Methods for treating newly diagnosed multiple myeloma using combination of antibody that specifically binds cd38, lenalidomide and dexamethasone

Abstract

To provide methods for treating subjects diagnosed as multiple myeloma.SOLUTION: Disclosed is a method for treating a subject newly diagnosed as multiple myeloma, comprising administering to the subject a combination therapy comprising daratumumab, lenalidomide and dexamethasone, where the method achieves more improved clinical efficacy endpoint than the clinical efficacy endpoint achieved by the administration of a combination of lenalidomide and dexamethasone.SELECTED DRAWING: None

Description

Technical Field

[0001] Disclosed herein is a method for treating multiple myeloma using an antibody that specifically binds to CD38 in combination with lenalidomide and dexamethasone.

[0002] (Sequence Listing) This application includes a sequence listing submitted via EFS-Web, the entire contents of which are incorporated herein by reference. The ASCII text file created on February 20, 2020 is named JBI6048WOPCT1ST25.txt and is 13 kilobytes in size.

Background Art

[0003] Multiple myeloma is a malignant disease of plasma cells characterized by uncontrolled and progressive proliferation of plasma cell clones. This disease reduces resistance to infection and causes significant bone destruction (accompanied by bone pain, pathologic fractures, and hypercalcemia), anemia, renal insufficiency, neurological complications, and hyperviscosity syndrome, leading to progressive morbidity and ultimately mortality.

[0004] Despite the availability of multi-drug therapies, multiple myeloma remains incurable with standard chemotherapy.

Summary of the Invention

Problems to be Solved by the Invention

[0005] There is still a need for new treatment options in a state-of-the-art setting that can provide deeper, more sustained efficacy and better long-term outcomes, including better control of the disease and maintenance of health-related quality of life. ​​​​​​

Means for Solving the Problem

[0006] The present disclosure provides a method for treating a subject newly diagnosed with multiple myeloma, comprising administering a combination therapy comprising daratumumab, 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.

[0007] The present disclosure also provides a method for 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 administration of daratumumab to the subject, wherein daratumumab is administered as combination therapy 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 for treating a subject having 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 a subject having multiple myeloma, and the combination therapy comprises daratumumab, lenalidomide, and dexamethasone.

[0009] ​​​​​​​​​​​​​​The present disclosure also provides a method of treating a subject having newly diagnosed multiple myeloma, administering to the subject a combination therapy that has been demonstrated to increase the likelihood of achieving a negative status for minimal residual disease (MRD) in a subject having newly diagnosed multiple myeloma, wherein the combination therapy comprises daratumumab, lenalidomide, and dexamethasone.

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

[0011] The present disclosure also provides a method of treating a subject having newly diagnosed multiple myeloma, administering to the subject a combination therapy that has been demonstrated to reduce the risk of progression or death of multiple myeloma in a subject having newly diagnosed multiple myeloma, wherein the combination therapy comprises daratumumab, lenalidomide, and dexamethasone.

[0012] The present disclosure also includes a method of treating a subject having newly diagnosed multiple myeloma, providing daratumumab to a healthcare professional (HCP), and treating the subject with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone, wherein the treatment is achieved when the subject is treated with a combination of lenalidomide and dexamethasone. Achieving an improved clinical efficacy endpoint as compared to the clinical efficacy endpoint including providing information to the HCP that achieving an improved clinical efficacy endpoint results in a new - diagnosed multiple myeloma subject receiving a combination therapy comprising daratumumab, lenalidomide, and dexamethasone, either by the HCP or by self - administration as directed by the HCP, thereby treating a new - diagnosed multiple myeloma subject.

[0013] The present disclosure also provides a method for providing daratumumab to an HCP for treating a new - diagnosed multiple myeloma subject 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, including providing information to the HCP that treatment with the combination therapy comprising daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint, and transporting daratumumab to the HCP or an authorized daratumumab retailer for the HCP to purchase daratumumab, thereby providing daratumumab to the HCP.

[0014] The present disclosure also provides treatment options for an HCP to treat a new - diagnosed multiple myeloma subject with a combination therapy comprising daratumumab, lenalidomide, Provided is a method of use, a combination therapy comprising daratumumab, lenalidomide, and dexamethasone Treatment with, when the subject is treated with a combination of lenalidomide and dexamethasone Compared to the clinical efficacy endpoints achieved, improved clinical efficacy endpoints To achieve, Manufacturing daratumumab, A combination therapy comprising daratumumab, lenalidomide, and dexamethasone has improved clinical Providing information to HCPs that the efficacy endpoints are achieved, and that the HCPs purchase dar Transporting daratumumab to HCPs or authorized daratumumab resellers for the HCPs to purchase daratumumab Thereby providing treatment options for HCPs.

Brief Description of the Drawings

[0015] The summary of the invention, as well as the embodiments for carrying out the following invention, should be read in conjunction with the accompanying drawings For the purpose of illustrating the disclosed method, the drawings show exemplary embodiments of the method However, the method is not limited to the specific embodiments disclosed herein The drawings are as follows.

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0016] All patents and patent applications cited herein (but not limited thereto) are hereby incorporated by reference into this specification as if fully set forth.

[0017] Certain aspects of the invention described herein for clarity in connection with separate embodiments It is understood that certain features may also be provided in combination within a single embodiment That is, unless clearly incompatible or specifically excluded, each individual embodiment is considered combinable with any other embodiment, and such a combination is considered to be a separate embodiment. Conversely, the different features of the invention described in the context of a single embodiment for purposes of brevity may be provided separately or as any partial combination Finally, embodiments may be described as part of a series of steps or as part of a more general structure but each step may be considered an independent embodiment in itself and combinable with others If a list is presented, it should be understood that, unless otherwise specified, each individual element of the list and all combinations of the list

[0018] are separate embodiments. 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" "About" means within the allowable error range for a particular value determined by one of ordinary skill in the art, which depends to some extent on the method by which the value is measured or determined, i.e., the limitations of the measurement system Unless otherwise explicitly stated elsewhere in the context of a particular assay, result, or embodiment or elsewhere in the specification, "about" means within the larger of the ranges of plus or minus one standard deviation or 5% in accordance with the practice of the art

[0019] It is meant that That is, it depends to some extent on the limitations of the measurement system, i.e., the method by which the value is measured or determined In the context of a particular assay, result, or embodiment, or elsewhere in the specification, unless otherwise explicitly stated "About" means within the larger of the ranges of plus or minus one standard deviation or 5% in accordance with the practice of the art That is, it means within the larger of the ranges of plus or minus one standard deviation or 5% in accordance with the practice of the art That is, it is meant that

[0020] "Approximately once a week" refers to an approximate number and includes every 7 days ± 2 days, that is, every 5 days to every 9 days. This is possible. Therefore, the dosing frequency of "once a week" can be every 5 days, every 6 days, every 7 days, every 8 days , or every 9 days.

[0021] "Approximately once every two weeks" refers to an approximate number and includes every 14 days ± 2 days, that is, every 12 days to every 1 6 days.

[0022] "Approximately once every three weeks" refers to an approximate number and includes every 21 days ± 2 days, that is, every 19 days to every 2 3 days.

[0023] "Approximately once every four weeks" refers to an approximate number and includes every 28 days ± 2 days, that is, every 26 days to every 3 0 days.

[0024] "Approximately once every five weeks" refers to an approximate number and includes every 35 days ± 2 days, that is, every 33 days to every 3 7 days.

[0025] "Approximately once every six weeks" refers to an approximate number and includes every 42 days ± 2 days, that is, every 40 days to every 3 8 days.

[0026] "Approximately twice a week" refers to an approximate number and means twice a week. For example, the first dose is on the first day of the week, and the second dose is on the second, third, fourth, fifth, sixth, or seventh day of the week. The first dose is on the second day of the week, and the second dose is on the third, fourth, fifth, sixth, or seventh day of the week. The first dose is on the third day of the week, and the second dose is on the fourth, fifth, sixth, or seventh day of the week. The first dose is on the fourth day of the week, and the second dose is on the fifth, sixth, or seventh day of the week. The first dose is on the fifth day of the week, and the second dose is on the sixth or seventh day of the week. The first dose is on the sixth day of the week and The second administration can be included on the 7th day.

[0027] "Adverse event" (AE) refers to any harmful medical event in subjects of a clinical study to which an antibody that specifically binds to CD38, such as daratumumab, is administered. An AE is not necessarily causally related to the treatment. Therefore, an AE can be any undesirable and unintended sign (including abnormal findings), symptom, or disease that is temporally associated with the use of a (investigational or non-investigational) pharmaceutical product, whether or not related to an antibody that specifically binds to CD38, such as daratumumab. An AE is not necessarily causally related to the treatment. Thus, an AE can be any undesirable and unintended sign (including abnormal findings), symptom, or disease that is temporally associated with the use of a (investigational or non-investigational) pharmaceutical product, whether or not related to an antibody that specifically binds to CD38, such as daratumumab. An AE is not necessarily causally related to the treatment. Therefore, an AE can be any undesirable and unintended sign (including abnormal findings), symptom, or disease that is temporally associated with the use of a (investigational or non-investigational) pharmaceutical product, whether or not related to an antibody that specifically binds to CD38, such as daratumumab. An AE is not necessarily causally related to the treatment. Therefore, an AE can be any undesirable and unintended sign (including abnormal findings), symptom, or disease that is temporally associated with the use of a (investigational or non-investigational) pharmaceutical product, whether or not related to an antibody that specifically binds to CD38, such as daratumumab. An AE is not necessarily causally related to the treatment. Therefore, an AE can be any undesirable and unintended sign (including abnormal findings), symptom, or disease that is temporally associated with the use of a (investigational or non-investigational) pharmaceutical product, whether or not related to an antibody that specifically binds to CD38, such as daratumumab.

[0028] The connective term "and / or" between a plurality of listed elements is understood to include both individual options and combinations of the listed options. For example, when two elements are connected by "and / or", the first option indicates that the first element is applicable without the second element. The second option indicates that the second element is applicable without the first element. The third option indicates that the first and second elements are applicable together. Any one of these options is included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied as used herein. The simultaneous applicability of two or more of the options is also included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied. The connective term "and / or" between a plurality of listed elements is understood to include both individual options and combinations of the listed options. For example, when two elements are connected by "and / or", the first option indicates that the first element is applicable without the second element. The second option indicates that the second element is applicable without the first element. The third option indicates that the first and second elements are applicable together. Any one of these options is included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied as used herein. The simultaneous applicability of two or more of the options is also included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied. The connective term "and / or" between a plurality of listed elements is understood to include both individual options and combinations of the listed options. For example, when two elements are connected by "and / or", the first option indicates that the first element is applicable without the second element. The second option indicates that the second element is applicable without the first element. The third option indicates that the first and second elements are applicable together. Any one of these options is included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied as used herein. The simultaneous applicability of two or more of the options is also included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied. The connective term "and / or" between a plurality of listed elements is understood to include both individual options and combinations of the listed options. For example, when two elements are connected by "and / or", the first option indicates that the first element is applicable without the second element. The second option indicates that the second element is applicable without the first element. The third option indicates that the first and second elements are applicable together. Any one of these options is included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied as used herein. The simultaneous applicability of two or more of the options is also included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied. The connective term "and / or" between a plurality of listed elements is understood to include both individual options and combinations of the listed options. For example, when two elements are connected by "and / or", the first option indicates that the first element is applicable without the second element. The second option indicates that the second element is applicable without the first element. The third option indicates that the first and second elements are applicable together. Any one of these options is included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied as used herein. The simultaneous applicability of two or more of the options is also included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied. The connective term "and / or" between a plurality of listed elements is understood to include both individual options and combinations of the listed options. For example, when two elements are connected by "and / or", the first option indicates that the first element is applicable without the second element. The second option indicates that the second element is applicable without the first element. The third option indicates that the first and second elements are applicable together. Any one of these options is included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied as used herein. The simultaneous applicability of two or more of the options is also included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied. The connective term "and / or" between a plurality of listed elements is understood to include both individual options and combinations of the listed options. For example, when two elements are connected by "and / or", the first option indicates that the first element is applicable without the second element. The second option indicates that the second element is applicable without the first element. The third option indicates that the first and second elements are applicable together. Any one of these options is included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied as used herein. The simultaneous applicability of two or more of the options is also included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied. The connective term "and / or" between a plurality of listed elements is understood to include both individual options and combinations of the listed options. For example, when two elements are connected by "and / or", the first option indicates that the first element is applicable without the second element. The second option indicates that the second element is applicable without the first element. The third option indicates that the first and second elements are applicable together. Any one of these options is included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied as used herein. The simultaneous applicability of two or more of the options is also included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied. The connective term "and / or" between a plurality of listed elements is understood to include both individual options and combinations of the listed options. For example, when two elements are connected by "and / or", the first option indicates that the first element is applicable without the second element. The second option indicates that the second element is applicable without the first element. The third option indicates that the first and second elements are applicable together. Any one of these options is included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied as used herein. The simultaneous applicability of two or more of the options is also included in the meaning, and thus it is understood that the requirements of the term "and / or" are satisfied.

[0029] "Antibody" belongs to any class, IgA, IgD, IgE, IgG, and IgM, or subclass IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4, and has a valence of It comprises an immunoglobulin molecule comprising either a κ or a λ light chain. As an antibody Examples 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 consists of a heavy chain variable region (VH) and a heavy chain constant region (domains CH 1, hinge, CH2, and CH3). Each light chain consists of a light chain variable region ( VL) and a light chain constant region (CL). The VH region and the VL region are further subdivided into hypervariable regions called complementarity determining regions (CDR) interspersed with framework regions (FR) . Each VH and VL is composed of three CDRs and four FR segments arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4

[0030] A "biological follow-on" (of an approved reference product / biological product) refers to a biological product that, although having minor differences in clinically inactive components, is clinically indistinguishable from the reference product in terms of safety, purity, and potency based on the data obtained from the following (a) - (c): (a) Analytical studies demonstrating that the biological product is highly similar to the reference product, although having minor differences in clinically inactive components ​​​​​​​​, (b) animal experiments (including toxicity evaluation), and / or (c) the standard formulation is approved The conditions of use and the conditions under which the use of the standard formulation is intended, and the safety, purity, and potency under one or more appropriate conditions of use such as the conditions for granting approval for the biologic follow-on product. Clinical studies (plural) sufficient to demonstrate (including immunogenicity and pharmacokinetics or pharmacodynamics evaluation) are required. The biologic follow-on product can be an interchangeable product that can serve as an alternative to the standard formulation at the pharmacy without the intervention of the prescribing healthcare provider. To comply with further criteria for "interchangeability", the biologic follow-on product is required to produce the same clinical results as the standard formulation in any given patient, and when the biologic follow-on product is administered to an individual multiple times, the risk of a decrease in safety or efficacy due to alternating or switching between the use of the biologic follow-on product and the use of the standard formulation does not exceed the risk when using the standard formulation without such alternating or switching. To the extent that the mechanism of action of the standard formulation is known, the biologic follow-on product utilizes the same mechanism of action with respect to the proposed conditions of use. The recommended, or presented conditions of use (plural) specified in the proposed labeling for the biologic follow-on product are already approved for the standard formulation. The route of administration, dosage form, and / or strength of the biologic follow-on product are the same as those of the standard formulation, and the biologic follow-on

[0031] "Cancer" refers to abnormal growth of cells that proliferate out of control and, in some cases, tend to metastasize (spread) to other areas of the patient's body.

[0032] "CD38" refers to human differentiation antigen group 38 protein, which is a glycoprotein expressed on immune cells including plasma cells, natural killer cells, and subsets of B cells and T cells.

[0033] "Clinical efficacy endpoint" or "clinical endpoint" refers to results indicating clinical utility, such as progression-free survival (PFS), time to disease progression (TTP), the period until the start of the next treatment, overall response rate (ORR), the proportion of subjects achieving partial response (PR), the proportion of subjects achieving very good partial response (VGPR), the proportion of subjects achieving complete response (CR), the proportion of subjects achieving stringent complete response (sCR), the proportion of subjects achieving minimal residual disease (MRD), or the proportion of subjects achieving both negativity for sCR and MRD, etc.

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

[0035] "Co-administration", "administration with", "administration in combination with", "in combination with", etc. include administration of the selected therapeutic agent or drug to a single patient, where the therapeutic agent or drug is administered by the same or different routes of administration, or at the same or different times, and are intended to include a treatment regimen. It is intended to include.

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

[0037] "Complementary determining region (CDR)" is the "antigen-binding site" in an antibody. CDRs are 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 H ealth, Bethesda, Md., 1991), or alternative descriptions (Lefranc et al., Dev Comparat Immunol 27:55-77, 20 03; see also). International ImMunoGe neTics (IMGT) database (http_ / / www_imgt_org) provides standardized numbering and definition 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 a strict complete response (sCR) during or after treatment.

[0039] "Comprising", "consisting essentially of", and "consisting of" are intended to imply the meaning generally accepted in patent terminology, that is, (i) "comprising" is synonymous with "including", "containing", or "characterized by", is inclusive or non-limiting, and does not exclude other unrecited elements or method steps, (ii) "consisting of" excludes any element, step, or component not specified in the claims, and (iii) "consisting essentially of" is the material or step specified, and limits the scope of the claims to those that do not materially affect the "basic and novel features(s)" of the claimed invention. Embodiments described with respect to the phrase "comprising" (or its equivalent) also provide, as embodiments, those independently described with respect to "consisting of" and "consisting essentially of". "Corticosteroid" refers to a class of steroid hormones produced by the adrenal cortex or produced synthetically, and refers to dexamethasone, methylprednisolone, prednisolone, and prednisone. Dexamethasone is commercially available under the trade name DECARON®. "Cycle" refers to a dosing 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 is the period during which a drug is administered

[0040]

[0041] ​​​​​​​​​​​​​​​It may include the number of days to be administered and a rest period during which the drug is not administered. The length of the cycle may vary and may be, for example, 2 weeks, 3 weeks, 28 days (or 4 weeks), 5 weeks, or 6 weeks.

[0042] In the context of administration, "daily" 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 that 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 and includes the heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2 , the HCDR3 of SEQ ID NO: 3, the light chain complementarity determining region 1 (LCDR 1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, the LCDR3 of SEQ ID NO: 6, the heavy chain variable region ( VH) of SEQ ID NO: 7, the light chain variable region (VL) of SEQ ID NO: 8, the heavy chain (HC) of SEQ ID NO: 9, and the 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 an active ingredient, including biosimilars of DARZ ALEX®.

[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. Dex The structure of samethazone is shown in Formula 1.

[0046] [Chemical formula]

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

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

[0049] "Drug product" (DP) generally refers to the final dosage form that contains, although not necessarily, an active pharmaceutical ingredient (e.g., drug substance) along with inactive ingredients, such as tablets, capsules, or solutions.

[0050] "Drug substance" (DS) refers to any substance or mixture of substances that is intended to be used in the manufacture of a drug (pharmaceutical) product and that, when used in the production of a drug, becomes the active ingredient of that drug product. Such substances are intended to provide a 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 efficacy" refers to the time between the day when efficacy (partial response (PR) or more) is first confirmed and the day when signs of progressive disease are first confirmed.

[0052] "Effective" means that in a subject who has been administered a therapeutic agent or drug or a combination of therapeutic agents or drugs, a therapeutic effect is provided for a given condition and dosing regimen. To be used, a therapeutic agent or drug (such as an antibody that specifically binds to CD38, such as daratumumab ), or refers to the dose or dosage of a therapeutic agent or combination of drugs. "Effective" means that for the subject's activities, functions, and responses, it is sufficient to reduce and / or prevent clinically significant impairments or to cause an improvement in a clinically significant condition in the subject. It is intended.

[0053] "Front-line" or "first-choice" therapy refers to the first treatment of a disease such as multiple myeloma administered to a subject.

[0054] "Glutamic acid derivative" refers to immunomodulatory drugs that are derivatives of glutamic acid such as lenalidomide, thalidomide, and pomalidomide. Lenalidomide is marketed under the trade name REVLIMID (registered trademark). Thalidomide is marketed under the trade name THALOMID (registered trademark) . Pomalidomide is marketed under the trade name POMALYST (registered trademark).

[0055] "Healthcare professional" (HCP) refers to a physician, nurse, nursing assistant, or a person working under the direct supervision of a physician or nurse, or a person working in a hospital or a place where treatment can be provided to a subject.

[0056] "High-dose chemotherapy" (HDC) and "autologous stem cell transplantation" (ASCT) refer to the treatment of subjects newly diagnosed with multiple myeloma who are considered suitable. Subjects under 65 years of age or subjects 65 years of age and older who have one or more co-existing diseases that are likely to have an adverse effect on the tolerance of HDC and A SCT have a risk of death and complications related to transplantation. Due to the weakened physical state to be increased, it is usually considered ineligible for HDC and ASCT (e.g., the subject is "ineligible"). Exemplary co-existing diseases are renal insufficiency. Ex amples. Exemplary HDC regimens are melphalan at a dose of 200 mg / m (with dose reduction based on age and renal function), cyclophosphamide and melphalan, carmustine, etop 2 oside, cytarabine, and melphalan (BEAM), high-dose idarubicin, cyclophosph amide, thiotepa, busulfan, and cyclophosphamide, busulfan and melphala n, and high-dose lenalidomide (Mahajan et al., Ther A dv 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 of these.

