Combination therapy using a CD38 antibody

Abstract

A method of administering an isolated anti-CD38 antibody in combination with lenalidomide or pomobdomide, and dexamethasone and optionally bortezomib for the treatment of multiple myeloma.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 859,631, filed on Jun. 10, 2019, which is hereby incorporated by reference in its entirety.

[0002] Sequence Listing This application contains a sequence listing that was submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, generated on Jun. 8, 2020, is named 101588 - 5012 - WO_ST25.txt and is 18 kilobytes in size.

[0003] The present invention describes a method for treating multiple myeloma by combination therapy, which comprises administering an anti - CD38 antibody or an antigen - binding fragment thereof.

Background Art

[0004] Multiple myeloma (MM) is a rare and often incurable malignant disease of plasma cells in the bone marrow, with a fairly high morbidity and mortality due to highly complex and diverse cytogenetic and molecular abnormalities. It accounts for approximately 1% of all cancers and approximately 13% of all blood cancers. Myeloma is most frequently diagnosed among people aged 65 - 74 years, with a median age of 69 years. The 5 - year survival rate of MM patients is approximately 50%. The clinical symptoms of MM result from bone marrow infiltration by malignant plasma cell clones, high levels of blood immunoglobulins and / or free light chains (FLC), immunosuppression, and end - organ damage. MM is characterized by, inter alia, hypercalcemia (resulting from bone resorption), kidney dysfunction (generally due to hypercalcemia, tumor infiltration, or hyperuricemia), anemia (resulting from tumor infiltration into the bone marrow and cytokine - mediated suppression of hematopoiesis), and lytic bone lesions (resulting from osteoclast - stimulating factors produced by malignant plasma cells). The symptoms vary and include bone pain, fractures, weakness, fatigue, bleeding, anemia, and infections resulting from immunodeficiency.

[0005] The prognosis in MM depends on both patient factors and tumor variables at the time of diagnosis. Patient-related factors include age, performance status, and renal function. Tumor variables include disease stage, cytogenetic abnormalities, and extramedullary disease, as well as light chain disease and IgA disease. The normal aging process is associated with age-related changes in organ function and metabolism, which can contribute to poor tolerance of cancer treatment and lead to poor outcomes in the elderly. Furthermore, chronological age and biological age may not correspond, and thus the presence of frailty, comorbidities, psychosocial function, and other impairments can complicate the management of MM and the tolerance of treatment regimens. Due to age and comorbidities, elderly patients with MM are usually ineligible for autologous transplantation, and thus the treatment plan for this patient population consists of only standard chemotherapeutic agents. Stem cell transplantation (SCT) is an important part of the treatment for patients under 65 years of age, but it is only one of many available treatment options. Some patients prefer to delay the complications of SCT, and thus the necessity and timing of this treatment must be adjusted according to the patient's situation.

[0006] The treatment of MM focuses on restricting the proliferation of myeloma cells and reducing disease symptoms. With a deeper understanding of biology, improvements in treatment strategies, and the introduction of drugs such as proteasome inhibitors (e.g., bortezomib, ixazomib, and carfilzomib); immunomodulatory drugs (e.g., lenalidomide and pomalidomide); and monoclonal antibodies (e.g., daratumumab and elotuzumab), there has been an improvement in the outcomes of MM patients in the last decade, but the course of the disease remains highly unpredictable among patients, characterized by variable durations of asymptomatic remission periods and frequent relapses with symptoms. Ultimately, the period without disease symptoms becomes shorter, and the disease becomes refractory to available treatment methods.

[0007] As MM progresses, complex factors such as decreased resistance to infection, anemia, and significant bone destruction uniformly prove fatal to the prognosis. Additionally, although there was an improvement in overall survival (OS), compared to patients under 65 years old, patients aged 65 - 74 years had fewer benefits, and patients aged 75 years and above had no benefits. Therefore, MM remains almost an incurable disease, highlighting the need and urgency to develop new treatment options for these patients.

