsed-refractory multiple myeloma. [Invention 115] 115. The combination therapy according to any one of inventions 107 to 114, wherein the daratumumab-containing drug product label comprises drug product interaction data reporting that clinical pharmacokinetic evaluation of daratumumab in combination with lenalidomide, pomalidomide, bortezomib, and dexamethasone showed no clinically relevant drug-drug interactions between daratumumab and lenalidomide, pomalidomide, bortezomib, and dexamethasone. [Invention 116] 116. The combination therapy according to any one of inventions 107 to 115, wherein the daratumumab-containing drug product label contains information that side effects of daratumumab include weakness, loss of appetite, bronchitis, and lung infections. [Invention 117] 117. The combination therapy according to any one of inventions 107 to 116, wherein said daratumumab-containing drug product labeling includes information regarding daratumumab's approved indications, dosage and administration, adverse reactions, drug interactions, use in specific populations, clinical pharmacology, nonclinical toxicology, clinical studies, and storage and handling, or any combination thereof. [Invention 118] The combination therapy according to any one of Inventions 94 to 117, wherein daratumumab comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. [Invention 119] 119. The combination therapy according to any one of Inventions 94 to 118, wherein daratumumab comprises a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8. [Invention 120] 119. The combination therapy according to any one of Inventions 94 to 119, wherein daratumumab is immunoglobulin IgG1 kappa (IgG1κ). [Invention 121] 121. The combination therapy according to any one of Inventions 94 to 120, wherein daratumumab comprises an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10. [Invention 122] 122. The combination therapy according to any one of inventions 94 to 121, wherein daratumumab is produced in a mammalian cell line. [Invention 123] 123. The combination therapy according to claim 122, wherein said mammalian cell line is a Chinese hamster ovary (CHO) cell line. [Invention 124] 124. The combination therapy according to claim 123, wherein the molecular weight of daratumumab is about 148 kDa. [Invention 125] 125. The combination therapy of claim 124, wherein dexamethasone can be substituted for a dexamethasone equivalent, said dexamethasone equivalent being methylprednisolone, prednisolone, prednisone, or betamethasone, or any combination thereof. [Invention 126] 1. A drug product comprising: daratumumab provided in a package containing one or more single-dose vials comprising daratumumab; and a drug product label comprising the information that treatment of subjects with newly diagnosed multiple myeloma with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when the subjects are administered a combination of lenalidomide and dexamethasone. [Invention 127] 127. The drug product of invention 126, wherein said one or more single dose vials contain 100 mg of daratumumab in 5 mL of solution, or 400 mg of daratumumab in 20 mL of solution. [Invention 128] 128. The drug product of invention 127, wherein the one or more single dose vials containing 100 mg of daratumumab in 5 mL of solution and the one or more single dose vials containing 400 mg of daratumumab in 20 mL of solution further comprise glacial acetic acid, mannitol, polysorbate 20, sodium acetate trihydrate, and sodium chloride. [Invention 129] 129. The drug product of invention 128, wherein the one or more single-dose vials containing 100 mg of daratumumab in 5 mL of solution contain 0.9 mg of glacial acetic acid, 127.5 mg of mannitol, 2 mg of polysorbate 20, 14.8 mg of sodium acetate trihydrate, 17.5 mg of sodium chloride, and water for injection, and the one or more single-dose vials containing 400 mg of daratumumab in 20 mL of solution contain 400 mg of daratumumab, 3.7 mg of glacial acetic acid, 510 mg of mannitol, 8 mg of polysorbate 20, 59.3 mg of sodium acetate trihydrate, 70.1 mg of sodium chloride, and water for injection. [Invention 130] 130. The drug product of any one of inventions 126 to 129, wherein said drug product label comprises the information that a recommended administration schedule for dexamethasone is about 16 mg / kg once weekly from weeks 1 to 8, once every two weeks from weeks 9 to 24, and once every four weeks thereafter; said recommended administration schedule for lenalidomide is about 25 mg per day on days 1 to 21 of repeated four-week cycles; and said recommended administration schedule for dexamethasone is about 20 mg per week or about 40 mg per week. [Invention 131] 131. The drug product of any one of inventions 126 to 130, wherein said drug product label comprises data from an open-label, randomized, active-controlled phase 3 study comparing treatment with daratumumab in combination with lenalidomide and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma. [Invention 132] 132. The drug product of claim 131, wherein said drug product label includes data that treatment with DRd resulted in about a 44% reduction in said risk of progression or death from multiple myeloma compared to treatment with Rd. [Invention 133] 133. The drug product of invention 131 or 132, wherein said drug product label comprises data that treatment with DRd resulted in about 79.3% of subjects achieving VGPR or better, about 24% of subjects achieving negativity for MRD, or about 47.6% of subjects achieving CR or better, or any combination thereof. [Invention 134] 134. The drug product of any one of inventions 131 to 133, wherein said drug product label comprises a Kaplan-Meier curve of progression-free survival (PFS) comparing subjects with newly diagnosed multiple myeloma treated with DRd to subjects with newly diagnosed multiple myeloma treated with Rd. [Invention 135] 135. The drug product of any