[0058] "Information" refers to the reported results from clinical trials and can be provided in written or electronic form, or orally , or can be available on the Internet.

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

[0060] "Label" and "labeling" are used interchangeably herein, and daratumumab On, in, or attached to a container or package that contains a drug such as, or otherwise electronically or Internet - available written, printed, or graphic all labels and displays of information. "Label" and "labeling" include the accompanying documents and prescription information.

[0061] Lenalidomide, a thalidomide analog, is an immunomodulatory drug with anti - angiogenesis and anti - tumor properties. Its chemical name is 3 - (4 - amino - 1 - oxo - 1,3 - dihydro - 2H - isoindol - 2 - yl) piperidine - 2,6 - dione and it has the structure shown in Formula 2. Lenalidomide is commercially

[0062] [Chemical formula]

[0063] "Minimal residual disease" (MRD) refers to a small number of clonal multiple myeloma cells remaining in a patient after treatment and / or

[0064] during remission. "MRD negative" or "negative status for MRD" refers to a ratio of 5 clonal multiple myeloma cells of 1:10×10 or less in a bone marrow

[0065] aspirate sample obtained from a subject. "MRD negative rate" refers to the proportion of subjects evaluated as

[0066] MRD negative at any time point after randomization. "Multiple myeloma" refers to a malignant disease of plasma cells Proliferation causes displacement of normal bone marrow, resulting in dysfunction of hematopoietic tissue and destruction of bone marrow structure and leads to a progressive morbidity rate and ultimate mortality rate.

[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] "Weight / volume percent" (w / v%) refers to the 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 administrations on the same day or different days . For example, the total dose may be 40 mg administered at 20 mg on the first day of the week and 20 mg on the third day .

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

[0073] ​"Progression-free survival" (PFS) means the time from the start of treatment to the first evidence of disease progression or death from any cause (whichever occurs first). For the purposes of the clinical trials described in this example, PFS is defined as the period from the randomization date of the study population until the first confirmation of progressive disease or death from any cause (whichever occurs first). This refers to the time to the first (whichever occurs first) evidence of disease progression or death from any cause from the start of treatment. For the purposes of the clinical trials described in this example, PFS is defined as the period from the randomization date of the study population until the first confirmation of progressive disease or death from any cause (whichever occurs first). For the purposes of the clinical trials described in this example, PFS is defined as the period from the randomization date of the study population until the first confirmation of progressive disease or death from any cause (whichever occurs first). This refers to the time to the first (whichever occurs first) evidence of disease progression or death from any cause from the start of treatment. For the purposes of the clinical trials described in this example, PFS is defined as the period from the randomization date of the study population until the first confirmation of progressive disease or death from any cause (whichever occurs first). This refers to the time to the first (whichever occurs first) evidence of disease progression or death from any cause from the start of treatment. For the purposes of the clinical trials described in this example, PFS is defined as the period from the randomization date of the study population until the first confirmation of 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 until the first occurrence of progression or death during subsequent treatment (whichever occurs first). This refers to the time to the first (whichever occurs first) evidence of disease progression or death from any cause from the start of treatment. For the purposes of the clinical trials described in this example, PFS2 is defined as the period from the randomization date of the study population until the first confirmation of progressive disease or death from any cause (whichever occurs first). This refers to the time to the first (whichever occurs first) evidence of disease progression or death from any cause from the start of treatment. For the purposes of the clinical trials described in this example, PFS2 is defined as the period from the randomization date of the study population until the first confirmation of progressive disease or death from any cause (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 the response to treatment and have the customary meanings understood by those skilled in the art of designing, conducting, or reviewing clinical trials. The response to treatment can be evaluated using the International Myeloma Working Group (IMWG) Uniform Response Criteria Consensus Recommendations, as shown in Table 1. This refers to the time to the first (whichever occurs first) evidence of disease progression or death from any cause from the start of treatment. For the purposes of the clinical trials described in this example, PD, SD, PR, VGPR, CR, and sCR are defined as the response to treatment and have the customary meanings understood by those skilled in the art of designing, conducting, or reviewing clinical trials. The response to treatment can be evaluated using the International Myeloma Working Group (IMWG) Uniform Response Criteria Consensus Recommendations, as shown in Table 1. This refers to the time to the first (whichever occurs first) evidence of disease progression or death from any cause from the start of treatment. For the purposes of the clinical trials described in this example, PD, SD, PR, VGPR, CR, and sCR are defined as the response to treatment and have the customary meanings understood by those skilled in the art of designing, conducting, or reviewing clinical trials. The response to treatment can be evaluated using the International Myeloma Working Group (IMWG) Uniform Response Criteria Consensus Recommendations, as shown in Table 1. This refers to the time to the first (whichever occurs first) evidence of disease progression or death from any cause from the start of treatment. For the purposes of the clinical trials described in this example, PD, SD, PR, VGPR, CR, and sCR are defined as the response to treatment and have the customary meanings understood by those skilled in the art of designing, conducting, or reviewing clinical trials. The response to treatment can be evaluated using the International Myeloma Working Group (IMWG) Uniform Response Criteria Consensus Recommendations, as shown in Table 1. This refers to the time to the first (whichever occurs first) evidence of disease progression or death from any cause from the start of treatment. For the purposes of the clinical trials described in this example, PD, SD, PR, VGPR, CR, and sCR are defined as the response to treatment and have the customary meanings understood by those skilled in the art of designing, conducting, or reviewing clinical trials. The response to treatment can be evaluated using the International Myeloma Working Group (IMWG) Uniform Response Criteria Consensus Recommendations, as shown in Table 1. This refers to the time to the first (whichever occurs first) evidence of disease progression or death from any cause from the start of treatment. For the purposes of the clinical trials described in this example, PD, SD, PR, VGPR, CR, and sCR are defined as the response to treatment and have the customary meanings understood by those skilled in the art of designing, conducting, or reviewing clinical trials. The response to treatment can be evaluated using the International Myeloma Working Group (IMWG) Uniform Response Criteria Consensus Recommendations, as shown in Table 1. This refers to the time to the first (whichever occurs first) evidence of disease progression or death from any cause from the start of treatment. For the purposes of the clinical trials described in this example, PD, SD, PR, VGPR, CR, and sCR are defined as the response to treatment and have the customary meanings understood by those skilled in the art of designing, conducting, or reviewing clinical trials. The response to treatment can be evaluated using the International Myeloma Working Group (IMWG) Uniform Response Criteria Consensus Recommendations, as shown in Table 1. This refers to the time to the first (whichever occurs first) evidence of disease progression or death from any cause from the start of treatment. For the purposes of the clinical trials described in this example, PD, SD, PR, VGPR, CR, and sCR are defined as the response to treatment and have the customary meanings understood by those skilled in the art of designing, conducting, or reviewing clinical trials. The response to treatment can be evaluated using the International Myeloma Working Group (IMWG) 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 a resistant disease during treatment. This refers to the time to the first (whichever occurs first) evidence of disease progression or death from any cause from the start of treatment. For the purposes of the clinical trials described in this example, 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 a resistant disease during treatment.

[0077] "Recurrence" refers to the resumption of a disease or the 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 (registered trademark) brand of daratumumab, which is compared to a biosimilar. The reference product is approved in the United States, among other things, based on a complete complement of safety and efficacy data.

[0079] "Safe", when referring to a therapeutic agent or drug (an antibody that specifically binds to CD38, such as daratumumab, etc.), a composition, dosage, dosing regimen, treatment, or method using the same, means the acceptable frequency and / or acceptable severity of adverse events (AE) and / or treatment-emergent adverse events (TEAE) compared to standard therapy (such as a combination of lenalidomide and dexamethasone, etc.) or another comparator drug: the risk ratio.

[0080] "Safe and effective" means a drug (an antibody that specifically binds to CD38, such as daratumumab, etc.) or a combination of drugs that elicits a desired biological response or drug response in the subject's biological system without the risk outweighing the effect of such a response, in accordance with the Revised Federal Food, Drug, and Cosmetic Act (secs. 201-902, 52 Stat. 1040 et seq., as revised; 21 U.S.C. §§ 321-392). Safety is such that the desired effect is achieved. To determine the maximum tolerated or optimal dose of a drug or drug combination required, experiments are evaluated in vitro, in animals, and in human clinical trials. Efficacy is evaluated in human clinical trials to determine whether the drug or drug combination demonstrates a health effect against a placebo or other intervention. A safe and effective drug or drug combination is given 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 a higher affinity than to other antigens. Typically, the antibody has an equilibrium dissociation constant (K d) of about 1×10 -8 M or less, for example, about 1×10 - 9 M or less, about 1×10 -10 M or less, about 1×10 -11 M or less, or about 1×10 -12 M or less and binds to CD38 with a K D that is typically at least 100-fold lower than the K for binding to a non-specific antigen (e.g., BSA, casein). K D d can be measured using standard procedures. However, an antibody that specifically binds to CD38 may cross-react with the same antigen (homolog) from other species, such as monkeys, e.g., Macaca fascicularis (cynomolgus, cyno), Pan troglodytes (chimpanzee, chimp), or Callithrix jacchus (common marmoset, marmoset). D D d can be measured using standard procedures. However, an antibody that specifically binds to CD38 may cross-react with the same antigen (homolog) from other species, such as monkeys, e.g., Macaca fascicularis (cynomolgus, cyno), Pan troglodytes (chimpanzee, chimp), or Callithrix jacchus (common marmoset, marmoset). laris (cynomolgus, cyno), Pan troglodytes (chimpanzee, chimp), or Callithrix jacchus (common marmoset, marmoset)) that is typically at least 100-fold lower than the K for binding to a non-specific antigen (e.g., BSA, casein). K d can be measured using standard procedures. However, an antibody that specifically binds to CD38 may cross-react with the same antigen (homolog) 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] "Therapeutically effective amount" refers to an amount effective to achieve a desired therapeutic result in the required dosages and periods. The therapeutically effective amount may vary depending on factors such as the condition of the individual, 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 indicating an effective therapeutic agent or combination of therapeutic agents include, for example, improvement in the health condition of the patient, reduction in tumor mass, cessation or attenuation of tumor growth, and / or 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 until the first signs of progressive disease are confirmed.

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

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

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

[0088] "Treat", "treating", or "treatment" refers to a therapeutic treatment. Individuals in need of treatment include subjects diagnosed as having a disorder or signs of a disorder. Subjects who can be treated include those who tend to have a disorder or are sensitive to a disorder. ​​​​​​​​​​​Those that have it or whose disorders can be prevented can also be mentioned. Beneficial or desired Clinical outcomes include symptom reduction, decreased disease severity, a stabilized (i.e., non-worsening ) disease state, delayed or blunted disease progression, improvement or alleviation of the disease state, remission of the disease (whether partial or complete), and extension of survival compared to the expected survival if the subject had not received treatment or had received another treatment .

[0089] "Treatment-emergent adverse event" (TEAE), as used herein, has the customary meaning understood by those skilled in the art of designing, conducting, or reviewing clinical trials and refers to an AE that is likely, probably attributable, or highly likely to be attributable to the use of an antibody that specifically binds to CD38, such as daratumumab, when the attribution is possible .

[0090] "Inadmissible adverse event" and "inadmissible adverse reaction" refer to all adverse or undesirable outcomes related to or caused by the administration of a pharmaceutical composition or therapeutic agent and the adverse or undesirable outcome has reached a level of severity such that the regulatory authority considers the pharmaceutical composition or therapeutic agent to be inadmissible for the proposed use.

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

[0092] Multiple myeloma Multiple myeloma causes significant morbidity and mortality. This is one of the most common hematological malignancies worldwide It accounts for about 1% of cancers and 13% of blood cancers. Approximately 50,000 patients per year are diagnosed with multiple myeloma in the EU and US, and 30,000 patients per year die from multiple myeloma. Most patients with multiple myeloma produce a monoclonal protein (abnormal protein, M-protein, or M-component), which is a dysfunctional immunoglobulin (Ig) or a fragment thereof. Loss of normal immunoglobulin levels in patients results in increased susceptibility to infection. Proliferating multiple myeloma cells displace normal bone marrow, leading to dysfunction of normal hematopoietic tissue and destruction of normal bone marrow architecture, which is reflected by clinical findings such as anemia, abnormal proteins in serum or urine, and bone resorption seen as diffuse osteopenia or lytic lesions on radiographs (Kyle et al., Mayo Clin Proc 78:21-33, 2003).

[0093] Furthermore, hypercalcemia, renal insufficiency or failure, and neurological complications are often seen. A very small number of patients with multiple myeloma are non-secretory. (Kyle and Rajkumar, Leukemia 23:3-9, 2009; Palumbo and Anderson, N Engl J Med 364:1046-1060, 2011). (Kyle and Rajkumar,Leukemia 23:3-9,200 9;Palumbo and Anderson,N Engl J Med 364: Normal immunoglobulin levels are impaired in patients, leading to susceptibility to infection. Proliferating multiple myeloma cells displace normal bone marrow, resulting in dysfunction of normal hematopoietic tissue and destruction of normal bone marrow architecture, which is reflected by clinical findings such as anemia, abnormal proteins in serum or urine, and bone resorption seen as diffuse osteopenia or lytic lesions on radiographs (Kyle et al., Mayo C lin Proc 78:21-33,2003). Furthermore, hypercalcemia, renal function low down or renal insufficiency, and neurological complications are often seen. A very small number of patients with multiple myeloma are non-secretory. (Kyle et al., Mayo Clin Proc 78:21-33, 2003). Furthermore, hypercalcemia, renal insufficiency or failure, and neurological complications are often seen. A very small number of patients with multiple myeloma are non-secretory. (Kyle et al.,Mayo C lin Proc 78:21-33,2003). Furthermore, hypercalcemia, renal function low down or renal insufficiency, and neurological complications are often seen. A very small number of patients with multiple myeloma are non-secretory.

[0094] Treatment options for multiple myeloma vary depending on age, comorbidities, disease aggressiveness, and related prognostic factors (Palumbo and Anderson, N Engl J Me d 364:1046-1060,2011). Patients newly diagnosed with multiple myeloma are typically categorized for subsequent approaches to treatment, usually determined by age and fitness for treatment. are classified into two subpopulations. Younger patients typically receive 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 combination of multiple drugs, including alkylating agents, high-dose steroids, and novel agents, is currently considered standard treatment. Generally, patients 65 years of age or older or those with significant comorbidities are usually not considered eligible for H DC and ASCT. For many years, oral combination melphalan -prednisone (MP) was considered standard treatment for patients with multiple myeloma not eligible for ASCT (Gay and Palumbo, Blood Revi ews 25:65-73,2011). The emergence of immunomodulatory agents (IMi D) and proteasome inhibitors (PI) has provided numerous new treatment options for newly diagnosed patients not suitable for transplantation-based therapy. .

[0095] Diagnosis of Multiple Myeloma Subjects with multiple myeloma meet the CRAB (calcium elevation, r enal insufficiency, anemia and bone abnor malities) (elevated calcium, reduced renal function, anemia, and bone abnormalities) criteria and have 10% or more clonal plasma cells, or plasmacytoma in bone or extramedullary by biopsy diagnosis, and 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 higher, or a urinary M-protein level of 200 mg / 24 hours or more, or - IgA, IgM, IgD, or IgE multiple myeloma: a serum M-protein level of 0.5 g / dL or more, or a urinary M-protein level of 200 mg / 24 hours or more, or - Light chain multiple myeloma without measurable disease in serum or urine: a serum immunoglobulin free light chain of 10 mg / dL or more, and an abnormal serum immunoglobulin kappa / lambda free light chain ratio.

[0096] CRAB criteria · Hypercalcemia: more than 0.25 mM / L (more than 1 mg / dL) above the upper limit of normal [ULN], or a serum calcium of more than 2.75 mM / L (more than 11 mg / dL) · Renal insufficiency: a creatinine clearance of less than 40 mL / min, or a serum creatinine of more than 177 μM / L (more than 2 mg / dL) · Anemia: hemoglobin more than 2 g / dL below the normal lower limit, hemoglobin less than 10 g / dL · Bone lesions: one or more lytic bone lesions on bone X-ray, CT, or PET-CT

[0097] The response to treatment can be evaluated using the International Myeloma a Working Group (IMWG) Unified Response Criteria Recommendations (Internati onal Uniform Response Criteria Consensus Recommendations), as shown in Table 1.

[0098]

Table 1

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

[0100] In some embodiments, the 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 having 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, the method achieving 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 comprises administering daratumumab to a subject or providing for such administration A method of treating a subject newly diagnosed with multiple myeloma who is ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), wherein daratumumab is administered as combination therapy 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. A method of treating a subject newly diagnosed with multiple myeloma who is ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), wherein daratumumab is administered as combination therapy 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. A method of treating a subject newly diagnosed with multiple myeloma who is ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), wherein daratumumab is administered as combination therapy 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. A method of treating a subject newly diagnosed with multiple myeloma who is ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), wherein daratumumab is administered as combination therapy 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. A method of treating a subject newly diagnosed with multiple myeloma who is ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), wherein daratumumab is administered as combination therapy 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 increase in the likelihood of achieving complete remission (CR) or greater, a very good partial remission (VGPR) or greater, an increase in the likelihood of achieving a negative status for minimal residual disease (MRD), a reduction in the risk of progression or death of multiple myeloma, an extension of progression-free survival (PFS), or an increase in the likelihood of achieving a 30-month progression-free survival rate. In some embodiments, the improved clinical efficacy endpoint is an increase in the likelihood of achieving complete remission (CR) or greater, a very good partial remission (VGPR) or greater, an increase in the likelihood of achieving a negative status for minimal residual disease (MRD), a reduction in the risk of progression or death of multiple myeloma, an extension of progression-free survival (PFS), or an increase in the likelihood of achieving a 30-month progression-free survival rate. In some embodiments, the improved clinical efficacy endpoint is an increase in the likelihood of achieving complete remission (CR) or greater, a very good partial remission (VGPR) or greater, an increase in the likelihood of achieving a negative status for minimal residual disease (MRD), a reduction in the risk of progression or death of multiple myeloma, an extension of progression-free survival (PFS), or an increase in the likelihood of achieving a 30-month progression-free survival rate. In some embodiments, the improved clinical efficacy endpoint is an increase in the likelihood of achieving complete remission (CR) or greater, a very good partial remission (VGPR) or greater, an increase in the likelihood of achieving a negative status for minimal residual disease (MRD), a reduction in the risk of progression or death of multiple myeloma, an extension of progression-free survival (PFS), or an increase in the likelihood of achieving a 30-month progression-free survival rate. In some embodiments, the improved clinical efficacy endpoint is an increase in the likelihood of achieving complete remission (CR) or greater, a very good partial remission (VGPR) or greater, an increase in the likelihood of achieving a negative status for minimal residual disease (MRD), a reduction in the risk of progression or death of multiple myeloma, an extension of progression-free survival (PFS), or an increase in the likelihood of achieving a 30-month progression-free survival rate.

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

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

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

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

[0113] The MRD status can be evaluated from a bone marrow aspirate sample, for example, using next generation sequencing (NGS) of immunoglobulin heavy and light chains. The updated, analytically validated version (version 2) of clonoSEQ® by Adaptive Biotechnologies can be used for the detection, quantification, and analysis of MRD.

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

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

[0116] The present disclosure also provides a method of treating a subject having newly diagnosed multiple myeloma, comprising administering to the subject having newly diagnosed multiple myeloma a combination therapy that has been demonstrated to reduce the risk of progression or death of It includes daratumumab, lenalidomide, and dexamethasone.

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

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

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

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

[0121] In some embodiments, the combination therapy is administered once a week for weeks 1 - 8, once every two weeks for weeks 9 - 24, and then once every four weeks, with administration of about 16 mg / kg of daratumumab, repeated administration of about 25 mg of lenalidomide per day on days 1 - 21 of a 4-week cycle, and administration of about 20 mg to about 40 mg of dexamethasone per week. It is a 4-week cycle, and on days 1 - 21 of the cycle, about 25 mg of lenalidomide is administered per day, and on days 1 - 21 of the cycle, about 20 mg to about 40 mg of dexamethasone is administered per week. It is a 4-week cycle, and on days 1 - 21 of the cycle, about 25 mg of lenalidomide is administered per day, and on days 1 - 21 of the cycle, about 20 mg to about 40 mg of dexamethasone is administered per week. It includes administration of about 20 mg to about 40 mg of dexamethasone per week.

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

[0123] Dexamethasone can be administered at about 20 mg on the day of daratumumab administration and 20 mg on the day after daratumumab administration. It can be administered.

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

[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 comprise 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 with 0.9% sodium chloride prior to administration.