[0008] In patients with newly diagnosed multiple myeloma (NDMM) for whom SCT is not planned as an initial treatment option, standard treatment options include regimens containing two to three of the following agents (prescription frequency varies by country): bortezomib, lenalidomide, thalidomide, cyclophosphamide, and corticosteroids (see, e.g., U.S. Patent Nos. 10,232,041; 9,944,711; 9,289,490; 9,040,050; and 8,877,899; and U.S. Patent Publications 20180117150; 20190127479; 20180235986; 20180022823; 20170224817; 20170121417; 20170107295; 20170008966; 20160130362; 20160067205; 20150231235; 20140161819; 20130302318; 20130209355; 20100092489; and 20100028346; and 20090148449). These regimens are used for the treatment of MM in the United States and show good tolerance for anti-myeloma activity. The lenalidomide-dexamethasone (Len-Dex) IMiD-based regimen is approved by the US Food and Drug Administration (FDA). The triple combination (bortezomib (Velcade), lenalidomide, and dexamethasone) is used in the United States based on improvement in progression-free survival (PFS). The choice of specific treatment in patients with NDMM, including whether to give a double or triple regimen, is often determined by the aforementioned patient and tumor factors (including but not limited to age, comorbidities, frailty, drug availability, and prognosis based on assessment of disease aggressiveness). The response to treatment is transient and prompts continued exploration of additional treatment options for patients, particularly for the elderly or newly diagnosed patients and those with a comorbidity burden.

[0009] CD38 is highly expressed on MM cells and at lower levels in other hematopoietic cells (such as lymphocytes and myeloid cells). This high level of expression on the surface of myeloma cells supports CD38 as an appropriate therapeutic target and was validated by the US FDA approval of the first anti-CD38 drug (daratumumab) in 2015 as a monotherapy for patients with progressive relapsed and / or refractory multiple myeloma (RRMM). Subsequent to the marketing approval, approvals of daratumumab in combination with standard anti-myeloma regimens followed for patients with less advanced RRMM and for patients with NDMM who are not eligible for stem cell transplantation. More recently, safety analyses of full-dose intravenous (IV) daratumumab added to a regimen of bortezomib, lenalidomide, and dexamethasone (VRd) demonstrated that the combination is tolerated in transplant-eligible patients. Full doses of daratumumab, either as monotherapy or in combination, have been shown to be active and safe in patients naive to previous CD38-directed therapies. The most frequent adverse reactions (≥20%) reported with daratumumab (either as monotherapy or in combination with standard anti-myeloma regimens) were infusion-related reactions (IRR), neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, fever, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, and upper respiratory tract infections. Daratumumab can cause severe and serious IRR, including anaphylactic reactions reported in approximately half of all patients. In addition, daratumumab binds to CD38 on red blood cells (RBCs), which is the mechanism of action that results in consistently positive indirect Coombs test results up to 6 months after the final daratumumab infusion. This binding masks serum antigens and can thus interfere with crossmatching and red blood cell antibody screening.

[0010] Monoclonal antibody AB79 binds to CD38 with high affinity and exhibits a binding profile and unique pharmacodynamic characteristics different from those of daratumumab. Preliminary evidence suggests that AB79 may be more selective and thus more potent than daratumumab. In a Phase 1 trial in healthy subjects (Study AB79-101), AB79 reduced peripheral blood and natural killer (NK) cell levels by >90% from baseline in all subjects receiving a single 0.06 mg / kg IV dose of AB79 (maximum observed concentration (C max ))). In contrast, comparable depletion of NK cells was not achieved with IV daratumumab administered to patients with RRMM at doses up to 24 mg / kg (>500 μg / mL average C max ). In healthy subjects, SC-delivered AB79 also reduced the levels of circulating plasmablasts in peripheral blood in a dose-dependent manner. Neutrophil, lymphocyte, monocyte, RBC, and platelet counts remained within the normal range for all dose cohorts. In an RRMM trial (Study AB79-1501), a potent reduction in plasmablasts was observed across patient cohorts. The results showed that SC administration of AB79 at doses of 45 mg to 600 mg (equivalent to approximately 0.6 mg to 8 mg / kg) reduced peripheral blood plasmablasts by 60% to 95% from baseline. Thus, AB79 may be efficient by eliminating cells expressing high levels of CD38, which could manifest as higher activity against tumor cells (e.g., a deeper response rate improved across the population of patients with multiple myeloma).