one of inventions 131 to 134, wherein said drug product label comprises data from a Phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, melphalan, and prednisone (D-VMP) with treatment with bortezomib, melphalan, and prednisone (VMP) in subjects with newly diagnosed multiple myeloma. [Invention 136] 136. The drug product of any one of inventions 131 to 135, wherein said drug product label comprises data from a phase 3 active-controlled trial comparing treatment with daratumumab in combination with lenalidomide and dexamethasone (DRd) with treatment with lenalidomide and dexamethasone (Rd) in relapsed, refractory, or relapsed-refractory multiple myeloma. [Invention 137] 137. The drug product of any one of inventions 131 to 136, wherein said drug product label comprises data from a phase 3 active-controlled trial comparing treatment with daratumumab in combination with bortezomib and dexamethasone (DVd) to treatment with bortezomib and dexamethasone (Vd) in relapsed, refractory, or relapsed-refractory multiple myeloma. [Invention 138] 138. The drug product of any one of inventions 131 to 137, wherein the drug product label comprises drug interaction data reporting that a clinical pharmacokinetic evaluation of daratumumab in combination with lenalidomide, pomalidomide, bortezomib, and dexamethasone showed no clinically relevant drug-drug interactions between daratumumab and lenalidomide, pomalidomide, bortezomib, and dexamethasone. [Invention 139] 184. The drug product of any one of inventions 131 to 183, wherein the drug product label includes the information that side effects of daratumumab include weakness, loss of appetite, bronchitis, and lung infection. [Invention 140] 139. The drug product according to any one of inventions 131 to 139, wherein said drug product labeling comprises information regarding daratumumab's approved indications, dosage and administration, adverse reactions, drug interactions, use in particular populations, clinical pharmacology, nonclinical toxicology, clinical studies, and storage and handling, or any combination thereof. [Invention 141] The drug product according to any one of inventions 126 to 140, wherein daratumumab comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6. [Invention 142] 142. The drug product according to any one of inventions 126 to 141, wherein daratumumab comprises a VH of SEQ ID NO: 7 and a VL of SEQ ID NO: 8. [Invention 143] 143. The drug product according to any one of inventions 126 to 142, wherein daratumumab is immunoglobulin IgG1 kappa (IgG1κ). [Invention 144] 144. The drug product according to any one of inventions 126 to 143, wherein daratumumab comprises an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10. [Invention 145] 145. The pharmaceutical product according to any one of inventions 126 to 144, wherein daratumumab is produced in a mammalian cell line. [Invention 146] 146. The pharmaceutical product of invention 145, wherein said mammalian cell line is a Chinese hamster ovary (CHO) cell line. [Invention 147] 147. The drug product of claim 146, wherein the molecular weight of daratumumab is about 148 kDa. [Invention 148] 1. A method of marketing a drug product comprising daratumumab, comprising: a) manufacturing daratumumab; and b) promoting the achievement of an improved clinical efficacy endpoint when the combination therapy comprising daratumumab, lenalidomide, and dexamethasone is administered to a subject with newly diagnosed multiple myeloma compared to the clinical efficacy endpoint achieved when the subject is administered a combination of lenalidomide and dexamethasone; performing steps a) and b) leads to an HCP purchasing the drug product, thereby selling the drug product; The method. [Invention 149] 149. The method of invention 148, wherein the promotion comprises including on said drug product label data from an open-label, randomized, active-controlled Phase 3 trial comparing treatment with daratumumab in combination with lenalidomide and dexamethasone (DRd) to treatment with lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma. [Invention 150] 149. The method of claim 149, wherein said drug product label further comprises data that treatment with DRd resulted in about a 44% reduction in said risk of progression or death from multiple myeloma compared to treatment with Rd. [Invention 151] The method of invention 150, wherein the drug product label further comprises a Kaplan-Meier curve of progression-free survival (PFS) comparing subjects with newly diagnosed multiple myeloma treated with DRd to subjects with newly diagnosed multiple myeloma treated with Rd. [Invention 152] 1. A method of marketing a drug product comprising daratumumab, comprising: i) manufacturing daratumumab; and ii) selling the drug product, wherein the drug product label includes instructions for treating a subject with newly diagnosed multiple myeloma with a combination of daratumumab, lenalidomide, and dexamethasone; The method. [Invention 153] The method of any one of Inventions 148 to 152, wherein daratumumab comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6. [Invention 154] The method according to any one of Inventions 148 to 153, wherein daratumumab comprises VH of SEQ ID NO: 7 and VL of SEQ ID NO: 8. [Invention 155] 155. The method according to any one of Inventions 148 to 154, wherein daratumumab is immunoglobulin IgG1 kappa (IgG1κ). [Invention 156] 156. The method according to any one of Inventions 148 to 155, wherein daratumumab comprises an HC of SEQ ID NO: 9 and an LC of SEQ ID NO: 10. [Invention 157] 157. The method according to any one of claims 148 to 156, wherein daratumumab is produced in a mammalian cell line. [Invention 158] 72. The method of claim 71, wherein the mammalian cell line is a Chinese hamster ovary (CHO) cell line. [Invention 159] The method of Invention 72, wherein the molecular weight of daratumumab is about 148 kDa.