[0130] ​In some embodiments, information that a combination therapy comprising daratumumab, lenalidomide, and dexamethasone is safe and effective is provided on the daratumumab-containing drug product label or package insert. This information is based on the results of the non-blind, randomized, placebo-controlled Phase 3 trial MAIA, listed as trial NCT02252172 in the ClinicalTrials.gov database.

[0131] In some embodiments, the daratumumab-containing drug product label includes information that the recommended dose of daratumumab is 16 mg / kg administered as an intravenous injection.

[0132] In some embodiments, the daratumumab-containing drug product label includes information that the recommended dosing schedule of daratumumab in combination with lenalidomide is once weekly for weeks 1-8, once every 2 weeks for weeks 9-24, and then once every 4 weeks.

[0133] In some embodiments, the daratumumab-containing drug product label includes information that the recommended dosing schedule of lenalidomide is 25 mg per day on days 1-21 of repeated 4-week cycles.

[0134] In some embodiments, the daratumumab-containing drug product label includes information that the recommended dosing schedule of dexamethasone is approximately 20 mg or approximately 40 mg per week.

[0135] In some embodiments, daratumumab, lenalidomide, and dexamethasone are administered according to the recommended dosing schedule.

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

[0137] In some embodiments, the daratumumab-containing drug product label includes data from an open-label, randomized, active-controlled phase 3 trial comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) to 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 trial NCT02252172.

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

[0140] In some embodiments, the daratumumab-containing drug product label includes data that treatment with DRd resulted in approximately 79.3% of subjects achieving VGPR or greater, approximately 24% of subjects achieving a negative status for MRD, or approximately 47.6% of subjects achieving CR or greater, 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) to treatment with bortezomib, melphalan, and prednisone (VMP) in subjects with newly diagnosed multiple myeloma. In some embodiments, the Phase 3 active-controlled trial is ALCYONE, listed in the ClinicalTrials.gov database as trial NCT02195479. 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) to treatment with lenalidomide and dexamethasone (Rd) in relapsed, refractory, or relapsed / refractory multiple myeloma. In some embodiments, the Phase 3 active-controlled trial is POLLUX, listed in the ClinicalTrials.gov database as trial NCT02076009.

[0143] 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) to treatment with bortezomib and dexamethasone (Vd) in relapsed, refractory, or relapsed / refractory multiple myeloma. In some embodiments, the Phase 3 active-controlled trial is ALCYONE, listed in the ClinicalTrials.gov database as trial NCT02195479. In some embodiments, the Phase 3 active-controlled trial is POLLUX, listed in the ClinicalTrials.gov database as trial NCT02076009.

[0144] 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) to treatment with bortezomib and dexamethasone (Vd) in relapsed, refractory, or relapsed / refractory multiple myeloma. In some embodiments, the Phase 3 active-controlled trial is ALCYONE, listed in the ClinicalTrials.gov database as trial NCT02195479. In some embodiments, the Phase 3 active-controlled trial is POLLUX, listed in the ClinicalTrials.gov database as trial NCT02076009. 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) to treatment with bortezomib and dexamethasone (Vd) in relapsed, refractory, or relapsed / refractory multiple myeloma.

[0145] In some embodiments, the Phase 3 active-controlled trial is ALCYONE, listed in the ClinicalTrials.gov database as trial NCT02195479. In some embodiments, the Phase 3 active-controlled trial is POLLUX, listed in the ClinicalTrials.gov database as trial NCT02076009. 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) to treatment with bortezomib and dexamethasone (Vd) in relapsed, refractory, or relapsed / refractory multiple myeloma.

[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) to treatment with bortezomib and dexamethasone (Vd) in relapsed, refractory, or relapsed / refractory multiple myeloma. In some embodiments, the Phase 3 active-controlled trial is ALCYONE, listed in the ClinicalTrials.gov database as trial NCT02195479. In some embodiments, the Phase 3 active-controlled trial is POLLUX, listed in the ClinicalTrials.gov database as trial NCT02076009. 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) to treatment with bortezomib and dexamethasone (Vd) in relapsed, refractory, or relapsed / refractory multiple myeloma.

[0147] In some embodiments, the Phase 3 active comparator trial is known as Trial NCT02136134 and CASTOR, as listed in the ClinicalTrials.gov database and is known as such.

[0148] In some embodiments, the daratumumab-containing drug product label reports drug interaction data indicating that the clinical pharmacokinetics 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 and includes drug interaction data. In some embodiments, the daratumumab-containing drug product label includes information that the side effects of daratumumab include fatigue, decreased appetite, bronchitis, and lung infections. In some embodiments, the daratumumab-containing drug product label includes information regarding the approved indications, dosages and administration, adverse reactions, drug interactions, use in specific populations, clinical pharmacology, non-clinical toxicology, clinical studies, and storage and handling of daratumumab, or any combination thereof. In some embodiments, daratumumab is the DARZALEX (registered trademark) brand of daratumumab.

[0149] In some embodiments, daratumumab is a biosimilar of the DARZALEX (registered trademark) brand of daratumumab. In some embodiments, daratumumab is a biosimilar of the DARZALEX (registered trademark) brand of daratumumab.

[0150] In some embodiments, daratumumab is a biosimilar of the DARZALEX (registered trademark) brand of daratumumab. In some embodiments, daratumumab is a biosimilar of the DARZALEX (registered trademark) brand of daratumumab. In some embodiments, daratumumab is a biosimilar of the DARZALEX (registered trademark) brand of daratumumab. In some embodiments, daratumumab is a biosimilar of the DARZALEX (registered trademark) brand of daratumumab.

[0151] In some embodiments, daratumumab is the DARZALEX (registered trademark) brand of daratumumab. In some embodiments, daratumumab is the DARZALEX (registered trademark) brand of daratumumab.

[0152] In some embodiments, daratumumab is the DARZALEX (registered trademark) brand of daratumumab. In some embodiments, daratumumab is a biosimilar of the DARZALEX (registered trademark) brand of daratumumab.

[0153] In some embodiments, daratumumab is the heavy chain complementarity determining region 1 (HC of SEQ ID NO: 1 DR1), HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, and light chain complementarity of SEQ ID NO: 4 Determining region 1 (LCDR1), SEQ ID NO: 5 of LCDR2, and SEQ ID NO: 6 of LCDR3 are included including.

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

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

[0156] Exemplary IgG1 constant domain sequences include the amino acid sequence of SEQ ID NO: 11. In the IgG1 constant domain, there are several mutations including mutations at positions 214, 356, 358, 422, 431, 435, or 436 (numbering of residues according to EU numbering). There are several mutations including mutations at positions 214, 356, 358, 422, 431, 435, or 436 (numbering of residues according to EU numbering) (e.g., well-known allotypes) (e.g., IMGT Web resource; IMGT repertoire (IG and TR); proteins and alleles; refer to 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 the heavy chain (HC) of SEQ ID NO: 9 and the light chain (LC) of SEQ ID NO: 1 0.

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

[0159] In some embodiments, the mammalian cell line is Chinese hamster ovary (Chinese ha mster ovary, a CHO cell line. In some embodiments, the mammalian cell line is He k cell line.

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

[0161] In some embodiments, dexamethasone can be replaced by a dexamethasone equivalent , and 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 having newly diagnosed multiple myeloma, providing daratumumab to a healthcare provider (HCP), treating the subject with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone such that an improved clinical efficacy endpoint is achieved compared to the clinical efficacy endpoint achieved when the subject is treated with a combination of lenalidomide and dexamethasone, and providing the HCP with information to that effect, and performing steps a) and b) such that a subject having newly diagnosed multiple myeloma is treated by the HCP or by self-administration as directed by the HCP with a combination therapy comprising daratumumab, lenalidomide, and dexamethasone, thereby treating the subject having newly diagnosed multiple myeloma.

[0163] The present disclosure also provides the HCP with daratumumab, lenalidomide, and dexamethasone for treating a subject having newly diagnosed multiple myeloma with a combination therapy Provided is a method of providing daratumumab, lenalidomide, and dexamethasone, and a combination therapy including the same, which achieves an improved clinical efficacy endpoint as compared with a clinical efficacy endpoint achieved when a subject is treated with a combination of lenalidomide and dexamethasone, manufacturing daratumumab, providing information to a healthcare provider (HCP) that a combination therapy including daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint, and transporting daratumumab to the HCP or an authorized distributor of daratumumab for purchase by the HCP, thereby providing daratumumab to the HCP.

[0164] Also provided is a method of providing treatment options for a subject newly diagnosed with multiple myeloma with a combination therapy including daratumumab, lenalidomide, and dexamethasone, wherein the combination therapy including daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint as compared with a clinical efficacy endpoint achieved when a subject is treated with a combination of lenalidomide and dexamethasone, manufacturing daratumumab, providing information to an HCP that a combination therapy including daratumumab, lenalidomide, and dexamethasone achieves an improved clinical efficacy endpoint, and transporting daratumumab to the HCP or an authorized distributor of daratumumab for purchase by the HCP, thereby providing treatment options for the HCP.

[0165] ​​​​​​​​​​​​Exemplary information is available from study NCT02252172 under ClinicalTrials_ gov database, known as MAIA. Clinical trial results from a controlled Phase 3 study.

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

[0167] In eligible subjects, ASCT may be combined with high-dose chemotherapy (HDC) as described herein. are provided together.

[0168] In some embodiments, a combination comprising daratumumab, lenalidomide, and dexamethasone. The combination therapy demonstrated VGPR or better in subjects with newly diagnosed multiple myeloma. It has been demonstrated that this increases the likelihood of achieving

[0169] In some embodiments, the likelihood of achieving VGPR or better is about 79% or greater. That's more than enough.

[0170] In some embodiments, a combination comprising daratumumab, lenalidomide, and dexamethasone. The combination therapy has been shown to be effective in patients with newly diagnosed multiple myeloma who have a negative MRD profile. It has been demonstrated that the use of

[0171] In some embodiments, the chance of achieving a negative status for MRD is about 24% or It's more than that.

[0172] In some embodiments, a combination comprising daratumumab, lenalidomide, and dexamethasone. The combination therapy achieved CR or better in subjects with newly diagnosed multiple myeloma. It has been demonstrated that this increases the likelihood of success.

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

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

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

[0176] In some embodiments, 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.

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

[0178] In some embodiments, the combination therapy comprises pre-administering dexamethasone as pre-medication on the day of daratumumab administration.

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

[0180] In some embodiments, the combination therapy comprises intravenous administration of daratumumab and oral administration of lenalidomide. ​​​​​​​​​​It includes oral administration and intravenous or oral administration of dexamethasone.

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

[0182] In some embodiments, each single-dose vial containing 100 mg of daratumumab in a 5 mL solution and each single-dose vial containing 400 mg of daratumumab in a 20 mL solution further contain 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 a 5 mL 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 a 20 mL 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 with 0.9% sodium chloride before administration.

[0185] In some embodiments, the combination containing daratumumab, lenalidomide, and dexamethasone ​​Information that a therapeutic regimen has achieved an improved clinically effective endpoint is provided on the daratumumab-containing drug product label.

[0186] In some embodiments, the daratumumab-containing drug product label includes 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 label includes information that the recommended dosing schedule of daratumumab in combination with lenalidomide is once weekly for weeks 1 through 8, once every 2 weeks for weeks 9 through 24, and then once every 4 weeks.

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

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

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

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

[0192] In some embodiments, a non-blind, randomized, active-controlled Phase 3 trial is the trial NCT0 enumerated in the ClinicalTrials.gov database as MAIA, known as

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

[0194] In some embodiments, the daratumumab-containing drug product label includes data that treatment with DRd resulted in approximately 79.3% of subjects achieving VGPR or greater, approximately 24% of subjects achieving a negative status for MRD, or approximately 47.6% of subjects achieving CR or greater, 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) to treatment with bortezomib, melphalan, and prednisone (VMP) in subjects with newly diagnosed multiple myeloma. ​​​​​​​​​​​

[0197] In some embodiments, the Phase 3 active comparator trial is known as Trial NCT02195479 enumerated in the ClinicalTrials.gov database, known as ALCYONE as known.

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

[0199] In some embodiments, the Phase 3 active comparator trial is known as Trial NCT02076009 enumerated in the ClinicalTrials.gov database, known as POLLUX as known.

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

[0201] In some embodiments, the Phase 3 active comparator trial is known as Trial NCT02136134 enumerated in the ClinicalTrials.gov database, known as CASTOR as known.

[0202] In some embodiments, the daratumumab-containing drug product label includes lenalidomide, pomali Clinical Pharmacokinetics of Daratumumab in Combination with Doxorubicin, Bortezomib, and Dexamethasone The evaluation reports drug interaction data indicating that there were no clinically relevant drug interactions between daratumumab and lenalidomide, pomalidomide, bortezomib, and dexamethasone.

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

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

[0205] In some embodiments, daratumumab is the DARZALEX (registered trademark) brand of daratumumab.

[0206] In some embodiments, daratumumab is a biosimilar of the DARZALEX (registered trademark) brand of daratumumab.

[0207] In some embodiments, 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.

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

[0209] ​​​​​​​​​​​ In some embodiments, daratumumab is immunoglobulin IgG1 kappa (IgG1 κ).

[0210] An exemplary IgG1 constant domain sequence includes the amino acid sequence of SEQ ID NO: 11. Within the IgG1 constant domain, there are several mutations including mutations at positions 214, 356, 358, 422, 431, 435, or 436 (numbering of residues according to EU numbering). (e.g., well-known allotypes)(e.g., IMGT web resource; IMGT repertoire le (IG and TR); proteins and alleles; see allotypes). Antibodies that bind specifically to CD38 may be any IgG1 allotype such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28.

[0211] In some embodiments, daratumumab includes the HC of SEQ ID NO: 9 and the 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 replaced by a dexamethasone equivalent , and the dexamethasone equivalent is methylprednisolone, prednisone, prednisolone, or betamethasone, or any combination thereof.

[0216] Combination Therapies and Pharmaceutical Products of the Present Disclosure The present disclosure also provides a combination therapy for treating a subject having newly diagnosed multiple myeloma, comprising daratumumab, lenalidomide, and dexamethasone, which 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. In some embodiments, the combination therapy of the present disclosure comprises about 16 mg / kg of daratumumab, about 25 mg of lenalidomide, and about 20 mg to about 40 mg of dexamethasone.

[0217] In some embodiments, the treatment of a subject having newly diagnosed multiple myeloma comprises administering to the subject about 16 mg / kg of daratumumab, about 25 mg of lenalidomide, and about 20 mg to about 40 mg of dexamethasone per week, once every week, once every two weeks, or once every four weeks.

[0218] In some embodiments, the treatment of a subject having newly diagnosed multiple myeloma comprises administering to the subject about 16 mg / kg of daratumumab, about 25 mg of lenalidomide, and about 20 mg to about 40 mg of dexamethasone per day on days 1 to 21 of each repeated four-week cycle, once weekly from weeks 1 to 8, once every two weeks from weeks 9 to 24, and then once every four weeks thereafter. In some embodiments, the combination therapy is demonstrated to increase the likelihood of achieving VGPR or greater in a subject having newly diagnosed multiple myeloma.

[0219]

[0220]

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

[0222] In some embodiments, combination therapy is demonstrated to increase the likelihood of achieving negativity for MRD in subjects with newly diagnosed multiple myeloma. or greater.

[0223] In some embodiments, the likelihood of achieving negativity for MRD is about 24% or more. or more.

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

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

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

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

[0228] In some embodiments, subjects with multiple myeloma are ineligible for autologous stem cell transplantation (ASCT). or death from multiple myeloma.

[0229] In some embodiments, combination therapy is facilitated by the manufacturer of daratumumab for the treatment of newly diagnosed multiple myeloma. The facilitation may be in the form of any product claim in print or broadcast. or broadcast. Promotional labeling, including brochures and materials mailed or provided to consumers, and other types of materials distributed by the manufacturer of a daratumumab-containing drug product, including drug product labels and prescribing information, in any form of publicly available record demonstrating that the treatment is safe and effective and has been approved by the FDA. In some embodiments, the combination therapy is promoted by the manufacturer of a daratumumab-containing drug product for the treatment of newly diagnosed multiple myeloma on the daratumumab-containing drug product label. In some embodiments, the daratumumab-containing drug product label includes data from an open-label, randomized, active-controlled phase 3 trial comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) to treatment with lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma. In some embodiments, the open-label, randomized, active-controlled phase 3 trial is known as MAIA and is listed in the ClinicalTrials.gov database as trial NCT02252172.

[0230] In some embodiments, the daratumumab-containing drug product label includes data that treatment with DRd resulted in an approximately 44% reduction in the risk of progression or death from multiple myeloma compared to treatment with Rd. In some embodiments, the daratumumab-containing drug product label includes data that treatment with DRd resulted in an approximately 44% reduction in the risk of progression or death from multiple myeloma compared to treatment with Rd.

[0231] In some embodiments, the daratumumab-containing drug product label includes data from an open-label, randomized, active-controlled phase 3 trial comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) to treatment with lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma. In some embodiments, the daratumumab-containing drug product label includes data from an open-label, randomized, active-controlled phase 3 trial comparing treatment with daratumumab, lenalidomide, and dexamethasone (DRd) to treatment with lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma. In some embodiments, the open-label, randomized, active-controlled phase 3 trial is known as MAIA and is listed in the ClinicalTrials.gov database as trial NCT02252172. In some embodiments, the daratumumab-containing drug product label includes data that treatment with DRd resulted in an approximately 44% reduction in the risk of progression or death from multiple myeloma compared to treatment with Rd.

[0232] In some embodiments, the open-label, randomized, active-controlled phase 3 trial is known as MAIA and is listed in the ClinicalTrials.gov database as trial NCT02252172. In some embodiments, the daratumumab-containing drug product label includes data that treatment with DRd resulted in an approximately 44% reduction in the risk of progression or death from multiple myeloma compared to treatment with Rd. In some embodiments, the open-label, randomized, active-controlled phase 3 trial is known as MAIA and is listed in the ClinicalTrials.gov database as trial NCT02252172.

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

[0234] In some embodiments, the daratumumab-containing drug product label includes data that treatment with DRd resulted in an approximately 44% reduction in the risk of progression or death from multiple myeloma compared to treatment with Rd. Approximately 79.3% of the subjects achieving VGPR or more, achieving a negative status for MRD, approximately 24% of the subjects achieving CR or more, or approximately 47.6% of the subjects achieving CR or more, or data resulting in 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. In some embodiments, the daratumumab-containing drug product label includes data from a

[0236] phase 3 active-controlled trial comparing treatment with daratumumab, bortezomib, melphalan, and prednisone (D-VMP) to treatment with bortezomib, melphalan, and prednisone (VMP) in subjects with newly diagnosed multiple myeloma. In some embodiments, the phase 3 active-controlled trial is the ALCYONE,

[0237] enumerated in the ClinicalTrials.gov database as trial NCT02195479. In some embodiments, the daratumumab-containing drug product label includes data from a phase 3 active-controlled trial comparing treatment with daratumumab, lenalidomide,

[0238] and dexamethasone (DRd) to treatment with lenalidomide and dexamethasone (Rd) in relapsed, refractory, or relapsed / refractory multiple myeloma. In some embodiments, the phase 3 active-controlled trial is the ALCYONE, enumerated in the ClinicalTrials.gov database as trial NCT02195479.

[0239] In some embodiments, the Phase 3 active comparator trial is known as Trial NCT02076009 and POLLUX, which is listed in the ClinicalTrials.gov database as such.

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

[0241] In some embodiments, the Phase 3 active comparator trial is known as Trial NCT02136134 and CASTOR, which is listed in the ClinicalTrials.gov database as such.

[0242] In some embodiments, the daratumumab-containing drug product label reports drug interaction data indicating that the 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 the side effects of daratumumab include fatigue, decreased appetite, bronchitis, and lung infections.

[0244] In some embodiments, the daratumumab-containing drug product label includes information that the approved uses of daratumumab ​​​​​​The indications, dosages and administrations, adverse reactions, drug interactions, use in specific populations, clinical pharmacology, non-clinical toxicology, clinical studies, as well as storage and handling, or any combination thereof are included.

[0245] In some embodiments, daratumumab is the DARZALEX (registered trademark) brand of daratumumab.

[0246] In some embodiments, daratumumab is a biosimilar of the DARZALEX (registered trademark) brand of daratumumab.

[0247] In some embodiments, 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.

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

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

[0250] Exemplary IgG1 constant domain sequences include the amino acid sequence of SEQ ID NO: 11. Within the IgG1 constant domain, there are several mutations including mutations at positions 214, 356, 358, 422, 431, 435, or 436 (numbering of residues according to EU numbering), for example, well-known allotypes (for example, see the IMGT Web resource; IMGT repertoire (IG and TR); proteins and alleles; allotypes). Specific for CD38 (for example, see the IMGT Web resource; IMGT repertoire (IG and TR); proteins and alleles; allotypes). The abnormally conjugated antibody may be any IgG1 allotype such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28.