[0011] Since a desired clinical response could be obtained with a small amount of the drug, the additional benefit regarding the higher potency of AB79 SC would be the convenience of administration. To date, other anti-CD38 antibodies (such as daratumumab and isatuximab) have to be administered as IV injections. The approved route of administration for daratumumab is an IV infusion given over several hours, which is not convenient for patients. The first IV infusion of daratumumab takes 7 - 9 hours (including time for premedication), subsequent doses require 4 - 6 hours per dose, and more time is required if there is an infusion reaction. To address this, a formulation of daratumumab containing human hyaluronidase administered subcutaneously (SC) is being investigated in clinical trials. Currently, the SC formulation of daratumumab in clinical development consists of 1800 mg of daratumumab in 15 mL of recombinant human hyaluronidase enzyme, which requires creating a subcutaneous cavity to store this relatively large volume, and approximately 3 - 5 minutes are required in the clinic to administer this formulation via syringe. The overall incidence of IRR with SC daratumumab is lower than that with IV administration (reported incidence was 16% for all grades and 8% for grades 3 and above, compared to an incidence of over 50% for all grades and about 9% for grades 3 and above with IV administration). Injection site reactions (consisting of induration, erythema, discoloration, and hematoma) were also reported in 16.7% of patients. Adverse events (TEAEs) expressed under grades 3 and 4 of treatment included lymphopenia (20%), as well as thrombocytopenia, neutropenia, and hypertension (each at 8%). Notably, not all patients respond to daratumumab-based therapies, and many patients ultimately develop a progressive disease characterized by aggressive and highly symptomatic clinical signs.

[0012] In contrast, no IRR was observed with SC administration of AB79 dosed at up to 600 mg. AB79 can be administered as a single SC injection of approximately 2 mL with a duration of less than 1 minute at doses of 300 mg or less without the need for hyaluronidase. Thus, the improved selectivity by AB79 leads to improved efficacy and tolerability compared to that reported for IV or SC of daratumumab, and patient convenience can be improved.

[0013] Although the initial trials of AB79 in the treatment of myeloma appear promising, considering the deficiencies of other therapies and the fatal prognosis of MM, there remains a need for new agents or combinations thereof that include a new generation of CD-38 targeted therapies with improved selectivity, higher potency, less toxicity, and improved patient convenience for continuation to improve the clinical outcomes of all patients.

SUMMARY OF THE INVENTION

[0014] Combinations of multiple drugs are important in front-line treatment of MM and demonstrate high response rates and extended PFS and OS. Facilitating available regimens with new drugs that provide synergistic non-overlapping mechanisms of action (MOA) can improve response rates and clinical benefit, which can then improve PFS and OS. A new generation of CD38-directed agents is required to delay disease progression, relieve symptoms, and promote the quality of life (QOL) of patients suffering from this devastating and merciless disease.

[0015] Provided herein is a method of treating a subject having a CD38-positive hematologic cancer, the method comprising administering an anti-CD38 antibody or antigen-binding fragment thereof in combination therapy.

[0016] In one aspect, the present invention provides a method of treating a subject having a CD38-positive blood cancer, comprising administering to the subject a therapeutically effective amount of a) an anti-CD38 antibody, b) lenalidomide, and c) a corticosteroid for a time sufficient to treat the CD38-positive blood cancer, wherein the anti-CD38 antibody comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0017] In a further aspect, the present invention provides a method of treating a subject having a CD38-positive blood cancer, comprising administering to the subject a therapeutically effective amount of a) an anti-CD38 antibody, b) pomalidomide, and c) a corticosteroid for a time sufficient to treat the CD38-positive blood cancer, wherein the anti-CD38 antibody comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0018] In a further aspect, the VH chain region described herein has the amino acid sequence of SEQ ID NO: 9, and the VL chain region described herein has the amino acid sequence of SEQ ID NO: 10.

