Reduction of corticosteroids during anti-CD38 therapy

Abstract

The present disclosure relates to a method of treating a hematological malignancy comprising administering to a subject a therapeutically effective amount of an anti-CD38 antibody and a corticosteroid for a period of time sufficient to treat the hematological malignancy, the dosing regimen including a reduction, elimination, or reduction followed by elimination of corticosteroid administration to the subject. The present disclosure also relates to a method of treating a hematological malignancy comprising administering to a subject a therapeutically effective amount of an anti-CD38 antibody and a corticosteroid dose <0.01 mg / kg / day, or an equivalent dose, for a period of time sufficient to treat the hematological malignancy. The present disclosure also relates to a method of treating a hematological malignancy comprising administering to a subject a therapeutically effective amount of an anti-CD38 antibody for a period of time sufficient to treat the hematological malignancy, the dosing regimen including a reduction, elimination, or reduction and elimination of corticosteroid use by the subject.

Description

[Technical field]

[0001] (Reference to electronically submitted sequence listing) This application contains a Sequence Listing, which has been submitted electronically via the Patent Center of the United States Patent and Trademark Office as a Sequence Listing in XML format with the file name "JBI6648WOPCT1 Sequence Listing.xml", a creation date of November 2, 2022, and a size of 39 Kb. The Sequence Listing submitted via the Patent Center is a part of this specification and is incorporated by reference in its entirety. [Background technology]

[0002] CD38 has functions in receptor-mediated adhesion and signal transduction, as well as mediating calcium mobilization through its ectoenzyme activity and NAD + CD38 is a type II membrane protein that catalyzes the formation of cyclic ADP-ribose (cADPR) from CD38 and also hydrolyzes cADPR to ADP-ribose (ADPR). CD38 mediates cytokine secretion and lymphocyte activation and proliferation (Funaro et al., J Immunol. 145(8):2390-96 (1990); Terhorst et al., Cell 23(3):771-80 (1981); Guse et al., Nature 398:70-73, 1999)) and is a protease that mediates extracellular NAD that has been implicated in regulating the regulatory T cell compartment via its NAD glycohydrolase activity. + (Adriouch et al., Microbes Infect. 14(14):1284-92 (2012) and Chiarugi et al., Nat Rev Cancer. 12(11):741-52 (2012)).

[0003] CD38 is expressed in many hematological malignancies, including B-cell acute lymphoblastic leukemia (ALL), B-cell chronic lymphocytic leukemia, B-cell non-Hodgkin's lymphoma, multiple myeloma, and T-cell ALL. CD38 is also expressed in B-cell disorders such as light chain amyloidosis, monoclonal gammopathy of undetermined type (MGUS), and smoldering multiple myeloma (SMM).

[0004] B-cell malignancies include B-cell chronic lymphocytic leukemia, mantle cell lymphoma, Burkitt's lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, hairy cell leukemia, primary effusion lymphoma, and AIDS-related non-Hodgkin's lymphoma. B-cell malignancies constitute more than 85% of diagnosed lymphomas.

[0005] Multiple myeloma (MM) is a B-cell malignancy characterized by the latent accumulation of secretory plasma cells in the bone marrow, with a low proliferation index and extended life span. The disease eventually attacks the bone and bone marrow, resulting in multiple tumors and lesions throughout the skeletal system. Approximately 1% of all cancers and slightly more than 10% of all hematologic malignancies can be attributed to MM. The incidence of MM is increased in the elderly population, with the median age at diagnosis being approximately 61 years. Summary of the Invention

[0006] For the treatment of hematological malignancies, such as MM and other B-cell malignancies, additional therapies based on anti-CD38 antibodies are needed.

[0007] The present disclosure relates generally to methods useful for treating hematological malignancies (eg, hematological cancers such as multiple myeloma).

[0008] In one aspect, the disclosure provides a method of treating a hematological malignancy, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody and a corticosteroid for a period of time sufficient to treat the hematological malignancy, wherein the dosing regimen includes a reduction, elimination, or reduction followed by elimination of administration of a corticosteroid to the subject.

[0009] In some embodiments, the corticosteroid comprises betamethasone, cortisol, cortisone, dexamethasone, glucocorticoids, hydrocortisone, methylprednisolone (MP), prednisolone, prednisone, triamcinolone, or a combination thereof. In some embodiments, the corticosteroid comprises MP, dexamethasone, prednisone, or a combination thereof.

[0010] In some embodiments, the corticosteroid administered to the subject is reduced by about 60% during a 28 day treatment cycle and then eliminated.

[0011] In some embodiments, the corticosteroid administered to the subject is reduced by about 60%, then reduced by 30%, and then eliminated during a 28 day treatment cycle.

[0012] In some embodiments, the corticosteroid administered to the subject is administered once and then removed during a 28 day treatment cycle.

[0013] In certain embodiments, the anti-CD38 antibody is administered once weekly, every two weeks, or every four weeks during a 28 day cycle. In particular embodiments, the anti-CD38 antibody is administered once weekly during cycle 1, every two weeks during cycles 2-5, and every four weeks thereafter.

[0014] In some embodiments, the method comprises: a) administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; and b) administering about 20 mg of a pre-dose corticosteroid (e.g., dexamethasone) intravenously on day 1.

[0015] In some embodiments, the method comprises: administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; administering about 100 mg of a pre-dose corticosteroid (e.g., MP) orally or intravenously on day 1; orally administering about 20 mg of a post-dose corticosteroid (e.g., MP) on days 1 and 2; Administering about 60 mg of a pre-dose corticosteroid (e.g., MP) orally or intravenously on day 8; and and orally administering about 20 mg of a post-dose corticosteroid (e.g., MP) on day 8.

[0016] In some embodiments, the method comprises: administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; administering about 100 mg of a pre-dose corticosteroid (e.g., MP) orally or intravenously on day 1; orally administering about 20 mg of a post-dose corticosteroid (e.g., MP) on days 1 and 2; administering about 60 mg of a pre-dose corticosteroid (e.g., MP) orally or intravenously on day 8; orally administering about 20 mg of a post-dose corticosteroid (e.g., MP) on day 8; Administering about 30 mg of a pre-dose corticosteroid (e.g., MP) orally or intravenously on day 15; and and orally administering about 20 mg of a post-dose corticosteroid (e.g., MP) on the 15th day.

[0017] In another aspect, the disclosure provides a method of treating a hematological malignancy in a subject in need thereof, comprising administering to the subject a treatment on a 28 day cycle, the treatment comprising: administering about 1,800 mg of an anti-CD38 antibody and about 30,000 U of hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; administering about 100 mg of a pre-dose corticosteroid on day 1; administering about 20 mg of a post-dose corticosteroid on days 1 and 2; administering about 60 mg of a pre-dose corticosteroid on day 8; administering about 20 mg of a post-dose corticosteroid on day 8; administering about 30 mg of a pre-dose corticosteroid on day 15; and and administering about 20 mg of a post-administration corticosteroid on day 15.

[0018] In another aspect, the disclosure provides a method of treating a hematological malignancy in a subject in need thereof, comprising administering to the subject a treatment on a 28 day cycle, the treatment comprising: administering about 1,800 mg of anti-CD38 antibody and about 30,000 U of rHuPH20 hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; administering about 100 mg of a pre-dose corticosteroid on day 1; administering about 20 mg of a post-dose corticosteroid on days 1 and 2; administering about 60 mg of a pre-dose corticosteroid on day 8; and and administering about 20 mg of a post-administration corticosteroid on day 8.

[0019] In another aspect, the disclosure provides a method of treating a hematological malignancy in a subject in need thereof, the method comprising administering to the subject a treatment in 28 day cycles, the treatment comprising: a) administering about 1,800 mg of an anti-CD38 antibody and about 30,000 U on days 1, 8, 15, and 22 of a 28 day cycle; and b) administering about 20 mg of a pre-dose corticosteroid on day 1.

[0020] In another aspect, the disclosure provides a method of treating a hematological malignancy, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody for a period of time sufficient to treat the hematological malignancy, wherein the dosing regimen results in a reduction, elimination, or reduction and elimination of corticosteroid use by the subject.

[0021] In another aspect, the disclosure provides a method of treating a hematological malignancy, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody and a corticosteroid dose <2 mg / kg / day, or equivalent, for a period of time sufficient to treat the hematological malignancy, hi some embodiments, a corticosteroid dose <0.05 mg / kg / day, or equivalent, is administered.

[0022] In another aspect, the disclosure provides a method of treating a hematological malignancy, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody, without concomitant administration of a corticosteroid, for a period of time sufficient to treat the hematological malignancy.

[0023] In another aspect, the disclosure provides a method of treating a hematological malignancy, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody for a period of time sufficient to treat the hematological malignancy, wherein disease control or complete remission is achieved and / or maintained at a corticosteroid dose of ≦2 mg / kg / day or equivalent. In some embodiments, disease control or complete remission is achieved and / or maintained at a corticosteroid dose of ≦0.05 mg / kg / day or equivalent.

[0024] In some embodiments, the method further comprises administering to the subject a pretreatment during a 28 day cycle, the pretreatment comprising: a) administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; and b) administering about 20 mg of a pre-dose corticosteroid (e.g., dexamethasone) intravenously on day 1.

[0025] In some embodiments, the method further comprises administering to the subject a pretreatment during a 28 day cycle, the pretreatment comprising: administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; administering about 100 mg of a pre-dose corticosteroid (e.g., MP) orally or intravenously on day 1; orally administering about 20 mg of a post-dose corticosteroid (e.g., MP) on days 1 and 2; Administering about 60 mg of a pre-dose corticosteroid (e.g., MP) orally or intravenously on day 8; and and orally administering about 20 mg of a post-dose corticosteroid (e.g., MP) on day 8.

[0026] In some embodiments, the method includes administering a pretreatment to the subject during a 28 day cycle, the pretreatment comprising: administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; administering about 100 mg of a pre-dose corticosteroid (e.g., MP) orally or intravenously on day 1; orally administering about 20 mg of a post-dose corticosteroid (e.g., MP) on days 1 and 2; administering about 60 mg of a pre-dose corticosteroid (e.g., MP) orally or intravenously on day 8; orally administering about 20 mg of a post-dose corticosteroid (e.g., MP) on day 8; Administering about 30 mg of a pre-dose corticosteroid (e.g., MP) orally or intravenously on day 15; and and orally administering about 20 mg of a post-dose corticosteroid (e.g., MP) on the 15th day.

[0027] In some embodiments, the hematological malignancy is a CD38-positive hematological malignancy. In certain embodiments, the CD38-positive hematological malignancy is multiple myeloma. In particular embodiments, the multiple myeloma is relapsed or refractory multiple myeloma.

[0028] In some embodiments, the anti-CD38 antibody is a) the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively; and / or b) comprising the amino acid sequences of light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 of SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11, respectively.

[0029] In certain embodiments, the anti-CD38 antibody comprises a heavy chain variable region (VH) sequence of SEQ ID NO: 4, a light chain variable region (VL) sequence of SEQ ID NO: 5, or both. In particular embodiments, the anti-CD38 antibody comprises a heavy chain sequence of SEQ ID NO: 12, a light chain sequence of SEQ ID NO: 13, or both.

[0030] In some embodiments, the anti-CD38 antibody is of the IgG1, IgG2, IgG3, or IgG4 subtype. In certain embodiments, the anti-CD38 antibody is of the IgG1 subtype. In particular embodiments, the anti-CD38 antibody is of the IgG1 / κ subtype. In some embodiments, the anti-CD38 antibody is daratumumab.

[0031] In certain embodiments, the pharmaceutical composition further comprises a hyaluronidase. In certain embodiments, the hyaluronidase is rHuPH20 recombinant hyaluronidase.

[0032] In some embodiments, the anti-CD38 antibody is administered as a pharmaceutical composition comprising about 1,200 mg to about 5,000 mg of the anti-CD38 antibody, hi some embodiments, the pharmaceutical composition comprises about 1,800 mg of the anti-CD38 antibody.

[0033] In some embodiments, the pharmaceutical composition further comprises hyaluronidase. In some embodiments, the hyaluronidase is rHuPH20 recombinant hyaluronidase. In some embodiments, the pharmaceutical composition comprises about 750 U to about 75,000 U of hyaluronidase. In some embodiments, the pharmaceutical composition comprises about 30,000 U of hyaluronidase.

[0034] In some embodiments, the anti-CD38 antibody and hyaluronidase are administered as a co-formulation.

[0035] In some embodiments, the anti-CD38 antibody is administered as a pharmaceutical composition comprising about 1,800 mg of anti-CD38 antibody and about 30,000 U of hyaluronidase.

[0036] In some embodiments, the pharmaceutical composition comprises: Approximately 4.9 mg of L-histidine, Approximately 18.4 mg of L-histidine hydrochloride monohydrate; Approximately 13.5 mg of L-methionine, Approximately 6 mg of polysorbate 20 (PS-20), and and about 735.1 mg sorbitol.

[0037] In some embodiments, the pharmaceutical composition has a pH of about pH 5.5. In other embodiments, the pharmaceutical composition has a pH of about pH 5.6.

[0038] In some embodiments, the pharmaceutical composition has a total volume of about 15 mL.

[0039] In some embodiments, the anti-CD38 antibody is administered subcutaneously.

[0040] In some embodiments, the subject is 18 years of age or older.

[0041] In some embodiments, the subject is anti-CD38 antibody treatment naive.

[0042] In some embodiments, the subject has previously received at least two lines of anti-myeloma therapy. In certain embodiments, the previously received at least two lines of anti-myeloma therapy include administration of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), hematopoietic stem cell transplantation (HSCT), maintenance therapy, or a combination thereof. In certain embodiments, the IMid is lenalidomide. In some embodiments, the PI is bortezomib, carfilzomib, or ixazomib. In certain embodiments, the HSCT is an autologous HSCT, and the two lines of therapy include an IMid and a PI.

[0043] In some embodiments, the subject is refractory to at least one line of therapy.

[0044] In some embodiments, the method induces at least a partial response in the subject. In certain embodiments, the response is partial in the subject.

[0045] In some embodiments, the method induces at least a very good partial response in the subject. In certain embodiments, the method induces a complete response in the subject. In particular embodiments, the method induces a stringent complete response in the subject.

[0046] In some embodiments, the method improves one or more outcome measures in the subject. In some embodiments, the one or more outcome measures include progression-free survival, duration of response, or at least partial response, or any combination thereof. In some embodiments, the one or more outcome measures include partial response, very good partial response, complete response, or stringent complete response.

[0047] In some embodiments, subjects experience improvement in one or more outcome measures that are consistent with subjects receiving anti-CD38 antibody administration and continued corticosteroid administration, in other words, the difference in improvement in subjects treated with the methods described herein and subjects treated without the reduction or elimination of corticosteroid administration is not (statistically) significant.

[0048] In some embodiments, subjects experience enhanced improvement in one or more outcome measures compared to subjects receiving anti-CD38 antibody administration and continued corticosteroid administration, in other words, subjects treated with the methods described herein and subjects treated without the reduction or elimination of corticosteroid administration experience improvement.

[0049] In some embodiments, the method further comprises administering to the subject one or more additional therapeutic agents. In certain embodiments, the one or more additional therapeutic agents comprise chimeric antigen receptor (CAR)-expressing T cells (CAR-T cells), CAR-expressing natural killer cells (CAR-NK cells), CAR-expressing macrophages (CAR-M cells), a chemotherapeutic agent, a bispecific antibody, an immune checkpoint inhibitor, or a combination thereof.

[0050] In some embodiments, the CAR-T cells (CART cells), CAR-NK cells, or CAR-M cells are allogeneic. In some embodiments, the CAR comprises an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain, the intracellular signaling domain comprising a T cell surface glycoprotein CD3 zeta chain component.

[0051] In some embodiments, the extracellular antigen binding domain binds to a G protein-coupled receptor family C group 5 member D (GPRC5D) antigen. In certain embodiments, the extracellular antigen binding domain binds to GPRC5D and CD3. In certain embodiments, the one or more additional therapeutic agents comprise an anti-GPRC5D CAR-T, and an anti-GPRC5D CAR-NK.

[0052] In some embodiments, the extracellular antigen binding domain binds to a B-cell maturation antigen (BCMA) antigen. In certain embodiments, the extracellular antigen binding domain binds to BCMA and CD3. In particular embodiments, the one or more additional therapeutic agents comprise an anti-BCMA CAR-T, and an anti-BCMA CAR-NK.

[0053] In certain embodiments, the immune checkpoint inhibitor comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, an anti-CTLA-4 antibody, or a combination thereof.

[0054] In some embodiments, the T cell redirector comprises a soluble bispecific antibody (bsAb) or a membrane-anchored chimeric antigen receptor, or a combination thereof. In some embodiments, the bispecific antibody binds to GPRC5D. In certain embodiments, the bispecific antibody binds to GPRC5D and CD3. In some embodiments, the bispecific antibody binds to BCMA. In certain embodiments, the bispecific antibody binds to BCMA and CD3. [Brief description of the drawings]

[0055] This patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0056] The foregoing will become apparent from the following more particular description of exemplary embodiments, as illustrated in the accompanying drawings, in which like reference characters represent the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the embodiments. [Figure 1] Figure 1 shows the study design for PAVO Part 3. Patients received either a 3-week taper schedule, a 2-week taper schedule, or a 1-week taper schedule. RRMM, relapsed or refractory multiple myeloma; DARA SC, subcutaneous daratumumab; rHuPH20, recombinant human hyaluronidase PH20; IV, intravenous; ORR, overall response rate; CR, complete response. Pre- and post-treatment medications included acetaminophen, diphenhydramine, montelukast, and methylprednisolone. Weekly in cycles 1 and 2, every 2 weeks in cycles 3-6, and every 4 weeks thereafter. [Figure 2A]FIG. 2 shows the corticosteroid taper schedule for each cohort. Patients in the 3-week taper cohort were corticosteroid-free by day 22 of cycle 1 (FIG. 2A), patients in the 2-week taper cohort were corticosteroid-free by day 15 of cycle 1 (FIG. 2B), and patients in the 1-week taper group were corticosteroid-free by day 8 of cycle 1 (FIG. 2C). C, cycle; CS, corticosteroid; D, day; DEX, dexamethasone; DLT, dose-limiting toxicity; IV, intravenous; MP, methylprednisolone; PO, oral. [Figure 2B] FIG. 2 shows the corticosteroid taper schedule for each cohort. Patients in the 3-week taper cohort were corticosteroid-free by day 22 of cycle 1 (FIG. 2A), patients in the 2-week taper cohort were corticosteroid-free by day 15 of cycle 1 (FIG. 2B), and patients in the 1-week taper group were corticosteroid-free by day 8 of cycle 1 (FIG. 2C). C, cycle; CS, corticosteroid; D, day; DEX, dexamethasone; DLT, dose-limiting toxicity; IV, intravenous; MP, methylprednisolone; PO, oral. [Figure 2C] FIG. 2 shows the corticosteroid taper schedule for each cohort. Patients in the 3-week taper cohort were corticosteroid-free by day 22 of cycle 1 (FIG. 2A), patients in the 2-week taper cohort were corticosteroid-free by day 15 of cycle 1 (FIG. 2B), and patients in the 1-week taper group were corticosteroid-free by day 8 of cycle 1 (FIG. 2C). C, cycle; CS, corticosteroid; D, day; DEX, dexamethasone; DLT, dose-limiting toxicity; IV, intravenous; MP, methylprednisolone; PO, oral. [Diagram 3] FIG. 1 shows serum daratumumab concentrations (μg / mL) over time (from baseline to cycle 1, day 22). FIG. 2 shows box plots of serum daratumumab concentrations over time in the pharmacokinetically evaluable population. [Figure 4]FIG. 1 shows serum daratumumab concentrations (μg / mL) over time (from cycle 2, day 1 onwards). FIG. 2 shows box plots of serum daratumumab concentrations over time in the pharmacokinetically evaluable population. [Diagram 5] Figure 1 shows response rates in the entire treated patient population. PR, partial response; VGPR, very good partial response; CR, complete response; ORR, overall response rate. Detailed Description of the Invention

[0057] A description of exemplary embodiments follows below.

[0058] Although exemplary embodiments have been particularly shown and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the embodiments encompassed by the appended claims.

[0059] Various publications, articles and patents are cited or described in the "Background" and throughout the specification, and each of these references is incorporated herein by reference in its entirety. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the specification is for the purpose of providing a context for the present invention. Such discussion is not an admission that any or all of these items constitute part of the prior art to any invention disclosed or claimed.

[0060] The present disclosure is based, at least in part, on the discovery that daratumumab treatment allows for rapid steroid tapering in patients with relapsed or refractory multiple myeloma.

[0061] "Relapse" refers to disease progression after an initial response to prior treatment, but more than 60 days after cessation of treatment. "Refractory disease" refers to less than 25 percent (%) decline in M ​​protein or disease progression during treatment or within 60 days after cessation of treatment.

[0062] In one aspect, the disclosure provides a method of treating a hematological malignancy, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody and a corticosteroid for a period of time sufficient to treat the hematological malignancy, wherein the dosing regimen includes a reduction, elimination, or reduction followed by elimination of corticosteroid administration to the patient.

[0063] In another aspect, the disclosure provides a method of treating a hematological malignancy, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody for a period of time sufficient to treat the hematological malignancy, wherein the dosing regimen results in a reduction, elimination, or reduction and elimination of corticosteroid use by the patient.

[0064] In another aspect, the disclosure provides a method of treating a hematological malignancy, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody and a corticosteroid dose of <2 mg / kg / day, or an equivalent dose, for a period of time sufficient to treat the hematological malignancy.

[0065] In another aspect, the disclosure provides a method of treating a hematological malignancy, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody, without concomitant administration of a corticosteroid, for a period of time sufficient to treat the hematological malignancy.

[0066] In another aspect, the disclosure provides a method of treating a hematological malignancy, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody for a period of time sufficient to treat the hematological malignancy, wherein disease control or complete remission is achieved and / or maintained at a corticosteroid dose of ≦2 mg / kg / day or equivalent.

[0067] Anti-CD38 antibody The term "CD38" refers to the CD38 protein (synonyms include ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP-ribose hydrolase 1). In some embodiments, CD38 is human CD38 (SEQ ID NO: 1). Human CD38 is a single-pass type II membrane protein, with amino acid residues 1 to 21 representing the cytoplasmic domain, amino acid residues 22 to 42 representing the transmembrane domain, and amino acid residues 43 to 300 representing the extracellular domain. Human CD38 has the amino acid sequence set forth in GenBank Accession No. NP001766. The amino acid sequences of SEQ ID NO: 1 to SEQ ID NO: 40 are set forth in Table 1.

[0068] [Table 1-1]

[0069] [Table 1-2]

[0070] In some embodiments, the anti-CD38 antibodies of the present disclosure bind to human CD38 (SEQ ID NO: 1). In some embodiments, the anti-CD38 antibodies are specific for a human CD38 epitope. "Epitope" refers to a portion of an antigen to which an antibody specifically binds. An epitope typically consists of a surface grouping of chemically active (such as polar, non-polar, or hydrophobic) moieties, such as amino acids or polysaccharide side chains, and may have specific three-dimensional structural characteristics as well as specific charge characteristics. An epitope may be composed of contiguous and / or discontinuous amino acids that form a conformational spatial unit. In discontinuous epitopes, amino acids in different parts of the linear sequence of the antigen are brought into close proximity in three-dimensional space due to folding of the protein molecule. In certain embodiments, the anti-CD38 antibodies bind at least to the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1). Antibodies that bind to a region of human CD38 (SEQ ID NO:1) having the sequence SKRNIQFSCKNIYR (SEQ ID NO:2) and a region having the sequence EKVQTLEAWVIHGG (SEQ ID NO:3) may be generated, for example, by immunizing mice with peptides having the amino acid sequences shown in SEQ ID NO:2 and SEQ ID NO:3, using standard methods and those described herein, and characterizing the resulting antibodies for binding to the peptides, for example, using ELISA or mutagenesis assays.

[0071] As used herein, the term "anti-CD38 antibody" refers to an immunoglobulin molecule capable of specifically binding to CD38 through at least one antigen recognition site located in the variable region of the immunoglobulin molecule. Typically, antibodies have an equilibrium dissociation constant (K D ) is typically taken as the K for binding to a non-specific antigen (e.g., BSA, casein) D At least 100 times smaller than about 1 × 10 -8 M or less, for example, about 1×10 -9 M or less, approximately 1×10 -10 M or less, approximately 1×10 -11 M or less, approximately 1×10 -12 K below M Dand binds to CD38. D may be measured using standard procedures. However, antibodies that specifically bind to CD38 may have cross-reactivity to other related antigens, e.g., the same antigen (homolog) from other species, such as monkeys, e.g., cynomolgus (cyno), chimpanzee (chimp), or common marmoset (marmoset). In one embodiment, the anti-CD38 antibody binds to an epitope on human CD38 that includes amino acid residues 233 to 246 and amino acid residues 267 to 280 of CD38.