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

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

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

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

[0255] In some embodiments, dexamethasone can be replaced by a dexamethasone equivalent, and the dexamethasone equivalent is methylprednisolone, prednisolone, prednisone, or betamethasone, or any combination thereof.

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

[0257] In some embodiments, the one or more single-dose vials are 1 in a 5 mL solution​​​​​ It contains 00 mg of daratumumab, or 400 mg of daratumumab in a 20 mL solution.

[0258] In some embodiments, one or two single-dose vials containing 100 mg of daratumumab in a 5 mL solution, and one or two or more single-dose vials containing 400 mg of daratumumab in a 20 mL solution further contain glacial acetic acid, mannitol, polysorbate 20, sodium acetate trihydrate, and sodium chloride. In some embodiments, one or two single-dose vials containing 100 mg of daratumumab in a 5 mL 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 two single-dose vials containing 400 mg of daratumumab in a 20 mL solution contain 400 mg of daratumumab, 3.7 mg of glacial

[0259] In some embodiments, the drug product label contains information that the recommended dosing schedule of dexamethasone is approximately 16 mg / kg once a week for weeks 1 - 8, once every two weeks for weeks 9 - 24, and then once every four weeks, and the recommended dosing schedule of lenalidomide is approximately 25 mg per day on days 1 - 21 of repeated 4-week cycles, and the recommended dosing schedule of dexamethasone is approximately 20 mg per week or approximately 40 mg per week. 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. mg of polysorbate 20, 14.8 mg of sodium acetate trihydrate, 17.5 mg of sodium chloride, and water for injection, and one or two single-dose vials containing 400 mg of daratumumab in a 20 mL 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. In some embodiments, the drug product label contains information that the recommended dosing schedule of dexamethasone is approximately 16 mg / kg once a week for weeks 1 - 8, once every two weeks for weeks 9 - 24, and then once every four weeks, and the recommended dosing schedule of lenalidomide is approximately 25 mg per day on days 1 - 21 of repeated 4-week cycles, and the recommended dosing schedule of dexamethasone is approximately 20 mg per week or approximately 40 mg per week. 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. 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 label contains information that the recommended dosing schedule of dexamethasone is approximately 16 mg / kg once a week for weeks 1 - 8, once every two weeks for weeks 9 - 24, and then once every four weeks, and the recommended dosing schedule of lenalidomide is approximately 25 mg per day on days 1 - 21 of repeated 4-week cycles, and the recommended dosing schedule of dexamethasone is approximately 20 mg per week or approximately 40 mg per week. In some embodiments, the drug product label contains information that the recommended dosing schedule of dexamethasone is approximately 16 mg / kg once a week for weeks 1 - 8, once every two weeks for weeks 9 - 24, and then once every four weeks, and the recommended dosing schedule of lenalidomide is approximately 25 mg per day on days 1 - 21 of repeated 4-week cycles, and the recommended dosing schedule of dexamethasone is approximately 20 mg per week or approximately 40 mg per week. In some embodiments, the drug product label contains information that the recommended dosing schedule of dexamethasone is approximately 16 mg / kg once a week for weeks 1 - 8, once every two weeks for weeks 9 - 24, and then once every four weeks, and the recommended dosing schedule of lenalidomide is approximately 25 mg per day on days 1 - 21 of repeated 4-week cycles, and the recommended dosing schedule of dexamethasone is approximately 20 mg per week or approximately 40 mg per week. In some embodiments, the drug product label contains information that the recommended dosing schedule of dexamethasone is approximately 16 mg / kg once a week for weeks 1 - 8, once every two weeks for weeks 9 - 24, and then once every four weeks, and the recommended dosing schedule of lenalidomide is approximately 25 mg per day on days 1 - 21 of repeated 4-week cycles, and the recommended dosing schedule of dexamethasone is approximately 20 mg per week or approximately 40 mg per week. In some embodiments, the drug product label contains information that the recommended dosing schedule of dexamethasone is approximately 16 mg / kg once a week for weeks 1 - 8, once every two weeks for weeks 9 - 24, and then once every four weeks, and the recommended dosing schedule of lenalidomide is approximately 25 mg per day on days 1 - 21 of repeated 4-week cycles, and the recommended dosing schedule of dexamethasone is approximately 20 mg per week or approximately 40 mg per week.

[0261] In some embodiments, the drug product label has the indication "newly diagnosed multiple myeloma." Daratumumab (DRd) in combination with lenalidomide and dexamethasone in patients An open-label study comparing treatment with lenalidomide and dexamethasone (Rd) , including data from a randomized, active-controlled phase 3 trial.

[0262] In some embodiments, the open-label, randomized, active-controlled Phase 3 study is Study NCT0 It is listed in the ClinicalTrials_gov database as 2252172. She is known as MAIA.

[0263] In some embodiments, the drug product labeling may include information regarding whether treatment with DRd is incompatible with treatment with Rd. Compared with placebo, the data showed that it reduced the risk of progression or death from multiple myeloma by approximately 44%. Includes data.

[0264] In some embodiments, the drug product labeling provides that treatment with DRd is indicative of VGPR or Approximately 79.3% of subjects achieved ≥ 100% MRD, and approximately 20% of subjects achieved MRD-negative status. 4% of subjects achieving CR or better, or approximately 47.6% of subjects achieving CR or better, or any of these The data includes data that has resulted in a combination of

[0265] In some embodiments, the drug product label includes a label for newly diagnosed, DRd-treated Subjects with multiple myeloma were randomized to receive either 100 mg or 100 mg once daily. Subjects with newly diagnosed multiple myeloma who were treated with Rd were randomized to receive either 100 mg or 100 mg once daily. Includes Kaplan-Meier curves of progression-free survival (PFS) for patients with and without RA compared with those without RA.

[0266] In some embodiments, the drug product label includes the following: daratumumab, bortezomib, melpha Treatment with lenalidomide and prednisone (VMP) includes data from a phase 3 active-controlled trial comparing it to treatment with bortezomib, melphalan, and prednisone (VMP). It includes data from a phase 3 active-controlled trial comparing it to treatment with bortezomib, melphalan, and prednisone (VMP).

[0267] In some embodiments, the phase 3 active-controlled trial is the ALCYONE trial, which is listed in the ClinicalTrials.gov database as NCT02195479 and is known as such.

[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. It 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 the POLLUX trial, which is listed in the ClinicalTrials.gov database as NCT02076009 and is known as such.

[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 bortezomib and dexamethasone (Vd) in relapsed, refractory, or relapsed / refractory multiple myeloma. It includes 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.

[0271] In some embodiments, the phase 3 active-controlled trial is the CASTOR trial, which is listed in the ClinicalTrials.gov database as NCT02136134 and is known as such. ​​​​​​​

[0272] In some embodiments, the drug product label reports that the clinical pharmacokinetic evaluation of daratumumab in combination with lenalidomide, pomalidomide, bortezomib, and dexamethasone did not show clinically relevant drug-drug interactions between daratumumab and lenalidomide, pomalidomide, bortezomib, and dexamethasone, and includes drug product interaction data. In some embodiments, the drug product label includes information that the side effects of daratumumab include fatigue, decreased appetite, bronchitis, and lung infection. In some embodiments, the drug product label includes information regarding the approved indications, dosage and administration, adverse reactions, drug interactions, use in specific populations, clinical pharmacology, non-clinical toxicology, clinical studies, and storage and handling of daratumumab, or any combination thereof. In some embodiments, daratumumab is the DARZALEX® brand of daratumumab.

[0273] In some embodiments, daratumumab is a biosimilar of the DARZALEX® brand of daratumumab.

[0274] In some embodiments, 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.

[0275]

[0276]

[0277]

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

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

[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 including mutations at positions 214, 356, 358, 422, 431, 435, or 436 (numbering of residues according to EU numbering) (e.g., well-known allotypes) (e.g., IMGT web resource; IMGT repert oire (IG and TR); proteins and alleles; see 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 HC of SEQ ID NO: 9 and LC of SEQ ID NO: 10and comprises

[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 pharmaceutical product comprising daratumumab, manufacturing daratumumab, ​​A combination therapy comprising daratumumab, lenalidomide, and dexamethasone, when administered to a subject newly diagnosed with multiple myeloma, promotes achieving improved clinical efficacy endpoints compared to the clinical efficacy endpoints achieved when the subject is administered a combination of lenalidomide and dexamethasone and includes causing an HCP to purchase the drug product by performing steps a) and b), thereby selling the drug product. The promotion may be in any published record form, including product claim advertising in 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 labels and prescribing information, demonstrating that the treatment is safe and effective and is approved by the FDA.

[0286] In some embodiments, the promotion includes on the drug product label data from an open-label, randomized, placebo-controlled Phase 3 trial comparing treatment with daratumumab in combination with lenalidomide and dexamethasone (DRd) to treatment with lenalidomide and dexamethasone (Rd) in patients newly diagnosed with multiple myeloma. In some embodiments, the drug product label further includes data that treatment with DRd resulted in a reduction of approximately 44% in the risk of progression or death from multiple myeloma compared to treatment with Rd. In some embodiments, the drug product label is for a newly diagnosed patient with multiple myeloma treated with DRd and is approved by the FDA.

[0287] In some embodiments, the promotion includes on the drug product label data from an open-label, randomized, placebo-controlled Phase 3 trial comparing treatment with daratumumab in combination with lenalidomide and dexamethasone (DRd) to treatment with lenalidomide and dexamethasone (Rd) in patients newly diagnosed with multiple myeloma. In some embodiments, the drug product label further includes data that treatment with DRd resulted in a reduction of approximately 44% in the risk of progression or death from multiple myeloma compared to treatment with Rd. In some embodiments, the drug product label is for a newly diagnosed patient with multiple myeloma treated with DRd

[0288] In some embodiments, the drug product label further includes data that treatment with DRd resulted in a reduction of approximately 44% in the risk of progression or death from multiple myeloma compared to treatment with Rd. In some embodiments, the drug product label is for a newly diagnosed patient with multiple myeloma treated with DRd and is approved by the FDA.

[0289] In some embodiments, the drug product label is for a newly diagnosed patient with multiple myeloma treated with DRd Comparing a subject with multiple myeloma to a subject newly diagnosed with multiple myeloma who has been treated with Rd, further including a Kaplan-Meier curve of progression-free survival (PFS).

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

[0291] In some embodiments, daratumumab is the DARZALEX (registered trademark) brand of daratumumab.

[0292] In some embodiments, daratumumab is a biosimilar of the DARZALEX (registered trademark) brand of daratumumab.

[0293] In some embodiments, daratumumab comprises 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.

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

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

[0296] An exemplary IgG1 constant domain sequence comprises the amino acid sequence of SEQ ID NO: 11. IgG1​​​​​​​ Within the constant domain, there are several mutations including mutations at positions 214, 356, 358, 422, 431, 435, or 436 (numbering of residues according to EU numbering). (e.g., well-known allotypes) (e.g., IMGT web resource; IMGT repertory of IG and TR; proteins and alleles; refer to 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 the heavy chain (HC) of SEQ ID NO: 9 and the light chain (LC) of SEQ ID NO: 1 0.

[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 as a first step in the purification process by removing solids by centrifugation or filtration. Antibodies can be purified by chromatography (e.g., ion exchange, affinity, size exclusion, and hydroxyapatite chromatography), gel filtration, centrifugation, or lysis exclusion, and hydroxyapatite chromatography), gel filtration, centrifugation, or lysis Standard, including any other available techniques for differential precipitation, ethanol precipitation, or antibody purification It can be further purified by a method. To reduce or eliminate antibody degradation during the purification process Phenylmethylsulfonyl fluoride (PMSF), leupeptin, pepstatin, or protease inhibitors such as aprotinin can be added at any or all stages to good effect. Those skilled in the art will appreciate that the exact purification technique will vary depending on the characteristics of the polypeptide or protein to be purified, the characteristics of the cells in which the polypeptide or protein is expressed, and the composition of the medium in which the cells were grown. The purified antibody is formulated into a pharmaceutical composition containing one or more excipients, packaged in a container such as a sealed bottle or a vessel such as a glass vial, and a label is attached to the container or included in the package. Alternatively, the purified antibody may be lyophilized and provided as a lyophilized powder in the container.

[0302] Although the invention has been described in general terms, embodiments of the invention are further disclosed in the following examples, which should not be construed as limiting the scope of the claims. Example 1: In subjects with multiple myeloma who are ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) and have not previously received treatment, a phase 3 trial comparing DARZALEX (registered trademark) (daratumumab), lenalidomide, and dexamethasone (DRd) with lenalidomide and dexamethasone (Rd) Objective and Hypothesis

[0303] Although the invention has been described in general terms, embodiments of the invention are further disclosed in the following examples, which should not be construed as limiting the scope of the claims. Objective and Hypothesis

[0304] Objective and Hypothesis Primary Objective The primary objective was to compare DARZALEX (registered trademark) (daratumumab), lenalidomide, and dexamethasone (DRd) with lenalidomide and dexamethasone (Rd) in subjects with multiple myeloma who are ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) and have not previously received treatment Primary Objective The primary objective The primary objective was to compare DARZALEX In subjects with newly diagnosed multiple myeloma, from the perspective of progression-free survival (PFS), to compare the efficacy of daratumumab (DARZALEX®) (DRd) in combination with lenalidomide and dexamethasone with the efficacy of lenalidomide and dexamethasone (Rd).

[0305] Secondary objectives The secondary objectives are as follows: · To evaluate clinical outcomes including the following: - Time to progression (TTP) - CR rate - MRD negativity rate - PFS2 (defined as the time from randomization to progression or death (whichever occurs first) during subsequent treatment) - Overall survival - Time to subsequent treatment - Rate of stringent CR (sCR) - Overall response rate (partial response [PR] or greater) - Proportion of subjects achieving very good partial response (VGPR) or greater - 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®) · To evaluate the treatment effect and healthcare economic / resource utilization on patient-reported outcomes · To evaluate the clinical efficacy of daratumumab (DARZALEX®) in combination with Rd in high-risk molecular subgroups

[0306] Investigational objectives​​​​​​​ ·Investigating biomarkers for predicting response or resistance to therapy ·Evaluating the persistence of MRD negativity

[0307] Overview of the trial design This is a randomized, open-label, placebo-controlled, parallel-group, multi-center trial in subjects ≥18 years of age with newly diagnosed multiple myeloma who are not candidates for HDC and ASCT Approximately 730 subjects are registered for this trial, with 365 subjects planned per treatment group Subject participation includes screening, treatment, and follow-up phases. The screening phase is up to 21 days prior to Day 1 of Cycle 1. The treatment phase continues from Day 1 of Cycle 1 until all study treatment is discontinued. For subjects assigned to DRd, daratumumab (DARZALEX®) is administered weekly for the first 8 weeks (Cycles 1–2), then every 2 weeks for 16 weeks (Cycles 3–6), then every 4 weeks (Cycles 7 and above) until disease progression or unacceptable toxicity. This amounts to 9 consecutive weeks of dosing at the start of the trial and a total of 23 doses in the first year. Lenalidomide is administered orally (PO) at a dose of 25 mg on Days 1–21 of each 28-day cycle, and dexamethasone is administered at a dose of 40 mg once weekly. Subjects in both treatment groups continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomized .

[0308] Subject participation includes screening, treatment, and follow-up phases. The screening phase is up to 21 days prior to Day 1 of Cycle 1. The treatment phase continues from Day 1 of Cycle 1 until all study treatment is discontinued. For subjects assigned to DRd, daratumumab (DARZALEX®) is administered weekly for the first 8 weeks (Cycles 1–2), then every 2 weeks for 16 weeks (Cycles 3–6), then every 4 weeks (Cycles 7 and above) until disease progression or unacceptable toxicity. This amounts to 9 consecutive weeks of dosing at the start of the trial and a total of 23 doses in the first year. Lenalidomide is administered orally (PO) at a dose of 25 mg on Days 1–21 of each 28-day cycle, and dexamethasone is administered at a dose of 40 mg once weekly. Subjects in both treatment groups continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomized The screening phase is up to 21 days prior to Day 1 of Cycle 1. The treatment phase continues from Day 1 of Cycle 1 until all study treatment is discontinued. For subjects assigned to DRd, daratumumab (DARZALEX®) is administered weekly for the first 8 weeks (Cycles 1–2), then every 2 weeks for 16 weeks (Cycles 3–6), then every 4 weeks (Cycles 7 and above) until disease progression or unacceptable toxicity. This amounts to 9 consecutive weeks of dosing at the start of the trial and a total of 23 doses in the first year. Lenalidomide is administered orally (PO) at a dose of 25 mg on Days 1–21 of each 28-day cycle, and dexamethasone is administered at a dose of 40 mg once weekly. Subjects in both treatment groups continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomized The treatment phase continues from Day 1 of Cycle 1 until all study treatment is discontinued. For subjects assigned to DRd, daratumumab (DARZALEX®) is administered weekly for the first 8 weeks (Cycles 1–2), then every 2 weeks for 16 weeks (Cycles 3–6), then every 4 weeks (Cycles 7 and above) until disease progression or unacceptable toxicity. This amounts to 9 consecutive weeks of dosing at the start of the trial and a total of 23 doses in the first year. Lenalidomide is administered orally (PO) at a dose of 25 mg on Days 1–21 of each 28-day cycle, and dexamethasone is administered at a dose of 40 mg once weekly. Subjects in both treatment groups continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomized For subjects assigned to DRd, daratumumab (DARZALEX®) is administered weekly for the first 8 weeks (Cycles 1–2), then every 2 weeks for 16 weeks (Cycles 3–6), then every 4 weeks (Cycles 7 and above) until disease progression or unacceptable toxicity. This amounts to 9 consecutive weeks of dosing at the start of the trial and a total of 23 doses in the first year. Lenalidomide is administered orally (PO) at a dose of 25 mg on Days 1–21 of each 28-day cycle, and dexamethasone is administered at a dose of 40 mg once weekly. Subjects in both treatment groups continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomized For subjects assigned to DRd, daratumumab (DARZALEX®) is administered weekly for the first 8 weeks (Cycles 1–2), then every 2 weeks for 16 weeks (Cycles 3–6), then every 4 weeks (Cycles 7 and above) until disease progression or unacceptable toxicity. This amounts to 9 consecutive weeks of dosing at the start of the trial and a total of 23 doses in the first year. Lenalidomide is administered orally (PO) at a dose of 25 mg on Days 1–21 of each 28-day cycle, and dexamethasone is administered at a dose of 40 mg once weekly. Subjects in both treatment groups continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomized For subjects assigned to DRd, daratumumab (DARZALEX®) is administered weekly for the first 8 weeks (Cycles 1–2), then every 2 weeks for 16 weeks (Cycles 3–6), then every 4 weeks (Cycles 7 and above) until disease progression or unacceptable toxicity. This amounts to 9 consecutive weeks of dosing at the start of the trial and a total of 23 doses in the first year. Lenalidomide is administered orally (PO) at a dose of 25 mg on Days 1–21 of each 28-day cycle, and dexamethasone is administered at a dose of 40 mg once weekly. Subjects in both treatment groups continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomized For subjects assigned to DRd, daratumumab (DARZALEX®) is administered weekly for the first 8 weeks (Cycles 1–2), then every 2 weeks for 16 weeks (Cycles 3–6), then every 4 weeks (Cycles 7 and above) until disease progression or unacceptable toxicity. This amounts to 9 consecutive weeks of dosing at the start of the trial and a total of 23 doses in the first year. Lenalidomide is administered orally (PO) at a dose of 25 mg on Days 1–21 of each 28-day cycle, and dexamethasone is administered at a dose of 40 mg once weekly. Subjects in both treatment groups continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomized This amounts to 9 consecutive weeks of dosing at the start of the trial and a total of 23 doses in the first year. Lenalidomide is administered orally (PO) at a dose of 25 mg on Days 1–21 of each 28-day cycle, and dexamethasone is administered at a dose of 40 mg once weekly. Subjects in both treatment groups continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomized This amounts to 9 consecutive weeks of dosing at the start of the trial and a total of 23 doses in the first year. Lenalidomide is administered orally (PO) at a dose of 25 mg on Days 1–21 of each 28-day cycle, and dexamethasone is administered at a dose of 40 mg once weekly. Subjects in both treatment groups continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomized This amounts to 9 consecutive weeks of dosing at the start of the trial and a total of 23 doses in the first year. Lenalidomide is administered orally (PO) at a dose of 25 mg on Days 1–21 of each 28-day cycle, and dexamethasone is administered at a dose of 40 mg once weekly. Subjects in both treatment groups continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomized This amounts to 9 consecutive weeks of dosing at the start of the trial and a total of 23 doses in the first year. Lenalidomide is administered orally (PO) at a dose of 25 mg on Days 1–21 of each 28-day cycle, and dexamethasone is administered at a dose of 40 mg once weekly. Subjects in both treatment groups continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomized This amounts to 9 consecutive weeks of dosing at the start of the trial and a total of 23 doses in the first year. Lenalidomide is administered orally (PO) at a dose of 25 mg on Days 1–21 of each 28-day cycle, and dexamethasone is administered at a dose of 40 mg once weekly. Subjects in both treatment groups continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. Subjects in the DRd group continue daratumumab (DARZALEX®) until disease progression or unacceptable toxicity. Randomized ​​​​​​​​​​​​​Stratify by International Classification of Disease (I vs II vs III), region (North America vs Others), and age (less than 75 years vs 75 years and above) using an equal allocation ratio of 1:1.