[0019] In a further aspect, the anti-CD38 antibody or antigen-binding fragment thereof described herein comprises the heavy chain amino acid sequence of SEQ ID NO: 11 and the light chain amino acid sequence of SEQ ID NO: 12.

[0020] In a further aspect, the anti-CD38 antibody described herein is an IgG1, IgG2, IgG3, or IgG4 isotype.

[0021] In an additional aspect, the anti-CD38 antibody described herein is of the IgG1 isotype.

[0022] In a further aspect, the anti-CD38 antibody or antigen-binding fragment thereof described herein is fully human.

[0023] In an additional aspect, the anti-CD38 antibody is AB79.

[0024] In a further aspect, the CD38-positive blood cancer described herein is multiple myeloma.

[0025] In an additional aspect, the CD38-positive blood cancer described herein is newly diagnosed multiple myeloma (NDMM) or untreated (naive) multiple myeloma.

[0026] In a further aspect, the CD38-positive blood cancer described herein has not been previously treated with a blood cancer drug.

[0027] In an additional aspect, the CD38-positive blood cancer described herein has not been previously treated with a multiple myeloma drug.

[0028] In a further aspect, the subject described herein has relapsed or refractory multiple myeloma (RRMM).

[0029] In an additional aspect, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered once a week at a dose of about 300 mg for two treatment cycles, once every two weeks at a dose of about 300 mg for the subsequent four treatment cycles, and then once every four weeks at a dose of about 300 mg for any subsequent treatment cycles, with one treatment cycle being 28 days.

[0030] In a further aspect, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered subcutaneously.

[0031] In an additional aspect, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered in the absence of hyaluronidase.

[0032] In a further aspect, the lenalidomide described herein is administered daily for 21 days out of each treatment cycle at a dose of about 2.5 to about 25 mg for up to 8 treatment cycles, with one treatment cycle being 28 days.

[0033] In an additional aspect, the lenalidomide described herein is administered orally.

[0034] In a further aspect, the pomalidomide described herein is administered daily for 21 days out of each treatment cycle at a therapeutically effective amount for up to 8 treatment cycles, with one treatment cycle being 28 days.

[0035] In an additional aspect, the pomalidomide described herein is administered orally.

[0036] In a further aspect, the corticosteroid described herein is dexamethasone.

[0037] In an additional aspect, the dexamethasone described herein is administered once weekly at a dose of about 20 to 40 mg for 1 to 8 treatment cycles, with one treatment cycle being 28 days.

[0038] In a further aspect, the dexamethasone described herein is administered once weekly at a dose of about 40 mg for 1 to 8 treatment cycles, with one treatment cycle being 28 days.

[0039] In an additional aspect, dexamethasone as described herein is administered orally or intravenously. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each treatment cycle.

[0040] In a further aspect, a method of treating a subject having a CD38-positive blood cancer as described herein further comprises administering a therapeutically effective amount of bortezomib.

[0041] In an additional aspect, bortezomib as described herein is administered once a week for about 0.7 - 1.3 mg / m 2 for 3 weeks out of 1 - 8 treatment cycles, and one treatment cycle is 28 days.

[0042] In a further aspect, bortezomib as described herein is administered subcutaneously.

[0043] In an additional aspect, the present invention provides a method of treating a subject having a CD38-positive blood cancer as described herein, comprising: a) an anti-CD38 antibody or an antigen-binding fragment thereof is administered on days 1, 8, 15, and 22 of the first two treatment cycles, on days 1 and 15 of the subsequent four treatment cycles, and on day 1 of any additional treatment cycles; b) lenalidomide is administered on days 1 - 21 of each treatment cycle; c) a corticosteroid is administered on days 1, 8, 15, and 22 of each of 1 - 8 treatment cycles, and one treatment cycle is 28 days.