[0072] As used herein, the term "antibody" refers to a full length antibody or an antigen-binding fragment of a full length antibody.

[0073] A full-length antibody comprises two heavy (H) chains and two light (L) chains interconnected by disulfide bonds or multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (V H ), and a heavy chain constant region (comprising domains CH1, hinge CH2, and CH3). Each light chain comprises a light chain variable region (V L ), and the light chain constant region (CL). H Area and V L The regions are interspersed within the framework regions (FR) and may be further divided into regions of hypervariability, termed Complementarity Determining Regions (CDRs). H and V L Each is composed of three CDR and four FR segments arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0074] The "complementarity determining region (CDR)" is the "antigen binding site" in an antibody. "CDR" refers to any of the art-recognized methods for identifying CDR residues of an antibody, such as those described by Kabat (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 based on sequence variability, Wu and Kabat, J Exp Med 132:211-50 (1970); Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., USDepartment of Health and Human Services, NIH Publication No. 91-3242 (1991)), Chothia ("Hypervariable regions" (HVR or HV) H1, H2, H3, L1, L2, and L3, Chothia & Lesk, Mol Biol 196:901-17 (1987); Chothia et al., (1989) Nature 342:877)), International It encompasses any CDR defined by the ImMunoGeneTics (IMGT) database (standardized numbering and definition of antigen-binding sites, www_imgt_org), AbM definition, or contact definition. The correspondence between CDR, HV, and IMGT descriptions is described in Lefranc et al., Dev.Comparat.Immunol.27:55-77 (2003). See also Al-lazikani et al., J Molec Biol 273:927-48 (1997), Almagro, J Mol Recognit 17:132-43 (2004), and hgmp.mrc.ac.uk and bioinf.org.uk / .Public and / or commercially available tools for identifying framework and / or CDR regions include IgBlast (www_ncbi_nlm_nih_gov / igblast / ), Scaligner (drugdesigntech, www_scaligner_com / ), IMGT rules and / or tools (www_imgt_org / IMGTScientificChart / Nomenclature / IMGT-FRCDRdefinition), Chothia canonical assignment (www_bioinf_org_uk / abs / Chothia_html), Antigen receptor Numbering And Receptor Calcification (ANARCI, opig.stats.ox.ac.uk / webapps / newsabdab / sabpred / anarci / ), or the Paratome web server (www_ofranlab_org) / paratome / , Kunik et al., Nucleic Acids Research 40(W1):W521-W524 (2012). Unless expressly stated otherwise, the terms "CDR", "HCDR1", "HCDR2", "HCDR3", "LCDR1", "LCDR2" and "LCDR3" as used herein include CDRs defined by any of the methods described above, e.g., by Kabat, Chothia and Lesk, or IMGT. Two antibodies are determined to have the same CDRs as each other with respect to HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and / or LCDR3 if the identity of their CDRs is determined for both antibodies using the same method.

[0075] In some embodiments, the anti-CD38 antibody is a) the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively; b) with the amino acid sequences of light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively; or c) Includes both a) and b).

[0076] In some embodiments, the anti-CD38 antibody is a) the amino acid sequences of HCDR1, HCDR2, and HCDR3 of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively; and b) comprising the amino acid sequences of LCDR1, LCDR2, and LCDR3 of SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11, respectively.

[0077] In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region (VH) amino acid sequence of SEQ ID NO: 4. In some embodiments, the anti-CD38 antibody comprises a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 4, e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO: 4. In some embodiments, the sequence identity is about 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%.

[0078] As used herein, the term "identical" or "having sequence identity" refers to the degree to which two amino acid sequences have the same residues at the same positions when the sequences are aligned to achieve the maximum level of identity, expressed as a percentage. In sequence alignment and comparison, typically, one sequence is designated as a reference sequence to which a test sequence is compared. The sequence identity between a reference sequence and a test sequence is expressed as the percentage of positions over the entire length of the reference sequence where the reference sequence and the test sequence share the same amino acid when aligned to achieve the maximum level of identity. As an example, if the test sequence has the same amino acid residues at 70% of the same positions over the entire length of the reference sequence when aligned to achieve the maximum level of identity, the two sequences are considered to have 70% sequence identity.

[0079] In some embodiments, the anti-CD38 antibody comprises a light chain variable region (VL) amino acid sequence of SEQ ID NO: 5. In some embodiments, the anti-CD38 antibody comprises a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 5, e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO: 5. In some embodiments, the sequence identity is about 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%.

[0080] In some embodiments, the anti-CD38 antibody is a) a VH amino acid sequence that is at least 95% identical to SEQ ID NO:4; b) a VL amino acid sequence that is at least 95% identical to SEQ ID NO:5; or c) Includes both a) and b).

[0081] In some embodiments, the anti-CD38 antibody is a) a VH amino acid sequence that is at least 95% identical to SEQ ID NO:4, and b) comprises a VL amino acid sequence that is at least 95% identical to SEQ ID NO:5.

[0082] In certain embodiments, the anti-CD38 antibody is a) the VH amino acid sequence of SEQ ID NO: 4; b) the VL amino acid sequence of SEQ ID NO:5, or c) Includes both a) and b).

[0083] In certain embodiments, the anti-CD38 antibody is a) the VH amino acid sequence of SEQ ID NO: 4, and b) comprises the VL amino acid sequence of SEQ ID NO:5.

[0084] In some embodiments, the anti-CD38 antibody comprises a heavy chain amino acid sequence that is at least 80% identical to SEQ ID NO:12, e.g., about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:4. In certain embodiments, the sequence identity is about 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the anti-CD38 antibody comprises the heavy chain amino acid sequence of SEQ ID NO:12.

[0085] In some embodiments, the anti-CD38 antibody comprises a light chain amino acid sequence that is at least 80% identical to SEQ ID NO:13, e.g., about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:13. In certain embodiments, the sequence identity is about 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the anti-CD38 antibody comprises a light chain amino acid sequence of SEQ ID NO:13.

[0086] In some embodiments, the anti-CD38 antibody is a) a heavy chain amino acid sequence that is at least 95% identical to SEQ ID NO:12; b) a light chain amino acid sequence that is at least 95% identical to SEQ ID NO: 13; or c) Includes both a) and b).

[0087] In some embodiments, the anti-CD38 antibody is a) a heavy chain amino acid sequence that is at least 95% identical to SEQ ID NO:12, and b) comprises a light chain amino acid sequence that is at least 95% identical to SEQ ID NO:13.

[0088] In some embodiments, the anti-CD38 antibody is a) the heavy chain amino acid sequence of SEQ ID NO: 12; b) the light chain amino acid sequence of SEQ ID NO: 13, or c) Includes both a) and b).

[0089] In some embodiments, the anti-CD38 antibody is a) the heavy chain amino acid sequence of SEQ ID NO: 12, and b) comprises the light chain amino acid sequence of SEQ ID NO:13.

[0090] In some embodiments, the anti-CD38 antibody is a) a VH of SEQ ID NO: 14 and a VL of SEQ ID NO: 15; b) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; c) a VH of SEQ ID NO: 18 and a VL of SEQ ID NO: 19, or d) comprising the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0091] In some embodiments, the anti-CD38 antibody is a) SEQ ID NO:14 and SEQ ID NO:15, respectively; b) SEQ ID NO: 16 and SEQ ID NO: 17, respectively; c) SEQ ID NO: 18 and SEQ ID NO: 19, respectively; or d) comprising the VH and VL amino acid sequences of SEQ ID NO:20 and SEQ ID NO:21, respectively.

[0092] Immunoglobulins may be assigned to five major classes, namely IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of the heavy chain constant domain. IgA is further subclassified into isotypes IgA1, IgA2. IgG is further subclassified into IgG1, IgG2, IgG3, and IgG4. Antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domain.

[0093] In some embodiments, the anti-CD38 antibody is of the IgG1, IgG2, IgG3, or IgG4 subtype. In some embodiments, the anti-CD38 antibody is of the IgG1 subtype. There is some variation (e.g., known allotypes) within the IgG1 constant domain, with variations at positions 214, 356, 358, 422, 431, 435, or 436 (numbering of residues according to EU numbering) (see, e.g., IMGT Web resources, IMGT Repertoire (IG and TR), Proteins and alleles, allotypes). The anti-CD38 antibody may be any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28. In some embodiments, the anti-CD38 antibody is of the κ subtype. In some embodiments, the anti-CD38 antibody is of the IgG1 / κ subtype.

[0094] The antibody can be of any species, such as a murine antibody, a human antibody, a chimeric antibody (e.g., a humanized antibody), etc. In some embodiments, the anti-CD38 antibody is a human antibody.

[0095] "Humanized antibody" refers to an antibody in which the antigen binding site is derived from a species other than human and the variable region framework is derived from a human immunoglobulin sequence. Because humanized antibodies may contain mutations intentionally introduced within the framework regions, such frameworks may not be exact copies of expressed human immunoglobulin or germline gene sequences.

[0096] "Human antibody" refers to an antibody having heavy and light chain variable regions in which both the framework and antigen binding sites are derived from sequences of human origin. If the antibody contains a constant region or a portion of a constant region, the constant region also is derived from sequences of human origin. Antibodies in which the antigen binding site is derived from a species other than human are not included in the definition of "human antibody."

[0097] A human antibody comprises a heavy or light chain variable region derived from a sequence of human origin, where the variable region of the antibody is obtained from a system using human germline immunoglobulin or rearranged immunoglobulin genes. Non-limiting exemplary systems include human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals carrying human immunoglobulin loci, such as mice or rats. Human antibodies typically contain amino acid differences compared to human germline or rearranged immunoglobulin sequences due to, for example, naturally occurring somatic mutations, deliberate substitutions in frameworks or antigen-binding sites, and substitutions introduced during cloning or VDJ recombination in the non-human animal. Typically, human antibodies are at least 80% identical in amino acid sequence to the amino acid sequences encoded by human germline or rearranged immunoglobulin genes. For example, about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. In some cases, the human antibody may contain consensus framework sequences obtained from human framework sequence analysis (see, e.g., Knappik et al., J. Mol. Biol. 296:57-86 (2000)), or synthetic HCDR3s incorporated into a human immunoglobulin gene library displayed on phage (see, e.g., Shi et al., J. Mol. Biol. 397:385-96 (2010) and WO 2009 / 085462).

[0098] In some embodiments, the anti-CD38 antibody is daratumumab. Daratumumab is an IgG1 / kappa subtype and is described in U.S. Patent No. 7,829,673. Daratumumab comprises the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively, and the LCDR1, LCDR2, and LCDR3 amino acid sequences of SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11, respectively. Daratumumab comprises the VH amino acid sequence of SEQ ID NO:4, and the VL amino acid sequence of SEQ ID NO:5. Daratumumab comprises the heavy chain amino acid sequence of SEQ ID NO:12, and the light chain amino acid sequence of SEQ ID NO:13.

[0099] In some embodiments, the daratumumab is the DARZALEX® brand of daratumumab or a biosimilar of the DARZALEX® brand of daratumumab. Daratumumab can be prepared by any method known in the art for preparing monoclonal antibodies, including but not limited to hybridoma production. For example, daratumumab can be produced in mammalian cell lines (e.g., CHO cell lines) using recombinant DNA technology. Daratumumab and methods of producing daratumumab are further described, for example, in WO2006099875, U.S. Patent No. 7,829,673, U.S. Patent No. 2015246123, and de Weers et al., J. Immunol. 186:1840-48 (2011), the contents of which are incorporated herein by reference.

[0100] In some embodiments, the anti-CD38 antibody comprises a mutation in at least one amino acid residue selected from those corresponding to E345, E430, S440, Q386, P247, I253, S254, Q311, D / E356, T359, E382, Y436, and K447 in the Fc region of a human IgG1 heavy chain to increase effector function. Non-limiting examples of effector functions include antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), antibody-mediated binding of opsonized antibodies to complement receptors, C1q binding, complement activation, complement-dependent cytotoxicity (CDCC), complement-dependent cytotoxicity (CDC), complement-enhanced cytotoxicity, downregulation, Fcγ receptor binding, FcRn binding, induction of apoptosis, internalization, oligomer (e.g., hexamer) formation, oligomer (e.g., hexamer) stability, opsonization, protein A binding, and protein G binding. Non-limiting examples of mutations, such as mutations that increase hexamer formation, hexamer stability, or both, can be found in WO 13 / 004842 and WO 20 / 012036, which are incorporated by reference in their entireties. In some embodiments, the anti-CD38 antibody is HexaBody-CD38 (GEN3014).

[0101] Other non-limiting examples of anti-CD38 antibodies that may be used in the methods of the invention include mAb003, mAb024, MOR-202 (MOR-03087), isatuximab, and anti-CD38 antibodies described in WO 05 / 103083, WO 06 / 125640, WO 07 / 042309, WO 08 / 047242, and WO 14 / 178820, etc. mAb003, which comprises the VH and VL amino acid sequences of SEQ ID NO:14 and SEQ ID NO:15, respectively, is described in U.S. Patent No. 7,829,673. mAb024, which comprises the VH and VL amino acid sequences of SEQ ID NO:16 and SEQ ID NO:17, respectively, is described in U.S. Patent No. 7,829,673. MOR-202 (MOR-03087) comprising the VH and VL amino acid sequences of SEQ ID NO: 18 and SEQ ID NO: 19, respectively, is described in U.S. Patent No. 8,088,896. Isatuximab comprising the VH and VL amino acid sequences of SEQ ID NO: 20 and SEQ ID NO: 21, respectively, is described in U.S. Patent No. 8,153,765. The VH and VL of mAb003, mAb024, MOR-202 or isatuximab, or combinations thereof, may be expressed as IgG1 / κ.

[0102] The anti-CD38 antibodies used in the methods of the invention may be selected de novo from, for example, a phage display library, where the phage are engineered to express human immunoglobulins or portions thereof, such as Fabs, single chain antibodies (scFvs), or unpaired or paired antibody variable regions (Knappik et al., J. Mol. Biol. 296:57-86 (2000); Krebs et al., J. Immunol. Meth. 254:67-84 (2001); Vaughan et al., Nature Biotechnology 14:309-14 (1996); Sheets et al., PITAS (US) 95:6157-62 (1998); Hoogenboom & Winter, J. Mol. Biol. 227:381 (1991); Marks et al., J. Mol. Biol. 222:581 (1991). CD38-binding variable domains can be isolated from phage display libraries expressing antibody heavy and light chain variable regions as fusion proteins with bacteriophage pIX coat protein, for example as described in Shi et al., J. Mol. Biol. 397:385-96 (2010) and WO 09 / 085462. Antibody libraries can be screened for binding to human CD38 extracellular domain, the resulting positive clones further characterized, and Fabs isolated from clonal lysates and subsequently cloned as full-length antibodies. Such phage display methods for isolating human antibodies are well established in the art. See, e.g., U.S. Patent Nos. 5,223,409, 5,403,484, 5,427,908, 5,571,698, 5,580,717, 5,885,793, 5,969,108, 6,172,197, 6,521,404, 6,544,731, 6,555,313, 6,582,915, and 6,593,081.

[0103] In some embodiments, the anti-CD38 antibody has a titer of about 1×10 as determined by surface plasmon resonance or KinExA as performed by one of skill in the art. -7 , 1×10 -8, 1×10 -9 , 1×10 -10 , 1×10 -11 , 1×10 -12 , 1×10 -13 , 1×10 -14 , or 1 × 10 -15 Dissociation constant (K D ) binds to human CD38. In some embodiments, the antibody binds to human CD38 at about 1×10 -8 K less than M D In some embodiments, the antibody binds to human CD38 at about 1 x 10 -9 K less than M D It binds to human CD38 at 100 ng / mL.

[0104] KinExA instruments, ELISA or competitive binding assays are well known to those skilled in the art. The measured affinity of a particular antibody / CD38 interaction may differ when measured under different conditions (e.g., osmolarity, pH). Thus, affinity and other binding parameters (e.g., K D , K on , K off Measurements of K are typically performed under standardized conditions and with standardized buffers. Those skilled in the art will appreciate that the internal error (measured as the Standard Deviation (SD)) of affinity measurements using, for example, Biacore 3000 or ProteOn can usually be in the range of 5-33% of the measurement result within the typical detection limit. Thus, K D The term "about" in the context of reflects the typical standard deviation in an assay. D is 1×10 -9 Typical SD for M is up to ±0.33×10 -9 It's M.

[0105] The term "antigen-binding fragment" refers to a portion of an immunoglobulin molecule (e.g., an antibody) that retains the antigen-binding properties of the parent full-length antibody. Non-limiting examples of antigen-binding fragments include HCDR1, HCDR2 and / or HCDR3, LCDR1, LCDR2 and / or LCDR3, V H area, V Lregion, Fab fragment, F(ab')2 fragment, Fd fragment, Fv fragment, and one V H Domain or one V L Examples include domain antibodies (dAbs) that consist of domains. H Domain and V L The domains can be linked together via synthetic linkers to form a variety of single chain antibody designs, where V H / V L Domains may be paired intramolecularly or V H Domain and V L When the domains are expressed by separate chains, they pair intermolecularly to form monovalent antigen-binding sites, such as single-chain Fvs (scFvs), or diabodies, see, e.g., WO 1998 / 44001, WO 1988 / 01649, WO 1994 / 13804, and WO 1992 / 01047.

[0106] In some embodiments, the anti-CD38 antibody is a human monoclonal antibody (mAb) or an antigen-binding fragment thereof.

[0107] The term "anti-CD38 antibody" is meant in a broad sense to include multiparatopic antibodies, monospecific and multispecific (e.g., bispecific) antibodies, monoclonal antibodies (including murine, human, humanized, and chimeric antibodies), dimeric, tetrameric, and multimeric antibodies, single chain antibodies, domain antibodies, and other modified or engineered configurations of immunoglobulin molecules that contain an antigen binding site of the required specificity.

[0108] "Monoclonal antibody" refers to an antibody population having a single amino acid composition in each heavy and each light chain, except for possible known modifications such as removal of the C-terminal lysine from the antibody heavy chain. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies may be monovalent, bivalent or polyvalent. Monoclonal antibodies may be monospecific or multispecific (e.g., bispecific). A monospecific antibody binds to one antigen epitope. The term monoclonal antibody includes multispecific antibodies such as bispecific or trispecific antibodies.

[0109] "Multispecific" refers to an antibody that specifically binds to at least two different antigens, or at least two different epitopes within an antigen, e.g., three, four, or five different antigens or epitopes. "Bispecific" refers to an antibody that specifically binds to two different antigens, or two different epitopes within the same antigen.

[0110] An "isolated antibody" refers to an antibody or antigen-binding fragment that is substantially free of other antibodies having different antigen specificities (e.g., an isolated anti-CD38 antibody is substantially free of antibodies that specifically bind to antigens other than human CD38). In the case of a bispecific antibody, the bispecific antibody specifically binds to two antigens of a subject and is substantially free of antibodies that specifically bind to antigens other than the two antigens of the subject. In some embodiments, the anti-CD38 antibody is at least 80% pure, e.g., about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% pure.

[0111] "Recombinant" includes antibodies and other proteins that are prepared, expressed, produced, or isolated by recombinant techniques.

[0112] "Variant" refers to a polypeptide or polynucleotide that differs from a reference polypeptide or polynucleotide by one or more modifications, such as, for example, a substitution, insertion, or deletion, or a combination thereof.

[0113] Pharmaceutical Compositions Anti-CD38 antibody In the methods of the present disclosure, the anti-CD38 antibody may be provided in a suitable pharmaceutical composition.

[0114] In some embodiments, the pharmaceutical composition comprises about 1,200 mg to about 5,000 mg of anti-CD38 antibody, for example, about 1,200 to 4,000, 1,300 to 4,000, 1,300 to 3,500, 1,400 to 3,500, 1,400 to 3,000, 1,500 to 3,000, 1,500 to 2,500, 1,600 to 2,500, 1,600 to 2,000, 1,700 to 2,000, 1,700 to 1,900, or 1,800 to 1,900 mg of anti-CD38 antibody. In certain embodiments, the pharmaceutical composition comprises about 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2500, 3,000, 3,500, 4,000, 4,500, or 5,000 mg of anti-CD38 antibody. In some embodiments, the pharmaceutical composition comprises about 1,200, 1,500, 1,800, or 2,000 mg of anti-CD38 antibody. In certain embodiments, the pharmaceutical composition comprises about 1,800 mg of anti-CD38 antibody.

[0115] The concentration of the anti-CD38 antibody included in the pharmaceutical composition can vary. In some embodiments, the pharmaceutical composition comprises about 1 mg / mL to about 180 mg / mL of an anti-CD38 antibody, for example, about 2-180, 2-175, 5-175, 5-170, 10-180, 10-170, 10-165, 20-165, 20-160, 20-140, 20-120, 40-160, 40-155, 40-120, 60-155, 60-150, 60-120, 80-150, 80-145, 80-120, 100-145, 100-140, 100-120, 110-140, 110-135, 115-135, 115-130, or 120-130 mg / mL of an anti-CD38 antibody.

[0116] In some embodiments, the pharmaceutical composition comprises about 1, 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, or 180 mg / mL of anti-CD38 antibody. In certain embodiments, the pharmaceutical composition comprises about 100 mg / mL of anti-CD38 antibody. In some embodiments, the pharmaceutical composition comprises about 140 mg / mL of anti-CD38 antibody. In certain embodiments, the pharmaceutical composition comprises about 120 mg / mL of anti-CD38 antibody.

[0117] The anti-CD38 antibodies may be lyophilized for storage and dissolved in a suitable carrier prior to use. This technique has been shown to be effective with conventional protein preparations, and well-known lyophilization and reconstitution techniques may be used.

[0118] Hyaluronidase In some embodiments, pharmaceutical compositions suitable for use in the methods of the present disclosure are formulated for subcutaneous administration. Non-limiting examples of formulations suitable for subcutaneous administration include solutions, suspensions, emulsions, and dry products that can be dissolved or suspended in a pharma- ceutically acceptable carrier for injection.

[0119] Typically, the extracellular matrix of the subcutaneous tissue becomes an issue when administering larger volumes subcutaneously, as is necessary for antibody solutions and compositions. The space outside the adipocytes in the subcutaneous tissue is not fluid, but a solid extracellular matrix of collagen fibrils embedded in a viscoelastic gel rich in glycosaminoglycans that buffers convective forces. The extracellular matrix limits the volume of drug that can be injected at a single site, as well as the rate and amount that reaches the vascular compartment. Hyaluronidase is an enzyme that breaks down hyaluronic acid (EC 3.2.1.35) and increases tissue permeability by reducing the viscosity of hyaluronan in the extracellular matrix. Thus, co-formulation or co-administration of antibodies with recombinant human hyaluronidase, such as rHuPH20, could increase the injection volume and bioavailability from subcutaneous injections.

[0120] In some embodiments, the pharmaceutical composition further comprises a hyaluronidase. In certain embodiments, the hyaluronidase is rHuPH20 recombinant hyaluronidase. rHuPH20 is a recombinant hyaluronidase (HYLENEX® recombinant) and is described in WO 2004 / 078140. In some embodiments, the hyaluronidase is rHuPH20 having the amino acid sequence of SEQ ID NO:22.

[0121] Hyaluronidase enzyme activity, including rHuPH20, can be defined by units per mL (U / mL) or total enzyme activity (U) in a particular preparation. The standard definition of 1 unit (U) of enzyme activity is the amount of enzyme that catalyzes the reaction of 1 nmol of substrate per minute.

[0122] In some embodiments, the pharmaceutical composition comprises about 750 U to about 75,000 U of hyaluronidase. In certain embodiments, the pharmaceutical composition comprises about 7,500 U to about 45,000 U of hyaluronidase. In certain embodiments, the pharmaceutical composition comprises about 30,000 U to about 45,000 U of hyaluronidase.

[0123] In some embodiments, the pharmaceutical composition comprises about 7,500, 8,000, 8,500, 9,000, 10,000, 15,000, 20,000, 21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,000, 28,000, 29,000, 30,000, 31,000, 32,000, 33,000, 34,000, , 35,000, 36,000, 37,000, 38,000, 39,000, 40,000, 41,000, 42,000, 43,000, 44,000, 45,000, 46,000, 47,000, 48,000, 49,000, 50,000, 55,000, 60,000, 65,000, 70,000, or 75,000 U of hyaluronidase. In certain embodiments, the pharmaceutical composition comprises about 30,000 U of hyaluronidase.