[0309] Means to prevent reactions related to injection include pre-injection medications with dexamethasone, acetaminophen (paracetamol), and anti-histamines before each daratumumab (DARZALEX® (registered trademark)) injection.

[0310] The follow-up phase starts when the subject discontinues all test treatments. Subjects who discontinue for reasons other than disease progression need to continue to receive disease evaluations according to the time and event schedule. The follow-up phase continues until death, loss to follow-up, withdrawal of consent, or end of the trial (whichever occurs first). After the clinical cut-off, data collection is reduced.

[0311] Independent Data Monitoring Committee (I DMC) is commissioned for this trial to review the results of efficacy and safety at the planned interim analysis. After the interim review, the IDMC gives recommendations regarding the continuation of the trial.

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

[0313] Subject population Important eligibility criteria include: being ≥ 18 years old, having symptomatic multiple myeloma and a defined diagnosis of measurable secretory disease, and having an ECOG performance status score of 0, 1, or 2. Subjects must be newly diagnosed and should not be considered candidates for high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT).

[0314] Dose and administration Daratumumab (DARZALEX®) (16 mg / kg) is administered by IV infusion to Group B subjects once weekly for the first 8 weeks, then once every 2 weeks for 16 weeks, and thereafter once every 4 weeks until confirmed progression, unacceptable toxicity, or end of the study.

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

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

[0317] Efficacy assessment / endpoints Disease assessment is 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 assessment must be carried out according to the schedule regardless of any changes to the dosing regimen.

[0318] ​The primary endpoint is PFS, which is defined as the period from the date of randomization to either progressive disease or death (whichever occurs first). Disease progression is determined according to the IMWG criteria. The secondary efficacy endpoints include the following. · The time to progression (TTP) is defined as the time from the date of randomization to the date when signs of PD are first confirmed, as defined by the IMWG criteria. For subjects who are not progressing, data are

[0319] truncated at the disease assessment date prior to the initiation of any subsequent anti-myeloma therapy. · The CR rate, defined as the proportion of subjects who achieve CR, as defined below: - Negative immunofixation of serum and urine, and - Disappearance of soft tissue plasmacytomas, and - Less than 5% plasma cells (PC) in the bone marrow - Quantitative negative serum M-protein by electrophoresis (SPEP), and for subjects with suspected daratumumab (DARZALEX®) interference with immunofixation, a reflex assay using an anti-idiotype antibody is utilized to confirm daratumumab (DARZALEX®) interference and exclude false-positive immunofixation. Subjects who have confirmed daratumumab (DARZALEX®) interference but meet all other clinical criteria for CR or sCR are considered CR / sCR. · The MRD negativity rate, defined as the proportion of subjects who are evaluated as MRD negative at any time point after randomization. · Progression-free survival during the next treatment (PFS2), defined as the time from randomization to progression or death (whichever occurs first) during the next treatment. Disease progression is based on the judgment of the study physician in charge. For those subjects who are still alive and have not progressed during the next treatment, follow-up is terminated on the last day of follow-up. · Overall survival (OS) measured from the randomization date to the date of death of the subject. If the subject is alive or the vital status is unknown, the subject's data is truncated at the date when the subject's survival was last confirmed. · Time to the start of the next treatment, defined as the time from randomization to the start of the next treatment. · Achieving a normal free light chain (FLC) ratio and the absence of clonal cells in the bone marrow by immunohistochemistry, immunofluorescence, 2 - 4 color flow cytometry, in addition to achieving CR, defined as the proportion of subjects achieving sCR. · Overall response rate (ORR), defined as the proportion of subjects achieving PR or better according to the IMWG criteria during or after the study treatment. · Proportion of subjects achieving VGPR and CR (including sCR) according to the IMWG criteria during or after the study treatment at the data cutoff, defined as the proportion of subjects achieving VGPR or better. · Time to response, defined as the time between randomization and the first efficacy assessment where the subject meets all criteria for PR or better. For non - responding subjects, the data is truncated at either the date of progressive disease or the absence of progressive disease in the last disease assessment before the start of subsequent anti - myeloma therapy. · Duration of response, calculated from the date when response (PR or better) was first confirmed to the date when signs of progressive disease were first confirmed as defined by the IMWG criteria. For non - progressing subjects, the data is truncated at the last disease assessment before the start of any subsequent anti - myeloma therapy. ·To evaluate the clinical efficacy of DRd in the high-risk molecular subgroup compared with Rd alone. To evaluate the clinical efficacy of DRd in the high-risk molecular subgroup compared with Rd alone. ·To evaluate the impact of DRd compared with Rd on the overall health perception reported by patients. To evaluate the impact of DRd compared with Rd on the overall health perception reported by patients.

[0320] Pharmacokinetics and immunogenicity evaluation For all subjects in Group B, obtain pharmacokinetic samples to determine the serum concentration of daratumumab (DARZALEX®). Collect venous blood samples (5 mL per sample) and determine the serum concentration of daratumumab (DARZALEX®). Divide the serum into three aliquots (one aliquot for pharmacokinetic analysis, one aliquot for daratumumab (DARZALEX®) analysis if appropriate, and one aliquot for reserve). For all subjects in Group B, obtain pharmacokinetic samples to determine the serum concentration of daratumumab (DARZALEX®). Collect venous blood samples (5 mL per sample) and determine the serum concentration of daratumumab (DARZALEX®). Divide the serum into three aliquots (one aliquot for pharmacokinetic analysis, one aliquot for daratumumab (DARZALEX®) analysis if appropriate, and one aliquot for reserve). For all subjects in Group B, obtain pharmacokinetic samples to determine the serum concentration of daratumumab (DARZALEX®). Collect venous blood samples (5 mL per sample) and determine the serum concentration of daratumumab (DARZALEX®). Divide the serum into three aliquots (one aliquot for pharmacokinetic analysis, one aliquot for daratumumab (DARZALEX®) analysis if appropriate, and one aliquot for reserve). For all subjects in Group B, obtain pharmacokinetic samples to determine the serum concentration of daratumumab (DARZALEX®). Collect venous blood samples (5 mL per sample) and determine the serum concentration of daratumumab (DARZALEX®). Divide the serum into three aliquots (one aliquot for pharmacokinetic analysis, one aliquot for daratumumab (DARZALEX®) analysis if appropriate, and one aliquot for reserve). For all subjects in Group B, obtain pharmacokinetic samples to determine the serum concentration of daratumumab (DARZALEX®). Collect venous blood samples (5 mL per sample) and determine the serum concentration of daratumumab (DARZALEX®). Divide the serum into three aliquots (one aliquot for pharmacokinetic analysis, one aliquot for daratumumab (DARZALEX®) analysis if appropriate, and one aliquot for reserve). For all subjects in Group B, obtain pharmacokinetic samples to determine the serum concentration of daratumumab (DARZALEX®). Collect venous blood samples (5 mL per sample) and determine the serum concentration of daratumumab (DARZALEX®). Divide the serum into three aliquots (one aliquot for pharmacokinetic analysis, one aliquot for daratumumab (DARZALEX®) analysis if appropriate, and one aliquot for reserve).

[0321] Biomarker evaluation Collect bone marrow aspirates at screening and after treatment. Classify subjects into the high-risk molecular subgroup and subject the baseline bone marrow aspirate samples to DNA and RNA sequencing to establish the myeloma clone for MRD monitoring. In addition to the planned bone marrow aspirate evaluation, collect whole blood samples from subjects for processing into plasma and PBMC. Collect bone marrow aspirates at screening and after treatment. Classify subjects into the high-risk molecular subgroup and subject the baseline bone marrow aspirate samples to DNA and RNA sequencing to establish the myeloma clone for MRD monitoring. In addition to the planned bone marrow aspirate evaluation, collect whole blood samples from subjects for processing into plasma and PBMC. Collect bone marrow aspirates at screening and after treatment. Classify subjects into the high-risk molecular subgroup and subject the baseline bone marrow aspirate samples to DNA and RNA sequencing to establish the myeloma clone for MRD monitoring. In addition to the planned bone marrow aspirate evaluation, collect whole blood samples from subjects for processing into plasma and PBMC. Collect bone marrow aspirates at screening and after treatment. Classify subjects into the high-risk molecular subgroup and subject the baseline bone marrow aspirate samples to DNA and RNA sequencing to establish the myeloma clone for MRD monitoring. In addition to the planned bone marrow aspirate evaluation, collect whole blood samples from subjects for processing into plasma and PBMC.

[0322] Safety evaluation Measure safety by evaluating adverse events, laboratory test results, ECG, vital sign measurements, physical examination findings, and ECOG performance status score. Measure safety by evaluating adverse events, laboratory test results, ECG, vital sign measurements, physical examination findings, and ECOG performance status score.

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

[0324] The long-term survival follow-up continues until 330 deaths are observed or until 7 years after randomization of the last subject. Therefore, this trial uses a log-rank test (two-sided alpha = 0.05) to achieve approximately 80% power to detect a 27% reduction in the risk of death (hazard ratio = 0.73) . . .

[0325] The response to the trial treatment and progressive disease are evaluated by a computer algorithm . For the primary endpoint of PFS, the primary analysis consists of a stratified log-rank test for comparison of the PFS distributions between the two treatment groups. The Kaplan-Meier method is used to estimate the overall PFS distribution for each treatment . . The treatment effect (hazard ratio) and its two-sided 95% confidence interval are estimated using a stratified Cox regression model with treatment as the only explanatory variable .

[0326] Rationale for DNA and Biomarker Sampling Collect biomarker samples and use DNA sequencing of immunoglobulin genes In addition, the clinical outcome for daratumumab (DARZALEX®) was evaluated based on MRD. To assess the depth of clinical response and determine response rates in specific molecular subgroups of multiple myeloma. Using DNA / RNA sequencing of multiple myeloma cells to identify high-risk genomics , deletion 17p, t(4;14), t(14;20), t(14;16), deletion 13, GE P signature, e.g., UAMS-70, and p53, BRAF, FGFR, IGH, P It allows for the assessment of mutations in I3K or other molecular subtypes associated with disease progression. Other biomarker targets include assessment of potential mechanisms of resistance, interindividual differences in clinical outcomes, and These include the identification of population subgroups that respond differently to treatment, or that are phenotypic.

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

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

[0329] 2.2.1 Subjects meet the CRAB (calcium elevation, renal dysfunction, anemia, and bone abnormalities) criteria. Confirmed multiple myeloma meeting the criteria above, ≥10% monoclonal bone marrow plasma cells, or biopsy There must be plasmacytoma present at diagnosis and measurable disease. Measurable disease as assessed by a central laboratory, as defined by any of the following: Disease: - IgG myeloma: serum monoclonal abnormality (M-protein) level ≥ 1.0 g / dL or a urinary M-protein level of 200 mg / 24 hours or more; -IgA, IgM, IgD, or IgE multiple myeloma: blood serum level ≥ 0.5 g / dL Serum M-protein level or urinary M-protein level of 200 mg / 24 hours or more, or -Light chain multiple myeloma without measurable disease in serum or urine: ≥ 10 mg / dL serum immunoglobulin free light chains and abnormal serum immunoglobulin kappa lambda free light chain ratios .

[0330] 3. Newly diagnosed and considered a candidate for high-dose chemotherapy with SCT for the following reasons: Not available: Are 65 years of age or older, or In subjects <65 years of age, the presence of significant comorbid condition(s) may be associated with a higher risk of developing comorbid disease than would be expected with stem cell transplantation. likely to adversely affect the tolerability of high-dose chemotherapy. Subject to review and approval of the intended guarantor.

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

[0332] 5. Subjects will have pre-treatment clinical laboratory values ​​that meet the following criteria during the screening phase: You need to: a) Hemoglobin ≥ 7.5g / dL (≥ 5mM / L, conventional red blood cell count ll, RBC] transfusion or use of recombinant human erythropoietin is permitted), b) 1.0 x 10 9 Absolute neutrophil count of ≥ 1 / L (granulocyte colony-stimulating factor [GCL] colony stimulating factor (GCSF) is permitted) c) For subjects in which less than 50% of bone marrow nucleated cells are plasma cells, ≥ 70 × 10 9 / L Platelet count, otherwise 50 × 10 9 / L ultra platelet count (transfusion is not permitted to achieve this minimum platelet count), ( d) Aspartate aminotransferase (AST) below 2.5 times the upper limit of normal (ULN), e) Alanine aminotransferase (ALT) below 2.5 times the ULN, f) Total bilirubin below 2.0 times the ULN, excluding subjects with congenital bilirubinemia such as Gilbert's syndrome (direct bilirubin below 2.0 times the ULN), g1) Creatinine clearance of 30 mL / min or more (for dose adjustment of lenalidomide in subjects with creatinine clearance of 30 - 50 mL / min). Creatinine clearance can be calculated using the Cockcroft - Gault formula or, for subjects with overweight or underweight, 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. The use of contraceptives by men or women should comply with local regulations regarding the use of contraceptive methods for subjects participating in clinical trials. Women who may be pregnant must either consistently refrain from heterosexual intercourse or agree to use two reliable methods of birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device (IUD), hormones (progesterone - only birth control pill or injection)​​​ or vasectomy of the partner, and one additional effective method of contraception (male latex or synthetic condom, pessary, or cervical cap) is included. Contraception should be initiated 4 weeks prior to dosing and continued for 3 months after the last dose of daratumumab (DARZALEX®). Reliable contraception is indicated even in the presence of a history of infertility, unless due to hysterectomy or bilateral oophorectomy.

[0334] 7. Males who are sexually active with females of childbearing potential must agree to use latex or synthetic condoms even if vasectomy has been successful. All males must also provide sperm during the study, for 4 weeks after the last dose of lenalidomide and for 3 months after the last dose of daratumumab (DARZALEX®).

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

[0336] 9. Each subject (or the subject's legal representative) must sign an informed consent form (ICF) indicating that they understand the purpose of the study and the procedures required and are willing to participate. The subject 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 is excluded from participation in this trial and

[0338] 1. The subject has 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; lytic bone lesions, anemia , hypercalcemia, and renal dysfunction associated with the M-protein; and (if determined) a plasma cell percentage of 10% or less in the bone marrow (Kyle et al., Mayo Clin Proc 78:21-33, 2003). Smoldering multiple myeloma is defined as asymptomatic multiple myeloma without organ or tissue dysfunction, end-organ damage (Kyle et al., Mayo Clin Proc 78:21-33, 2003, Kyle et al., N Engl J Med 356:2582-2590, 2007) (Kyle et al., Mayo Clin Proc 78:21-33, 2003, Kyle et al., N Engl J Med 356:2582-2590, 2007) Clin Proc 78:21-33, 2003, Kyle et al., N Engl J Med 356:2582-2590, 2007)

[0339] 2. The subject has Waldenström disease or another condition with an IgM M-protein in the absence of clonal plasma cell infiltration with lytic bone lesions .

[0340] 3. The subject has had previous or current systemic therapy or SCT for multiple myeloma, except for emergency use of corticosteroids in the short term (equivalent to 4 days of dexamethasone 40 mg / day) before treatment .

[0341] 4. The subject has a history of malignancy (other than multiple myeloma) within 5 years before randomization (cutaneous squamous cell carcinoma and basal cell carcinoma, and cervical intraepithelial carcinoma, or as determined by the principal investigator of the trial ​​​​In the opinion, in line with the medical monitor of the clinical trial sponsor, the minimum recurrence risk within 5 years Malignant tumors considered cured by

[0342] 5. The subject has received radiotherapy within 14 days from randomization.

[0343] 6. The subject has received plasma exchange within 28 days from randomization.

[0344] 7. The subject shows clinical signs of leptomeningeal involvement in multiple myeloma.

[0345] 8.8.1a) The subject has known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second , FEV1) less than 50% of the predicted normal value. The FEV1 test is necessary for patients suspected of having COPD, and it should be noted that if the FEV1 is less than 50% of the predicted normal value, the subject must be excluded. 8.1b) The subject has had known moderate or severe persistent asthma within the past 2 years or currently has asthma with poor control of any classification. (Note that subjects with currently controlled intermittent asthma or controlled mild persistent asthma are acceptable in the study.)

[0346] 9. The subject has human immunodeficiency virus (HIV) or hepatitis B (hepatitis B surface antigen [HBsAg], or tests for antibodies to hepatitis B surface antigen and core antigen [anti-HBs and anti-HBc, respectively]​​​ defined by positivity for), or hepatitis C (seroreactive against anti-HCV antibody positive, or HCV-RN A quantitative positivity) is known.

[0347] 10. The subject has any concurrent medical or psychiatric condition or disease (e.g., active systemic infection, uncontrolled diabetes, acute diffuse infiltrative lung disease) that may interfere with the conduct or outcome of the trial or pose a risk to participation in this trial in the opinion of the investigator-in-charge. or psychiatric condition or disease (e.g., active systemic infection, uncontrolled diabetes, acute diffuse infiltrative lung disease).

[0348] 11. The subject has clinically significant heart disease, including: · Myocardial infarction within 1 year prior to randomization, or unstable, or uncontrolled disease / condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association class III-IV) · Uncontrolled arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4, grade 3 or higher), or clinically significant ECG abnormality · Screening 12-lead ECG showing a baseline Q T interval corrected by Fridericia's formula (QTcF) greater than 470 milliseconds

[0349] 12. The subject has known allergy, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies, or human proteins, or their excipients (see respective prescribing information or investigational drug brochure), or known sensitivity to mammalian-derived products. are known allergies, hypersensitivities, or intolerances to corticosteroids, monoclonal antibodies, or human proteins, or their excipients (see respective prescribing information or investigational drug brochure), or known sensitivities to mammalian-derived products. allergy, hypersensitivity, or intolerance, or known sensitivity to mammalian-derived products. ​has a property.

[0350] 13. The subject has plasma cell leukemia (according to the World Health Organization n [WHO] criteria: with a plasma cell absolute count of more than 2 × 10 9 / L and more than 20% of the cells in the peripheral blood), or has the POEMS (polyneuropathy, organomeg aly, endocrinopathy, monoclonal protein, an d skin changes) syndrome (polyneuritis, organomegaly, endocrine disorder, monoclonal onal protein, and skin changes). has a property.

[0351] 14. It is known or suspected that the subject cannot comply with the test protocol (for example, due to alcohol dependence, drug dependence, or mental disorder). The subject, in the opinion of the principal investigator of the clinical trial, participation is not in the best interest of the subject (for example, endangering well-being), or has some condition that may interfere with, limit, or confound the evaluations specified in the protocol. The subject is taking any prohibited drug. has a property. has a property. has a property.

[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 (registered trademark)) while registered in this trial. Alternatively, the subject is a man who is planning to become the father of a child within 4 weeks after the last dose of lenalidomide or within 3 months after the last dose of daratumumab (DARZALEX (registered trademark)) while registered in this trial. has a property. has a property. has a property. has a property.

[0353] 16. The subject has undergone major surgery within two weeks before randomization, or has not fully recovered from the surgery, or there is a planned surgery during the period when the subject is expected to participate in this trial. Vertebroplasty or kyphoplasty is not considered major surgery.

[0354] 17. The subject is receiving investigational drugs (including investigational vaccines), or has used invasive investigational medical devices within four weeks before randomization, or is currently enrolled in an interventional trial.

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

[0356] 19. Occurrence of gastrointestinal diseases that may significantly change the absorption of oral drugs.