[0044] In a further aspect, the present invention provides a method of treating a subject having a CD38-positive blood cancer as described herein, comprising: a) an anti-CD38 antibody or antigen-binding fragment thereof is administered on days 1, 8, 15, and 22 of the first two treatment cycles, on days 1 and 15 of the subsequent four treatment cycles, and on day 1 of any additional treatment cycles; b) pomalidomide is administered on days 1 to 21 of each treatment cycle; c) a corticosteroid is administered on days 1, 8, 15, and 22 of each of the 1 to 8 treatment cycles, wherein one treatment cycle is 28 days.

[0045] In an additional aspect, the present invention provides a method of treating a subject having a CD38-positive blood cancer as described herein, comprising: a) an anti-CD38 antibody or antigen-binding fragment thereof is administered on days 1, 8, 15, and 22 of the first two treatment cycles, on days 1 and 15 of the subsequent four treatment cycles, and on day 1 of any additional treatment cycles; b) lenalidomide is administered on days 1 to 21 of each treatment cycle; c) a corticosteroid is administered on days 1, 8, 15, and 22 of each of the 1 to 8 treatment cycles, wherein one treatment cycle is 28 days; and further comprising administering a therapeutically effective amount of bortezomib.

[0046] In a further aspect, bortezomib as described herein is administered once a week at a dose of about 0.7 to 1.3 mg / m 2 for 3 weeks out of each of the 1 to 8 treatment cycles, wherein one treatment cycle is 28 days.

[0047] In an additional aspect, bortezomib as described herein is administered on days 1, 8, and 15 of each treatment cycle.

[0048] In a further aspect, the CD38-positive blood cancer described herein is newly diagnosed multiple myeloma (NDMM), and the subject is a patient in whom stem cell transplantation is not planned as an initial treatment method.

[0049] In an additional aspect, the subjects described herein receive premedication 1 to 3 hours before the start of AB79 administration on each dosing day, and the premedication includes an antipyretic substance and an antihistamine substance. In some embodiments, the antipyretic substance is selected from the group consisting of acetaminophen, aspirin, ibuprofen, and naproxen.

[0050] In a further aspect, the antipyretic substance described herein is acetaminophen and is administered orally at a dose of about 650 - 1000 mg. In some embodiments, acetaminophen is administered at a dose of about 650 mg. In some embodiments, acetaminophen is administered at a dose of about 700 mg. In some embodiments, acetaminophen is administered at a dose of about 750 mg. In some embodiments, acetaminophen is administered at a dose of about 800 mg. In some embodiments, acetaminophen is administered at a dose of about 850 mg. In some embodiments, acetaminophen is administered at a dose of about 900 mg. In some embodiments, acetaminophen is administered at a dose of about 950 mg. In some embodiments, acetaminophen is administered at a dose of about 1000 mg.

[0051] In an additional aspect, the antihistamine substance described herein is diphenhydramine or an equivalent, and is administered orally or intravenously at a dose of about 25 mg to 50 mg. In some embodiments, the antihistamine substance is selected from the group consisting of brompheniramine, chlorpheniramine (Chlor-Trimeton), and diphenhydramine. In some embodiments, the antihistamine substance is administered at a dose of about 25 mg. In some embodiments, the antihistamine substance is administered at a dose of about 30 mg. In some embodiments, the antihistamine substance is administered at a dose of about 35 mg. In some embodiments, the antihistamine substance is administered at a dose of about 40 mg. In some embodiments, the antihistamine substance is administered at a dose of about 45 mg. In some embodiments, the antihistamine substance is administered at a dose of about 50 mg.

[0052] In a further aspect, the premedication described herein further comprises montelukast or an equivalent leukotriene inhibitor.