[0124] In some embodiments, the pharmaceutical composition contains about 50 U / mL to about 5,000 U / mL of hyaluronidase, for example, about 50-2,000, 500-5,000, 500-4,000, 500-2,000, 800-4,000, 800-3,500, 1,000-5,000, 1,000-3,500, 1,000-3,000, 1,200-3,000, 1,200-2,500, 1,500-2,500, 1,500-2,200, 1,800-2,200, 1,800-2,000, or 2,000-5,000 U / mL of hyaluronidase.

[0125] In some embodiments, the pharmaceutical composition comprises at least about 500 U / mL, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, Contains 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700, 4,800, 4,900, or 5,000 U / mL hyaluronidase.

[0126] In some embodiments, the pharmaceutical composition comprises about 50 U / mL of hyaluronidase. In certain embodiments, the pharmaceutical composition comprises about 500 U / mL of hyaluronidase. In other embodiments, the pharmaceutical composition comprises about 5,000 U / mL of hyaluronidase. In certain embodiments, the pharmaceutical composition comprises about 2,000 U / mL of hyaluronidase.

[0127] In some embodiments, the pharmaceutical composition comprises about 1,200, 1,400, 1,600, 1,800, 2,000, 2,200, 2,400, 2,600, 2,800, 3,000, or 5,000 mg of an anti-CD38 antibody and about 30,000 U of hyaluronidase. In certain embodiments, the pharmaceutical composition comprises about 1,200, 1,400, 1,600, 1,800, 2,000, 2,200, 2,400, 2,600, 2,800, 3,000, or 5,000 mg of an anti-CD38 antibody and about 45,000 U of hyaluronidase. In certain embodiments, the pharmaceutical composition comprises about 1,800 mg of an anti-CD38 antibody and about 30,000 U of hyaluronidase.

[0128] Additional information regarding daratumumab and hyaluronidase can be found, for example, in the prescribing information of the DARZALEX FASPRO® product insert (www_janssenlabels_com / package-insert / product-monograph / prescribing-information / DARZALEX+Faspro-pi.pdf), which is incorporated herein by reference.

[0129] Pharmaceutical composition refers to the product obtained by combining an anti-CD38 antibody with a hyaluronidase, and includes both fixed and non-fixed combinations.

[0130] A "fixed combination" refers to a single pharmaceutical composition comprising two or more compounds, e.g., an anti-CD38 antibody and a hyaluronidase, administered together in the form of a single entity or dosage. In some embodiments, the pharmaceutical composition comprising an anti-CD38 antibody and a hyaluronidase is a fixed combination.

[0131] A "non-fixed combination" refers to separate pharmaceutical compositions, each comprising one or more compounds, such as an anti-CD38 antibody and a hyaluronidase, or unit dosage form, that are administered either simultaneously, concurrently, or sequentially as separate entities without specific time restrictions, such administration providing effective levels of the two compounds in the subject. In some embodiments, the pharmaceutical composition comprising an anti-CD38 antibody and a hyaluronidase is a non-fixed combination.

[0132] Pharmaceutically acceptable carriers In some embodiments, the pharmaceutical composition is formulated as a solution.

[0133] A "pharmaceutical acceptable carrier" refers to an ingredient in a pharmaceutical composition other than an active ingredient that is not toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives. A carrier may be a diluent, adjuvant, excipient, or solvent with which the anti-CD38 antibody is administered. Such solvents may be liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. For example, 0.4% saline and 0.3% glycine may be used. These solutions are sterile and generally free of particulate matter. They may be sterilized by conventional, well-known sterilization techniques (e.g., filtration). The compositions may contain pharmaceutical acceptable auxiliary substances required to approximate physiological conditions, such as pH adjusting and buffering agents, stabilizers, thickening agents, lubricants, coloring agents, and the like. The concentration of anti-CD38 antibodies in such pharmaceutical formulations may vary widely, i.e., from less than about 0.5% by weight, up to at least about 1% by weight, up to 15% or 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight. The concentration is selected primarily based on the required dose, fluid volumes, viscosities, etc., according to the mode of administration. Suitable vehicles and formulations, including other human proteins, such as human serum albumin, are described, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition, Troy, DB ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp691-1092 (e.g., pages 958-89).

[0134] In some embodiments, pharmaceutical compositions suitable for use in the methods of the present disclosure further comprise one or more pharma- ceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical composition other than the active ingredient that is non-toxic to a subject and should not interfere with the effectiveness of the active ingredient. Pharmaceutically acceptable carriers include, but are not limited to, those commonly used in the field of pharmaceutical manufacturing, particularly antibody pharmaceutical manufacturing. A carrier may be a diluent, adjuvant, excipient, or solvent administered with an anti-CD38 antibody. Such a solvent may be a liquid, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. For example, 0.4% saline and 0.3% glycine may be used. These solutions are sterile and generally free of particulate matter. They may be sterilized by conventional and well-known sterilization techniques (e.g., filtration). The composition may contain pharma- ceutically acceptable auxiliary substances required to approximate physiological conditions, such as pH adjusting and buffering agents, stabilizers, thickeners, lubricants, and colorants. The concentration of anti-CD38 antibodies in such pharmaceutical formulations may vary widely, for example from less than about 0.5% by weight, usually at least about 1% by weight, up to 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight. The concentration is selected primarily based on the required dose, fluid volume, viscosity, and the like, according to the particular mode of administration selected. Suitable vehicles and formulations, including other human proteins, such as human serum albumin, are described, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition, Troy, DB ed., Lipincott Williams and Wilkins, Philadelphia, Pa. 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092 (see especially pp. 958-89).

[0135] Non-limiting examples of pharma- ceutically acceptable carriers include physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, such as salts, buffers, antioxidants, sugars, aqueous or nonaqueous carriers, preservatives, wetting agents, surfactants or emulsifiers, or combinations thereof.

[0136] Non-limiting examples of buffers that can be used are acetate, citrate, formate, succinate, phosphate, carbonate, malate, aspartate, histidine, borate, Tris buffer, HEPPSO, and HEPES.

[0137] Non-limiting examples of antioxidants that can be used are ascorbic acid, methionine, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, lecithin, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, and tartaric acid.

[0138] Non-limiting examples of amino acids that can be used are histidine, isoleucine, methionine, glycine, arginine, lysine, L-leucine, trileucine, alanine, glutamic acid, L-threonine, and 2-phenylamine.

[0139] Non-limiting examples of surfactants that may be used include polysorbates (e.g., polysorbate-20 or polysorbate-80), poloxamers (e.g., poloxamer 188), triton, sodium octyl glycoside, lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine, lauryl-, myristyl-, linoleyl-, or stearyl-sarcosine, linoleyl-, myristyl-, or cetyl-betaine, lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl), myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine, sodium methyl cocoyl-, or disodium methyl oleyl-taurate, and the MONAQUA® series (Mona Industries, Inc. (Paterson, NJ), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (eg, PLURONICS™, PF68, etc.).

[0140] Non-limiting examples of preservatives that may be used are phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof.

[0141] Non-limiting examples of sugars that may be used are monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, such as glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, dextran, erythritol, glycerol, arabitol, siritol, sorbitol, mannitol, melibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, glucitol, maltitol, lactitol, or isomaltulose.

[0142] Non-limiting examples of salts that can be used are acid addition salts and base addition salts. Acid addition salts include those derived from non-toxic inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, and the like, and non-toxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium, and the like, and non-toxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like. In some embodiments, the salt is sodium chloride (NaCl).

[0143] The amount of pharma- ceutically acceptable carrier(s) in a pharmaceutical composition may be determined empirically based on the activity of the carrier(s) and the desired properties of the formulation, e.g., stability and / or minimal oxidation.

[0144] In some embodiments, the pharmaceutical composition comprises histidine at a concentration of about 1 mM to about 50 mM, e.g., about 2-50, 2-40, 5-50, 5-40, 5-30, 5-20, 5-15, 5-10, 10-30, or 10-20 mM. In some embodiments, the pharmaceutical composition comprises histidine at a concentration of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mM. In certain embodiments, the pharmaceutical composition comprises histidine at a concentration of about 10 mM. In particular embodiments, the pharmaceutical composition comprises L-histidine at a concentration of about 2.1 mM and L-histidine hydrochloride monohydrate at a concentration of about 5.9 (e.g., 5.8-5.9) mM.

[0145] In some embodiments, the pharmaceutical composition contains methionine at a concentration of about 0.1 mg / mL to about 5 mg / mL, for example, about 0.1 to 4.5, 0.1 to 4.0, 0.1 to 2.5, 0.2 to 5.0, 0.2 to 4.0, 0.2 to 3.5, 0.3 to 3.5, 0.3 to 3.0, 0.4 to 3.0, 0.4 to 2.5, 0.5 to 2.5, 0.5 to 4.0, 0.5 to 3.0, 0.5 to 2.0, 0.6 to 2.0, 0.6 to 1.5, 0.7 to 1.5, 0.7 to 1.2, 0.8 to 1.2, 0.8 to 1.0, 1.0 to 3.0, or 1.0 to 2.0 mg / mL. In certain embodiments, the pharmaceutical composition comprises methionine at a concentration of about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 mg / mL.

[0146] In some embodiments, the pharmaceutical composition comprises a polysorbate.

[0147] In some embodiments, the pharmaceutical composition comprises polysorbate-20 (PS-20). In certain embodiments, the pharmaceutical composition comprises PS-20 at a concentration of about 0.01% (w / v) to about 0.1% (w / v), for example, about 0.01-0.08%, 0.01-0.06%, 0.01-0.05%, 0.01-0.04%, 0.02-0.1%, 0.02-0.08%, 0.02-0.06%, 0.03-0.06%, 0.03-0.05%, 0.04-0.08%, or 0.04-0.05% (w / v). In certain embodiments, the pharmaceutical composition comprises PS-20 at a concentration of about 0.04% (w / v).

[0148] In some embodiments, the pharmaceutical composition comprises polysorbate-80 (PS-80). In certain embodiments, the pharmaceutical composition comprises PS-80 at a concentration of about 0.01% (w / v) to about 0.08% (w / v), e.g., about 0.01-0.04%, 0.02-0.1%, 0.02%-0.08%, or 0.04-0.08% (w / v). In some embodiments, the pharmaceutical composition comprises PS-80 at a concentration of about 0.01% (w / v), 0.02% (w / v), 0.03% (w / v), 0.04% (w / v), 0.05% (w / v), 0.06% (w / v), 0.07% (w / v), 0.08% (w / v), 0.09% (w / v), or 0.1% (w / v).

[0149] In some embodiments, the pharmaceutical composition comprises PS-20 and PS-80. In certain embodiments, the pharmaceutical composition comprises PS-20 and PS-80 at a concentration of about 0.01% (w / v) to about 0.08% (w / v), e.g., about 0.01-0.04%, 0.02-0.1%, 0.02%-0.08%, or 0.04-0.08% (w / v). In some embodiments, the pharmaceutical compositions comprise PS-20 and PS-80 at a concentration of about 0.01% (w / v), 0.02% (w / v), 0.03% (w / v), 0.04% (w / v), 0.05% (w / v), 0.06% (w / v), 0.07% (w / v), 0.08% (w / v), 0.09% (w / v), or 0.1% (w / v).

[0150] In some embodiments, the pharmaceutical composition comprises a sugar.

[0151] In some embodiments, the pharmaceutical composition contains a saccharide at a concentration of about 50 mM to about 500 mM, for example, about 50-450, 50-400, 50-350, 60-500, 60-450, 70-450, 70-400, 80-400, 80-350, 90-350, 90-300, 100-450, 100-400, 100-350, 100-300, 150-400, 150-350, 200-350, 200-325, 225-325, 225-300, 250-300, or 250-275 mM. In certain embodiments, the pharmaceutical composition comprises a saccharide at a concentration of about 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500 mM.

[0152] In some embodiments, the sugar is sorbitol.

[0153] In some embodiments, the pharmaceutical composition contains sorbitol at a concentration of about 50 mM to about 500 mM, e.g., about 50-450, 50-400, 50-350, 100-450, 100-400, 100-350, 100-300, 150-400, 150-350, 200-350, 200-325, 225-325, 225-300, 250-300, or 250-275 mM. In certain embodiments, the pharmaceutical composition comprises sorbitol at a concentration of about 50, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500 mM. In certain embodiments, the pharmaceutical composition comprises sorbitol at a concentration of about 270 mM.

[0154] In some embodiments, the sugar is sucrose.

[0155] In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of about 50 mM to about 500 mM, e.g., 50-450, 50-400, 50-350, 100-350, or 100-200 mM. In some embodiments, the pharmaceutical composition comprises sucrose at a concentration of about 50, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500 mM.

[0156] In some embodiments, the pharmaceutical composition comprises mannitol.

[0157] In certain embodiments, the pharmaceutical composition comprises mannitol at a concentration of about 100 mM to about 180 mM, e.g., about 105-180, 105-175, 110-175, 110-170, 115-170, 115-165, 120-165, 120-160, 125-160, 125-155, 130-155, 130-150, or 140-180 mM. In some embodiments, the pharmaceutical composition comprises mannitol at a concentration of about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, or 180 mM. In some embodiments, the pharmaceutical composition comprises mannitol at a concentration of about 140 mM.

[0158] In some embodiments, the pharmaceutical composition comprises acetic acid.

[0159] In certain embodiments, the pharmaceutical composition comprises acetic acid at a concentration of about 1 mM to about 50 mM, e.g., about 2-50, 2-45, 5-45, 5-40, 10-40, 10-35, 15-35, 15-30, or 20-30 mM. In some embodiments, the pharmaceutical composition comprises acetic acid at a concentration of about 10, 15, 20, 25, 30, 35, 40, 45, or 50 mM. In particular embodiments, the pharmaceutical composition comprises acetic acid at a concentration of about 25 mM.

[0160] In some embodiments, the pharmaceutical composition comprises NaCl.

[0161] In some embodiments, the pharmaceutical composition comprises NaCl at a concentration of about 20 mM to about 100 mM, e.g., about 20-90, 30-90, 30-80, 40-80, 40-70, or 50-70 mM. In certain embodiments, the pharmaceutical composition comprises NaCl at a concentration of about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mM. In particular embodiments, the pharmaceutical composition comprises NaCl at a concentration of about 60 mM.

[0162] In some embodiments, the pharmaceutical composition comprises sodium acetate.

[0163] In some embodiments, the pharmaceutical composition comprises sodium acetate at a concentration of about 10 mM to about 50 mM, e.g., about 15-50, 15-45, 20-45, 20-40, 25-40, or 25-35. In certain embodiments, the pharmaceutical composition comprises sodium acetate at a concentration of about 10, 15, 20, 25, 30, 35, 40, 45, or 50 mM. In particular embodiments, the pharmaceutical composition comprises sodium acetate at a concentration of about 30 mM.

[0164] In some embodiments, the pharmaceutical composition has a pH of about 5.0 to about 7.0, e.g., about pH 5.0 to about pH 6.0, about pH 5.3 to about pH 5.8. In certain embodiments, the pharmaceutical composition has a pH of about 5.5. In other embodiments, the pharmaceutical composition has a pH of about 5.6.

[0165] In some embodiments, the pharma- ceutically acceptable carrier comprises histidine, methionine, mannitol, sorbitol, polysorbate 20, polysorbate 80, or combinations thereof, and one or more salts (e.g., sodium chloride (NaCl), sodium acetate, etc.), and the pharmaceutical composition has a pH of 5-7.

[0166] In some embodiments, the pharmaceutical composition comprises: Approximately 1,800 mg of daratumumab and Approximately 30,000 units of rHuPH20 recombinant hyaluronidase; Approximately 4.9 mg of L-histidine, Approximately 18.4 mg of L-histidine hydrochloride monohydrate; Approximately 13.5 mg of L-methionine, Approximately 6 mg of polysorbate 20, and about 735.1 mg sorbitol, The pharmaceutical composition has a pH of about 5.5.

[0167] In some embodiments, the pharmaceutical composition comprises: Approximately 120 mg / ml of daratumumab; Approximately 2,000 U / mL of rHuPH20 recombinant hyaluronidase; Approximately 2.1 mM L-histidine; About 5.8 mM L-histidine hydrochloride monohydrate; Approximately 6.0 mM L-methionine; Approximately 0.04% w / v polysorbate 20, and about 270 mM sorbitol, The pharmaceutical composition has a pH of about 5.5.

[0168] In some embodiments, the pharmaceutical composition comprises: Approximately 1,800 mg of daratumumab and Approximately 30,000 units of rHuPH20 recombinant hyaluronidase; Approximately 4.9 mg of L-histidine, Approximately 18.4 mg of L-histidine hydrochloride monohydrate; Approximately 13.5 mg of L-methionine, Approximately 6 mg of polysorbate 20, and about 735.1 mg sorbitol, The pharmaceutical composition has a pH of about 5.6.

[0169] In some embodiments, the pharmaceutical composition comprises: Approximately 120 mg / ml of daratumumab; Approximately 2,000 U / mL of rHuPH20 recombinant hyaluronidase; Approximately 2.1 mM L-histidine; About 5.8 mM L-histidine hydrochloride monohydrate; Approximately 6.0 mM L-methionine; About 0.04% w / v polysorbate 20, and about 270 mM sorbitol, The pharmaceutical composition has a pH of about 5.6.

[0170] In some embodiments, the pharmaceutical composition comprises: a) about 60 mg / mL to about 180 mg / mL (e.g., about 120 mg / mL) of an anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v PS-20 at about pH 5.5; and b) about 30,000 U to about 45,000 U of hyaluronidase in 10 mM L-histidine, 130 mM NaCl, 10 mM L-methionine, 0.02% w / v PS-80 at about pH 6.5.

[0171] In some embodiments, the pharmaceutical composition comprises: a) about 60 mg / mL to about 180 mg / mL (e.g., about 120 mg / mL) of an anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v PS-20 at about pH 5.5; and b) Approximately 30,000 U of hyaluronidase in 10 mM L-histidine, 130 mM NaCl, 10 mM L-methionine, 0.02% w / v PS-80 at pH 6.5.

[0172] In some embodiments, the pharmaceutical composition comprises: a) about 60 mg / mL to about 180 mg / mL (e.g., about 120 mg / mL) of an anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v PS-20 at about pH 5.5; and b) about 45,000 U of hyaluronidase in 10 mM L-histidine, 130 mM NaCl, 10 mM L-methionine, 0.02% w / v PS-80 at about pH 6.5.

[0173] In some embodiments, the pharmaceutical composition comprises: a) about 1 mg / mL to about 180 mg / mL of an anti-CD38 antibody; b) about 50 U / mL to about 5,000 U / mL of hyaluronidase; c) about 5 mM to about 50 mM histidine; d) about 50 mM to about 400 mM sorbitol; Optionally, the pharmaceutical composition comprises: e) about 0.01% w / v to about 0.1% w / v PS-20, and / or f) about 0.1 mg / mL to about 2.5 mg / mL of methionine.

[0174] In some embodiments, the pharmaceutical composition comprises: a) about 100 mg / mL to about 140 mg / mL (for example, about 120 mg / mL) of an anti-CD38 antibody; b) about 50 U / mL to about 5,000 U / mL of hyaluronidase; c) about 10 mM histidine, and d) about 100 mM to about 300 mM sorbitol.

[0175] Optionally, the pharmaceutical composition comprises: e) about 0.01% w / v to about 0.04% w / v of PS-20, and f) about 1 mg / mL to about 2 mg / mL of methionine.

[0176] In some embodiments, the pharmaceutical composition comprises: a) about 120 mg / mL of an anti-CD38 antibody; b) about 2,000 U / mL of rHuPH20; c) about 10 mM histidine; d) about 300 mM sorbitol; e) about 0.04% w / v PS-20, and f) about 1 mg / mL methionine, and the pH is about 5.5.

[0177] In some embodiments, the pharmaceutical composition comprises: a) about 120 mg / mL of an anti-CD38 antibody; b) about 2,000 U / mL of rHuPH20; c) about 10 mM histidine; d) about 300 mM sorbitol; e) about 0.04% w / v PS-20, and f) about 2 mg / mL methionine, and the pH is about 5.5.

[0178] In some embodiments, the pharmaceutical composition comprises: a) about 120 mg / mL of an anti-CD38 antibody; b) about 2,000 U / mL of rHuPH20; c) about 10 mM histidine; d) about 300 mM sorbitol; e) about 0.01% w / v PS-20, and f) about 2 mg / mL methionine, and the pH is about 5.5.

[0179] In some embodiments, the pharmaceutical composition comprises: a) about 120 mg / mL of an anti-CD38 antibody; b) about 2,000 U / mL of rHuPH20; c) about 10 mM histidine; d) about 300 mM sorbitol; e) about 0.02% w / v PS-20, and f) about 2 mg / mL methionine, and the pH is about 5.5.

[0180] In some embodiments, the pharmaceutical composition comprises: a) about 120 mg / mL of an anti-CD38 antibody; b) about 2,000 U / mL of rHuPH20; c) about 10 mM histidine; d) about 300 mM sorbitol; e) about 0.06% w / v PS-20, and f) about 2 mg / mL methionine, and the pH is about 5.5.

[0181] Pharmaceutical compositions comprising anti-CD38 antibodies can be prepared by any method known in the art in view of the present disclosure. For example, anti-CD38 antibodies can be mixed with one or more pharma- ceutically acceptable excipients to obtain a solution. The solution can be stored as a liquid in a suitable vial, protected from light, at a temperature of about 2°C to 8°C until administration to a subject.

[0182] In some embodiments, a pharmaceutical composition is prepared by mixing about 20 mg / mL of an anti-CD38 antibody with about 1.0 mg / mL of rHuPH20 (75-150 kU / mL), and then the mixture is administered to a subject, where the anti-CD38 antibody is in about 25 mM sodium acetate, about 60 mM sodium chloride, about 140 mM D-mannitol, about 0.04% polysorbate 20, and has a pH of about 5.5, and the rHuPH20 is in about 10 mM L-histidine, about 130 mM NaCl, about 10 mM L-methionine, and about 0.02% polysorbate 80, and has a pH of about 6.5.

[0183] Administration "Treat", "treating" or "treatment" refers to a therapeutic procedure whose purpose is to slow (reduce) an undesirable physiological change or disease progression (e.g., slowing the development or spread of tumors or tumor cells) or to provide a beneficial or desired clinical outcome during treatment. Beneficial or desired clinical outcomes include alleviation of symptoms, reduction in the extent of disease, a stable (i.e., not worsening) disease state, a delay or slowing of disease progression, lack of metastasis, an improvement or mitigation of a disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival compared to the expected survival if the subject were not receiving treatment. Subjects in need of treatment include subjects who already have an undesirable physiological change or disease, as well as subjects who are predisposed to having a physiological change or disease.

[0184] Daratumumab is indicated for the treatment of adult patients with multiple myeloma, for example, as monotherapy, in patients who have received at least three prior therapies including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are dually refractory to a PI and an immunomodulatory agent. Additional information regarding daratumumab can be found, for example, in the prescribing information of the DARZALEX® product insert (www_janssenlabels_com / package-insert / product-monograph / prescribing-information / DARZALEX-pi.pdf), which is incorporated herein by reference.

[0185] A "therapeutically effective amount" refers to an amount effective, at the dosage and for the duration required, to achieve the desired therapeutic result. The therapeutically effective amount may vary, depending on factors such as the individual's medical condition, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, an improvement in the patient's health status, a reduction in tumor burden, a halt or slowing of tumor growth, and / or the absence of metastasis of cancer cells to other locations in the body.

[0186] "Inhibits growth" (e.g., when referring to tumor cells) refers to a measurable decrease in tumor cell growth or tumor tissue in vitro or in vivo when contacted with a therapeutic agent or combination of therapeutic agents compared to the growth of the same tumor cell or tumor tissue in the absence of the therapeutic agent or combination of therapeutic agents. Inhibition of tumor cell or tumor tissue growth in vitro or in vivo may be at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99% or 100%.

[0187] Anti-CD38 antibodies may also be administered prophylactically to reduce the risk of cancer progression, delay the onset of events in the progression of cancer, and / or reduce the risk of recurrence when the cancer goes into remission, which may be particularly useful in patients where other biological factors make it difficult to locate a tumor known to be present.

[0188] The mode of administration of the anti-CD38 antibody may be any suitable parenteral administration, including, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, pulmonary, transmucosal (oral, intranasal, intravaginal, rectal), etc.

[0189] In some embodiments, the anti-CD38 antibody is administered subcutaneously. "Subcutaneous administration" refers to administration under the skin, where a drug or therapeutic agent is injected into the tissue layer between the skin and muscle. Agents administered via subcutaneous administration are generally absorbed more slowly than when injected intravenously.

[0190] "Dosage" refers to information regarding the amount of a therapeutic agent or drug taken by a subject and the frequency of times the therapeutic agent is taken by a subject. "Dose" refers to the amount or quantity of a therapeutic agent or drug taken each time.