[0357] Prevention of infusion reactions Premedication for subjects receiving daratumumab (DARZALEX®) is administered as follows. On the day of daratumumab (DARZALEX®) infusion, the subject receives the following drugs before infusion: · Within approximately 1 hour before daratumumab (DARZALEX®) infusion, acetaminophen 650 - 1000 mg IV or orally (PO) · Within approximately 1 hour before infusion after cycle 6, an antihistamine (diphenhydramine 25 - 50 mg IV or PO, or equivalent, but avoid IV use of promethazine). If the subject has not had a reaction related to the infusion and is intolerant to the antihistamine, modifications are permitted at the discretion of the responsible investigator. · Within approximately 1 hour before daratumumab (DARZALEX®) infusion, dexamethasone ​​​​​​​Tazone 40 mg IV (preferred) or PO. For subjects over 75 years old or with low body weight (body mass index, BMI < 18.5), dexamethasone 20 mg may be administered as appropriate. Equivalent intermediate-acting or long-acting corticosteroids may be substituted. On the day the subject receives this dose of dexamethasone at the clinic, dexamethasone is not self-administered at home. If the weekly Tazone dose is reduced to less than 10 mg due to adverse events during the trial, a minimum of 10 mg IV of dexamethasone should be continued before daratumumab (DARZALEX®) injection. If necessary, all pre-injection medications may be administered outside the clinic on the day of injection, provided they are administered within 3 hours before injection. For subjects at higher risk of respiratory complications (i.e., subjects with mild asthma or subjects with COPD with FEV1 < 80%), the following post-injection medications should be considered: · Antihistamine (diphenhydramine or equivalent) · Short-acting β2-adrenergic receptor agonist, e.g., salbutamol aerosol · Control medications for lung diseases (e.g., inhaled corticosteroids for subjects with asthma ± long-acting β2-adrenergic receptor agonist, long-acting bronchodilators for subjects with COPD, e.g., tiotropium or salmeterol ± inhaled corticosteroids) Reduction of lenalidomide dose

[0358]

[0359] Pre-injection medications

[0360] ​​​​​​​​​​​​Lenalidomide dosage adjustments should follow the approved labeling as follows. · Starting dose: 25 mg · Dose level 1: 15 mg · Dose level 2: 10 mg · Dose level 3: 5 mg

[0361] Dosage adjustments should be based on the highest grade of toxicity attributable to lenalidomide. After initiation of lenalidomide, subsequent lenalidomide dosage adjustments are based on the treatment tolerance of the individual subject. If the treating physician determines that an adverse event may be related to lenalidomide, dosage adjustments can be made even if not specified in this protocol.

[0362] Response category Disease evaluations are to 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 evaluations must be performed according to schedule regardless of any changes to the dosing regimen.

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

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

[0365] Example 2: In subjects with previously untreated multiple myeloma who are ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), daratumumab (D ARZALEX®), lenalidomide, and dexamethasone (DRd) were compared to len alidomide and dexamethasone (Rd) in a phase 3 trial - interim analysis at the median of 28 months of follow-up 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 in combination with daratumumab (DARZA LEX®) (daratumumab (DARZALEX®) group), and treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival. The test protocol is described in Example 1.

[0366] After a median follow-up of 28 months, the median progression-free survival was not achieved in the daratumumab (DARZALEX®) group compared to 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 significantly higher in daratumumab (DARZALEX®) and daratumumab (DARZALEX®), respectively. The mortality rates in the control and target groups were 47.6% vs. 24.9%, respectively (P<0.0001). 7.3% of patients in the control group compared with 7.3% in the daratumumab (DARZALEX®) group In the study, 24.2% of patients were negative for minimal residual disease (10 5 1 tumor per 10 white blood cells Tumor cell threshold (P<0.0001). Daratumumab (DARZALEX®) The most common (>10%) grade 3 / 4 adverse event in the control arm was 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. compared with 4.9%).

[0367] Daratumumab (DARZALEX®) plus lenalidomide and dexamethasone Zon is being evaluated in patients with newly diagnosed myeloma who are not eligible for autologous stem cell transplantation. , significantly reduced the risk of disease progression or death compared with lenalidomide and dexamethasone alone Higher rates of neutropenia and pneumonitis were seen with daratumumab (DARZALEX). (registered trademark) group.

[0368] In this randomized, open-label, active-controlled, multicenter, Phase 3 study, patients were randomized to In 2015, the company was awarded the 2016 Gold Medal for Excellence in Business, with facilities in 14 countries across Europe, the Middle East and the Asia-Pacific region. Patients were enrolled between March 2013 and January 2017. The Committee approved the Protocol. Harmonisati International Conference The trial was conducted in accordance with the principles of the Guidelines on Good Clinical Practice. All patients provided written informed consent. Janssen Research & Development, LLC served as the sponsor of this trial and compiled / maintained the data. All patients provided written informed consent. Janssen Research & Development, LLC served as the sponsor of this trial and compiled / maintained the data. The trial was conducted in accordance with the principles of the Guidelines on Good Clinical Practice. All patients provided written informed consent. Janssen Research & Development, LLC served as the sponsor of this trial and compiled / maintained the data. The trial was conducted in accordance with the principles of the Guidelines on Good Clinical Practice. All patients provided written informed consent. Janssen Research & Development, LLC served as the sponsor of this trial and compiled / maintained the data.

[0369] Patients Eligible patients had newly diagnosed multiple myeloma (Rajkumar et al., Lancet Oncol 15: e538 - e548, 2014) and an Eastern Cooperative Oncology Group performance status of 2 or less, and were ineligible for high - dose chemotherapy with stem - cell transplantation due to age (65 years or older) or comorbidities. Patients had a hemoglobin of 7.5 g / dL or more, an absolute neutrophil count of 1.0×10 / L or more, a platelet count of 70×10 / L or more (more than 50×10 / L if less than 50% of the bone marrow nucleated cells were plasma cells), 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 of 30 mL / min or more, and corrected serum calcium of 14 mg / dL or less. Eligible patients had newly diagnosed multiple myeloma (Rajkumar et al., Lancet Oncol 15: e538 - e548, 2014) and an Eastern Cooperative Oncology Group performance status of 2 or less, and were ineligible for high - dose chemotherapy with stem - cell transplantation due to age (65 years or older) or comorbidities. Patients had a hemoglobin of 7.5 g / dL or more, an absolute neutrophil count of 1.0×10 9 / L or more, a platelet count of 70×10 / L or more, a platelet count of 70×10 9 / L or more (more than 50×10 / L if less than 50% of the bone marrow nucleated cells were plasma cells), 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 of 30 mL / min or more, and corrected serum calcium of 14 mg / dL or less. 9 / L or more (more than 50×10 / L if less than 50% of the bone marrow nucleated cells were plasma cells), 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 of 30 mL / min or more, and corrected serum calcium of 14 mg / dL or less. / L or more (more than 50×10 / L if less than 50% of the bone marrow nucleated cells were plasma cells), 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 of 30 mL / min or more, and corrected serum calcium of 14 mg / dL or less.

[0370] Study Treatment An interactive web - response system (1:1 ratio) was used to administer daratumumab (DARZALEX®) in combination with lenalidomide and dexamethasone (DARZ An interactive web - response system (1:1 ratio) was used to administer daratumumab (DARZALEX®) in combination with lenalidomide and dexamethasone (DARZ Mumab (DARZALEX® group), or lenalidomide and dexamethasone alone (control group), patients were randomized. Patients were stratified by International Staging System (ISS; I vs II vs III ), region (North America vs others), and age (less than 75 years vs 75 years or older).

[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. For patients aged over 75 or with a body mass index less than 18.5 kg / m 2 , dexamethasone was administered at a dose of 20 mg once a week. Patients in the daratumumab (DARZALEX® ) group also received intravenous daratumumab (DARZALEX®) 16 mg / kg once a week in cycles 1-2, every 2 weeks in cycles 3-6, and then every 4 weeks thereafter. Premedication was administered to manage infusion reactions .

[0372] Endpoints and evaluations The primary endpoint was progression-free survival (time from randomization to either disease progression or death ). Secondary efficacy endpoints were progression-free duration, complete response rate, stringent complete response rate, minimal residual disease negativity rate (at a threshold of 1 tumor cell per 10 5 white blood cells), time from randomization to progression or death (whichever occurred first) during subsequent treatment (progression-free survival 2 ), overall survival, overall response rate, proportion of patients achieving very good partial response or better, time to response and duration of response, efficacy in high-risk molecular subgroups, and safety . Progressive disease was defined by the International Myeloma Working​​ Group criteria (Rajkumar et al., Blood 117:4691-4 695,2011; Durie et al., Leukemia 20:1467-1 473,2006) were determined according to.

[0373] The central laboratory performed disease evaluations (serum and 24-hour urine samples) every 28 days for 2 years, then every 8 weeks until disease progression. For patients with positive serum immunofixation and daratumumab (DARZAL EX (registered trademark)) interference, a reflex assay was used to confirm complete response (McCudden et al., Clin Chem Lab Med 54: 1095-1104,2016). Minimal residual disease was evaluated in bone marrow aspirates taken at baseline, at the time of suspected complete response or stringent complete response (undetectable M-protein in two consecutive serum and urine electrophoresis tests), and at 12, 18, 24, and 30 months after the first dose in patients who achieved complete response or more (Next-generation sequencing assay (clonoSEQ( registered trademark)) version 2.0; Adaptive Biotechnologies).

[0374] Safety analyses included adverse event evaluations graded according to NCI-CTCAE version 4, electrocardiograms, clinical laboratory tests, physical examinations , and vital signs.

[0375] Statistical analysis The primary analysis population included all patients randomized in the intention-to-treat population. The safety population included patients who received any dose of the investigational treatment. For the primary endpoint of progression-free survival, a stratified log-rank test was used. The treatment effect and 95% confidence interval (CI) were the only explanations Estimation was performed using a stratified Cox regression model with treatment as a variable. The time to other events The efficacy endpoints were analyzed similarly. Response to the study treatment and progressive disease were evaluated by the aforementioned validated computer algorithm (Dimopoulos et al., N Engl J Med 375:1319-1331 2016, Pal umbo et al., N Engl J Med 375:754-766,201 6). Continuous variables, categorical variables, and variables of time to events were summarized using descriptive statistics, frequency distribution tables, and the Kaplan-Meier method, respectively. The stratified Cochran-M antel-Haenszel test was used to analyze binary endpoints. If the primary e ndpoint was statistically significant, the following secondary endpoints were tested sequentially, as ordered here (each with an overall two-sided alpha of 0.05): Complete response rate or more, very good partial response or more, and negative status for minimal residual disease, overall response rate, and overall survival.

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

[0377] The sample size of 730 patients was estimated to provide 80% power at a two-sided Using the log-rank test at the alpha level, a 25% reduction in the risk of progression or death was detected in the daratumumab (DAR ZALEX (registered trademark)) group compared with the control group.

[0378] Results Patients and Treatments Of the 737 registered patients, 368 and 369 were randomized to the daratumumab ( DARZALEX (registered trademark)) group and the control group, respectively. Baseline demographic characteristics and clinical characteristics were well balanced (Table 2). The median age was 73. 0 years (range, 45 - 90), and 14.3% of the patients had a high-risk cytogenetic profile. The median time since diagnosis was 0.9 months (range, 0 - 14.5).

[0379] Among the randomized patients, 729 patients (364 in the daratumumab (DARZALEX (registered trademark)) group and 365 in the control group) received at least one study treatment ( 365 in the daratumumab (DARZALEX (registered trademark)) group) received at least a single dose of the study treatment. As of the clinical cutoff date (September 24, 2018), 118 patients (32.4%) in the daratumumab (D ARZALEX (registered trademark)) group and 207 patients in the control group (56.7%) 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 in the daratumumab (DARZALEX (registered trademark)) group ​(Range: 0.1 - 40.4), and 21.3 months (range: 0.03 - 40.6) in the control group and the median number of cycles received was 27 (range: 1 - 44) vs 22 (range: 1 - 43) It was. The median relative dose intensity of daratumumab (DARZALEX®) (dose administered vs planned dose ratio) 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 proportion of lenalidomide dose modifications due to adverse events occurring during treatment was reported in the daratumumab (DARZALEX®) group vs the control group and included discontinuation of dosing (20.9% vs 17.0% respectively), or delay, reduction, re - incrementation, or skip of dosing (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] Efficacy At the median follow - up period of 28.0 months (range: 0 - 41.4), a total of 240 events of disease progression or death occurred (in 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 estimate of the 30 - month progression - free survival rate was 70.6% (95% CI, 65.0 - 75.4) in the (DARZALEX®) group ​, and was 55.6% (95% CI, 49.5 - 61.3) in the control group. During progression-free survival The median was not achieved in the daratumumab (DARZALEX®) group (95% CI, not estimable) compared with 31.9 months (95% CI, 28.9 - not estimable) in the control group (P < 0.0001). In the time-to-event analysis of disease progression, 179 events (66 patients [17.9%] in the daratumumab (DARZALEX®) group vs 113 patients [30.6%] in the control group) were observed, and the median progression-free period was not achieved in the daratumumab (DARZALEX®) group compared with 35.8 months (95% CI, 31.4 - not estimable) in the control group (hazard ratio, 0.47; 95% CI, 0.35 - 0.64; P < 0.0001).

[0383] The pre-specified subgroup analysis of progression-free survival confirmed the superiority of the daratumumab (DARZALEX®) group over the control group across all subgroups except for patients with liver impairment (Figure 2). The progression-free survival effect was maintained in patients 75 years of age and older (hazard ratio, 0.63; 95% CI, 0.44 - 0.92), and in patients with a historically poor prognosis (including those with a high-risk cytogenetic profile (hazard ratio, 0.85; 95% CI, 0.44 - 1.65) and ISS stage III (hazard ratio, 0.72; 95% CI, 0.48 - 1.09)). The hazard ratio for disease progression or death was lower for patients with a daratumumab (DARZALEX®) group compared with patients with a standard-risk cytogenetic profile (hazard ratio, 0.49) than for patients with a high-risk cytogenetic profile, but the results were not significant in both subgroups. ​ worked favorably. A small number of patients with a high-risk cytogenetic profile limit the interpretation of these findings.

[0384] Among the treatment-intent population (e.g., all subjects registered and randomized to treatment), patients in the daratumumab (DARZALEX®) group had 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

[0385] was 92.9% in the daratumumab (DARZALEX®) group and 81.3% in the control group (p<0.0001). The higher rate of deeper responses in the daratumumab (DARZALEX®) 5 per group was more than three times higher in the daratumumab (DARZALEX®) group vs the control group ( 24.2% vs 7.3%, P<0.0001) and was demonstrated by negativity for minimal residual disease (at a threshold of 1 tumor cell per 10

[0386] leukocytes) (Table 3). Patients with negativity for minimal residual disease demonstrated longer progression-free survival compared with patients with positivity, regardless of the investigational The update is in progress.

[0387] The median duration of response was 34.7 months (95% CI, 30.8–not estimable) in the control group compared with 34.7 months in the control group. In comparison, this was not achieved in the daratumumab (DARZALEX®) group (95 %CI, not estimable). Median time to first response among responders was 0.01 in both arms. The median time to complete response or better was 1.05 months with daratumumab (DA The mean mean mean median survival was 10.4 months in the RZALEX® group and 11.2 months in the control group. Small residual disease-negative events accumulated more rapidly in the daratumumab (DARZALEX®) arm. It piled up.

[0388] The progression-free survival benefit observed with daratumumab (DARZALEX®) was Longer progression-free survival in the daratumumab (DARZALEX®) group than in the placebo group As demonstrated by 2, the median was achieved in both treatment arms and maintained with subsequent treatment. hazard ratio, 0.70; 95% CI, 0.51 to 0.96; P = 0.027 8), and the 36-month progression-free survival rate2 was 77.1% in the (DARZALEX®) group ( 95% CI, 70.6 to 82.3), and 65.2% (95% CI, 54.2 to 82.3) in the control group. A total of 155 progression or death events occurred while patients were receiving subsequent treatment. No adverse events were observed in 68 patients in the daratumumab (DARZALEX®) group and and 87 patients in the control group).

[0389] [Table 3]

[0390] safety Table 4 summarizes the most common adverse events of any grade during treatment for the safety population (in more than 30% of patients in any group), or grade 3 or 4 adverse events (in more than 10% of patients in any group). 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 incidence of infections of any grade was 86.3% in the daratumumab (DARZALEX®) group and 73.4% in the control group, and the incidence of grade 3 or 4 infections was 32.1% and 23.3% respectively. Severe 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 the trial treatment was 7.1% in the daratumumab (DARZALEX®) group and 15.9% in the control group. Discontinuation of the trial treatment due to infection was 0.5% in the daratumumab (DARZALEX®) group and 1.4% in the control group. Compared with 1 patient (0.3%) in the control group, none of the patients in the daratumumab (DARZALEX®) group discontinued treatment due to neutropenia. Adverse events leading to death were in 25 of the daratumumab (DARZALEX®) group

[0391]

[0392] identified in 6.9% of human patients (6.9%) and 23 patients (6.3%) in the control group, most common was pneumonia, occurring in 0.5% and 0.8% of patients, respectively. Invasive secondary primary malignancies were reported in 12 (3 .3%) patients (2.7% solid tumors; 0.5% hematological malignancies) in the daratumumab (DARZALEX®) group and 1 3 (3.6%) patients (3.0% solid; 0.5% hematological) in the control group.

[0393] Infusion-related reactions associated with daratumumab (DARZALEX®) were reported in 40.9% of patients, 2.7% were grade 3 or 4 events (1 patient reported grade 4 hypertension), and no grade 5 events were reported. Infusion-related reactions usually occurred during the first infusion (in 98.0% of patients with infusion reactions), and only 1 patient discontinued daratumumab (DARZALEX®) treatment due to an infusion-related reaction (grade 4 hypertension). ))

[0394]

Table 4

[0395] Example 3: Efficacy and safety of daratumumab (DARZALEX®) (DRd) combined with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for transplantation: MAIA DRd significantly reduced the risk of progression or death by 44% in transplant-ineligible NDMM patients compared to Rd in the primary analysis of the phase 3 MAIA trial (Example 2). This patient effect of age on: MAIA DRd was significantly superior to Rd in reducing the risk of progression or death by 44% in transplant-ineligible NDMM patients in the primary analysis of the phase 3 MAIA trial (Example 2). This patient ​​ To investigate the impact of age on the efficacy and safety of D-Rd versus Rd in a cohort of patients, subgroup analyses were performed within patients aged less than 75 years and 75 years and older.

[0396] Methods: Ineligible transplant NDMM patients were randomized 1:1 to Rd±DARA, stratified by age (less than 75 years vs 75 years and older), ISS (I, II, III), and region (North America vs the rest). In the standard Rd regimen, patients received lenalidomide 25 mg PO QD on days 1-21, along with dexamethasone 40 mg PO on days 1, 8, 15, and 22 of a 28-day cycle until progression. A subset of patients received 10 mg of lenalidomide and 20 mg of dexamethasone at the start of treatment. In the DRd arm, patients received daratumumab (DARZALEX) 16 mg / kg IV QW for cycles 1-2, Q2W for cycles 3-6, and Q4W thereafter until progression. PFS was the primary endpoint.

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

[0398] Conclusion: DRd patients received less lenalidomide than the Rd group, regardless of age. The efficacy of DRd in patients aged less than 75 years and 75 years or older was consistent with the ITT population, and DR d demonstrated acceptable tolerability regardless of age. Combined with the phase 3 ALCYONE trial these trials confirm the clinical efficacy of daratumumab (DARZALEX®) in addition to standard therapy in transplant-ineligible NDMM patients aged 75 years or 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 a regimen containing an immunomodulatory agent or bortezomib [see Dosage and Administration (2) and Clinical Studies (14)] 1 · As monotherapy in patients who have received at least 3 prior therapies including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double refractory to a PI and an immunomodulatory agent

[0403] 2 Dosage and Administration 2.1 Recommended Dosage and Schedule ​· Administer the pre - dose and post - infusion medications [see Dosage and Administration (2.2)] · Administer only by 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 immediate access to emergency equipment and appropriate medical support to manage an infusion reaction if it occurs [see Warnings and Precautions for Use (5.1)]

[0404] The DARZALEX dosing schedule in Table 1 is for combination therapy (4 - week cycle regimen) and the following monotherapy regimens: - For patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT), combination therapy with lenalidomide and low - dose dexamethasone 2 - For patients with relapsed / refractory multiple myeloma, combination therapy with lenalidomide or pomalidomide and low - dose dexamethasone - For patients with relapsed / refractory multiple myeloma, monotherapy.

[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

[0407] For dosing instructions of combination medications administered with DARZALEX, refer to clinical studies ( 14) Please refer to 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 newly diagnosed with 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 3-weekly dosing schedule is given at week 7. b The first dose of the 4-weekly dosing schedule is given at week 55.

[0411] For dosing instructions on combination drugs administered with DARZALEX, please refer to clinical study 14.1).

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

[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 once - every - three - week dosing schedule is given at week 10. b The first dose of the once - every - four - week dosing schedule is given at week 25.

[0415] For dosing instructions of combination agents administered with DARZALEX, refer to the clinical study ( 14.2) and the manufacturer's prescribing information.

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

[0417] Management of infusion rate and infusion reaction Administer DARZALEX infusions intravenously at the infusion rates described in Table 4 below. Consider a step - wise increase in the infusion rate only in the absence of an infusion reaction. Consider a step - wise increase in the infusion rate only in the absence of an infusion reaction.

[0418] To facilitate administration, the initially prescribed 16 mg / kg dose for the first week may be divided into two consecutive days, i.e., 8 mg / kg on each of Day 1 and Day 2. Refer to Table 4 below. To facilitate administration, the initially prescribed 16 mg / kg dose for the first week may be divided into two consecutive days, i.e., 8 mg / kg on each of Day 1 and Day 2. Refer to Table 4 below. Refer to Table 4 below.