[0053] In an additional aspect, the montelukast or equivalent leukotriene inhibitor described herein is administered at a dose of about 5 mg to 15 mg. In some embodiments, montelukast or an equivalent leukotriene inhibitor is administered at a dose of 5 mg. In some embodiments, montelukast or an equivalent leukotriene inhibitor is administered at a dose of 10 mg. In some embodiments, montelukast or an equivalent leukotriene inhibitor is administered at a dose of 15 mg.

[0054] In one aspect, the present invention provides a method for treating MM, comprising administering a therapeutically effective amount of AB79 in combination with (a) lenalidomide and dexamethasone, or (b) lenalidomide, dexamethasone, and bortezomib to a subject having MM.

[0055] In one aspect, the present invention provides a method for treating MM, the method comprising administering a therapeutically effective amount of AB79 in combination with pomalidomide and dexamethasone to a subject having MM.

[0056] In one aspect, the present invention provides a method for treating MM, the method comprising subcutaneously administering a therapeutically effective amount of AB79 in combination with (a) lenalidomide and dexamethasone, or (b) lenalidomide, dexamethasone, and bortezomib to a subject having MM.

[0057] In one aspect, the present invention provides a method for treating MM, the method comprising subcutaneously administering a therapeutically effective amount of AB79 in combination with pomalidomide and dexamethasone to a subject having MM.

[0058] In one aspect, the anti-CD38 antibody is administered in the absence of hyaluronidase.

[0059] In one embodiment, the CD38-positive blood cancer is multiple myeloma (MM). In one embodiment, the CD38-positive blood cancer is newly diagnosed multiple myeloma (NDMM) or untreated multiple myeloma. In one embodiment, the CD38-positive blood cancer is NDMM and stem cell transplantation is not planned as an initial treatment for patients having the CD38-positive blood cancer. In one embodiment, the CD38-positive blood cancer is relapsed or refractory multiple myeloma (RRMM). In one embodiment, the CD38-positive blood cancer has not been previously treated with a blood cancer drug. In one embodiment, the CD38-positive blood cancer has not been previously treated with a multiple myeloma drug.

[0060] In one embodiment, the anti-CD38 antibody is administered once a week at a dose of about 300 mg for the first two treatment cycles, once every two weeks at a dose of about 300 mg for the subsequent four treatment cycles, and then once every four weeks at a dose of about 300 mg for any subsequent treatment cycles, with one treatment cycle being 28 days. In one embodiment, the anti-CD38 antibody is administered subcutaneously. In one embodiment, the anti-CD38 antibody is AB79.

[0061] In one embodiment, lenalidomide is administered daily for 21 days of each treatment cycle at a dose of about 2.5 - 25 mg for up to eight treatment cycles, with one treatment cycle being 28 days. In one embodiment, lenalidomide is administered daily for 21 days of each treatment cycle at a dose of about 25 mg for up to eight treatment cycles, with one treatment cycle being 28 days. In one embodiment, lenalidomide is administered orally.

[0062] In one embodiment, dexamethasone is administered once a week at a dose of about 20 - 40 mg for 1 - 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 20 - 40 mg for 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 20 - 40 mg for one treatment cycle, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 20 - 40 mg for two treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 20 - 40 mg for three treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 20 - 40 mg for four treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 20 - 40 mg for five treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 20 - 40 mg for six treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 20 - 40 mg for seven treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 20 - 40 mg for eight treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered orally or intravenously. In one embodiment, dexamethasone is administered once a week at a dose of about 20 mg for 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 25 mg for 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 30 mg for 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles, and one treatment cycle is 28 days.In one embodiment, dexamethasone is administered once a week at a dose of about 35 mg for 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 40 mg for 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 20 mg for 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 25 mg for 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 30 mg for 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 35 mg for 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered once a week at a dose of about 40 mg for 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered orally or intravenously.