[0191] In some embodiments, the dose of the anti-CD38 antibody is about 10 mg to about 2,400 mg per administration, e.g., about 10-2,400, 10-2,000, 20-2,000, 20-1,500, 50-1,500, 50-1,000, 100-1,000, 100-500, or 200-500 mg per administration. In certain embodiments, the dose of the anti-CD38 antibody is about 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, or 2,400 mg per administration. In a specific embodiment, the dose of anti-CD38 antibody is about 1,800 mg per administration.

[0192] In some embodiments, the anti-CD38 antibody is administered subcutaneously without recombinant human hyaluronidase. In other embodiments, the anti-CD38 antibody is administered subcutaneously with recombinant human hyaluronidase.

[0193] The pharmaceutical composition administered may comprise about 1,800 mg of anti-CD38 antibody and about 30,000 U of hyaluronidase. In some embodiments, the concentration of the anti-CD38 antibody in the pharmaceutical composition is about 120 mg / ml. The pharmaceutical composition comprising the anti-CD38 antibody and hyaluronidase may be administered subcutaneously in the abdomen.

[0194] The pharmaceutical composition of the present invention may be administered as a non-fixed combination.The pharmaceutical composition of the present invention may also be administered as a fixed combination, such as a unit dosage form (or dosage unit form).Fixed combinations can be advantageous in terms of ease of administration and uniformity of dosage.

[0195] In some embodiments, the pharmaceutical composition (e.g., comprising an anti-CD38 antibody and hyaluronidase) is administered in a total volume of about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 mL. In certain embodiments, the pharmaceutical composition is administered in a total volume of about 80, 90, 100, 110, or 120 mL. In other embodiments, the pharmaceutical composition is administered in a total volume of about 10-20 mL, e.g., about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mL. In certain embodiments, the pharmaceutical composition has a total volume of about 15 mL. The total amount administered is typically lower for fixed combinations compared to non-fixed combinations.

[0196] The pharmaceutical compositions of the present disclosure may also be administered as a fixed combination, eg, in unit dosage form.

[0197] In some embodiments, the unit dosage form comprises: an anti-CD38 antibody in an amount of about 1,200 mg to about 4,000 mg; and Optionally, rHuPH20 in an amount of about 30,000 U to about 75,000 U.

[0198] In some embodiments, the unit dosage form comprises: an anti-CD38 antibody in an amount of about 1,200 mg to about 2,400 mg; and Optionally, rHuPH20 in an amount of about 30,000 U to about 45,000 U.

[0199] In some embodiments, the unit dosage form comprises: an anti-CD38 antibody in an amount of about 1,200 mg to about 1,800 mg; and Optionally, rHuPH20 in an amount of about 30,000 U to about 45,000 U.

[0200] In some embodiments, the unit dosage form comprises: An anti-CD38 antibody in an amount of about 1,200 mg to about 5,000 mg (for example, about 1,800 mg); histidine at a concentration of about 5 mM to about 15 mM (for example, about 7.9 mM); Sorbitol at a concentration of about 100 mM to about 300 mM (for example, about 270 mM); PS-20 at a concentration of about 0.01% (w / v) to about 0.05% (w / v) (for example, about 0.04% (w / v)), Methionine at a concentration of about 0.8 mg / mL to about 2 mg / mL (e.g., about 0.9 mg / mL); and Optionally, rHuPH20 in an amount of about 30,000 U to about 75,000 U (e.g., about 30,000 U); The pharmaceutical composition has a pH of about 5.5 or about 5.6.

[0201] In some embodiments, the unit dosage form comprises: An anti-CD38 antibody in an amount of about 1,200 mg to about 2,400 mg (for example, about 1,800 mg); histidine at a concentration of about 5 mM to about 10 mM (for example, about 7.9 mM); Sorbitol at a concentration of about 250 mM to about 300 mM (for example, about 270 mM); PS-20 at a concentration of about 0.03 to 0.05% (w / v) (e.g., about 0.04% (w / v)), Methionine at a concentration of about 0.8 to 1 mg / mL (e.g., about 0.9 mg / mL); and Optionally, rHuPH20 in an amount of about 30,000 U to about 45,000 U (e.g., about 30,000 U); The pharmaceutical composition has a pH of about 5.5 or about 5.6.

[0202] In some embodiments, the unit dosage form comprises: an anti-CD38 antibody in an amount of about 1,800 mg; histidine at a concentration of about 7.9 mM; Sorbitol at a concentration of about 270 mM; PS-20 at a concentration of about 0.04% (w / v); Methionine at a concentration of about 0.9 mg / mL, and Optionally, rHuPH20 in an amount of about 30,000 U; The pharmaceutical composition has a pH of about 5.5 or about 5.6.

[0203] In some embodiments, the unit dosage form comprises: an anti-CD38 antibody in an amount of about 1,800 mg; histidine at a concentration of about 7.9 mM; Sorbitol at a concentration of about 270 mM; PS-20 at a concentration of about 0.04% (w / v); Methionine at a concentration of about 0.9 mg / mL, and and optionally, rHuPH20 in an amount of about 45,000 U; The pharmaceutical composition has a pH of about 5.5 or about 5.6.

[0204] In some embodiments, the unit dosage form of the pharmaceutical composition is stored in a container selected from a vial, cartridge, syringe, prefilled syringe, or disposable pen.

[0205] In some embodiments, a total dosage of anti-CD38 antibody may be administered to a subject in a single subcutaneous injection, or in multiple, eg, 1, 2, 3, 4, 5 or more subcutaneous injections.

[0206] In some embodiments, each subcutaneous injection lasts for about 1 minute to about 60 minutes, e.g., about 10-55, 15-55, 15-50, 20-50, 20-45, 25-45, 25-40, 30-40, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 3-10, 3-9, 3-8, 3-7, 3-6, or 3-5 minutes. In certain embodiments, each subcutaneous injection lasts for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes. In certain embodiments, each subcutaneous injection lasts for about 3 minutes to about 5 minutes.

[0207] In some embodiments, the pharmaceutical composition is administered once daily, once weekly, once every two weeks, once monthly, once every two months, once every three months, once every four months, once every six months, or once every nine months for a period of one day, one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, nine months, one year, 18 months, or two years or more.

[0208] Administration of the pharmaceutical composition (e.g., comprising an anti-CD38 antibody and hyaluronidase) may be repeated after 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, or longer. Repeated courses of treatment are also possible as is administration over time. Repeated administration may be at the same dose or at different doses. For example, the pharmaceutical composition comprising an anti-CD38 antibody and hyaluronidase may be administered once a week for 8 weeks, then once every 2 weeks for 16 weeks, then once every 4 weeks.

[0209] In some embodiments, the anti-CD38 antibody is administered once a week, every two weeks, or every four weeks during a 28 day cycle. In some embodiments, the anti-CD38 antibody is administered once a week during cycle 1, every two weeks during cycles 2-5, and every four weeks thereafter.

[0210] In some embodiments, the total dosage of the pharmaceutical composition is administered to the subject in a single subcutaneous injection per administration. In certain embodiments, the pharmaceutical composition is administered in a total volume of about 15 mL.

[0211] In some embodiments, the total dosage of the pharmaceutical composition is administered to the subject in multiple subcutaneous injections per administration, for example, 2, 3, 4, or 5 injections.

[0212] In some embodiments, the anti-CD38 antibody is administered intravenously (eg, by intravenous infusion).

[0213] In some embodiments, the total dose of the anti-CD38 antibody is about 10 mg to about 600 mg per administration, for example, about 10 to 550, 15 to 550, 15 to 500, 25 to 500, 25 to 450, 40 to 450, 40 to 400, 60 to 400, 60 to 350, 100 to 350, 100 to 300, 150 to 300, 150 to 250, or 200 to 250 mg per administration. In certain embodiments, the total dose of anti-CD38 antibody is about 10, 20, 25, 30, 40, 50, 60, 70, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, or 600 mg per administration.

[0214] The administration of anti-CD38 antibody may be repeated, for example after 1, 2, 3, 4, 5 or 6 days, 1, 2, 3, 4, 5, 6 or 7 weeks, or 1, 2, 3, 4, 5 or 6 months or more. Repeated courses of treatment are also possible as is chronic administration. Repeated administration may be at the same or different doses. For example, anti-CD38 antibody may be administered by intravenous infusion at 8 mg / kg or 16 mg / kg at weekly intervals for 8 weeks, followed by administration at 8 mg / kg or 16 mg / kg every 2 weeks for another 16 weeks, followed by administration at 8 mg / kg or 16 mg / kg every 4 weeks.

[0215] In some embodiments, the anti-CD38 antibody is administered at 16 mg / kg once per week for 8 weeks, followed by 16 mg / kg once every 2 weeks for 16 weeks, then 16 mg / kg once every 4 weeks until discontinued.

[0216] In some embodiments, the anti-CD38 antibody is administered at 8 mg / kg once per week for 8 weeks, then 8 mg / kg once every 2 weeks for 16 weeks, then 8 mg / kg once every 4 weeks until discontinued.

[0217] In some embodiments, the anti-CD38 antibody is administered at 16 mg / kg once per week for 4 weeks, followed by 16 mg / kg once every 2 weeks for 16 weeks, then 16 mg / kg once every 4 weeks until discontinued.

[0218] In some embodiments, the anti-CD38 antibody is administered at 8 mg / kg once per week for 4 weeks, followed by 8 mg / kg once every 2 weeks for 16 weeks, then 8 mg / kg once every 4 weeks until discontinued.

[0219] In some embodiments, the intravenous infusion is administered over 15, 30, 45, or 60 minutes. In some embodiments, the intravenous infusion is administered over 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours.

[0220] The dose of anti-CD38 antibody administered to a patient is sufficient to ameliorate or at least partially prevent the disease being treated (a "therapeutically effective amount"). Non-limiting examples of therapeutically effective amounts include about 0.005 mg to about 100 mg / kg, such as about 0.05 to 30, 5 to 25, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg.

[0221] For example, the anti-CD38 antibody can be administered at a daily dose in an amount of about 0.1 to 100 mg / kg, e.g., about 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90, or 100 mg / kg per day, using single or divided doses every 24, 12, 8, 6, 4, or 2 hours, or a combination thereof. In some embodiments, the administration of the compound may be provided on at least one of the following days: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or on at least one of the following weeks: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or any combination thereof, after initiation of treatment.

[0222] Fixed unit doses of, for example, 50, 100, 200, 500, or 1000 mg may be given. In some embodiments, the dose is based on the surface area of ​​the patient, for example, 500, 400, 300, 250, 200, or 100 mg / m 2 The dosage may also depend on the disease. Typically, 1 to 8 doses may be administered to treat MM, for example, 1, 2, 3, 4, 5, 6, 7 or 8 doses. In some embodiments, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more doses may be administered.

[0223] The anti-CD38 antibody may be administered as a maintenance treatment, for example, once a week for a period of six months or more.

[0224] In a specific embodiment, a pharmaceutical composition comprising about 1,800 mg of an anti-CD38 antibody (e.g., daratumumab) and about 30,000 U of hyaluronidase (e.g., rHuPH20 recombinant hyaluronidase) is administered in a 28 day cycle, once weekly during cycle 1, every two weeks during cycles 2 through 5, and every four weeks thereafter.

[0225] In a specific embodiment, a pharmaceutical composition comprising about 1,800 mg of an anti-CD38 antibody (e.g., daratumumab) and about 30,000 U of hyaluronidase (e.g., rHuPH20 recombinant hyaluronidase) is administered in a 28 day cycle, once weekly during cycle 1 (e.g., days 1, 8, 15, and 22), every two weeks during cycles 2 through 5 (e.g., days 1 and 15), and every four weeks thereafter (e.g., day 1).

[0226] In some embodiments, the dosing regimen of the method results in a reduction, elimination, or reduction and elimination of corticosteroid use by the subject.

[0227] Corticosteroid tapering In one aspect, the disclosure provides a method of treating a hematological malignancy (e.g., a CD38-positive hematological malignancy such as MM), comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody and a corticosteroid for a period of time sufficient to treat the hematological malignancy, wherein the dosing regimen includes a reduction, elimination, or reduction followed by elimination of administration of corticosteroid to the subject.

[0228] The anti-CD38 antibody can be any one of the anti-CD38 antibodies described herein.

[0229] Non-limiting examples of corticosteroids include betamethasone, cortisol, cortisone, dexamethasone, glucocorticoids, hydrocortisone, methylprednisolone (MP), prednisolone, prednisone, and triamcinolone. In some embodiments, corticosteroids refer to a class of steroid hormones produced in the adrenal cortex or synthetically produced. In some embodiments, corticosteroids comprise, consist essentially of, or consist of dexamethasone, methylprednisolone, prednisolone, prednisone.

[0230] In some embodiments, the corticosteroid is administered simultaneously with administration of the anti-CD38 antibody (eg, subcutaneously).

[0231] The corticosteroid may be administered by any suitable method known in the art.

[0232] In some embodiments, the corticosteroid is administered orally.

[0233] In some embodiments, the corticosteroid is administered parenterally (eg, intravenously).

[0234] In some embodiments, the corticosteroid is re-administered simultaneously with administration of the anti-CD38 antibody.

[0235] In some embodiments, the corticosteroid is readministered following (eg, immediately after) administration of the anti-CD38 antibody.

[0236] In some embodiments, the corticosteroid is readministered about 1 minute to about 15 minutes after administration of the anti-CD38 antibody.

[0237] In some embodiments, the corticosteroid is readministered about 0.5 hours to about 10 hours after administration of the anti-CD38 antibody, e.g., about 1-10 hours, 2-10 hours, 4-10 hours, 6-10 hours, or 7-9 hours after administration of the anti-CD38 antibody.

[0238] In some embodiments, the corticosteroid is readministered about 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours after administration of the anti-CD38 antibody.

[0239] In some embodiments, the corticosteroid administered prior to administration of the anti-CD38 antibody and the corticosteroid readministered after administration of the anti-CD38 antibody are the same.

[0240] In some embodiments, the corticosteroid administered prior to administration of the anti-CD38 antibody and the corticosteroid re-administered after administration of the anti-CD38 antibody are different.

[0241] In some embodiments, prednisone is administered orally about 1 to about 2 hours prior to subcutaneous administration of the anti-CD38 antibody and is readministered orally about 7 to 9 hours after administration of the anti-CD38 antibody.

[0242] In some embodiments, the anti-CD38 antibody is administered once a week, every two weeks, or every four weeks during a 28 day cycle. In certain embodiments, the anti-CD38 antibody is administered once a week during cycle 1, every two weeks during cycles 2-5, and every four weeks thereafter.

[0243] In some embodiments, the corticosteroid administered to the subject is reduced by at least about 20% (e.g., during a 28 day treatment cycle), e.g., reduced by at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% (e.g., during a 28 day treatment cycle). In some embodiments, the corticosteroid administered to the subject is reduced by about 20-95% (e.g., during a 28 day treatment cycle), e.g., by about 25-95%, 25-90%, 30-90%, 30-85%, 35-85%, 35-80%, 40-80%, 40-75%, 45-75%, 45-70%, 50-70%, 55-65%, or 55-60% (e.g., during a 28 day treatment cycle). In some embodiments, the corticosteroid administered to the subject is reduced by about 60%. In certain embodiments, the corticosteroid is eliminated. In certain embodiments, during a 28 day treatment cycle, the corticosteroid administered to the subject is reduced by about 60% and then eliminated.

[0244] In some embodiments, the corticosteroid administered to the subject is administered at least 1, 2, 3, 4, 5, or 6 times during a 28 day treatment cycle and then removed. In some embodiments, the corticosteroid administered to the subject is administered once during a 28 day treatment cycle and then removed.

[0245] In some embodiments, the method comprises administering to a subject, during a 28 day cycle: a) administering subcutaneously about 1,800 mg of an anti-CD38 antibody and about 30,000 U of hyaluronidase on days 1, 8, 15, and 22; and b) administering about 20 mg of a pre-dose corticosteroid intravenously on day 1 of a 28 day cycle.

[0246] In some embodiments, the method comprises administering to a subject, during a 28 day cycle: administering about 1,800 mg of anti-CD38 antibody and about 30,000 U of rHuPH20 hyaluronidase on days 1, 8, 15, and 22; administering about 100 mg of a pre-dose corticosteroid on day 1; administering about 20 mg of a post-dose corticosteroid on days 1 and 2; administering about 60 mg of a pre-dose corticosteroid on day 8; and and administering about 20 mg of a post-administration corticosteroid on day 8 of a 28 day cycle.

[0247] In some embodiments, the method comprises administering to a subject, during a 28 day cycle: administering about 1,800 mg of an anti-CD38 antibody and about 30,000 U of hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; administering about 100 mg of a pre-dose corticosteroid on day 1; administering about 20 mg of a post-dose corticosteroid on days 1 and 2; administering about 60 mg of a pre-dose corticosteroid on day 8; administering about 20 mg of a post-dose corticosteroid on day 8; administering about 30 mg of a pre-dose corticosteroid on day 15; and and administering about 20 mg of a post-administration corticosteroid on day 15 of a 28 day cycle.

[0248] In another aspect, the disclosure provides a method of treating a hematological malignancy in a subject in need thereof, the method comprising administering to the subject a treatment in 28 day cycles, the treatment comprising: a) administering about 1,800 mg of an anti-CD38 antibody and about 30,000 U on days 1, 8, 15, and 22; and b) administering about 20 mg (or an equivalent dose) of a pre-dose corticosteroid on day 1 of a 28 day cycle.

[0249] In another aspect, the disclosure provides a method of treating a hematological malignancy in a subject in need thereof, the method comprising administering to the subject a treatment in 28 day cycles, the treatment comprising: administering about 1,800 mg of anti-CD38 antibody and about 30,000 U of rHuPH20 hyaluronidase on days 1, 8, 15, and 22; administering about 100 mg of a pre-dose corticosteroid on day 1; administering about 20 mg of a post-dose corticosteroid on days 1 and 2; administering about 60 mg of a pre-dose corticosteroid on day 8; and and administering about 20 mg of a post-dose corticosteroid on day 8 of a 28 day cycle.

[0250] In another aspect, the disclosure provides a method of treating a hematological malignancy in a subject in need thereof, the method comprising administering to the subject a treatment in 28 day cycles, the treatment comprising: administering about 1,800 mg of anti-CD38 antibody and about 30,000 U of hyaluronidase on days 1, 8, 15, and 22; administering about 100 mg of a pre-dose corticosteroid on day 1; administering about 20 mg of a post-dose corticosteroid on days 1 and 2; administering about 60 mg of a pre-dose corticosteroid on day 8; administering about 20 mg of a post-dose corticosteroid on day 8; administering about 30 mg of a pre-dose corticosteroid on day 15; and and administering about 20 mg of a post-administration corticosteroid on day 15 of a 28 day cycle.

[0251] Dexamethasone In some embodiments, the corticosteroid comprises, consists essentially of, or consists of dexamethasone, which is sold under the trade name DECARON®.

[0252] Daratumumab in combination with dexamethasone is indicated for the treatment of adult patients with multiple myeloma or light-chain amyloidosis. "In combination with" means that two or more therapeutic agents are administered to a subject together in a mixture, simultaneously as single agents, or sequentially in any order as single agents. For example, the combination of lenalidomide and dexamethasone in newly diagnosed multiple myeloma patients ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy; the combination of bortezomib, thalidomide, and dexamethasone in newly diagnosed multiple myeloma patients eligible for autologous stem cell transplant; the combination of bortezomib and dexamethasone in multiple myeloma patients who have received at least one prior therapy; the combination of carfilzomib and dexamethasone in multiple myeloma patients who have received one to three prior lines of therapy; the combination of pomalidomide and dexamethasone in multiple myeloma patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor; and the combination of bortezomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed light chain amyloidosis. Additional information regarding daratumumab in combination with dexamethasone can be found, for example, in the DARZALEX® product insert prescribing information (www.janssenlabels.com / package-insert / product-monograph / prescribing-information / DARZALEX-pi.pdf), which is incorporated herein by reference.

[0253] In some embodiments, dexamethasone administered to a subject (e.g., orally or intravenously) is reduced by at least about 20% (e.g., during a 28 day treatment cycle), e.g., reduced by at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% (e.g., during a 28 day treatment cycle). In some embodiments, the dexamethasone administered to the subject is reduced by about 20-95% (e.g., during a 28 day treatment cycle), e.g., by about 25-95%, 25-90%, 30-90%, 30-85%, 35-85%, 35-80%, 40-80%, 40-75%, 45-75%, 45-70%, 50-70%, 55-65%, or 55-60% (e.g., during a 28 day treatment cycle). In some embodiments, the dexamethasone administered to the subject is reduced by at least about 60%. In certain embodiments, dexamethasone is excluded. In certain embodiments, the dexamethasone administered to the subject is reduced by at least about 60% and then excluded during the 28 day treatment cycle.

[0254] In some embodiments, administration of dexamethasone prior to administration of an anti-CD38 antibody (eg, administration of DARZALEX FASPRO®) is reduced.

[0255] In some embodiments, the dexamethasone administered to the subject is less than about 20 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle), for example, less than about 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle). In some embodiments, the dexamethasone administered to the subject is about 0-20 mg (or equivalent dose) (e.g., during a 28 day treatment cycle), for example, about 0-19, 1-19, 1-18, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11, 9-11, or 9-10 mg (or equivalent dose) (e.g., during a 28 day treatment cycle). In some embodiments, the dexamethasone administered to the subject is less than about 8 mg (or equivalent dose) (e.g., during a 28 day treatment cycle). In certain embodiments, dexamethasone is excluded. In certain embodiments, the dexamethasone administered to the subject is less than about 8 mg (or equivalent dose) and then excluded during a 28 day treatment cycle.

[0256] In some embodiments, administration of dexamethasone following administration of an anti-CD38 antibody (eg, administration of DARZALEX FASPRO®) is reduced.

[0257] In some embodiments, the method includes administering a treatment to a subject during a 28 day cycle, the treatment comprising: a) administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22; and b) administering about 20 mg (or an equivalent dose) of pre-dose dexamethasone intravenously on day 1 of a 28 day cycle.

[0258] In another aspect, the disclosure provides a method of treating a hematological malignancy in a subject in need thereof, the method comprising administering to the subject a treatment in 28 day cycles, the treatment comprising: a) administering about 1,800 mg of an anti-CD38 antibody and about 30,000 U on days 1, 8, 15, and 22; and b) administering about 20 mg (or an equivalent dose) of pre-dose dexamethasone on day 1 of a 28 day cycle.

[0259] Methylprednisolone (MP) In some embodiments, the corticosteroid is methylprednisolone (MP). For administration of MP as a pre- or post-medication, see, e.g., the DARZALEX® prescribing information product insert.

[0260] In some embodiments, MP administered to a subject (e.g., orally or intravenously) is reduced by at least about 20% (e.g., during a 28 day treatment cycle), e.g., reduced by at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% (e.g., during a 28 day treatment cycle). In some embodiments, the MP administered to the subject is reduced by about 20-95% (e.g., during a 28 day treatment cycle), e.g., about 25-95%, 25-90%, 30-90%, 30-85%, 35-85%, 35-80%, 40-80%, 40-75%, 45-75%, 45-70%, 50-70%, 55-65%, or 55-60% (e.g., during a 28 day treatment cycle). In some embodiments, the MP administered to the subject is reduced by at least about 60%. In certain embodiments, the MP is eliminated. In certain embodiments, the MP administered to the subject is reduced by at least about 60% and then eliminated during a 28 day treatment cycle.

[0261] In some embodiments, administration of MP prior to administration of an anti-CD38 antibody (eg, administration of DARZALEX FASPRO®) is reduced.

[0262] In some embodiments, the MP administered to the subject prior to administration of the anti-CD38 antibody is less than about 100 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle), for example, less than about 90, 80, 70, 60, 50, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2 or 1 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle). In some embodiments, the MP administered to the subject prior to administration of the anti-CD38 antibody is about 0-100 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle), for example, about 0-90, 1-90, 1-80, 2-80, 2-70, 3-70, 3-60, 4-60, 4-50, 5-50, 5-40, 10-40, 10-35, 15-35, 15-30, 20-30, or 20-25 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle). In some embodiments, the MP administered to the subject prior to administration of the anti-CD38 antibody is less than about 40 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle). In certain embodiments, the MP administered to the subject prior to administration of the anti-CD38 antibody is excluded. In certain embodiments, less than about 40 mg (or an equivalent dose) of MP is administered to the subject prior to administration of the anti-CD38 antibody and is subsequently cleared during the 28 day treatment cycle.