[0419]

Table 10

[0420] For any grade / severity of infusion reaction, immediately interrupt DARZALEX infusion and manage the symptoms. Management of the infusion reaction may require further reduction of the infusion rate or discontinuation of D ARZALEX treatment as may be further necessary [see Warnings and Precautions (5.1 )]. · Grade 1 - 2 (mild - moderate): Once the reaction symptoms have resolved, resume infusion at a rate less than half of the rate at which the reaction occurred . If the patient experiences no further reaction symptoms, the infusion rate increase may be resumed at clinically appropriate increments and intervals up to a maximum rate of 200 mL / hour (Table 4). · Grade 3 (severe): Consider resuming infusion at a rate less than half of the rate at which the reaction occurred once the reaction symptoms have resolved . If the patient experiences no further symptoms, resume the infusion rate increase at the increments and intervals outlined in Table 4. In the event of a recurrence of Grade 3 symptoms, repeat the above procedure. Permanently discontinue DARZAL EX upon the third occurrence of a Grade 3 or greater infusion reaction . · Grade 4 (life - threatening): Permanently discontinue DARZALEX treatment

[0421] 2.2 Recommended concomitant medications Pre - infusion medications Administer the following pre - infusion medications 1 - 3 hours prior to each infusion of DARZALEX to reduce the risk of infusion reaction in all patients : · Corticosteroid (long - acting or intermediate - acting) Monotherapy: Methylprednisolone 100 mg, or an equivalent administered intravenously. After the second infusion, co​ The dose of glucocorticosteroid can be reduced (oral or intravenous methylprednisolone 60 mg ). Combination therapy: Before each DARZALEX infusion, administer 20 mg of dexamethasone (or equivalent). If dexamethasone is the corticosteroid specified in the background regimen, the dex amethasone treatment dose will instead serve as premedication on the day of DARZALEX infusion [Clinical study (14)]. 3 Dexamethasone is administered intravenously before the first DARZALEX infusion, and oral administration is considered before subsequent infusions. Additional corticosteroids specified in the background regimen (e.g., prednisone) should not be taken on the day of DARZALEX infusion when the patient receives dexamethasone (or equivalent) as premedication. · Antipyretic (oral acetaminophen 650 - 1000 mg) · Antihistamine (oral or intravenous diphenhydramine 25 - 50 mg or equivalent).

[0422] Post - infusion medications For all patients, post - infusion medications are administered as follows to reduce the risk of delayed infusion reactions : Monotherapy: On each of the 2 days after all DARZALEX infusions (starting on the day after the infusion), oral corticosteroid (20 mg of methylprednisolone, or equivalent medium - acting or long - acting corticosteroid dose according to local standards ) is administered. Combination therapy: Consider administering a low dose of oral methylprednisolone (less than 20 mg ) or equivalent on the day after DARZALEX infusion. However, for corticosteroids specified in the background regimen (e.g., dexamethasone, prednisone), if administered on the day after DARZALEX infusion, additional post-infusion medications may not be required [see Clinical Studies (14)]. 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 serious infusion reaction after the first 4 infusions, these additional post-infusion inhaled medications may be discontinued.

[0423] In addition, 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 serious infusion reaction after the first 4 infusions, these additional post-infusion inhaled medications may be discontinued.

[0424] Prophylaxis for Herpes Zoster Reactivation To prevent herpes zoster reactivation within 1 week after starting DARZALEX, initiate antiviral prophylaxis and continue for 3 months after treatment [see Adverse Reactions (6.1)].

[0425] 2.3 Dose Modification Reduction of the DARZALEX dose is not recommended. Administration delays may be necessary to allow for recovery of blood counts in the event of hematologic toxicities [see Warnings and Precautions (5.3, 5.4)]. For information regarding drugs administered in combination with DARZALEX, see the prescribing information of the manufacturer.

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

[0427] Prepare the infusion solution using aseptic technique as follows: · Calculate the dose (mg), total volume (mL) of DARZALEX solution required, and the number of DARZALEX vials required based on the patient's actual body weight. ​​​​​​​​​ ·Verify that the DARZALEX solution is colorless to light yellow. Do not use if opaque particles, discoloration , or other foreign matter is present. ·Remove from the infusion bag / container a volume of 0.9% Sodium Chloride Injection, USP equal to the required volume of the DARZALEX solution. ·Withdraw the required amount of DARZALEX solution and add it to an infusion bag / container containing 0.9% Sodium Chloride Injection, USP to dilute to the appropriate volume [see Dosage and Administration (2.1)]. The infusion bag / container should be made of polyvinyl chloride (PVC), polypropylene (PP), poly ethylene (PE), or a polyolefin blend (PP + PE). Dilute under appropriate aseptic conditions. Discard any unused portion remaining in the vial. ·Gently invert the bag / container to mix the solution. Do not shake. ·Parenteral drug products should be visually inspected for particulate matter and discoloration immediately before administration, whenever 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 is observed. ·Since DARZALEX does not contain a preservative, administer the diluted solution immediately at room temperature 15°C to 25°C (59°F to 77°F) and room lighting. The diluted solution can be maintained at room temperature for a maximum of 15 hours (including infusion time). ·If not used immediately, the diluted solution can be refrigerated at 2°C to 8°C (36°F to 46°F) ​The solution may be stored under heat and protected from light for up to 24 hours prior to administration. Do not freeze.

[0428] 2.5 Administration If stored in a refrigerator, allow the solution to come to room temperature. In-line, sterile, nonpyrogenic, low protein binding polyether sulfonate Polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometers) The dilute solution is administered by intravenous infusion using the administration set made of polyurethane (poly urethane (PU), polybutadiene (PBD), PVC, PP, or P It must be made in either E. Do not store any unused portions of the injection solution for reuse. Waste materials should also be disposed of in accordance with local requirements. Do not inject DARZALEX with other medications through the same intravenous line.

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

[0430] 4 Contraindications DARZALEX is used in the treatment of severe hypersensitivity to daratumumab or any of the components of the formulation ( Contraindicated in patients with a history of anaphylactic reactions (e.g., anaphylactic shock) [Warnings and Use] See Cautions (5.1) and Adverse Reactions (6.3) above.

[0431] 5. Warnings and Precautions 5.1 Injection reaction DARZALEX may cause severe and / or serious injection reactions, including anaphylactic reactions. In clinical trials, approximately half of all patients experienced injection reactions. Most injection reactions occurred during the first injection and were Grade 1 - 2 [see Adverse Reactions (6.1)]. Injection reactions may also occur with subsequent injections. Almost all reactions occurred during the injection or within 4 hours after completion of DARZALEX. In clinical trials, injection reactions occurred up to 48 hours after the injection before the post - injection drug was introduced. Severe reactions, including bronchospasm, hypoxia, hypertension, laryngeal edema, and pulmonary edema, occurred. Signs and symptoms can 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, itching, and hypotension [see Adverse Reactions (6.1)].

[0432] Premedicate patients with antihistamines, antipyretics, and corticosteroids. Monitor patients frequently throughout all infusions. Interrupt DARZALEX infusion for any severity of reaction and initiate medical management as needed. Permanently discontinue DARZALEX therapy and initiate appropriate emergency treatment if an anaphylactic reaction or life - threatening (Grade 4) reaction occurs. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when restarting the injection [see Dosage and Administration (2.1)].

[0433]

[0434]

[0435] ​​​​​​​​​​​​​To reduce the risk of delayed infusion reactions, oral corticosteroids are administered to all patients after DARZALEX infusion [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. For patients with chronic obstructive pulmonary disease, consider prescribing short-acting and long-acting bronchodilators and inhaled corticosteroids.

[0436] 5.2 Interference with Serum Testing Daratumumab binds to CD38 on red blood cells (RBCs) and causes a positive indirect antiglobulin test (indirect Coombs test). The positive indirect antiglobulin test via daratumumab can persist up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs obscures the detection of antibodies to trace antigens in the patient's serum [see Reference (15)]. Determination of the patient's ABO and Rh blood types is not affected [see Drug Interactions (7.1)].

[0437] Inform the transfusion center of this interference with serum testing and notify the blood bank that the patient has received DARZALEX. Classify and screen patients before initiation of 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 regularly during treatment according to the manufacturer's prescribing information. Monitor patients with neutropenia for signs of infection. ​​​Do. If a delay in DARZALEX administration is required to enable neutrophil recovery There is. Dose reduction of DARZALEX is not recommended. Consider supportive therapy with growth factors Do.

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

[0441] For background therapy, monitor complete blood count values periodically during treatment according to the manufacturer's prescribing information To enable platelet recovery, a delay in DARZALEX administration may be required. Dose reduction of DARZALEX is not recommended. Consider transfusion supportive therapy. Do.

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

[0443] 6 Adverse Reactions The following clinically significant adverse reactions are also described 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, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the actual rates observed. The safety data described below reflect the exposure to DARZALEX (16 mg / kg) in 1530 patients with multiple myeloma, including 1374 patients who received DARZALEX in combination with a background regimen in DARZALEX ALEX and 156 patients who received DARZALEX as monotherapy.

[0445] The safety data described below reflect the exposure to DARZALEX (16 mg / kg) in 1530 patients with multiple myeloma, including 1374 patients who received DARZALEX in combination with a background regimen in DARZALEX ALEX and 156 patients who received DARZALEX as monotherapy. 1374 patients who received DARZALEX in combination with a background regimen in DARZALEX ALEX and 156 patients who received DARZALEX as monotherapy 1530 patients with multiple myeloma 4

[0446] Newly Diagnosed Multiple Myeloma Combination Therapy with Lenalidomide and Dexamethasone (DRd) The adverse reactions described in the following table reflect the exposure to DARZALEX in the daratumumab-lenalidomide-dexamethasone (DRd) group for a median treatment period of 25.3 months (range: 0.1 to 40.44 months) and in the lenalidomide-dexamethasone group (Rd) for a median treatment period of 21.3 months (range: 0.03 to 40.64 months) in the Phase 3 randomized controlled trial MAIA. 25.3 months (range: 0.1 to 40.44 months) 21.3 months (range: 0.03 to 40.64 months) 5 The most frequent (≥20%) adverse reactions were infusion reactions, 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 to the Rd group were dehydration (DRd 2% vs. Rd <1%), bronchitis (DRd 4% vs. Rd 2%), and pneumonia (DRd 4% vs. Rd 2%). ​​​​​​It was 15% (vs Rd 8%). 6

[0447]

Table 11

[0448] Laboratory abnormalities that worsen during treatment from the baseline listed in Table 6.

[0449]

Table 12

[0450] Combination therapy with bortezomib, melphalan, and prednisone The adverse reactions described in Table 7 are those in the Phase 3 randomized controlled trial ALCYONE, for the daratumumab, bortezomib, melphalan, and prednisone (D-VMP) group, for a median treatment period of 14. 7 months (range: 0 to 25.8 months), and for the VMP group, a median treatment period of 12 months (range: 0.1 to 14.9 months), reflecting exposure to DARZALEX. The most frequent adverse reactions (at a frequency higher than at least 5% in the D-VMP group and 20 % or more) were infusion reactions, upper respiratory tract infections, and peripheral edema. Serious adverse reactions in the D-VMP group at an incidence rate higher than at least 2% compared to the VMP group were pneumonia (D-VMP 1 % vs VMP 4%), upper respiratory tract infections (D-VMP 5% vs VMP 1%), and pulmonary edema (D-VMP 2% vs VMP 0%).

[0451]

Table 13

[0452] Laboratory abnormalities that worsen during treatment from the baseline listed in Table 8.

[0453]

Table 14

[0454] Relapsed / Refractory Multiple Myeloma Combination therapy with lenalidomide and dexamethasone The adverse reactions described in Table 9 are those in the phase 3 randomized controlled trial POLLUX, for daratumuma - lenalidomide - dexamethasone (DRd) group for a median treatment period of 13.1 months (range: 0 - 20 .7 months), and for the lenalidomide - dexamethasone group (Rd) for a median treatment period of 12.3 months (range: 0.2 - 20.1 months), reflecting exposure to DARZALEX The most frequent adverse reactions (≥20%) were infusion reactions, diarrhea, nausea, fatigue , fever, upper respiratory tract infection, muscle spasms, cough, and dyspnea. The overall incidence of serious adverse reactions was 49% in the DRd group compared to 42% in the Rd group. Serious adverse reactions with an incidence rate at least 2% higher in the D Rd group compared to 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) of patients in the Rd group. was associated with.

[0456]

Table 15

[0457] Laboratory abnormalities that worsen during treatment from the baseline listed in Table 10.

[0458]

Table 16

[0459] Combination Therapy with Bortezomib and Dexamethasone The adverse reactions described in Table 11 are those in the phase 3 active drug-controlled trial CASTOR, for daratumumab in the daratumumab-bortezomib-dexamethasone (DVd) group for a median treatment period of 6.5 months (range: 0 to 14 .8 months), and for a median treatment period of 5.2 months (range: 0.2 to 8.0 months) in the bortezomib-dexamethasone group (Vd), reflecting exposure to DARZALEX. The most frequent adverse reactions (more than 20%) were infusion reactions, diarrhea, peripheral edema, upper respiratory infections, peripheral sensory neuropathy, cough, and dyspnea. The overall incidence of serious adverse reactions was 42% in the DVd group compared with 34% in the Vd group. Serious adverse reactions with an incidence of at least 2% higher in the DVd group compared with the Vd group were upper respiratory infections (DVd 5% vs Vd 2%), diarrhea, and atrial fibrillation (DVd 2% for each vs V d 0%). Adverse reactions led to discontinuation in 7% (n = 18) of patients in the DVd group vs 9% (n = 22) in the Vd group.

[0460]

[0461]

Table 17

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

[0463]

Table 18

[0464] Combination therapy with pomalidomide and dexamethasone The adverse reactions described in Table 13 reflect the exposure to DARZALEX, pomalidomide, and dexamethasone (DPd) at the median of the 6-month (range: 0.03 to 16.9 months) treatment period in EQUULEUS. The most frequent adverse reactions (more than 20%) were infusion reactions, diarrhea, constipation, nausea, vomiting, fatigue, fever, upper respiratory tract infection, muscle spasms, back pain, joint pain, dizziness, insomnia, cough, and dyspnea. The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in 5% or more of patients included pneumonia (7%). Adverse reactions led to discontinuation in 13% of patients. 5% or more of patients reported serious adverse reactions, including pneumonia (7%). Adverse reactions led to discontinuation in 13% of patients. Adverse reactions led to discontinuation in 13% of patients.

[0465]

Table 19

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

[0467]

Table 20

[0468] Monotherapy Safety data reflect exposure to DARZALEX at 16 mg / kg in 156 adult patients with relapsed and refractory multiple myeloma treated in three open-label clinical trials. The median treatment duration was 3.3 months (range: 0.03 to 2 0.04 months). Serious adverse reactions were reported in 51 patients (33%). The most frequent serious adverse reactions were pneumonia (6%), general health deterioration (3%), and fever (3% )).

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

[0470] Table 15 shows adverse reactions occurring in at least 10% of patients. Table 16 describes grade 3-4 laboratory abnormalities reported at a rate of 10% or more.

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

[0472] [Table 22]

[0473] Infusion Reactions 9 In clinical trials (monotherapy and combination therapy, N = 1530), the incidence of any-grade infusion reactions was 40% with the first (16 mg / kg, week 1) infusion of DARZALEX, 2% with the second-week infusion, and cumulatively 4% with subsequent infusions. Less than 1% of patients had grade 3 / 4 infusion reactions at the second week or subsequent infusions.

[0474] The median time to onset of reactions was 1.5 hours (range: 0 - 72.8 hours). The incidence of infusion modifications due to reactions 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, cold sensation, throat irritation, vomiting, and nausea.

[0476] In EQUULEUS, patients receiving daratumumab combination therapy (n = 97) were given the first 16 mg / kg daratumumab dose in week 1, divided into 2 days, i.e., 8 mg / kg was administered on day 1 and day 2 respectively. The incidence of reactions related to any grade of infusion was 42%, with 36% of patients experiencing reactions on day 1 of week 1, 4% on day 2 of week 1, and 8% experiencing infusion reactions during subsequent infusions. The median time to onset of reactions was 1.8 hours (range : 0.1 - 5.4 hours). The incidence of infusion interruption due to reactions was 30%. The median infusion duration was 4.2 hours on day 1 of week 1, 4.2 hours on day 2 of week 1, and 3.4 hours for subsequent infusions.

[0477] Herpes zoster virus reactivation Prevention of herpes zoster virus reactivation has been recommended for patients in some clinical trials of DARZALEX. In monotherapy trials, herpes zoster was reported in 3% of patients. In monotherapy trials, herpes zoster was reported in 2 - 5% of patients receiving DARZALEX.

[0478] Infections In patients receiving DARZALEX combination therapy, grade 3 or 4 infections were reported as follows: Trials in relapsed / refractory patients: DVd: 21%, Vd: 19%, DRd: 27%, Rd: 23%, DPd: 28% Trials in newly diagnosed patients: D - VMP: 23%, VMP: 1 ​​​​​5%, DRd: 32%, Rd: 23%. 10 Pneumonia was the most commonly reported severe (grade 3 or 4) infection across the trials. In the active-controlled trials, treatment discontinuation due to infections (1 - 4%) and fatal infections was generally rare and balanced between the DARZALEX-containing regimens and the active control group. Fatal infections were mainly 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. In addition, the positive incidence of antibodies (including neutralizing antibodies) observed in the assay can be influenced by several factors including assay method, 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 to other products in other studies may be misleading. In clinical trials of patients with multiple myeloma treated with DARZALEX as monotherapy or in combination therapy, 0 out of 111 evaluable monotherapy patients and 2 out 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.

[0480] 6.3 Post-marketing experience The following adverse reactions were 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 indirect antiglobulin test (indirect Coombs test) Daratumumab binds to CD38 on RBCs and interferes with compatibility tests including antibody screening and crossmatching. Methods to mitigate daratumumab interference include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding [see reference literature (15)], or genotyping. Kell phenotyping is also sensitive to DTT treatment, so after excluding or identifying alloantibodies using DTT-treated RBCs, K-negative units should be supplied. If emergency transfusion is required, non-crossmatched ABO / RhD-compatible RBCs can be given according to the practices of the local blood bank.

[0482]

[0483] Interference with serum protein electrophoresis and immunofixation tests Daratumumab can be detected in serum protein electrophoresis (SPE) and immunofixation (IFE) assays used to monitor disease monoclonal immunoglobulin (M-protein). This results in false-positive SPE and IFE assay results in patients with IgG kappa myeloma protein and affects the initial assessment of complete response according to International Myeloma Working Group (IMWG) criteria. In patients with a persistently very good partial response where daratumumab interference is suspected, for the initial assessment of complete response ​​​​​​​​​​To facilitate determination of efficacy, use the FDA-approved DARZALEX-specific IFE assay to distinguish daratumumab from any remaining endogenous M-protein in the patient's serum. Consider using the FDA-approved DARZALEX-specific IFE assay to distinguish daratumumab from any remaining endogenous M-protein in the patient's serum. Consider this.

[0484] 8 Use in Specific Populations 8.1 Pregnancy Summary of Risks There is no human data informing the risks associated with the use of DARZALEX during pregnancy. Animal studies have not been conducted. However, there are clinical considerations [see Clinical Considerations]. The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defects, stillbirth, or other adverse outcomes. In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. There is no human data informing the risks associated with the use of DARZALEX during pregnancy. Animal studies have not been conducted. However, there are clinical considerations [see Clinical Considerations]. The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defects, stillbirth, or other adverse outcomes. In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defects, stillbirth, or other adverse outcomes. In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. All pregnancies have a background risk of birth defects, stillbirth, or other adverse outcomes. In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

[0485] Clinical Considerations Fetal / Newborn Adverse Reactions Immunoglobulin G1 (IgG1) monoclonal antibodies cross the placenta. Based on its mechanism of action, DARZALEX may cause depletion of fetal bone marrow cells or lymphocytes and decreased bone density. Delay administration of live vaccines to neonates and infants exposed to DARZALEX in utero until hematologic evaluation is complete. Immunoglobulin G1 (IgG1) monoclonal antibodies cross the placenta. Based on its mechanism of action, DARZALEX may cause depletion of fetal bone marrow cells or lymphocytes and decreased bone density. Delay administration of live vaccines to neonates and infants exposed to DARZALEX in utero until hematologic evaluation is complete. Based on its mechanism of action, DARZALEX may cause depletion of fetal bone marrow cells or lymphocytes and decreased bone density. Delay administration of live vaccines to neonates and infants exposed to DARZALEX in utero until hematologic evaluation is complete. Based on its mechanism of action, DARZALEX may cause depletion of fetal bone marrow cells or lymphocytes and decreased bone density. Delay administration of live vaccines to neonates and infants exposed to DARZALEX in utero until hematologic evaluation is complete.

[0486] Data Animal Data Mice with gene modification to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. Affected the white blood cell population. Mice with gene modification to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. Affected the white blood cell population. In cynomolgus monkeys exposed to daratumumab or other monoclonal antibodies during pregnancy, infant monkeys had reversibly reduced white blood cell counts.