Claims

1. A combination pharmaceutical for use in a method for treating multiple myeloma, comprising: a) the combination drug comprises an anti-CD38 antibody, lenalidomide, and dexamethasone (DRd); b) the anti-CD38 antibody is of the IgG1 kappa (IgG1κ) isotype and comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8; c) the method comprises treating multiple myeloma in newly diagnosed subjects and comprises excluding subjects with baseline liver dysfunction; and d) administration of the pharmaceutical combination to the subject achieves improved progression-free survival (PFS) and PFS2 compared to the PFS and first subsequent treatment progression-free survival (PFS2) achieved when the subject receives a combination of lenalidomide and dexamethasone (Rd); The combination drug.

2. A pharmaceutical composition comprising an anti-CD38 antibody for use in a method for treating multiple myeloma in combination with lenalidomide and dexamethasone, a) the anti-CD38 antibody is of the IgG1 kappa (IgG1κ) isotype and comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8; b) the method comprises treating multiple myeloma in newly diagnosed subjects and comprises excluding subjects with baseline liver dysfunction; and c) administering to said subject said pharmaceutical composition in combination with lenalidomide and dexamethasone (DRd) achieves improved progression-free survival (PFS) and PFS2 compared to the PFS and first subsequent treatment progression-free survival (PFS2) achieved when said subject is administered a combination of lenalidomide and dexamethasone (Rd); The pharmaceutical composition.

3. The pharmaceutical combination of claim 1 or the pharmaceutical composition of claim 2, wherein the subject is ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT).

4. The pharmaceutical combination of claim 1 or 3, or the pharmaceutical composition of claim 2 or 3, wherein the anti-CD38 antibody comprises a heavy chain (HC) of SEQ ID NO: 9 and a light chain (LC) of SEQ ID NO:

10.

5. The combination drug according to any one of claims 1, 3 and 4, or the pharmaceutical composition according to any one of claims 2 to 4, wherein the anti-CD38 antibody is daratumumab.

6. The pharmaceutical combination of any one of claims 1 and 3 to 5, comprising about 16 mg / kg of an anti-CD38 antibody, about 25 mg of lenalidomide, and about 20 mg to about 40 mg of dexamethasone; or the pharmaceutical composition of any one of claims 2 to 5, wherein the DRd comprises about 16 mg / kg of an anti-CD38 antibody, about 25 mg of lenalidomide, and about 20 mg to about 40 mg of dexamethasone.

7. wherein the administering a) administering approximately 16 mg / kg of anti-CD38 antibody once weekly from weeks 1 to 8, once every two weeks from weeks 9 to 24, and once every four weeks thereafter; b) administering approximately 25 mg of lenalidomide per day on days 1-21 of repeated 4-week cycles; and c) administering about 20 mg to about 40 mg of dexamethasone per week; The pharmaceutical combination according to any one of claims 1 and 3 to 6, or the pharmaceutical composition according to any one of claims 2 to 6, comprising:

8. The combination pharmaceutical of any one of claims 1 and 3 to 7, or the pharmaceutical composition of any one of claims 2 to 7, wherein dexamethasone is administered as a premedication on the day of administration of the anti-CD38 antibody.

9. The pharmaceutical combination according to any one of claims 1 and 3 to 8, or the pharmaceutical composition according to any one of claims 2 to 8, wherein the anti-CD38 antibody is administered intravenously, lenalidomide is administered orally, and dexamethasone is administered intravenously or orally.

10. The pharmaceutical combination according to any one of claims 1 and 3 to 9, or the pharmaceutical composition according to any one of claims 2 to 9, wherein lenalidomide, dexamethasone, or both lenalidomide and dexamethasone are self-administered.

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