[0263] In some embodiments, the MP administered to the subject prior to administration of the anti-CD38 antibody is less than about 60 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle), e.g., less than about 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle). In some embodiments, the MP administered to the subject prior to administration of the anti-CD38 antibody is less than about 0-60 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle), e.g., about 0-55, 1-55, 1-50, 2-50, 2-45, 3-45, 3-40, 4-40, 4-35, 5-35, 5-30, 10-30, 10-25, 15-25, or 15-20 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle). In some embodiments, less than about 24 mg (or an equivalent dose) of MP is administered to the subject prior to administration of the anti-CD38 antibody (e.g., during a 28 day treatment cycle). In certain embodiments, less than about 24 mg (or an equivalent dose) of MP is administered to the subject prior to administration of the anti-CD38 antibody is cleared. In certain embodiments, less than about 24 mg (or an equivalent dose) of MP is administered to the subject prior to administration of the anti-CD38 antibody and is subsequently cleared during a 28 day treatment cycle.

[0264] In some embodiments, the MP administered to the subject prior to administration of the anti-CD38 antibody is less than about 30 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle), e.g., less than about 25, 20, 18, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle). In some embodiments, the MP administered to the subject prior to administration of the anti-CD38 antibody is less than about 0-30 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle), e.g., about 0-25, 1-25, 1-20, 2-20, 2-18, 3-18, 3-15, 4-15, 4-10, 5-10, 5-9, 6-9, 6-8, or 7-8 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle). In some embodiments, less than about 12 mg (or an equivalent dose) of MP is administered to the subject prior to administration of the anti-CD38 antibody (e.g., during a 28 day treatment cycle). In certain embodiments, less than about 12 mg (or an equivalent dose) of MP is administered to the subject prior to administration of the anti-CD38 antibody is cleared. In certain embodiments, less than about 12 mg (or an equivalent dose) of MP is administered to the subject prior to administration of the anti-CD38 antibody and is subsequently cleared during a 28 day treatment cycle.

[0265] In some embodiments, administration of MP following administration of an anti-CD38 antibody (eg, administration of DARZALEX FASPRO®) is reduced.

[0266] In some embodiments, the MP administered to the subject following administration of the anti-CD38 antibody is less than about 20 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle), for example, less than about 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle). In some embodiments, the MP administered to the subject after administration of the anti-CD38 antibody is about 0-20 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle), for example, about 0-19, 1-19, 1-18, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11, 9-11, or 9-10 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle). In some embodiments, the MP administered to the subject after administration of the anti-CD38 antibody is less than about 8 mg (or an equivalent dose) (e.g., during a 28 day treatment cycle). In certain embodiments, the MP administered to the subject after administration of the anti-CD38 antibody is excluded. In certain embodiments, the subject is administered less than about 8 mg (or an equivalent dose) of MP following anti-CD38 antibody administration and is subsequently cleared during a 28 day treatment cycle.

[0267] In some embodiments, both administration of MPs prior to administration of anti-CD38 antibody and administration of MPs following administration of anti-CD38 antibody are reduced.

[0268] In some embodiments, the method includes administering a treatment to a subject during a 28 day cycle, the treatment comprising: administering about 1,800 mg of anti-CD38 antibody and about 30,000 U of rHuPH20 hyaluronidase on days 1, 8, 15, and 22; administering about 100 mg of pre-dose MP on day 1; administering about 20 mg of post-administration MP on days 1 and 2; administering about 60 mg of pre-dose MP on day 8; and administering about 20 mg of post-administration MP on day 8 of a 28 day cycle.

[0269] In some embodiments, the method includes administering a treatment to a subject during a 28 day cycle, the treatment comprising: administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22; administering about 100 mg of pre-dose MP orally or intravenously on day 1; orally administering about 20 mg of post-administration MP on days 1 and 2; administering about 60 mg of pre-dose MP orally or intravenously on day 8; orally administering about 20 mg of post-dose MP on day 8; administering about 30 mg of pre-dose MP orally or intravenously on day 15; orally administering about 20 mg of post-dose MP on day 15 of a 28 day cycle.

[0270] Prednisone In some embodiments, the corticosteroid is prednisone.

[0271] Daratumumab in combination with prednisone is indicated for the treatment of adult patients with multiple myeloma, for example in combination with bortezomib, melphalan, and prednisone, in newly diagnosed patients who are ineligible for autologous stem cell transplant. Additional information regarding daratumumab in combination with prednisone can be found, for example, in the DARZALEX® prescribing information product insert.

[0272] In some embodiments, the prednisone administered (e.g., orally) to a subject is reduced by at least about 20% (e.g., during a 28 day treatment cycle), e.g., reduced by at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% (e.g., during a 28 day treatment cycle). In some embodiments, the prednisone administered to the subject is reduced by about 20-95% (e.g., during a 28 day treatment cycle), e.g., by about 25-95%, 25-90%, 30-90%, 30-85%, 35-85%, 35-80%, 40-80%, 40-75%, 45-75%, 45-70%, 50-70%, 55-65%, or 55-60% (e.g., during a 28 day treatment cycle). In some embodiments, the prednisone administered to the subject is reduced by at least about 60%. In certain embodiments, the prednisone administered to the subject is eliminated. In certain embodiments, the prednisone administered to the subject is reduced by at least about 60% and then eliminated during a 28 day treatment cycle.

[0273] In some embodiments, administration of prednisone following administration of an anti-CD38 antibody (eg, administration of DARZALEX FASPRO®) is reduced.

[0274] In some embodiments, the prednisone administered to the subject following administration of the anti-CD38 antibody is about 60 mg / m 2 (or an equivalent dose), e.g., about 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 mg / m (e.g., during a 28 day treatment cycle) 2 (or an equivalent dose). In some embodiments, the amount of prednisone administered to the subject after administration of the anti-CD38 antibody is less than about 0-60 mg / m 2 (or equivalent dose), for example, about 0-55, 1-55, 1-50, 2-50, 2-45, 3-45, 3-40, 4-40, 4-35, 5-35, 5-30, 10-30, 10-25, 15-25, or 15-20 mg / m 2(or an equivalent dose). In some embodiments, the prednisone administered to the subject after administration of the anti-CD38 antibody is about 24 mg / m 2 (or an equivalent dose). In certain embodiments, prednisone administered to the subject is excluded. In particular embodiments, the prednisone administered to the subject after administration of the anti-CD38 antibody is less than about 24 mg / m 2 (or equivalent dose) and is subsequently eliminated during the 28 day treatment cycle.

[0275] In some embodiments, administration of prednisone prior to administration of an anti-CD38 antibody (eg, administration of DARZALEX FASPRO®) is reduced.

[0276] In some embodiments, the prednisone administered to the subject prior to administration of the anti-CD38 antibody is about 60 mg / m 2 (or an equivalent dose), e.g., about 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 mg / m (e.g., during a 28 day treatment cycle) 2 (or an equivalent dose). In some embodiments, the amount of prednisone administered to the subject prior to administration of the anti-CD38 antibody is less than about 0-60 mg / m2 (e.g., during a 28 day treatment cycle). 2 (or equivalent dose), for example, about 0-55, 1-55, 1-50, 2-50, 2-45, 3-45, 3-40, 4-40, 4-35, 5-35, 5-30, 10-30, 10-25, 15-25, or 15-20 mg / m 2 (or an equivalent dose). In some embodiments, the prednisone administered to the subject prior to administration of the anti-CD38 antibody is about 24 mg / m 2 (or an equivalent dose). In certain embodiments, prednisone is excluded. In particular embodiments, the prednisone administered to the subject prior to administration of the anti-CD38 antibody is less than about 24 mg / m 2 (or equivalent dose) and is subsequently eliminated during the 28 day treatment cycle.

[0277] In some embodiments, both prednisone administration prior to administration of the anti-CD38 antibody and prednisone administration following administration of the anti-CD38 antibody are reduced.

[0278] 'Cortisone-free' treatments In another aspect, the disclosure provides a method of treating a hematological malignancy, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody, without concomitant administration of a corticosteroid, for a period of time sufficient to treat the hematological malignancy.

[0279] In another aspect, the disclosure provides a method of treating a hematological malignancy, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody and a corticosteroid dose <2.0 mg / kg / day, or an equivalent dose, for a period of time sufficient to treat the hematological malignancy.

[0280] In another aspect, the disclosure provides a method of treating a hematological malignancy, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody for a period of time sufficient to treat the hematological malignancy, wherein disease control or complete remission is achieved and / or maintained at a corticosteroid dose of ≦2.0 mg / kg / day or equivalent.

[0281] Non-limiting examples of corticosteroids include betamethasone, cortisol, cortisone, dexamethasone, glucocorticoids, hydrocortisone, methylprednisolone (MP), prednisolone, prednisone, and triamcinolone. In some embodiments, corticosteroids refer to a class of steroid hormones produced in the adrenal cortex or synthetically produced. In some embodiments, corticosteroids comprise, consist essentially of, or consist of dexamethasone, methylprednisolone, prednisolone, prednisone.

[0282] In some embodiments, the dose of corticosteroid is less than, or an equivalent dose of, about 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.8, 0.5, 0.2, 0.1, 0.08, 0.05, 0.02, 0.01, 0.008, 0.005, 0.002, or 0.001 mg / kg / day.

[0283] In some embodiments, the dose of corticosteroid is less than, or an equivalent dose of, about 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.8, 0.5, 0.2, 0.1, 0.08, 0.05, 0.02, 0.01, 0.008, 0.005, 0.002, or 0.001 mg / m2 / day.

[0284] In some embodiments, the method further comprises administering to the subject a prior treatment, hi some embodiments, the prior treatment has a 28 day cycle.

[0285] In some embodiments, the prior treatment comprises a cycle of 28 days. a) administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22; and b) administering about 20 mg of pre-dose dexamethasone intravenously on day 1 of a 28 day cycle.

[0286] In certain embodiments, the prior treatment comprises a cycle of 28 days, administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22; administering about 100 mg of pre-dose methylprednisolone (MP) orally or intravenously on day 1; orally administering about 20 mg of post-administration MP on days 1 and 2; Administering about 60 mg of pre-administration MP orally or intravenously on day 8; and orally administering about 20 mg of post-dose MP on day 8 of a 28 day cycle.

[0287] In certain embodiments, the prior treatment comprises a cycle of 28 days, administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22; administering about 100 mg of pre-dose methylprednisolone (MP) orally or intravenously on day 1; orally administering about 20 mg of post-administration MP on days 1 and 2; administering about 60 mg of pre-dose MP orally or intravenously on day 8; orally administering about 20 mg of post-dose MP on day 8; Administering about 30 mg of pre-administration MP orally or intravenously on day 15; and orally administering about 20 mg of post-dose MP on day 15 of a 28 day cycle.

[0288] In some embodiments, the corticosteroid is administered prior to (eg, immediately prior to) administration (eg, subcutaneous administration) of the anti-CD38 antibody.

[0289] In some embodiments, the corticosteroid is administered about 1 minute to about 5 hours prior to administration of the anti-CD38 antibody, e.g., about 1-15 minutes, 5-15 minutes, 10-15 minutes, 0.5-5 hours, 0.5 minutes to 4 hours, 1-4 hours, or 1-2 hours prior to administration of the anti-CD38 antibody (e.g., subcutaneous administration). In certain embodiments, the corticosteroid is administered about 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours prior to administration of the anti-CD38 antibody (e.g., subcutaneous administration).

[0290] In some embodiments, the corticosteroid comprises or consists of prednisone, hi some embodiments, the prednisone is administered the day after administration (e.g., subcutaneously) of the anti-CD38 antibody in the prior treatment.

[0291] Hematological malignancies In some embodiments, the hematological malignancy is a CD38-positive hematological malignancy. "CD38-positive hematological malignancy" refers to hematological malignancies characterized by the presence of tumor cells expressing CD38, including leukemia, lymphoma, and myeloma. Non-limiting examples of such CD38-positive hematological malignancies include precursor B-cell lymphoblastic leukemia / lymphoma and B-cell non-Hodgkin's lymphoma, acute promyelocytic leukemia, acute lymphoblastic leukemia, and mature B-cell neoplasms, such as B-cell chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), B-cell acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL) (low-grade lymphoma), and follicular lymphoma (FL) (low-grade lymphoma). These include: cutaneous follicle center lymphoma, marginal zone B-cell lymphoma (MALT type, nodal and splenic types), hairy cell leukemia, diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), plasmacytoma, multiple myeloma, plasma cell leukemia, post-transplant lymphoproliferative disorder, light chain amyloidosis, Waldenstrom's macroglobulinemia, plasma cell leukemia, and anaplastic large cell lymphoma (ALCL).

[0292] In some embodiments, the CD38-positive hematological malignancy is a plasma cell dyscrasia. In some embodiments, the CD38-positive hematological malignancy is multiple myeloma (MM), acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia, smoldering multiple myeloma (SMM), or a combination thereof. In certain embodiments, the plasma cell dyscrasia is light chain amyloidosis, MM, or Waldenstrom's macroglobulinemia.

[0293] In certain embodiments, the plasma cell disorder is MM. In some embodiments, the MM is light chain MM (LCMM), nonsecretory MM (NSMM), solitary plasmacytoma (SP), extramedullary plasmacytoma (EMP), monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), immunoglobulin D MM (IgD MM) or immunoglobulin E (IgE) MM, or a combination thereof. In some embodiments, the MM is newly diagnosed MM (NDMM). In some embodiments, the MM is relapsed or refractory MM (RRMM).

[0294] In some embodiments, the hematological malignancy is a hematological malignancy. The term "cancer" refers to diseases caused by the uncontrolled division of cells in parts of the body.

[0295] Additional medications In some embodiments, the method further comprises administering to the subject one or more additional therapeutic agents.

[0296] In some embodiments, the anti-CD38 antibody and the one or more additional therapeutic agents are administered simultaneously, hi other embodiments, the anti-CD38 antibody and the one or more additional therapeutic agents are administered separately (e.g., sequentially).

[0297] In some embodiments, the one or more additional therapeutic agents comprise chimeric antigen receptor (CAR)-expressing T cells (CAR-T cells), CAR-expressing natural killer cells (CAR-NK cells), CAR-expressing macrophages (CAR-M cells), chemotherapeutic agents, bispecific antibodies, immune checkpoint inhibitors, T cell redirectors, radiation therapy, surgery, standard of care, or a combination thereof.

[0298] Chimeric antigen receptor (CAR)-expressing T cells (CAR-T cells) In some embodiments, the one or more additional therapeutic agents comprise T cells expressing a chimeric antigen receptor (CAR) (CAR-T cells). CAR T cells are described in International Application No. PCT / IB2018 / 001619, the contents of which are incorporated herein by reference.

[0299] In some embodiments, the CAR comprises an extracellular antigen binding domain, a transmembrane domain, and an intracellular signaling domain.

[0300] In one embodiment, the intracellular signaling domain comprises a T cell surface glycoprotein CD3 zeta chain component.

[0301] In some embodiments, the extracellular antigen-binding domain binds to G protein-coupled receptor family C group 5 member D (GPRC5D). The terms "G protein-coupled receptor family C group 5 member D" and "GPRC5D" specifically encompass human GPRC5D protein as described, for example, in GenBank Accession No. BC069341, NCBI Reference Sequence: NP_061124.1, and UniProtKB / Swiss-Prot Accession No. Q9NZD1 (see also Brauner-Osborne et al., Biochim Biophys Acta. 1518(3):237-48 (2001)). The term "GPRC5D" encompasses proteins that include mutations (e.g., point mutations), fragments, insertions, deletions, and splice variants of full-length wild-type human GPRC5D. The term "GPRC5D" also encompasses post-translational modifications of the GPRC5D amino acid sequence. Post-translational modifications include, but are not limited to, N-linked glycosylation and O-linked glycosylation.

[0302] In some embodiments, the extracellular antigen binding domain binds to GPRC5D and CD3. In some embodiments, the one or more additional therapeutic agents include anti-GPRC5D CAR-T and / or anti-GPRC5D CAR-NK, or a combination thereof. Non-limiting examples of CARs targeting GPRC5D can be found in PCT Publication Nos. WO2016090312 and WO2020148677, the contents of which are incorporated herein by reference.

[0303] In some embodiments, the extracellular antigen-binding domain binds to B-cell maturation antigen (BCMA). Human and mouse amino acid and nucleic acid sequences of BCMA can be found in public databases (e.g., GenBank, UniProt, or Swiss-Prot). See, for example, UniProt / Swiss-Prot accession numbers Q02223 (human BCMA) and O88472 (mouse BCMA).

[0304] In some embodiments, the extracellular antigen binding domain binds to BCMA and CD3. In some embodiments, the one or more additional therapeutic agents comprise an anti-BCMA CAR-T, and / or an anti-BCMA CAR-NK, or a combination thereof. Non-limiting examples of CARs that target BCMA can be found in WO2013154760, WO2016014789, WO2016094304, WO2017025038, and WO2018028647, the contents of which are incorporated herein by reference.

[0305] T cell redirector In some embodiments, the T cell redirector comprises a soluble bispecific antibody (bsAb) or a membrane-anchored chimeric antigen receptor, or a combination thereof.

[0306] In some embodiments, the bispecific antibody binds to GPRC5D and CD3. Non-limiting examples of bispecific antigen-binding molecules that bind to GPRC5D and CD3 can be found in WO2018017786, the contents of which are incorporated herein by reference.

[0307] In some embodiments, the soluble bispecific antibody binds to BCMA and CD3. Non-limiting examples of bispecific antigen binding molecules that bind to BCMA and CD3 can be found in WO2017031104, the contents of which are incorporated herein by reference.

[0308] Immune checkpoint inhibitors In some embodiments, the one or more additional therapeutic agents comprises an immune checkpoint inhibitor.

[0309] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, or an anti-CTLA-4 antibody.

[0310] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody comprises the following VH and VL amino acid sequences: a) SEQ ID NO:23 and SEQ ID NO:24, respectively; b) SEQ ID NO:25 and SEQ ID NO:26, respectively; c) SEQ ID NO: 33 and SEQ ID NO: 34, respectively; or d) SEQ ID NO: 35 and SEQ ID NO: 36, respectively.

[0311] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody comprises the following VH and VL amino acid sequences: a) SEQ ID NO:27 and SEQ ID NO:28, respectively; b) SEQ ID NO: 29 and SEQ ID NO: 30, respectively; or c) SEQ ID NO: 31 and SEQ ID NO: 32, respectively.

[0312] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L2 antibody.

[0313] In some embodiments, the immune checkpoint inhibitor is an anti-LAG3 antibody. Non-limiting examples of anti-LAG-3 antibodies include those described in WO 2010 / 019570.

[0314] In some embodiments, the immune checkpoint inhibitor is an anti-TIM-3 antibody. In some embodiments, the anti-TIM-3 antibody comprises the following VH and VL amino acid sequences: a) SEQ ID NO: 37 and SEQ ID NO: 38, respectively; or b) SEQ ID NO: 39 and SEQ ID NO: 40, respectively.

[0315] In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 antibody. A non-limiting example of an anti-CTLA-4 antibody is ipilimumab.

[0316] Anti-PD-1, anti-PD-L1, anti-PD-L2, anti-LAG3, anti-TIM3 and anti-CTLA-4 antibodies may be generated de novo.

[0317] In some embodiments, the anti-CD38 antibody and the immune checkpoint inhibitor are administered simultaneously. In some embodiments, the anti-CD38 antibody and the immune checkpoint inhibitor are administered sequentially or separately.

[0318] Hematopoietic stem cell transplantation (HSCT) In some embodiments, the one or more additional therapeutic agents comprise a hematopoietic stem cell transplant (HSCT). A "hematopoietic stem cell transplant" is a transplant of blood stem cells derived from bone marrow (in this case known as a bone marrow transplant), blood (e.g., peripheral blood and umbilical cord blood), or amniotic fluid. "Receiving a hematopoietic stem cell transplant" means that the patient has already received, is receiving, or will receive a HSCT.

[0319] In some embodiments, the HSCT is allogeneic. In some embodiments, the HSCT is autologous or syngeneic (i.e., the donor is a twin). Autologous HSCT involves extraction of HSCs from the subject and freezing the harvested HSCs. After bone marrow ablation, the subject's stored HSCs are transplanted back into the subject. Allogeneic HSCT involves HSCs obtained from an allogeneic HSC donor with a compatible HLA type with the subject.

[0320] In some embodiments, the subject has completed chemotherapy and / or radiation therapy prior to HSCT.

[0321] The patient may be treated with chemotherapy and / or radiation therapy prior to HSCT (so-called pre-transplant preparation) to eradicate some or all of the patient's hematopoietic cells prior to transplantation. The patient may also be treated with immunosuppressants in the case of allogeneic HSCT. An exemplary pre-transplant preparation treatment is high-dose melphalan (see, e.g., Skinner et al., Ann. Intern. Med. 140:85-93 (2004); Gertz et al., Bone Marrow Transplant 34:1025-31 (2004); Perfetti et al., Haematologica 91:1635-43 (2006)). Radiation therapy that may be used in pre-transplant treatment may be performed according to protocols generally known in the art. Radiation therapy may be provided simultaneously, sequentially, or separately from the anti-CD38 antibody.

[0322] Radiation therapy In some embodiments, the methods of the present invention further comprise administering a form of radiation therapy, surgery, or a combination thereof. Non-limiting examples of radiation therapy include external beam radiation therapy, intensity modulated radiation therapy (IMRT), focused radiation therapy, and any form of radiosurgery, including Gamma Knife, CyberKnife, Linac, and interstitial radiation (e.g., radioactive seed implants, GliaSite balloon).

[0323] Focused radiation methods that may be used include stereotactic radiosurgery, fractionated stereotactic radiosurgery, and intensity-modulated radiation therapy (IMRT). In stereotactic radiosurgery, it is clear that radiation involves precise delivery to tumor tissue, e.g., brain tumors, while avoiding surrounding non-tumor normal tissue. The dose of radiation applied by stereotactic radiosurgery may vary, but is typically between 1 Gy and about 30 Gy, and may encompass intermediate ranges, e.g., between 1-5, 10, 15, 20, 25, and up to 30 Gy. Due to the non-invasive fixation device, stereotactic radiation does not need to be delivered in a single treatment. The treatment plan can be reliably reproduced from day to day, thereby allowing multiple fractionated radiation doses to be delivered. When used to treat tumors over time, radiosurgery is referred to as "fractionated stereotactic radiosurgery" or FSR. In contrast, stereotactic radiosurgery refers to treatment in a single session. Fractionated stereotactic radiosurgery may result in a high treatable ratio, i.e., a high percentage of tumor cells killed and less impact on normal tissue. Tumor and normal tissue respond differently to a single high dose of radiation and multiple low doses of radiation. A single high dose of radiation may kill more normal tissue than multiple low doses of radiation. Thus, multiple low doses of radiation may kill more tumor cells while sparing normal tissue. The dose of radiation applied by fractionated stereotactic radiosurgery may range from 1 Gy to about 50 Gy, and may include intermediate ranges in hypofractionated doses, including, for example, 1-5, 10, 15, 20, 25, 30, 40, and up to 50 Gy. Intensity-modulated radiation therapy (IMRT) may also be used. IMRT is an advanced mode of high-precision three-dimensional conformal radiation therapy (3DCRT) that uses a computer-controlled linear accelerator to deliver precise doses of radiation to a malignant tumor or to specific regions within the tumor. In 3DCRT, the profile of each radiation beam is shaped to match the target profile from the beam vector image (BEV) using a multi-leaf collimator (MLC), thereby creating many beams. In IMRT, the intensity of the radiation beam is modulated into multiple small doses, allowing the radiation dose to be more precisely matched to the three-dimensional (3D) shape of the tumor.IMRT therefore allows higher radiation doses to be focused on areas within the tumor while minimizing the dose to surrounding normal critical structures. IMRT improves the ability to conform the treatment volume to the concave shape of the tumor, for example, when the tumor overlies vulnerable structures such as the spinal cord, major organs, or blood vessels.

[0324] Subject The terms "subject" and "patient" may be used interchangeably herein. A "patient in need thereof" or "subject in need thereof" refers to a mammalian subject, preferably a human, diagnosed with or suspected of having a disease to which an anti-CD38 antibody is or has been administered according to the methods of the invention. A "patient in need thereof" or "subject in need thereof" includes subjects already having an undesirable physiological change or disease, as well as subjects predisposed to having said physiological change or disease.

[0325] In some embodiments, the subject is 18 years of age or older, e.g., 18 to 40 years of age, 18 to 45 years of age, 18 to 50 years of age, 18 to 55 years of age, 18 to 60 years of age, 18 to 65 years of age, 18 to 70 years of age, 18 to 75 years of age, 40 to 75 years of age, 45 to 75 years of age, 50 to 75 years of age, 55 to 75 years of age, 60 to 75 years of age, 65 to 75 years of age, 60 to 75 years of age, 40 years of age or older, 45 years of age or older, 50 years of age or older, 55 years of age or older, 60 years of age or older, 65 years of age or older, 70 years of age or older, or 75 years of age or older. In some embodiments, the subject is a child. In some embodiments, the subject is 18 years of age or younger, e.g., 0-18 years of age, 0-12 years of age, 0-16 years of age, 0-17 years of age, 2-12 years of age, 2-16 years of age, 2-17 years of age, 2-18 years of age, 3-12 years of age, 3-16 years of age, 3-17 years of age, 3-18 years of age, 4-12 years of age, 4-16 years of age, 4-17 years of age, 4-18 years of age, 6-12 years of age, 6-16 years of age, 6-17 years of age, 6-18 years of age, 9-12 years of age, 9-16 years of age, 9-17 years of age, 9-18 years of age, 12-16 years of age, 12-17 years of age, or 12-18 years of age.