[0487] 8.2 Lactation Summary of Risks There is no information on the presence of daratumumab in human breast milk, its effects on infants breastfed with it, or its effects on breast milk secretion. Human IgG is known to be present in human breast milk. Published data suggest that antibodies in breast milk do not enter the bloodstream of newborns and infants in substantial amounts.

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

[0489] 8.3 Reproductive Women and Men Contraception To avoid fetal exposure, reproductive women should use effective contraception during treatment and for 3 months after discontinuation of DARZALEX treatment.

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

[0491] 8.5 Geriatric Use Of the 1530 patients who received DARZALEX at the recommended dose, 48% were 65 to 75 years old and 22% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients [see Clinical Study (14)]. 13、14

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

[0493] DARZALEX is supplied as a colorless to pale yellow preservative-free solution for intravenous infusion in single-dose vials. The pH is 5.5. DARZALEX needs to be diluted with 0. 9% Sodium Chloride Injection, USP [see Dosage and Administration (2.4 )].

[0494] Each 20 mL single-dose vial of DARZALEX 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 5 mL single-dose vial of DARZALEX 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 is involved in receptor-mediated adhesion, signal transduction, and ​​​​​​​​​​Daratumumab has multiple functions, including regulating cyclase and hydrolase activity. by binding to D38 and directly inducing apoptosis via Fc-mediated cross-linking. and complement dependent cytotoxicity (CDC), antibody-dependent antibody dependent cell mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). Human IgG1κ inhibits proliferation of CD38-expressing cells by selective immune-mediated cytolysis Monoclonal antibody (mAb). Myeloid-derived suppressor cells (CD38+MDSC), control sexual T cells (CD38+T reg ), and B cells (CD38+B regs ) is a subset of , which is reduced by daratumumab.

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

[0498] Cardiac Electrophysiology DARZALEX, as a large protein, is capable of direct ion channel interaction. The effect is low. There is no evidence from non-clinical or clinical data to support this claim.

[0499] 12.3 Pharmacokinetics As a single-agent therapy at 1 to 24 mg / kg, or in combination with other therapies at 1 to 16 mg / kg Over the dose range of DARZALEX, the increase in the area under the concentration-time curve (AUC) was supra-proportional to the dose.

[0500] Following the recommended dose of 16 mg / kg when DARZALEX was administered as a single-agent therapy or in combination therapy, the mean maximum serum concentration (C) value at the end of weekly dosing was approximately 2.7 to 3 times higher compared to the mean serum C after the first dose. The mean ± standard deviation (SD) trough serum concentration (C) at the end of weekly dosing was 573 + 332 μg / mL when DARZALEX was administered as a single-agent therapy, and 502 ± 196 to 607 ± 231 μg / mL when DARZALEX was administered in combination therapy. The first dose fractionation resulted in a different PK profile on day 1 compared to a single dose. However, similar C max and C concentrations were predicted and observed after the administration of the second dose fraction on day 2 of week 1. max min max min

[0501] When DARZALEX was administered as a single-agent therapy, the daratumumab steady state was achieved in approximately 5 months (up to the 21st infusion) upon entering a 4-weekly dosing period, and the mean ± SD ratio of steady state C to C after the first max dose was 1.6 ± 0.5. max

[0502] Distribution At the recommended dose of 16 mg / kg, the mean ± SD central volume of distribution was When administered as a monotherapy, it was 4.7 ± 1.3 L, and when DARZALEX was administered as combination therapy, it was 4.4 ± 1.5 L.

[0503] Discontinuation Daratumumab clearance decreased with increasing dose and multiple administrations. With monotherapy and at the recommended dose of 16 mg / kg of DARZALEX, 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 was on average 15 - 23 days when administered as combination therapy. 15

[0504] Specific Populations The following population characteristics had no clinically significant effect on the pharmacokinetics of daratumumab in patients administered DARZALEX as monotherapy or combination therapy: gender, age (3 1 - 93 years), mild [total bilirubin 1 - 1.5 times the upper limit of normal (ULN), or aspartate aminotransaminase above ULN (aspartate aminotransaminase, AST)], and moderate (total bilirubin 1.5 - 3 times ULN and any AST) hepatic impairment, or renal impairment [creatinine clearance (CLcr) 1 5 - 89 mL / min]. The effect of severe (total bilirubin above 3 times ULN and any AST) hepatic impairment is unknown. Weight gain increased the central volume of distribution and daratumumab clearance supporting a weight-based dosing regimen.

[0505] Drug Interactions ​Daratumumab in combination with lenalidomide, pomalidomide, bortezomib, and dexamethasone Clinical pharmacokinetic evaluation of daratumumab did not show clinically relevant drug-drug interactions between daratumumab and these small molecule drugs. 16

[0506] 13 Non-clinical toxicity 13.1 Carcinogenicity, mutagenicity, reproductive toxicity Carcinogenicity or genotoxicity studies with daratumumab have not been conducted. Animal studies to evaluate the potential impact of daratumumab on reproduction or development, or to determine the potential impact on reproductive ability in males or females, have not been conducted.

[0507] 14 Clinical studies 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 (oral, once daily, 25 mg on days 1-21 of a repeated 28-day [4-week] cycle) 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, the dexamethasone dose was given as a premedication. Dose adjustments for lenalidomide and dexamethasone were applied according to the manufacturer's prescribing information. ​​​​​​​​​​​Treatment was continued in both groups until progression or unacceptable toxicity occurred. 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. Most were white (92%), 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 an International Staging System (ISS) stage I, 43% had ISS stage II, and 29% had disease of ISS stage III. Efficacy was evaluated by progression-free survival (PFS) according to the International Myeloma Working Group (IMWG) criteria. MAIA demonstrated an improvement in progression-free survival (PFS) in the DRd group compared with the Rd group. The median PFS was not reached in the DRd group and was 31.9 months in the Rd group ( 18、19

[0509] 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. 2

[0510] 0

Table B

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

[0512]

Table 23

[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 . 23 The 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 therapy with bortezomib, melphalan, and prednisone (VMP) in patients ineligible for autologous stem cell transplantation ALCYONE (NCT02195479), an open - label, randomized, placebo - controlled phase 3 trial was conducted in patients with newly diagnosed multiple myeloma to evaluate bortezomib, melphalan DARZALEX 16 mg / kg (D-VMP) in combination with bortezomib and prednisone The treatment with it was compared to the treatment with VMP. Bortezomib was administered subcutaneously (SC) at a dose of 1.3 mg / m 2 body surface area twice weekly at weeks 1, 2, 4, and 5 of the first 6-week cycle (cycle 1; 8 administrations), followed by once weekly at weeks 1, 2, 4, and 5 of eight 6-week cycles (cycles 2 - 9; 4 administrations per cycle). Melphalan at 9 mg / m and prednisone at 60 mg / m 2 were orally administered on days 1 - 4 of nine 6-week cycles (cycles 1 - 9). DARZALEX treatment was continued until disease progression or unacceptable toxicity 2 . 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

[0515] . The median age was 71 years (range: 40 - 93 years), and 30% of the patients were 75 years or older . Most were white (85%), 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 the patients had ISS stage I, 42% had ISS stage II, and 38% had ISS stage III disease . Efficacy was evaluated by PFS based on the IMWG criteria . ALCYONE demonstrated an improvement in PFS in the D-VMP group compared to the VMP group .

[0516] ​​No. The PFS median was not achieved in the D-VMP group and was 18.1 months (95% CI: 16.53, 19.91) in the VMP group (HR = 0.5; 95% CI: 0.38, 0.6 5; 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

[0520] In 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 was 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 in patients with multiple myeloma who have received at least one prior therapy. DARZALEX 16mg / kg (D) in combination with domide and low-dose dexamethasone Treatment with lenalidomide and low-dose dexamethasone (Rd) was compared with treatment with lenalidomide and low-dose dexamethasone (Rd) Lenalidomide (administered orally daily on days 1 to 21 of repeated 28-day [4-week] cycles) 25 mg once a day), low-dose oral or intravenous dexamethasone 40 mg / week (or age 75 or older) For patients with a BMI of 18.5 or above, the dose is reduced to 20 mg / week. On the day of DARZALEX infusion, a 20 mg dexamethasone dose was administered pre-infusion. The remaining dose was given on the day following the infusion. In this case, a total dose of 20 mg was given as DARZALEX pre-infusion medication. Dose adjustments of lenalidomide and dexamethasone were applied according to the latest reports. Treatment continued in both groups until uncontrollable 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 age of patients was 65 years (range 34-89 years), with 11% being 75 age 10 or older, 59% were male, 69% were white, 18% were Asian, and 3% were African American. Patients were African American. Patients had received a median of one prior therapy. Sixty-three percent of patients The majority of patients (8%) had received prior autologous stem cell transplantation (ASCT). 6%) had received prior PI, 55% of patients had received prior immunomodulatory agents ( including 18% of patients who had received prior lenalidomide), 44% of patients had received both prior PI and immunomodulatory agents. At baseline, 27% of patients had been refractory to their last treatment. Eighteen percent (18%) of patients were refractory only to PI, and 21% were refractory to bortezomib. Efficacy was evaluated by PFS based on IMWG criteria.

[0523] POLLUX demonstrated an improvement in PFS in the DRd group compared with the Rd group. The median PFS was not reached in the DRd group and was 18.4 months in the Rd group (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

[0527] Among responders, the median time to response was 1 month in the DRd group (range: 0.9 ​​​Duration of response was 1.1 months (range: 0.9-10 months) in the Rd group and 1.2 months (range: 0.9-13 months) in the Rd group. The median was not reached in the D-VMP group (range: 1+ to 19.8+ months) and was 1 The median mean median time to maturity was 7.4 months (range: 1.4+ to 18.5+ months).

[0528] At a median follow-up of 13.5 months, 75 deaths were noted, 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 in patients with multiple myeloma who have received at least one prior therapy. DARZALEX 16mg / kg (DVd) in combination with Zomib and dexamethasone Treatment with bortezomib was compared with treatment with bortezomib and dexamethasone (Vd). Zomib was administered in 2 of 21-day (3-week) treatment cycles repeated for a total of 8 cycles. 1.3 mg / m twice weekly (days 1, 4, 8, and 11) 2 Dose by body surface area, SC Dexamethasone was administered by injection or IV infusion at each of the eight bortezomib cycles. 20 mg dose (bortezomib cyclin) on days 1, 2, 4, 5, 8, 9, 11, and 12 of 80 mg / week for 2 out of 3 weeks of the first week of the year) or for those aged 75 years or older or younger than 18.5 years BMI, poorly controlled diabetes, or previous intolerance to steroid therapy For patients with DARZALEX, a reduced dose of 20 mg was administered orally on the day of DARZALEX infusion. A dose of 20 mg of dexamethasone was administered as a pre-infusion medication. In patients who were tapered, a total dose of 20 mg of DARZALEX was given as a pre-infusion. While daratumumab was given until disease progression, bortezomib and dexamethasone were given in both treatment groups for 8 three-week cycles. However, in the DVd group, dex amethasone 20 mg was continued as a pre-daratumumab agent. Dose adjustments for 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 daratumumab group and the control group . The median patient age was 64 years (range 30 - 88 years), 12% were 75 years or older, 57% were male, 87% were white, 5% were Asian, and 4% were African American. Patients had a median of 2 prior treatments, and 61% of patients had previously received autologous stem cell transplantation (ASCT). Sixty-nine percent (69%) of patients had previously received a PI (66% had received bortezomib), and 76% of patients had received immunomodulatory drugs (42% had received lenalidomide). At baseline, 32 % of patients were refractory to their last treatment, and the proportion of patients refractory to any specific prior treatment was generally well balanced between treatment groups. Thirty-three percent (33%) of patients were refractory to immunomodulatory drugs only, and 24% of patients in the DVd group and 33% of patients in the Vd group were refractory to lenalidomide, respectively. Efficacy was evaluated by PFS based on IMWG criteria .

[0531] CASTOR demonstrated an improvement in PFS in the DVd group compared to the Vd group. PF The median was not achieved in the DVd group and was 7.2 months in the Vd group (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

[0535] In 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 was 7 .9 months (1.4+ - 12+ months) in the Vd group.

[0536] With a median follow - up of 7.4 months, 65 deaths were observed, 29 in the DVd group and 36 in the Vd group.

[0537] Combination therapy with pomalidomide and dexamethasone EQUULEUS (NCT01998971) was in patients who had received previous PIs and immunomodulatory agents One hundred and three patients with multiple myeloma received DARZALEX at 16 mg / kg in combination with pomalidomide and low-dose dexamethasone until disease progression. Pomalidomide (4 mg once daily orally on days 1 - 21 of a repeated 28-day [4-week] cycle) was administered with low-dose oral or intravenous dexamethasone 40 mg / week (reduced to 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 dexamethasone dose was given as a premedication, and the remainder was given the day after the infusion. In the case of patients with a reduced dexamethasone dose, the entire 20 mg dose was given as a DARZALEX premedication.

[0538] The median patient age was 64 years (range: 35 - 86 years), and 8% of the patients were 75 years of age or older. The patients in the trial had received a median of 4 prior therapies. Seventy-four percent (74%) of the patients had received a prior ASCT. Ninety-eight percent (98%) of the patients had received prior bortezomib treatment, and 33% of the patients had received prior carfilzomib. All patients had received prior lenalidomide treatment, and 98% of the patients had been previously treated with the combination of bortezomib and lenalidomide. Eighty-nine percent (89%) of the patients were refractory to lenalidomide, 71% were refractory to bortezomib, and 64% of the patients were refractory to the combination of bortezomib and lenalidomide.

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

[0540]

Table 27

[0541] The median time to response was 1 month (range: 0.9 - 2.8 months). Time to Response The median was 13.6 months (range: 0.9+ - 14.6+ months).

[0542] Monotherapy SIRIUS (NCT01985126) was an open - label trial evaluating DARZ ALEX monotherapy in patients with relapsed or refractory multiple myeloma who had received at least 3 prior treatments containing a proteasome inhibitor and an immunomodulatory agent or were double - refractory to a proteasome inhibitor and an immunomodulatory agent 106 patients received DARZA LEX 16 mg / kg administered with pre - and post - infusion medications. Treatment continued until unacceptable toxicity or disease progression The median patient age was 63.5 years (range: 31 - 84 years), 49% were male, and 7 9% were white. Patients had received a median of 5 prior treatments. Eighty percent of patients

[0543] had received a previous autologous stem cell transplant (ASCT). Prior treatments included bortezomib (99% ), lenalidomide (99%), pomalidomide (63%), and carfilzomib (50% ). At baseline, 97% of patients were refractory to their last treatment, 95% were refractory to both a proteasome inhibitor (PI) and an immunomodulatory agent, and 77% were refractory to an alkylating agent The efficacy results were determined using the IMWG criteria by an Independent Review Co

[0544] ​​It was based on the overall response rate determined by the committee's evaluation (see Table 22).

[0545]

Table 28

[0546] The median time to response was 1 month (range: 0.9 - 5.6 months). Time to response The median 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. In 42 patients, DARZALEX 16 mg / kg was administered 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. The study patients had received a median of 4 prior therapies. 74% of the patients had received a prior ASCT. Prior therapies included bortezomib (100%), lenalidomide (95%), pomalidomide (36%), and carfilzomib (19%). At baseline, 76% of the patients were refractory to their last therapy, 64% were refractory to both a PI and an immunomodulatory agent, and 60% were refractory to an alkylating agent.

[0549] The overall response rate was 36% (95% CI: 21.6, with 1 CR and 3 VGPRs​​​​​​​​​ It was 52.0%. The median time to response was 1 month (range: 0.5 to 3.2 months). The median response duration 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 interfe rence with blood compatibility testing, T ransfusion, 55:1545 - 1554 (http: / / onliselib rary.wiley.com / doi / 10.1111 / trf.13069 / epd f, accessible at).

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

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

[0553] Do not freeze or shake. Protect from light. This product does not contain a preservative.

[0554] 17 Patient Counseling Information ​​​Advise the patient to read the FDA-approved Patient Label (Patient Information).

[0555] Infusion reaction Instruct the patient to seek immediate treatment for any of the following signs and symptoms of an infusion reaction and report. · Itching of the nose, runny nose, or nasal congestion; 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 the patient to contact a healthcare provider if the patient has a fever[See Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

[0557] Thrombocytopenia · Advise the patient to notify a healthcare provider if the patient notices signs of rash or bleeding[See Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

[0558] Interference with Laboratory Tests Advise the patient to inform healthcare providers, including the blood bank / staff, that the patient is receiving DARZALEX in the event of a planned blood transfusion[See Warnings and Precautions (5.2) and Adverse Reactions (7.1)].

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

[0560] Manufacturer: Janssen Biotech, Inc. Horsham, PA 19044 U.S. License No. 1864 (Copyright) 2015 Janssen Pharmaceutical Compan ies

[0561]

Table F

Claims

1. A pharmaceutical combination for use in a method of treating a patient with newly diagnosed multiple myeloma, comprising: The pharmaceutical combination a) an anti-CD38 antibody of the IgG1 kappa (IgG1κ) isotype comprising a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8; b) about 25 mg of lenalidomide; and c) about 20 mg of dexamethasone; and 10. A pharmaceutical combination comprising:

2. A pharmaceutical combination for use in a method of treating a patient with newly diagnosed multiple myeloma, comprising: The pharmaceutical combination a) an anti-CD38 antibody of the IgG1κ isotype comprising a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8; b) about 25 mg of lenalidomide; and c) about 20 mg of dexamethasone or its equivalent; Including, A pharmaceutical combination wherein said dexamethasone equivalent is methylprednisolone, prednisolone, prednisone, or betamethasone, or any combination thereof.

3. A pharmaceutical combination described in claim 1 or 2, wherein the molecular weight of the anti-CD38 antibody is approximately 148 kDa.

4. A pharmaceutical combination described in any one of claims 1 to 3, wherein the anti-CD38 antibody is produced in a mammalian cell line.

5. The pharmaceutical combination of claim 4, wherein the mammalian cell line is a Chinese hamster ovary (CHO) cell line.

6. A pharmaceutical combination described in any one of claims 1 to 5, wherein the anti-CD38 antibody comprises a heavy chain of SEQ ID NO: 9 and a light chain of SEQ ID NO:

10.

7. A pharmaceutical combination described in any one of claims 1 to 5, wherein the anti-CD38 antibody is daratumumab.

8. The pharmaceutical combination of claim 1, wherein the method comprises administering the anti-CD38 antibody to the patient at a dose of about 16 mg / kg.

9. The method comprises, for the patient: a) administering about 16 mg / kg of the 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 about 25 mg of lenalidomide per day on days 1 through 21 of repeated 4-week cycles; c) administering about 20 mg of dexamethasone per week; The pharmaceutical combination according to any one of claims 1 to 8.

10. The pharmaceutical combination according to any one of claims 1 to 9, wherein the method comprises administering dexamethasone as a premedication on the day of administration of the anti-CD38 antibody.

11. The method comprising: administering the anti-CD38 antibody intravenously, administering the lenalidomide orally, and administering the dexamethasone intravenously or orally. The pharmaceutical combination according to any one of claims 1 to 10.

12. The pharmaceutical combination of any one of claims 1 to 11, wherein the patient is ineligible for autologous stem cell transplantation (ASCT).

13. A pharmaceutical combination according to any one of claims 1 to 12, wherein the method achieves an improved clinical efficacy endpoint compared to the clinical efficacy endpoint achieved when lenalidomide and dexamethasone are administered alone.

14. The improved clinical efficacy endpoint, increased likelihood of achieving a complete response (CR) or better; increased likelihood of achieving a very good partial response (VGPR) or better; increased likelihood of achieving negative status for minimal residual disease (MRD); reducing the risk of progression or death from multiple myeloma; Prolonged progression-free survival (PFS), or an increased likelihood of achieving progression-free survival at 30 months; or any combination thereof, The pharmaceutical combination of claim 13.

15. A pharmaceutical combination described in claim 13 or 14, wherein the likelihood of achieving a complete response or better is about 47% or more.

16. A pharmaceutical combination described in any one of claims 13 to 15, wherein the likelihood of achieving the very good partial response or better is about 79% or more.

17. The pharmaceutical combination of any one of claims 13 to 16, wherein the probability of achieving a negative state for the MRD is about 24% or more.

18. A pharmaceutical combination described in any one of claims 13 to 17, wherein the risk of progression or death from multiple myeloma is reduced by approximately 44%.

19. A pharmaceutical combination according to any one of claims 1 to 18, wherein the method achieves improved progression-free survival (PFS2) with first subsequent treatment compared to PFS2 achieved when administering lenalidomide and dexamethasone alone.

20. A pharmaceutical combination according to any one of claims 1 to 19, wherein the method achieves improved progression-free survival (PFS) compared to the PFS achieved when administering lenalidomide and dexamethasone alone.

21. The pharmaceutical combination of any one of claims 1 to 20, wherein the method achieves a complete response or better rate of 47.6%.

22. A pharmaceutical combination described in any one of claims 1 to 21, wherein the method achieves an MRD negativity rate of 24.2%.

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