[0326] In some embodiments, the subject has stage I (e.g., ISS stage I) multiple myeloma. In other embodiments, the subject has stage II (e.g., ISS stage II) multiple myeloma. In yet other embodiments, the subject has stage III (e.g., ISS stage III) multiple myeloma.

[0327] In some embodiments, the subject has an IgG myeloma. In some embodiments, the subject has an IgA myeloma. In some embodiments, the subject has a light chain only myeloma.

[0328] In some embodiments, the subject has been diagnosed with multiple myeloma for at least about 1 month, e.g., at least about 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 18 months, 2 years, 30 months, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, or 20 years.

[0329] In some embodiments, the subject is refractory to at least one line of therapy. In certain embodiments, the subject has received at least one line of anti-myeloma therapy, for example, at least two, three, four, five, six, seven, or eight lines of prior anti-myeloma therapy. In certain embodiments, the subject has previously received at least two lines of anti-myeloma therapy. In certain embodiments, the at least two prior lines of anti-myeloma therapy include hematopoietic stem cell transplantation (HSCT), proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), maintenance therapy, or a combination thereof. In some embodiments, the prior lines of anti-myeloma therapy include proteasome inhibitors and immunomodulatory drugs.

[0330] In some embodiments, the hematopoietic stem cell transplant is an allogeneic stem cell transplant (ASCT).

[0331] In some embodiments, the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib. In certain embodiments, the proteasome inhibitor is bortezomib.

[0332] In certain embodiments, the immunomodulatory agent is lenalidomide.

[0333] In some embodiments, the cancer has standard risk cytogenetics. In some embodiments, the subject has high risk cytogenetics. Cytogenetic abnormalities can be determined based on suitable methods well known to those of skill in the art, such as fluorescent in situ hybridization or karyotyping.

[0334] In some embodiments, the subject is anti-CD38 treatment naive (ie, the subject has never received anti-CD38 treatment).

[0335] Effectiveness According to embodiments of the present disclosure, various factors may be analyzed to determine whether a particular treatment regimen (e.g., pre-dose steroid taper, post-dose steroid taper, or both) is an effective approach in treating a hematological malignancy (e.g., RRMM).

[0336] In some embodiments, the method comprises: a) a ≥ 50% reduction in serum M protein and a ≥ 90% reduction in 24-hour urinary M protein; b) A ≥ 50% reduction in serum M protein and a 24-hour reduction in urinary M protein of < 200 mg / 24 hours; c) a ≥ 50% decrease in the difference between involved and uninvolved FLC levels; d) ≥ 50% reduction in bone marrow PCs; e) A ≥ 50% reduction in size of a soft tissue plasmacytoma, or These combinations result.

[0337] In some embodiments, the method induces at least a partial response (PR) in the subject (e.g., according to International Myeloma Working Group (IMWG) criteria). IMWG PR criteria: (>=) 50 percent (%) reduction in serum M protein and >= 90% reduction in urinary M protein in 24 hours, or less than (<) 200 milligrams (mg) / 24 hours, and if serum and urine M protein were not measurable, then instead of the M protein criteria, the difference between involved and uninvolved free light chain (FLC) levels had to be reduced by >= 50%, and if serum and urine M protein were not measurable and serum-free photoassay was also not measurable, then instead of M protein, bone marrow plasma cells (PC) had to be reduced by >= 50%, provided that the baseline bone marrow plasma cell percentage was >= 30%. In addition to the above criteria, a >= 50% reduction in size of soft tissue plasmacytoma was also required, if present at baseline. See also, e.g., supplementary appendix to Lokhorst HM et al., N Engl J Med. (2015), 373(13):1207-19.

[0338] In some embodiments, the methods result in a ≧90% reduction in serum M protein+urinary M protein<100 mg / 24 hr. In certain embodiments, serum and urinary M components are detectable by immunofixation but not by electrophoresis.

[0339] In certain embodiments, the method induces at least a very good partial response (VGPR) in the subject (eg, according to IMWG criteria).

[0340] In some embodiments, the method comprises: a) Negative immunofixation in serum and urine, b) disappearance of soft tissue plasmacytomas; c) <5% PCs in bone marrow, or These combinations result.

[0341] In some embodiments, the method comprises: a) Negative immunofixation in serum and urine, b) disappearance of soft tissue plasmacytomas, and c) yields <5% of PCs in bone marrow.

[0342] In certain embodiments, the method induces a complete response (CR) in the subject (eg, according to IMWG criteria).

[0343] In some embodiments, the method comprises: a) Negative immunofixation in serum and urine, b) disappearance of soft tissue plasmacytomas; c) <5% PC in bone marrow; d) normal FLC ratio, and e) the absence of clonal PCs by immunohistochemistry, immunofluorescence, or two- to four-color flow cytometry.

[0344] In certain embodiments, the method induces a stringent complete response (sCR) in the subject (eg, according to IMWG criteria).

[0345] In some embodiments, the method results in stable disease (SD) according to IMWG criteria.

[0346] In some embodiments, the methods are used to treat a patient population.

[0347] In some embodiments, the patient population achieves an overall response rate (ORR) of at least about 25.0%, e.g., at least about 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, or 55.0%. "ORR" refers to the proportion of subjects who achieve a complete or partial response according to IMWG criteria during or after the study treatment. In certain embodiments, the ORR is at least about 35.0% or 40.0%. In some embodiments, the ORR is about 25.0-55.0%, e.g., about 30.0-55.0%, 30.0-50.0%, 35.0-50.0%, 35.0-45.0%, or 40.0-45.0%. In certain embodiments, the ORR is at least about 40.0-45.0%. In some embodiments, the ORR is about 25.0%, 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, or 55.0%.

[0348] In some embodiments, the patient population achieves a very good partial response (VGPR) rate of at least about 5.0% or greater during or after treatment, e.g., a rate of at least about 10%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 16.0%, 17.0%, 18.0%, 19.0%, 20.0%, 21.0%, 22.0%, 23.0%, 24.0%, 25.0%, 26.0%, 27.0%, 28.0%, 29.0%, 30%, 31.0%, 32.0%, 33.0%, 34.0%, 35.0%, 36.0%, 37.0%, 38.0%, 39.0%, or 40% during or after treatment. In certain embodiments, the percentage of VGPR or higher is at least about 10%, 15.0%, 20.0%, 25.0%, or 30.0%. In some embodiments, the percentage of VGPR or higher is about 5.0 to 50.0%, for example, about 10.0 to 50.0%, 10.0 to 45.0%, 15.0 to 45.0%, 15.0 to 40.0%, 15.0 to 37.50%, 20.0 to 37.50%, 20.0 to 35.00%, 25.0 to 35.00%, 25.0 to 30.00%, or 30.0 to 35.0%.

[0349] In some embodiments, the method results in a duration of response (DR) of at least about 9 months, e.g., at least about 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 ​​months, 54 months, or 60 months. "Duration of response" or "DR" refers to the time from the date of first documented response (PR or better) to the date of first documented progressive disease (PD), as defined by the IMWG criteria. IMWG Criteria for PD: 25% increase from minimum response in any one of the following: serum M component (absolute increase must be >=0.5 grams / dL), urine M component (absolute increase must be >=200 mg / 24 hours), Participants without measurable serum and urine M protein levels: difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be >10 milligrams / dL (mg / dL)), Participants without measurable serum and urine M protein levels and without measurable disease by FLC levels: bone marrow PC% (absolute percentage must be >=10%), unequivocal development of new bone lesions or soft tissue plasmacytomas or an increase in size of bone lesions or tissue plasmacytomas, and development of hypercalcemia (serum calcium >11.5 mg / dL) that can only be attributed to a PC proliferative disorder. See also, e.g., supplementary appendix to Lokhorst HM et al., N Engl J Med. (2015), 373(13):1207-19.

[0350] In some embodiments, the method results in a progression-free survival (PFS) of at least about 9 months, e.g., at least about 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 ​​months, 54 months, or 60 months. "Progression-free survival" or "PFS" refers to the time from the date of randomization to disease progression (PD) or death from any cause, whichever occurs first.

[0351] In some embodiments, the method provides a time to partial response (PR) of about 12 months or less, e.g., about 11 months or less, 10 months or less, 9 months or less, 8 months or less, 7 months or less, 6 months or less, 5 months or less, 4 months or less, 3 months or less, 2 months or less, or 1 month or less. "Time to partial response (PR) or better (PR)" refers to the time from the first administration of investigational drug to the date of first documented response (CR or PR, or better than PR).

[0352] In some embodiments, the method improves one or more outcome measures in the subject. In some embodiments, the one or more outcome measures include progression-free survival, duration of response, or duration of at least partial response, or any combination thereof. In some embodiments, the one or more outcome measures include partial response, very good partial response, complete response, or stringent complete response.

[0353] In some embodiments, subjects experience improvement in one or more outcome measures that are consistent with subjects receiving anti-CD38 antibody administration and continued corticosteroid administration, in other words, the difference in improvement in subjects treated with the methods described herein and subjects treated without the reduction or elimination of corticosteroid administration is not (statistically) significant.

[0354] In some embodiments, subjects experience enhanced improvement in one or more outcome measures compared to subjects receiving anti-CD38 antibody administration and continued corticosteroid administration, in other words, subjects treated with the methods described herein and subjects treated without the reduction or elimination of corticosteroid administration experience improvement.

[0355] safety According to embodiments of the present disclosure, various factors may be analyzed to determine whether a particular treatment regimen (e.g., pre-dose steroid taper, post-dose steroid taper, or both) is a safe approach in treating a hematological malignancy (e.g., RRMM).

[0356] The term "safe" as used herein, in relation to a pharmaceutical composition, dose, dosing regimen, treatment or method, or in relation to a therapeutic agent comprising an anti-CD38 antibody (such as daratumumab), refers to the following beneficial benefit: the frequency and / or severity of adverse events (AEs) and / or treatment-emergent adverse events (TEAEs) is at an acceptable risk ratio compared to standard of care or other comparator.

[0357] "A method of providing safe treatment" or "a method of providing safe administration" refers to an administration method that is effective to provide the benefit of a therapeutic or pharmaceutical composition without causing unacceptable adverse events when administered to a subject.

[0358] "Adverse event" or "AE" refers to any untoward medical occurrence in a subject administered an antibody that specifically binds to CD38, such as daratumumab. An AE does not necessarily have a causal relationship to the treatment. Thus, an AE can be any untoward and unintended sign (including an abnormal finding), symptom, or disease that is temporally associated with the use of a medicinal product (investigational or non-investigational), whether or not related to an antibody that specifically binds to CD38, such as daratumumab.

[0359] "Treatment-emergent adverse event" (TEAE), as used herein, has its customary meaning as understood by one of ordinary skill in the art of designing, conducting, or reviewing clinical trials, and refers to an AE that is considered to be associated with the use of an antibody that specifically binds CD38 if it is attributable, likely attributable, or highly likely attributable.

[0360] In some embodiments, the subject is free of TEAEs of any grade during or after treatment. Non-limiting examples of TEAEs of any grade include anemia, arthralgia, asthenia, cough, diarrhea, dizziness, erythema, fatigue, headache, muscle spasms, nasopharyngitis, nausea, peripheral edema, pain in extremities, fever, and upper respiratory tract infection.

[0361] In some embodiments, subjects are free of grade 3 / 4 TEAEs during or after treatment. Non-limiting examples of grade 3 / 4 TEAEs include anemia, bone pain, lymphopenia, and neutropenia.

[0362] "Unacceptable Adverse Event" and "Unacceptable Adverse Reaction" means any adverse or undesirable outcome associated with or caused by the administration of a pharmaceutical composition or therapeutic agent, which adverse or undesirable outcome reaches a level of severity such that a regulatory authority deems the pharmaceutical composition or therapeutic agent unacceptable for the proposed use. When used in connection with subcutaneous administration of an anti-CD38 antibody, examples of unacceptable adverse events or reactions include thrombocytopenia, neutropenia, severe systemic injection-related reactions, and the inability to tolerate CD38 antibodies to reach levels below certain specified levels. + These include, but are not limited to, cell depletion.

[0363] The safety of a particular dose of subcutaneously administered anti-CD38 antibody can be assessed, for example, by immunogenicity studies (e.g., measuring the production of anti-daratumumab antibodies), evaluating changes in CD38 expression levels, evaluating the extent and duration of depletion of CD38-expressing cell numbers (e.g., percentage of plasma cells, natural killer (NK) cells, total lymphocytes), and determining effects on blood biomarkers such as serum proteins (e.g., cytokines, chemokines, and inflammatory proteins) by protein profiling. The safety of subcutaneously administered anti-CD38 antibody can also be monitored by physical examination of the subject, observation of local injection site reactions, systemic injection-related reactions, and other allergic reactions, electrocardiograms, laboratory tests, vital signs, and monitoring of concomitant medications, as well as other adverse events.

[0364] Pharmacokinetics and immunogenicity In some embodiments, the method further comprises measuring the production of antibodies specific for the anti-CD38 antibody in the subject following subcutaneous administration of the anti-CD38 antibody.

[0365] In some embodiments, the method further comprises determining a change in CD38 expression levels in the subject following subcutaneous administration of the anti-CD38 antibody.

[0366] In some embodiments, the method further comprises measuring the extent of depletion of CD38-expressing cells in the subject following subcutaneous administration of an anti-CD38 antibody.

[0367] In some embodiments, the method further comprises measuring the serum concentration of the anti-CD38 antibody, e.g., on day 1 of cycle 3 (pre-administration). In certain embodiments, the serum concentration of the anti-CD38 antibody (e.g., daratumumab) is between about 500 μg / mL and about 800 μg / mL, e.g., about 525-800, 525-775, 550-775, 550-750, 575-750, 575-725, 600-725, or 600-700 μg / mL. In certain embodiments, the serum concentration of the anti-CD38 antibody (e.g., daratumumab) is about 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, or 800 μg / mL.

[0368] In some embodiments, the method further comprises measuring the duration of depletion of CD38-expressing cells in the subject following subcutaneous administration of the anti-CD38 antibody, hi certain embodiments, the CD38-expressing cells comprise plasma cells, NK cells, lymphocytes, or a combination thereof.

[0369] In some embodiments, the method further comprises profiling biomarkers in the subject following subcutaneous administration of the anti-CD38 antibody. In certain embodiments, the biomarkers comprise blood biomarkers. In particular embodiments, the biomarkers comprise serum proteins (e.g., cytokines, chemokines, and inflammatory proteins).

[0370] In some embodiments, the method further comprises the step of physically examining the subject after subcutaneous administration of the anti-CD38 antibody.

[0371] In some embodiments, the method further comprises detecting an allergic reaction in the subject (e.g., a local injection site reaction or a systemic injection-related reaction).

[0372] In some embodiments, the methods further comprise the step of performing an electrocardiogram on the subject following subcutaneous administration of the anti-CD38 antibody.

[0373] In some embodiments, when used in relation to subcutaneous administration of daratumumab, "safe treatment" and "safe administration" refer to the treatment of CD38 cells, such as plasma cells, NK cells, T cells, B cells, etc. + In certain embodiments, "safe treatment" and "safe administration" refer to a reduction in adverse events, including, but not limited to, a reduction in depletion of CD38 cells, particularly NK cells and / or plasma cells. In certain embodiments, "safe treatment" and "safe administration" refer to a reduction in the depletion of CD38 cells, particularly NK cells and / or plasma cells, resulting from subcutaneous administration of an anti-CD38 antibody (such as daratumumab), preferably at least 4 weeks after administration of daratumumab. + This means that less than 80% of cells (e.g., plasma cells, NK cells, T cells, B cells, etc.) are depleted. NK cells are a type of lymphocyte (white blood cell) and a component of the innate immune system. NK cells are cytotoxic and contribute to host rejection of, for example, tumor and virus-infected cells.

[0374] NK cells are a type of cytotoxic lymphocyte that are important for the innate immune system and express CD38 + NK cells are one of the important effector cells for ADCC-mediated depletion of cells. NK cells are known to express CD38, so the number of circulating NK cells may decrease after anti-CD38 antibody treatment. Furthermore, plasma cells express CD38, so they are susceptible to anti-CD38 antibody-mediated cell lysis. Plasma cells are white blood cells that secrete antibody molecules that recognize, bind, and initiate neutralization or degradation of foreign substances. NK cell and plasma cell depletion is measured relative to the amount of NK cells and plasma cells in the subject before administration of anti-CD38 antibody. NK cell and plasma cell depletion can be determined using any method known in the art in view of the present disclosure, including but not limited to flow cytometry.

[0375] In some embodiments, the subject is less than about 80% depleted of NK cells about 4 weeks after subcutaneous administration of the anti-CD38 antibody, e.g., less than about 70%, 60%, 50%, 40%, 30%, 20%, or 10% depleted of NK cells about 4 weeks after subcutaneous administration of the anti-CD38 antibody.

[0376] In some embodiments, the subject is less than about 80% depleted of NK cells about two weeks after subcutaneous administration of the anti-CD38 antibody, e.g., less than about 70%, 60%, 50%, 40%, 30%, 20%, or 10% depleted of NK cells about two weeks after subcutaneous administration of the anti-CD38 antibody.

[0377] In some embodiments, the subject is less than about 80% depleted of plasma cells about 4 weeks after subcutaneous administration of the anti-CD38 antibody, e.g., less than about 70%, 60%, 50%, 40%, 30%, 20%, or 10% depleted of plasma cells about 4 weeks after subcutaneous administration of the anti-CD38 antibody.

[0378] In some embodiments, the subject is less than about 80% depleted of plasma cells about two weeks after subcutaneous administration of the anti-CD38 antibody, e.g., less than about 70%, 60%, 50%, 40%, 30%, 20%, or 10% depleted of plasma cells about two weeks after subcutaneous administration of the anti-CD38 antibody.

[0379] When lists are presented, unless otherwise stated, it is to be understood that each individual element of that list and every combination of that list is a separate embodiment. 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."

[0380] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise specified, certain terms used herein have the meanings set forth herein. All patents, published patent applications and publications cited herein are incorporated by reference as if fully set forth herein. It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless otherwise clear from the context.

[0381] Unless otherwise stated, any numerical value, such as a concentration or concentration range, described herein should be understood in all cases as being modified by the term "about". Thus, numerical values ​​typically include ±10% of the described value. For example, a dosage of 10 mg includes 9 mg to 11 mg. As used herein, the use of numerical ranges expressly includes all possible subranges, all individual numerical values ​​within the range, including integers and fractions of values ​​within the range, unless otherwise expressly specified in the context.

[0382] Throughout this specification and the claims that follow, unless the context otherwise requires, "comprise" and variations of terms such as "comprises" and "comprising" will be understood to imply the inclusion of a specified integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps. As used herein, the term "comprising" can be replaced with the terms "containing" or "including," or, as sometimes used herein, with the term "having."

[0383] As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Whenever used herein in the context of an aspect or embodiment of the invention, any of the above terms "comprise", "contain", "include", and "have" can be replaced with the term "comprise" or "consist essentially of" in order to vary the scope of the disclosure.

[0384] As used herein, the connective term "and / or" between multiple listed elements is understood to encompass both individual and combined options. For example, when two elements are connected by "and / or," the first option refers to the first element being applicable without the second element. The second option refers to the second element being applicable without the first element. The third option refers to the first and second elements being applicable together. Any one of these options is understood to be within the meaning of the term "and / or" as used herein and therefore meets the requirements. Two or more options that are simultaneously applicable are also understood to be within the meaning of "and / or" and therefore meet the requirements of the term.

[0385] "About" means within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on the limitations of how the value is measured or determined, i.e., the measurement system. In the context of a particular assay, result, or embodiment, unless expressly stated otherwise in the Examples or elsewhere herein, "about" means within one standard deviation, or up to 5%, whichever is greater, as per practice in the art. EXAMPLES

[0386] Daratumumab is a human IgGκ monoclonal antibody that targets CD38 and has been used both directly on tumors (de Weers et al., J Immunol 186(3):1840-48 (2011); Lammerts et al., Blood 124(21):3474 (2014); Overdijk et al., J Immunol 197(3):807-13 (2016); Overdijk et al., MAbs 7(2):311-21 (2015)) and via immunomodulatory (Adams et al., Cytometry A 95(3):279-89 (2019); Casneuf et al., Leukemia 35:573-84 (2020); Krejcik et al., Blood 128(3):384-94 (2016)). Daratumumab is approved for the treatment of relapsed or refractory multiple myeloma (RRMM) as a monotherapy or in combination with standard treatment regimens. Daratumumab 16 mg / kg is approved for intravenous (IV) infusion in monotherapy or combination regimens for the treatment of relapsed or refractory multiple myeloma (RRMM) or newly diagnosed multiple myeloma (NDMM) (DARZALEX® (daratumumab) Injection, Intravenous Use (www_janssenlabels_com / package-insert / product-monograph / prescribing-information / DARZALEX-pi.pdf) (2022)), (DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) Injection, Intravenous Use (www_janssenlabels_com / package-insert / product-monograph / prescribing-information / DARZALEX+Faspro-pi.pdf) (2022)).

[0387] In clinical studies, the median duration of the first, second, and subsequent daratumumab IV infusions was approximately 7 hours, 4 hours, and 3 hours, respectively (DARZALEX® (daratumumab) Injection, Intravenous Use (www_janssenlabels_com / package-insert / product-monograph / prescribing-information / DARZALEX-pi.pdf) (2022)). Additionally, infusion-related reactions (IRRs) have been reported with daratumumab, occurring primarily during the first infusion and generally being mild to moderate in severity and manageable (DARZALEX® (daratumumab) injection, intravenous use (www_janssenlabels_com / package-insert / product-monograph / prescribing-information / DARZALEX-pi.pdf) (2022); Chari et al., Blood 130(8):974-81 (2017); Dimopoulos et al., N Engl J Med 375(14):1319-31 (2016); Lokhorst et al., N Engl J Med 373(13):1207-19 (2015); Lonial et al., Lancet 387(10027):1551-60(2016); Mateos et al., N Engl J Med 378(6):518-28(2018); Palumbo et al., N Engl J Med 375(8):754-66(2016)).

[0388] Because IV administration of daratumumab requires longer infusion times and has a rate of treatment-related IRRs, subcutaneous delivery methods have been developed that aim to reduce infusion times without compromising the safety and efficacy of daratumumab treatment, thereby improving convenience for patients and healthcare professionals (Chari et al., Blood 134(5):421-31 (2019); Mateos et al., Lancet Haematol 7(5):e370-e380 (2020); San-Miguel et al., Haematologica 106(6):1725-32 (2021); Usmani et al., Blood 134(8):668-77 (2019)).

[0389] The Phase 1 PAVO clinical trial was the first study to evaluate the safety, pharmacokinetics, and efficacy of subcutaneous (SC) administration of daratumumab in combination with recombinant human hyaluronidase PH20 (rHuPH20, ENHANZE® drug delivery technology, Halozyme, Inc., San Diego, CA) (DARA SC) in patients with RRMM. In Part 1 of PAVO, a combined delivery formulation of daratumumab (20 mg / mL) and rHuPH20 (DARA MD) was administered over 20-30 minutes using a syringe pump at doses of 1,2000 mg and 1,800 mg, demonstrating that DARA SC administration is feasible in patients with RRMM. Safety, pharmacokinetic (PK), immunogenicity, and efficacy results for the 1,800 mg dose of DARA MD were consistent with those associated with IV daratumumab, eliciting deep and durable responses (Usmani et al., Blood 134(8):668-77 (2019). In part 2 of the study, patients were administered a concentrated premixed SC formulation of daratumumab (DARA SC, 1,800 mg daratumumab (2,000 U / mL, 15 mL) coformulated with 30,000 U rHuPH20) by manual subcutaneous injection into the abdomen over 3–5 minutes. The tolerability profile of DARA SC was consistent with that of IV daratumumab, and no new safety concerns were observed. DARA SC reduced administration time and demonstrated a lower IRR rate in patients with RRMM. DARA SC achieved maximum C values ​​similar to or greater than those achieved with IV daratumumab. troughThe efficacy of DARA SC was similar to that previously observed with daratumumab IV (Usmani et al., Blood 128(1):37-44 (2016)). After 14.2 months of follow-up in PAVO Part 2, the overall response rate (ORR) was 52%, with a median response duration of 15.7 months (San-Miguel et al., Haematologica 106(6):1725-32 (2020)). After 7.5 months of follow-up in the phase 3 COLUMBA trial, the overall response rate was 41% for DARA SC and 37% for DARA IV, with median duration of response not being reached in either group (Mateos et al., Lancet Haematol 7(5):e370-e380 (2020)). Based on efficacy and safety data of DARA SC in patients with multiple myeloma (Mateos et al., Lancet Haematol 7(5):e370-e380 (2020)), DARA SC has received approval in the United States, European Union, and other countries globally as a monotherapy for RRMM and in combination for the treatment of RRMM or NDMM (DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)) injection, for intravenous use (www_janssenlabels_com / package-insert / product-monograph / prescribing-information / DARZALEX+Faspro-pi.pdf) (2022).

[0390] Corticosteroids serve as an important component of treatment plans for patients with multiple myeloma. However, long-term use of corticosteroids can introduce additional toxicity into treatment plans that currently include up to four individual drugs, which can subsequently negatively impact the quality of life of patients with multiple myeloma. Indeed, patients have shown a preference for treatment plans that limit the use of steroids (Parsons et al., BMC Cancer 19(1):264 (2019)). Furthermore, the immunosuppressive effects of corticosteroids may reduce the efficacy of immunotherapies in cancer treatment, such as checkpoint inhibitors, T cell redirectors, or chimeric antigen receptor (CAR) T cell therapy (Arbour et al., J Clin Oncol 36(28)):2872-78 (2018); Namuduri et al., Expert Rev Hematol. 9(6):511-13 (2016); Strati P et al., Blood 137(23):3272-76 (2021); Kauer J et al., J Immunother Cancer 8(1):e000621 (2020)). Thus, corticosteroids can be continued as part of combination treatment for cancer patients, but tapering corticosteroids may achieve consistent tolerability without loss of efficacy, especially with DARA SC. Part 3 of the PAVO study was conducted to evaluate the safety of various schedules before and after corticosteroid tapering during DARA SC administration.

[0391] Example 1. Method Study design and patient population The PAVO (MMY1004) study is a three-part, open-label, non-randomized, multicenter, phase 1b study. Detailed eligibility criteria have been published previously (San-Miguel et al., Haematologica 106(6):1725-32 (2021); Usmani et al., Blood 134(8):668-77 (2019)). Briefly, eligible patients aged ≥18 years had measurable RRMM, had ≥2 prior lines of therapy including proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), had an Eastern Cooperative Oncology Group performance status (ECOG PS) score ≤2, and had no prior treatment with daratumumab or other anti-CD38 therapy (Figure 1). Safety was assessed with an emphasis on IRR, and corticosteroids were tapered and discontinued.

[0392] treatment The objective of Part 3 was to evaluate the safety of daratumumab 1,800 mg subcutaneous (SC) delivery after 3-week, 2-week, and 1-week tapers without pre- and post-dose corticosteroids, scheduled to assess the safety of daratumumab SC administration without corticosteroids. A total of 42 participants were treated. In Part 3, patients received daratumumab SC by manual subcutaneous (SC) injection (over 3-5 minutes, alternating abdominal locations) according to the approved IV monotherapy administration schedule (Figure 1) as follows: DARA SC (DARA 1,800 mg + rHuPH20 Patients received 30,000 U, 15 mL) once a week during cycles 1 and 2, every 2 weeks during cycles 3-6, and every 4 weeks thereafter. In addition, patients also received a 3-, 2-, or 1-week steroid taper schedule (Figure 2). The 3-week taper schedule (eliminating corticosteroids by cycle 1 day 22) consisted of pre-dose oral (PO) / IV (cycle 1 day 1, 100 mg; cycle 1 day 8, 60 mg; cycle 1 day 15, 30 mg) and post-dose PO (cycle 1 day 1, 20 mg for 2 days; cycle 1 day 8, 20 mg for 1 day; cycle 1 day 15, 20 mg for 2 days). The 2-week taper schedule (eliminating corticosteroids by cycle 1 day 15) consisted of MP given PO / IV pre-dose (cycle 1 day 1, 100 mg; cycle 1 day 8, 60 mg) and post-dose PO (cycle 1 day 1, 20 mg for 2 days; cycle 1 day 8, 20 mg for 1 day). The 1-week taper schedule (eliminating corticosteroids by cycle 1 day 8) consisted of dexamethasone 20 mg IV pre-dose on cycle 1 day 1 with no post-dose.

[0393] Three-week, two-week, and one-week steroid tapering schedules were evaluated by a "3+3" design, followed by cohort expansion to approximately 15 patients (three-week and two-week tapering cohorts) or 12 patients (one-week tapering cohort). Dose-limiting toxicity (DLT) evaluation periods in the three-week, two-week, and one-week tapering cohorts were cycle 1 day 1 to cycle 2 day 4, cycle 1 day 1 to cycle 1 day 25, and cycle 1 day 1 to cycle 1 day 11, respectively. DLTs were defined as grade 4 IRRs within 72 hours after injection or grade 3 IRRs within 72 hours after injection that did not improve with slowing or discontinuation of injection and included supportive and symptomatic care. Grade 3 or grade 4 IRRs were qualified as DLTs only if they occurred during corticosteroid tapering or discontinuation (excluding cycle 1 day 1). In the 3-week and 2-week groups, the IRR reported on day 1 of cycle 1 was not considered a DLT because corticosteroids had not yet been tapered or discontinued. Up to approximately 12 patients could be enrolled in the 1-week tapering schedule to be evaluable for safety, including IRR.

[0394] Evaluation items and evaluation The primary endpoint was safety of pre- and post-steroid tapering. Key secondary endpoints included overall response rate (ORR) and complete response rate (CR).

[0395] Safety assessments included treatment-emergent adverse events (TEAEs), serious adverse events, and IRRs. All toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 (National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE): version 4.03).

[0396] For pharmacokinetic analysis, DARA SC serum concentrations were assessed from blood samples taken pre-dose on cycle 3 day 1. For immunogenicity assessment, anti-daratumumab antibodies in serum and anti-rHuPH20 antibodies in plasma were assessed pre-dose on cycle 1 day 1, cycle 1 day 15, cycle 2 day 22, cycle 4 day 1, and after 4 and 8 weeks of treatment. The presence of anti-daratumumab and / or anti-rHuPH20 antibodies was assessed for classification as neutralizing antibodies.

[0397] Efficacy was assessed by response assessment according to the International Myeloma Working Group (IMWG) consensus recommendations (Durie et al., Leukemia 20(9):1467-73 (2006); Rajkumar et al., Blood 117(18):4691-95 (2011)). Disease assessment was performed by a central laboratory.

[0398] statistical analysis No formal statistical hypothesis testing was performed in PAVO Part 3. Data were summarized descriptively. Continuous variables were summarized using number of observations, mean, and standard deviation (SD), coefficient of variation, median, and range, as appropriate. Categorical variables were summarized using number of observations and percentages, as appropriate. Response duration and PFS were estimated using the Kaplan-Meier method.

[0399] The safety and efficacy population, defined as all patients who received ≥1 dose of study drug, was the primary population for analysis. The pharmacokinetic analysis set included all subjects who received at least 1 dose of study drug and had at least one pharmacokinetic sample concentration value after the first drug dose. The pharmacokinetic evaluable population was defined as all patients who received ≥1 dose of study drug and provided ≥1 post-infusion pharmacokinetic sample. The immunogenicity population was defined as all patients who received ≥1 dose of study drug and provided ≥1 post-infusion immunogenicity sample.

[0400] Example 2. Patient Pharmacokinetics and Demographics A total of 42 patients were enrolled in PAVO Part 3 (3-week taper cohort, n=15; 2-week taper cohort, n=15; 1-week taper cohort, n=12). Overall, the median age was 69.5 years (range: 52–86 years) and the median weight was 77.8 kg (range: 44.0–151.3). At baseline, 92.9% (39 / 42) of patients had an ECOG PS score ≤1. The median time from diagnosis was 5.9 years (range: 0.7–19.2), and the median number of prior lines of therapy was 3 (range: 2–7). A total of 19 (45.2%) patients were refractory to PIs and IMiDs. Of the 31 patients with available cytogenetic data, 8 (25.8%) patients had high-risk cytogenetic abnormalities (Table 2).

[0401] The median (range) follow-up was 8.3 months for the full treatment group, 9.2 (1.9-25.5) months for the 3-week taper cohort, 11.1 (1.7-24.0) months for the 2-week taper cohort, and 8.3 (0.4-13.1) months for the 1-week taper cohort. The full treatment population included all patients who received at least one dose of study drug. The median treatment duration was 6.5 months for all steroid taper groups. Patients in the 3-week taper cohort received a median (range) 18 (5-38) doses of DARA SC. Patients in the 2-week taper cohort received a median (range) 17 (5-33) doses of DARA SC. Patients in the 1-week taper cohort received a median (range) 18 (2-25) doses of DARA SC. Thirteen (86.7%) patients in the 3-week and 2-week taper cohorts, respectively, and seven (58.3%) patients in the 1-week taper cohort discontinued treatment, with most discontinuations due to progressive disease (10 [66.7%], 12 [80.0%], and five [41.7%] patients, respectively). At the time of analysis, a total of two (13.3%), two (13.3%), and five (41.7%) patients in the 3-week, 2-week, and 1-week taper cohorts, respectively, were still receiving treatment.

[0402] Example 3. Safety, Pharmacokinetics, Immunogenicity and Efficacy Treatment-emergent adverse events All patients experienced at least one TEAE, regardless of steroid taper cohort (Tables 3–5). A total of 21 (50.0%) patients reported grade ≥3 TEAEs, a total of 18 (42.9%) patients reported grade 3 / 4 TEAEs, and 16 (38.1%) patients experienced serious TEAEs. In the 3-week taper cohort, the most common TEAE of any grade was nausea, occurring in 8 (53.5%) patients, and the most common TEAE of grade ≥3 was lymphopenia, occurring in 2 (13.3%) patients (Table 3). In the 2-week taper cohort, the most common TEAE was nasopharyngitis (5 patients [33.3%]), and the most common TEAE of grade ≥3 was neutropenia (3 patients [20.0%]). In the 1-week taper cohort, the most common TEAEs were anemia, diarrhea, asthenia, and peripheral edema (each in 4 [33.3%] patients), and the most common grade ≥ 3 TEAE was anemia, which occurred in 2 (16.7%) patients. A total of 6 patients died during the study. Grade 5 TEAEs occurred in 2 (16.7%) patients in the 1-week taper cohort (staphylococcal pneumonia and pulmonary embolism) and 1 (6.7%) patient in the 2-week taper group (deteriorating general health). One patient in the 3-week taper cohort died from complications of diffuse large B-cell lymphoma (DLBCL). Additionally, 3 patients (one in each cohort) died from progressive disease during the study period. TEAEs leading to death were reported in two participants in the 1-week taper cohort (pulmonary embolism and staphylococcal pneumonia); neither event was treatment-related. No deaths were reported in the 2-week and 3-week taper cohorts.

[0403] TEAEs in the system organ class (SOC) of general disorders and administration site conditions were the most common in all three parts (71.1% in Part 1, 72.0% in Part 2, and 71.4% in Part 3), followed by the SOC of infections and infestations (71.1%, 72.0%, and 64.3%, respectively). The most frequently reported serious TEAEs were in the SOC of infections and infestations (17.8% in Part 1, 12.0% in Part 2, and 11.9% in Part 3), and general disorders and administration site conditions (6.7%, 8.0%, and 4.8%, respectively). The most frequently reported grade ≥3 TEAEs were lymphopenia (20.0% in Part 2) and anemia (15.6% in Part 1 and 9.5% in Part 3).

[0404] No new deaths have been reported within 30 days of the last dose of study treatment since the clinical cutoff (CCO) in the previous analyses of Parts 1, 2, and 3. There were no COVID-19-related deaths.

[0405] No additional IRRs were reported since the CCO in the previous analysis.

[0406] Nausea was more frequent in the 3-week taper cohort (53% of participants) compared with 20% and 16.7% in the 2-week and 1-week taper cohorts, respectively. Serious TEAEs occurred in 6 (40.0%) participants in the 3-week group, 6 (40.0%) in the 2-week group, and 4 (33.3%) in the 1-week group. Nervous system disorders were more frequent in the 3-week cohort (46.7%) compared with the 2-week (26.7%) and 1-week cohorts (16.7%). Details of the most common TEAEs (>10%) are shown in Tables 3 and 4.

[0407] Grade ≥3 TEAEs were reported in 60% of participants in the 3-week taper cohort, 53.3% of participants in the 2-week taper cohort, and 33.3% of participants in the 1-week taper cohort. In the 3-week taper cohort, the most common TEAE of any grade was nausea, occurring in 8 patients (53.3%), and the most common grade ≥3 (grade 3 / 4) TEAE was lymphopenia, occurring in 2 patients (13.3%) (Tables 3 and 4). In the 2-week group, the most common TEAE was nasopharyngitis (5 patients [33.3%]), and the most common grade ≥3 (grade 3 / 4) TEAE was neutropenia (3 patients [20.0%]). In the 1-week group, the most common TEAEs were anemia, diarrhea, asthenia, and peripheral edema (each in 4 [33.3%] patients), and the most common grade ≥3 (grade 3 / 4) TEAE was anemia, which occurred in 2 (16.7%) patients. For details, see Tables 3-5.

[0408] Infusion-related reactions A total of 5 (11.9%) patients experienced an IRR, all of which occurred during the first dose of DARA SC. In the 3-week, 2-week, and 1-week taper cohorts, IRRs were reported by 0 (0%), 3 (20.0%), and 2 (16.7%) patients, respectively. The most common IRRs (occurring in ≥5% of patients) were chills and fever (3 [7.1%] patients each). IRRs for tachycardia, elevated blood pressure, and oropharyngeal pain were reported by 1 (2.4%) patient each. All IRRs occurred during the first dose of DARA SC (administration on cycle 1, day 1), had a median onset time of 79 (range, 31–555) minutes, resolved on the same day, and did not occur after steroid taper. IRRs were generally mild, with only one grade 3 IRR (elevated blood pressure, 2-week taper cohort, resolved on the day of onset), and none were subject to dose-limiting toxicity (no grade 4 IRRs were reported). None of the IRRs met the definition of a DLT or led to patient treatment interruption or discontinuation.

[0409] Pharmacokinetics In the entire pharmacokinetically evaluable population (n=37), the mean (standard deviation (SD)) daratumumab serum concentration on day 1 of cycle 3 was 676 (314) μg / mL. In the 3-week, 2-week, and 1-week taper cohorts, the mean (SD) daratumumab serum concentrations on day 1 of cycle 3 were 604 (280), 731 (382), and 706 (270) μg / mL after weekly administration of DARA SC, respectively. Pharmacokinetic results after administration of 1,800 mg DARA SC were similar to those for 3-week, 2-week, and 1-week steroid tapers and consistent with previous reports for DARA SC (Mateos et al., Lancet Haematol. 7(5):e370-e380 (2020)). Changes in serum concentrations of daratumumab during cycle 1 are shown in Figure 3, and changes in serum concentrations of daratumumab from cycle 2 onwards are shown in Figure 4.

[0410] immunogenicity Among patients in the daratumumab immunogenicity evaluable population (n=41), no patients tested positive for the presence of anti-daratumumab antibodies. Among patients evaluable for rHuPH20 immunogenicity in the 3-week, 2-week, and 1-week taper cohorts, 6 (40.0%), 3 (20.0%), and 1 (9.1%) patients tested positive for treatment-emergent anti-rHuPH20 antibodies. None of the anti-rHuPH20 antibodies were neutralizing and did not correlate with injection site reactions.

[0411] Effectiveness In the total treated population (n=42), with a median follow-up of 8.3 months, the ORR was 40.5% (95% CI: 25.6%, 56.7%), with 10 (23.8% (95% CI: 12.1%, 39.5%) of all treated patients) patients achieving ≥VGPR and 2 (4.8% (95% CI: 0.6%, 16.2%) of all treated patients) patients achieving ≥CR (Figure 5). In the 3-week taper cohort, the ORR was 40.0%, with 3 (20.0%) patients achieving ≥VGPR and 1 (6.7%) patient achieving ≥CR. In the 2-week taper cohort, the ORR was 40.0%, with 5 (33.3%) patients achieving ≥VGPR and no patients achieving ≥CR. In the 1-week taper cohort, the ORR was 41.7%, with 2 (16.7%) patients achieving ≥ VGPR and 1 (8.3%) patient achieving ≥ CR.

[0412] Among responders in the response-evaluable population (n=17), the median time to first response and median time to best response were 1.0 and 1.1 months, respectively. In the 3-week, 2-week, and 1-week taper cohorts, the median time to best response was 1.5, 1.9, and 1.0 months, respectively. The median duration of response was 16.7 months in the 2-week taper cohort and was not reached in the 3-week and 1-week taper cohorts at the time of clinical cutoff. The 9-month response rates were 83.3%, 83.3%, and 100% in the 3-week, 2-week, and 1-week taper cohorts, respectively.

[0413] At clinical cutoff, median PFS was 5.9 months, with an estimated 9-month PFS rate of 40.7% for all treated patients. With median follow-up of 9.2, 11.1, and 8.3 months for the 3-week, 2-week, and 1-week taper cohorts, median PFS was 5.9, 4.7, and 7.4 months for the 3-week, 2-week, and 1-week taper cohorts, respectively. Estimated 9-month PFS rates were 40.0%, 36.1%, and 46.7% for the 3-week, 2-week, and 1-week taper cohorts, respectively.

[0414] Response rates (Figure 5) were consistent with those observed in the primary analysis of the phase 3 COLUMBA study (Mateos et al., Lancet Haematol. 7(5):e370-e380 (2020)). Overall response rates were 40.0% (95% CI, 16.3%-67.7%) in both the 3-week and 2-week groups and 41.7% (95% CI, 15.2%-72.3%) in the 1-week group. The rates of very good partial response or better were 20.0% (95% CI, 4.3%-48.1%) in the 3-week group, 33.3% (95% CI, 11.8%-61.6%) in the 2-week group, and 16.7% (95% CI, 2.1%-48.4%) in the 1-week group, respectively. Among responders, median duration of response was 16.7 months in the 2-week group. Median duration of response was not reached in either the 3-week or 1-week groups. For all patients treated in part 3 (N=42), median progression-free survival (PFS) was 5.9 months, with an estimated 9-month PFS rate of 40.7%. In the primary analysis of COLUMBA, median PFS for DARA SC was 5.6 months (Mateos et al., Lancet Haematol. 7(5):e370-e380 (2020)).

[0415] The results suggest that rapid corticosteroid tapering is tolerable in RRMM patients receiving DARA SC and does not reduce the efficacy of DARA SC in these patients. These data will guide future DARA SC combination treatments when it is preferable to limit concomitant corticosteroids (T cell redirectors, CAR-T, or checkpoint inhibitors).

[0416] This study of 42 RRMM patients receiving DARA SC demonstrated that rapid corticosteroid tapering over 1-3 weeks was tolerable in RRMM patients receiving DARA SC, and PK, immunogenicity, and safety results were consistent with previous reports of DARA SC. Patients receiving DARA SC with corticosteroid tapering demonstrated similar efficacy to patients receiving DARA IV (Lokhorst HM et al., N Engl J Med. 2015, 373(13):1207-19 and Lonial et al., Lancet 387(10027):1551-60 (2016)).

[0417] Corticosteroids, such as dexamethasone and prednisone, have been widely used to treat multiple myeloma for over 50 years. However, it is well established that, despite their potent activity in multiple myeloma, long-term use of corticosteroids can lead to cumulative toxicity and other clinical sequelae (Burwick et al., Ann Hematol 98(1):19-28 (2019)). Thus, the clinical benefits of corticosteroid use in multiple myeloma must be balanced against the potential risks to patients in terms of toxicity and quality of life. Indeed, in a Canadian study evaluating treatment preferences in patients with RRMM, patients preferred treatments that would extend life expectancy versus those that would limit corticosteroid use because of the adverse effects of corticosteroid use, such as insomnia, cognitive impairment, and mood disorders (Parsons et al., BMC Cancer 19(1):264 (2019)). Therefore, it is important to identify effective treatment regimens that limit corticosteroid use for patients experiencing associated toxicities.

[0418] Pharmacokinetic and immunogenicity results were consistent with those previously reported in parts 1 and 2 of this study. Subcutaneous administration of DARA SC with 3-week, 2-week, and 1-week corticosteroid tapering schedules appeared to result in similar mean serum daratumumab concentrations. In all three cohorts in part 3, no patients evaluable for daratumumab immunogenicity were positive for anti-daratumumab antibodies, indicating a low risk of immunogenicity when daratumumab is administered subcutaneously.

[0419] Daratumumab-based dosing regimens consistently demonstrate efficacy in patients with NDMM and RRMM. However, daratumumab treatment is administered in combination with corticosteroids, such as dexamethasone and prednisone, to reduce IRR. Part 3 of the PAVO study aimed to determine whether corticosteroid tapering with DARA SC treatment could maintain adequate tolerability without losing efficacy in the setting of IRR. Findings presented here demonstrate that corticosteroid tapering is safe in patients with RRMM receiving DARA SC. Specifically, the tolerability profile in three cohorts with different corticosteroid tapering schedules was comparable to previous reports of daratumumab, with no increase in IRR rates (Mateos et al., Lancet Haematol. 7(5):e370-e380 (2020); San-Miguel et al., Haematologica 106(6):1725-32 (2021); Usmani et al., Blood 134(8):668-77 (2019)).

[0420] Importantly, these results suggest that corticosteroid tapering does not diminish the efficacy of DARA SC, as patients who received DARA SC while tapering corticosteroids achieved similar efficacy in terms of response rate and duration of response compared to patients who received dartumumab SC monotherapy in the presence of corticosteroids. (Mateos et al., Lancet Haematol. 7(5):e370-e380 (2020); San-Miguel et al., Haematologica 106(6):1725-32 (2021); Usmani et al., Blood 134(8):668-77 (2019)). The ORR across the three cohorts combined was 40.5% (95%CI: 25.6%, 56.7%), with 10 patients (23.8% (95%CI: 12.1%, 39.5%)) achieving ≥ VGPR. In comparison, the ORR observed with DARA MD 1,800 mg in PAVO part 1 (median follow-up, 8.3 months) was 42.2% (Usmani et al., Blood 134(8):668-77 (2019)). In PAVO part 2 (median follow-up, 14.2 months), the ORR with DARA SC was 52% (San-Miguel et al., Haematologica 106(6):1725-32 (2021)). In the COLUMBA study, with a median follow-up of 7.5 months, the ORR was 41% for DARA SC and 37% for DARA IV (Mateos et al., Lancet Haematol. 7(5):e370-e380 (2020)).

[0421] Newer immunotherapy treatment strategies, including bispecific T cell redirecting antibodies and chimeric antigen receptor (CAR) T cell therapy, have demonstrated efficacy in RRMM patients (Zhou et al., Front Immunol. 11:620-312 (2020); Usmani et al., Lancet 398(10301):665-74 (2021); Verkleij et al., Blood Adv. 5(8):2196-2215 (2021)). However, patients experiencing treatment toxicities, including cytokine release syndrome, may be administered corticosteroids to manage side effects. Unfortunately, corticosteroids may interfere with the antitumor efficacy of newer immunotherapy agents. For example, corticosteroids are contraindicated for CAR T cell infusions because they may suppress CAR T cell activity (Zhou et al., Front Immunol. 11:620-312 (2020); Yakoub-Agha et al., Haematologica 105(2):297-316 (2020)). Furthermore, a retrospective study demonstrated that the use of higher cumulative doses of corticosteroids was associated with shorter PFS and OS outcomes in patients with relapsed or refractory large B-cell lymphoma treated with CAR T cell therapy (Strati et al., Blood. 137(23):3272-76 (2021)). Furthermore, another retrospective study demonstrated that baseline corticosteroid use was associated with poorer outcomes in patients with non-small cell lung cancer treated with PDL1 blockade (Arbour et al., J Clin Oncol 36(28):2872-78 (2018)). While additional studies are warranted, the findings presented here may guide the future use of DARA SC combination therapy, including CAR T cell therapy, bispecific antibodies, and checkpoint inhibitors, where it may be preferable to avoid or limit the use of concurrent corticosteroids.

[0422] This study of 42 patients with RRMM receiving DARA SC demonstrated that rapid corticosteroid tapering over 1 to 3 weeks was safe with no increased risk of IRR, and pharmacokinetic, immunogenicity, and safety results were consistent with previous reports of DARA SC.In conclusion, these findings demonstrate that corticosteroid tapering over 1 to 3 weeks is safe and does not compromise efficacy in patients with relapsed / refractory multiple myeloma receiving DARA SC.

[0423] Daratumumab is approved for the treatment of patients with multiple myeloma (MM). Safety, pharmacokinetics, and efficacy data from part 3 of the phase 1b PAVO study investigating three pre- and post-dose corticosteroid tapering schedules during subcutaneous daratumumab (DARA SC) treatment have been reported. Patients with MM who had received ≥2 prior lines of therapy received DARA SC (daratumumab 1,800 mg + rHuPH20 30,000 U, 15 mL) QW in cycles 1-2, Q2W in cycles 3-6, and Q4W thereafter. Patients also received a 3-week taper schedule with methylprednisolone (no corticosteroids by cycle 1 day 22) (PO / IV pre-, PO post-), ​​a 2-week taper schedule with methylprednisolone (no corticosteroids by cycle 1 day 15) (PO / IV pre-, PO post-), ​​or a 1-week taper schedule with dexamethasone (no corticosteroids by cycle 1 day 8) (IV pre-). The primary endpoint was safety. Patients (3 weeks: n=15, 2 weeks: n=15, 1 week: n=12) received a median of 3 prior lines of therapy. No new safety concerns or increased IRR rates were observed with the rapid corticosteroid taper. IRRs were reported in 5 patients (11.9%), which were generally mild and occurred with the first DARA SC dose. No IRRs occurred with subsequent DARA SC doses. The mean serum DARA concentrations (μg / mL) on day 1 (pre-dose) of cycle 3 were 604, 731, and 706 μg / mL in the 3-week, 2-week, and 1-week groups, respectively. The median follow-up period was 8.3 months, and the overall response rate was 40.5%. The median follow-up periods were 9.2, 11.1, and 8.3 months in the 3-week, 2-week, and 1-week groups, respectively, and the overall response rates were 40.0%, 40.0%, and 41.7%. Rapid corticosteroid tapering over 3 weeks is safe in patients with relapsed / refractory MM receiving DARA SC. These data will guide future DARA SC treatment plans, where limiting concurrent corticosteroids is preferred.

[0424] [Table 2] ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ASCT, autologous stem cell transplant; PI, proteasome inhibitor; IMiD, immunomodulatory agent. a Staging of ISS is derived based on a combination of serum beta2-microglobulin and albumin. b By electrophoretic method. c Cytogenetic abnormalities were based on in situ fluorescent hybridization or karyotyping. Percentages were calculated based on the number of patients in each treatment group.

[0425] [Table 3] TEAE: treatment-emergent adverse event.

[0426] [Table 4] Key Table: CF = coformulation. Adverse events will be reported using MedDRA version 23.1. Percentages are calculated using the number of subjects in each group as the denominator.

[0427] [Table 5] Key Table: CF = coformulation. Adverse events will be reported using MedDRA version 23.1. Percentages are calculated using the number of subjects in each group as the denominator.

[0428] The teachings of all patents, published patents, and references cited herein are incorporated by reference in their entirety.

[0429] Although exemplary embodiments have been particularly shown and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the embodiments encompassed by the appended claims.

[0430] Embodiment 1. A method of treating a hematological malignancy comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody and a corticosteroid for a period of time sufficient to treat the hematological malignancy, wherein the dosing regimen includes a reduction, elimination, or reduction followed by elimination of administration of corticosteroid to the subject. 2. The method of embodiment 1, wherein the corticosteroid administered to the subject is reduced by about 60% and then eliminated during a 28-day treatment cycle. 3. The method of embodiment 1, wherein the corticosteroid administered to the subject is reduced by about 60%, then reduced by 30%, and then eliminated during a 28 day treatment cycle. 4. The method of any one of embodiments 1-3, wherein the corticosteroid administered to the subject is administered once and then removed during a 28 day treatment cycle. 5. The method of any one of embodiments 1-4, wherein the anti-CD38 antibody is administered once a week, every two weeks, or every four weeks during a 28 day cycle. 6. The method of any one of embodiments 1-4, wherein the anti-CD38 antibody is administered once a week during cycle 1, every two weeks during cycles 2-5, and every four weeks thereafter. 7. The method of embodiment 1, comprising administering to the subject a treatment during a 28 day cycle, the treatment comprising: administering about 1,800 mg of an anti-CD38 antibody and about 30,000 U of hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; administering about 100 mg of a pre-dose corticosteroid on day 1; administering about 20 mg of a post-dose corticosteroid on days 1 and 2; administering about 60 mg of a pre-dose corticosteroid on day 8; administering about 20 mg of a post-dose corticosteroid on day 8; administering about 30 mg of a pre-dose corticosteroid on day 15; and 2. The method of embodiment 1, comprising administering about 20 mg of a post-administration corticosteroid on day 15 of a 28 day cycle. 8. The method of embodiment 1, comprising administering to the subject a treatment during a 28 day cycle, the treatment comprising: administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22; administering about 100 mg of pre-dose methylprednisolone (MP) orally or intravenously on day 1; orally administering about 20 mg of post-administration MP on days 1 and 2; administering about 60 mg of pre-dose MP orally or intravenously on day 8; orally administering about 20 mg of post-dose MP on day 8; Administering about 30 mg of pre-administration MP orally or intravenously on day 15; and orally administering about 20 mg of post-dose MP on day 15 of a 28 day cycle. 9. The method of embodiment 1, comprising administering to the subject a treatment during a 28 day cycle, the treatment comprising: administering about 1,800 mg of anti-CD38 antibody and about 30,000 U of rHuPH20 hyaluronidase on days 1, 8, 15, and 22; administering about 100 mg of a pre-dose corticosteroid on day 1; administering about 20 mg of a post-dose corticosteroid on days 1 and 2; administering about 60 mg of a pre-dose corticosteroid on day 8; and 2. The method of embodiment 1, comprising administering about 20 mg of a post-administration corticosteroid on day 8 of a 28 day cycle. 10. The method of embodiment 1, comprising administering to the subject a treatment during a 28 day cycle, the treatment comprising: administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22; administering about 100 mg of pre-dose methylprednisolone (MP) orally or intravenously on day 1; orally administering about 20 mg of post-administration MP on days 1 and 2; Administering about 60 mg of pre-administration MP orally or intravenously on day 8; and orally administering about 20 mg of post-dose MP on day 8 of a 28 day cycle. 11. The method of embodiment 1, comprising administering to the subject a treatment during a 28 day cycle, the treatment comprising: administering about 1,800 mg of anti-CD38 antibody and about 30,000 U of hyaluronidase subcutaneously on days 1, 8, 15, and 22; 2. The method of embodiment 1, comprising administering about 20 mg of a pre-dose corticosteroid intravenously on day 1 of a 28 day cycle. 12. The method of embodiment 1, comprising administering to the subject a treatment during a 28 day cycle, the treatment comprising: a) administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22; and b) administering about 20 mg of pre-dose dexamethasone intravenously on day 1 of a 28 day cycle. 13. A method of administering treatment to a subject in need thereof for a hematological malignancy, comprising administering the treatment to the subject during a 28 day cycle, the treatment comprising: administering about 1,800 mg of an anti-CD38 antibody and about 30,000 U of hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; administering about 100 mg of a pre-dose corticosteroid on day 1; administering about 20 mg of a post-dose corticosteroid on days 1 and 2; administering about 60 mg of a pre-dose corticosteroid on day 8; administering about 20 mg of a post-dose corticosteroid on day 8; administering about 30 mg of a pre-dose corticosteroid on day 15; and and administering about 20 mg of a post-administration corticosteroid on day 15. 14. A method of administering treatment to a subject in need thereof for a hematological malignancy, comprising administering the treatment to the subject during a 28 day cycle, the treatment comprising: administering about 1,800 mg of anti-CD38 antibody and about 30,000 U of rHuPH20 hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; administering about 100 mg of a pre-dose corticosteroid on day 1; administering about 20 mg of a post-dose corticosteroid on days 1 and 2; administering about 60 mg of a pre-dose corticosteroid on day 8; and and administering about 20 mg of a post-dose corticosteroid on day 8. 15. A method of administering treatment to a subject in need thereof for a hematological malignancy, comprising administering to the subject the treatment on a 28 day cycle, the treatment comprising: a) administering about 1,800 mg of an anti-CD38 antibody and about 30,000 U on days 1, 8, 15, and 22; and b) administering about 20 mg of a pre-dose corticosteroid on day 1. 16. A method of treating a hematological malignancy comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody and a corticosteroid dose <0.05 mg / kg / day, or an equivalent dose, for a period of time sufficient to treat the hematological malignancy. 17. The method of embodiment 16, wherein a corticosteroid dose of <0.01 mg / kg / day or equivalent is administered. 18. A method of treating a hematological malignancy comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD38 antibody for a period of time sufficient to treat the hematological malignancy, wherein disease control or complete remission is achieved and / or maintained at a corticosteroid dose of ≦0.05 mg / kg / day or equivalent. 19. The method of embodiment 18, wherein disease control or complete remission is achieved and / or maintained at a corticosteroid dose of ≦0.01 mg / kg / day or equivalent. 20. The method of embodiment 18, wherein disease control or complete remission is achieved and / or maintained without concomitant administration of corticosteroids. 21. The method of any one of embodiments 16-20, further comprising administering to the subject an up-front therapy during the 28 day cycle, the up-front therapy comprising: administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; administering about 100 mg of pre-dose methylprednisolone (MP) orally or intravenously on day 1; orally administering about 20 mg of post-administration MP on days 1 and 2; administering about 60 mg of pre-dose MP orally or intravenously on day 8; orally administering about 20 mg of post-dose MP on day 8; Administering about 30 mg of pre-administration MP orally or intravenously on day 15; and The method of any one of embodiments 16-20, comprising orally administering about 20 mg of post-administration MP on day 15. 22. The method of any one of embodiments 16-20, further comprising administering to the subject an up-front therapy during the 28 day cycle, the up-front therapy comprising: administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; administering about 100 mg of pre-dose methylprednisolone (MP) orally or intravenously on day 1; orally administering about 20 mg of post-administration MP on days 1 and 2; Administering about 60 mg of pre-administration MP orally or intravenously on day 8; and The method of any one of embodiments 16-20, comprising orally administering about 20 mg of post-administration MP on day 8 of a 28 day cycle. 23. The method of any one of embodiments 16-20, further comprising administering to the subject an up-front therapy during the 28 day cycle, the up-front therapy comprising: a) administering subcutaneously about 1,800 mg of daratumumab and about 30,000 U of rHuPH20 recombinant hyaluronidase on days 1, 8, 15, and 22 of a 28 day cycle; and b) administering about 20 mg of pre-dose dexamethasone intravenously on day 1. 24. The method of any one of embodiments 1-23, wherein the corticosteroid comprises betamethasone, cortisol, cortisone, dexamethasone, glucocorticoids, hydrocortisone, methylprednisolone (MP), prednisolone, prednisone, triamcinolone, or a combination thereof. 25. The method of any one of embodiments 1-23, wherein the corticosteroid comprises dexamethasone, methylprednisolone, prednisone, or a combination thereof. 26. The method of any one of embodiments 1 to 25, wherein the hematological malignancy is a CD38-positive hematological malignancy. 27. The method of any one of embodiments 1-25, wherein the hematological malignancy is multiple myeloma. 28. The method of embodiment 27, wherein the multiple myeloma is relapsed or refractory multiple myeloma. 29. The method according to any one of the preceding claims, wherein the anti-CD38 antibody is a) the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively; and / or b) The method according to any one of embodiments 1 to 28, comprising the amino acid sequences of light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively. 30. The method of embodiment 29, wherein the anti-CD38 antibody comprises a heavy chain variable region (VH) sequence of SEQ ID NO: 4, a light chain variable region (VL) sequence of SEQ ID NO: 5, or both. 31. The method of embodiment 29, wherein the anti-CD38 antibody comprises the heavy chain sequence of SEQ ID NO: 12, the light chain sequence of SEQ ID NO: 13, or both. 32. The method of any one of embodiments 1-31, wherein the anti-CD38 antibody is of the IgG1, IgG2, IgG3, or IgG4 subtype. 33. The method of embodiment 32, wherein the anti-CD38 antibody is of the IgG1 subtype. 34. The method of embodiment 33, wherein the anti-CD38 antibody is of the IgG1 / κ subtype. 35. The method of any one of embodiments 1-28, wherein the anti-CD38 antibody is daratumumab. 36. The method of any one of embodiments 1 to 35, wherein the anti-CD38 antibody is administered as a pharmaceutical composition comprising about 1,200 mg to about 5,000 mg of anti-CD38 antibody. 37. The method of embodiment 36, wherein the pharmaceutical composition comprises about 1,800 mg of an anti-CD38 antibody. 38. The method of embodiment 36 or 37, wherein the pharmaceutical composition further comprises hyaluronidase. 39. The method of embodiment 38, wherein the hyaluronidase is rHuPH20 recombinant hyaluronidase. 40. The method of embodiment 38 or 39, wherein the pharmaceutical composition comprises from about 750 U to about 75,000 U of hyaluronidase. 41. The method of embodiment 40, wherein the pharmaceutical composition comprises about 30,000 U of hyaluronidase. 42. The method of any one of embodiments 36-41, wherein the anti-CD38 antibody and hyaluronidase are administered as a co-formulation. 43. The method according to any one of embodiments 36 to 42, wherein the pharmaceutical composition comprises: Approximately 4.9 mg of L-histidine, Approximately 18.4 mg of L-histidine hydrochloride monohydrate; Approximately 13.5 mg of L-methionine, Approximately 6 mg of polysorbate 20 (PS-20), and 43. The method of any one of embodiments 36-42, further comprising about 735.1 mg sorbitol. 44. The method of any one of embodiments 36-43, wherein the pharmaceutical composition has a pH of about pH 5.5. 45. The method of any one of embodiments 36-43, wherein the pharmaceutical composition has a pH of about pH 5.6. 46. ​​The method of any one of embodiments 36-45, wherein the pharmaceutical composition has a total volume of about 15 mL. 47. The method of any one of embodiments 1 to 46, wherein the anti-CD38 antibody is administered subcutaneously. 48. The method of any one of embodiments 1-47, wherein the subject is 18 years of age or older. 49. The method of any one of embodiments 1-48, wherein the subject is anti-CD38 treatment naive. 50. The method of any one of embodiments 1-48, wherein the subject has previously received at least two lines of anti-myeloma therapy. 51. The method of embodiment 50, wherein the at least two prior lines of anti-myeloma therapy include administration of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), hematopoietic stem cell transplant (HSCT), maintenance therapy, or a combination thereof. 52. The method of embodiment 51, wherein the IMid is lenalidomide. 53. The method of embodiment 51 or 52, wherein the PI is bortezomib, carfilzomib, or ixazomib. 54. The method of any one of embodiments 51 to 53, wherein the HSCT is an autologous HSCT. 55. The method of any one of embodiments 51-53, wherein the two therapeutic lines include an IMid and a PI. 56. The method of any one of embodiments 1-55, wherein the subject is refractory to at least one line of therapy. 57. A method for inducing at least a partial response in a subject, the method being described in any one of embodiments 1 to 56. 58. A method for inducing a partial response in a subject, the method according to embodiment 57. 59. The method of any one of embodiments 1 to 56, which induces at least a very good partial response in a subject. 60. A method for inducing a complete response in a subject, the method according to embodiment 59. 61. A method for inducing a stringent complete response in a subject, the method according to embodiment 59. 62. A method for improving one or more outcome measures in a subject, the method being described in any one of embodiments 1-61. 63. The method of embodiment 62, wherein the one or more outcome measures comprise progression-free survival, duration of response, or at least partial response, or any combination thereof. 64. The method of embodiment 62, wherein the one or more outcome measures comprise partial response, very good partial response, complete response, or stringent complete response. 65. The method of any one of embodiments 1-61, wherein the subject experiences an improvement in one or more outcome measures consistent with subjects receiving anti-CD38 antibody administration and continued corticosteroid administration. 66. The method of any one of embodiments 1-61, wherein the subject experiences an improvement in one or more outcome measures compared to subjects receiving anti-CD38 antibody administration and continued corticosteroid administration. 67. The method of any one of embodiments 1-66, further comprising administering to the subject one or more additional therapeutic agents. 68. The method of embodiment 67, wherein the one or more additional therapeutic agents comprise chimeric antigen receptor (CAR)-expressing T cells (CAR-T cells), CAR-expressing natural killer cells (CAR-NK cells), CAR-expressing macrophages (CAR-M cells), a chemotherapeutic agent, a bispecific antibody, an immune checkpoint inhibitor, a T cell redirector, or a combination thereof. 69. The method of embodiment 68, wherein the CAR-T cells, CAR-NK cells, or CAR-M cells are allogeneic. 70. The method of embodiment 68 or 69, wherein the CAR comprises an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. 71. The method of embodiment 70, wherein the intracellular signaling domain comprises a T cell surface glycoprotein CD3 zeta chain component. 72. The method of embodiment 70 or 71, wherein the extracellular antigen-binding domain binds to G protein-coupled receptor family C group 5 member D (GPRC5D). 73. The method of embodiment 72, wherein the extracellular antigen-binding domain binds to GPRC5D and CD3. 74. The method of embodiment 72 or 73, wherein the one or more additional therapeutic agents comprise an anti-GPRC5D CAR-T, an anti-GPRC5D CAR-NK, or a combination thereof. 75. The method of embodiment 70, wherein the extracellular antigen-binding domain binds to B-cell maturation antigen (BCMA). 76. The method of embodiment 75, wherein the extracellular antigen-binding domain binds to BCMA and CD3. 77. The method of embodiment 75 or 76, wherein the one or more additional therapeutic agents comprises an anti-BCMA CAR-T, an anti-BCMA CAR-NK, or a combination thereof. 78. The method of any one of embodiments 68-77, wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, an anti-CTLA-4 antibody, or a combination thereof. 79. The method of any one of embodiments 68-78, wherein the T cell redirector comprises a soluble bispecific antibody (bsAb) or a membrane-anchored chimeric antigen receptor, or a combination thereof. 80. The method of embodiment 79, wherein the soluble bispecific antibody binds to GPRC5D and CD3. 81. The method of embodiment 79, wherein the soluble bispecific antibody binds to BCMA and CD3.

Claims

1. A pharmaceutical combination for use in a method for treating a hematological malignancy in a subject in need thereof, comprising an anti-CD38 antibody and a pre-administration corticosteroid; a) the anti-CD38 antibody comprises a heavy chain variable region (VH) of SEQ ID NO: 4 and a light chain variable region (VL) of SEQ ID NO: 5; b) the anti-CD38 antibody is administered subcutaneously; c) during a 28-day treatment cycle, after the first dose of the anti-CD38 antibody, the subject's pre-administration of a corticosteroid is reduced, eliminated, or reduced and then eliminated; Pharmaceutical combinations.

2. The pre-dose corticosteroid administered to the subject during the 28-day treatment cycle comprises: a) reduced by approximately 60% and then removed; b) reduced by about 60%, then by about 30%, and then eliminated; or c) The pharmaceutical combination of claim 1, which is administered once and then removed.

3. The pharmaceutical combination described in claim 1, wherein the 28-day treatment cycle is cycle 1.

4. 4. The pharmaceutical combination of claim 3, wherein the anti-CD38 antibody is administered once weekly during cycle 1, every two weeks during cycles 2 through 5, and every four weeks thereafter.

5. The pharmaceutical combination of claim 1, wherein said method comprises administering to said subject during said 28 day cycle: administering a pharmaceutical composition comprising about 1,800 mg of an anti-CD38 antibody and having about 30,000 U of hyaluronidase enzyme activity on days 1, 8, 15, and 22; about 100 mg of pre-dose corticosteroid administered on day 1; about 20 mg of post-dose corticosteroid on days 1 and 2; about 60 mg of pre-dose corticosteroid administered on day 8; about 20 mg of post-dose corticosteroid administered on day 8; administering about 30 mg of a pre-dose corticosteroid on day 15; and Approximately 20 mg of post-dose corticosteroids should be administered on day 15.

6. The pharmaceutical combination of claim 5, wherein said method comprises administering to said subject during said 28 day cycle: subcutaneously administering the pharmaceutical composition, wherein the hyaluronidase is rHuPH20 recombinant hyaluronidase, on days 1, 8, 15, and 22; approximately 100 mg of pre-dose methylprednisolone (MP) administered orally or intravenously on day 1; orally administering about 20 mg of post-dose MP on days 1 and 2; about 60 mg of pre-dose MP administered orally or intravenously on day 8; Oral administration of approximately 20 mg of post-dose MP on day 8; Administering approximately 30 mg of pre-dose MP orally or intravenously on day 15; and Approximately 20 mg of post-dose MP should be administered orally on the 15th day.

7. The pharmaceutical combination of claim 1, wherein said method comprises administering to said subject during said 28 day cycle: administering a pharmaceutical composition comprising about 1,800 mg of an anti-CD38 antibody and having about 30,000 U of hyaluronidase enzyme activity on days 1, 8, 15, and 22; about 100 mg of pre-dose corticosteroid administered on day 1; about 20 mg of post-dose corticosteroid on days 1 and 2; administering about 60 mg of a pre-dose corticosteroid on day 8; and Approximately 20 mg of corticosteroids should be administered on day 8.

8. The pharmaceutical combination of claim 7, wherein said method comprises administering to said subject during said 28 day cycle: subcutaneously administering the pharmaceutical composition, wherein the hyaluronidase is rHuPH20 recombinant hyaluronidase, on days 1, 8, 15, and 22; approximately 100 mg of pre-dose methylprednisolone (MP) administered orally or intravenously on day 1; orally administering about 20 mg of post-dose MP on days 1 and 2; Administering approximately 60 mg of pre-dose MP orally or intravenously on day 8; and Approximately 20 mg of post-dose MP should be administered orally on the 8th day.

9. The pharmaceutical combination of claim 1, wherein said method comprises administering to said subject during said 28 day cycle: a) subcutaneously administering on days 1, 8, 15, and 22 a pharmaceutical composition comprising about 1,800 mg of an anti-CD38 antibody and having about 30,000 U of hyaluronidase enzyme activity; and b) Approximately 20 mg of pre-dose corticosteroid is administered intravenously on Day 1, followed by removal.

10. The pharmaceutical combination of claim 9, wherein said method comprises administering to said subject during said 28 day cycle: a) subcutaneously administering the pharmaceutical composition, wherein the hyaluronidase is rHuPH20 recombinant hyaluronidase, on days 1, 8, 15, and 22; and b) Approximately 20 mg of pre-dose dexamethasone will be administered intravenously on Day 1, followed by removal.

11. A pharmaceutical combination for use in a method for treating a hematological malignancy in a subject in need thereof, comprising an anti-CD38 antibody and a pre-administration corticosteroid; a) the anti-CD38 antibody comprises a heavy chain variable region (VH) of SEQ ID NO: 4 and a light chain variable region (VL) of SEQ ID NO: 5; b) the anti-CD38 antibody is administered subcutaneously; c) the pre-dose corticosteroid is administered at a dose of <0.05 mg / kg / day; Pharmaceutical combinations.

12. 12. The pharmaceutical combination of claim 11, wherein the corticosteroid is administered at a dose of <0.01 mg / kg / day.

13. A pharmaceutical combination for use in a method for treating a hematological malignancy in a subject in need thereof, comprising an anti-CD38 antibody and a pre-administration corticosteroid; a) the anti-CD38 antibody comprises a heavy chain variable region (VH) of SEQ ID NO: 4 and a light chain variable region (VL) of SEQ ID NO: 5; b) the anti-CD38 antibody is administered subcutaneously; c) disease control or complete remission is achieved and / or maintained with a pre-dose corticosteroid dose of ≦0.05 mg / kg / day; Pharmaceutical combinations.

14. The pharmaceutical combination of claim 13, wherein the disease control or complete remission is achieved and / or maintained with a pre-administration corticosteroid dose of ≦0.01 mg / kg / day.

15. The pharmaceutical combination described in claim 1, wherein the hematological malignancy is a CD38-positive hematological malignancy.

16. The pharmaceutical combination described in claim 1, wherein the hematological malignancy is multiple myeloma.

17. The pharmaceutical combination of claim 1, wherein the anti-CD38 antibody comprises a heavy chain sequence of SEQ ID NO: 12 and a light chain sequence of SEQ ID NO:

13.

18. The pharmaceutical combination of claim 1, wherein the anti-CD38 antibody is daratumumab.

19. 19. The pharmaceutical combination of claims 1-5, 7, 9, 11-18, wherein the pre-administration corticosteroid comprises betamethasone, cortisol, cortisone, dexamethasone, glucocorticoid, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, or a combination thereof.

20. The pharmaceutical combination of claim 19, wherein the pre-administration corticosteroid comprises dexamethasone, methylprednisolone, prednisone, or a combination thereof.

Images