[0063] In one embodiment, the method of the present invention further comprises administering a therapeutically effective amount of bortezomib. In one embodiment, bortezomib is Velcade® (Takeda). In one embodiment, bortezomib is administered once a week at a dose of about 0.7 - 1.3 mg / m 2 for 3 weeks out of 1 - 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered once a week at a dose of about 0.7 - 1.3 mg / m 2 for 3 weeks out of 1 - 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered once a week at a dose of about 0.7 mg / m 2administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 0.8 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 0.9 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 1.0 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 1.1 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 1.2 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 1.3 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered subcutaneously.

[0064] In one embodiment, bortezomib is administered at a dose of about 0.7 - 0.9 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 0.7 - 1.0 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 0.7 - 1.1 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 0.7 - 1.2 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 0.7 - 1.3 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 0.8 - 1.0 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 0.8 - 1.1 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 0.8 - 1.2 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 0.8 - 1.3 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 0.9 - 1.1 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 0.9 - 1.2 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 0.9-1.3 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 1.0-1.2 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 1.0-1.3 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered at a dose of about 1.1-1.3 mg / m for 3 weeks out of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles 2 administered once a week at a dose of, and one treatment cycle is 28 days. In some embodiments, bortezomib is administered subcutaneously.

[0065] In one embodiment, a) the anti-CD38 antibody is administered on days 1, 8, 15, and 22 of the first two treatment cycles, on days 1 and 15 of the subsequent four treatment cycles, and on day 1 of any additional treatment cycles; b) lenalidomide is administered on days 1 to 21 of each treatment cycle; c) dexamethasone is administered on days 1, 8, 15, and 22 of each of the first 1 to 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of one treatment cycle, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of two treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of three treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of four treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of five treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of six treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of seven treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of eight treatment cycles, and one treatment cycle is 28 days.

[0066] In one embodiment, a) the anti-CD38 antibody is administered on days 1, 8, 15, and 22 of the first two treatment cycles, on days 1 and 15 of the subsequent four treatment cycles, and on day 1 of any additional treatment cycles; b) lenolidomide is administered on days 1 to 21 of each treatment cycle; c) dexamethasone is administered on days 1, 8, 15, and 22 of each of the first 1 to 8 treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of each of the first 1 to 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of one treatment cycle, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of two treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of three treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of four treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of five treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of six treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of seven treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of eight treatment cycles, and one treatment cycle is 28 days.In one embodiment, bortezomib is administered on days 1, 8, and 15 of 1, 8, or 15 treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of one treatment cycle, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of two treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of three treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of four treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of five treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of six treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of seven treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of eight treatment cycles, and one treatment cycle is 28 days. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of one treatment cycle; d) bortezomib is administered on days 1, 8, and 15 of one treatment cycle, and one treatment cycle is 28 days. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of two treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of two treatment cycles, and one treatment cycle is 28 days. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of three treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of three treatment cycles, and one treatment cycle is 28 days.In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of four treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of four treatment cycles, and one treatment cycle is 28 days long. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of five treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of five treatment cycles, and one treatment cycle is 28 days long. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of six treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of six treatment cycles, and one treatment cycle is 28 days long. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of seven treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of seven treatment cycles, and one treatment cycle is 28 days long. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of eight treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of eight treatment cycles, and one treatment cycle is 28 days long.

[0067] In one embodiment, pomalidomide is administered daily at a therapeutically effective amount for up to eight treatment cycles, for 21 days of each treatment cycle, and one treatment cycle is 28 days long. In one embodiment, pomalidomide is administered orally.

[0068] In one embodiment, a) the anti-CD38 antibody is administered on days 1, 8, 15, and 22 of the first two treatment cycles, on days 1 and 15 of the subsequent four treatment cycles, and on day 1 of any additional treatment cycles; b) pomalidomide is administered on days 1 to 21 of each treatment cycle; c) corticosteroids are administered on days 1, 8, 15, and 22 of each of the 1 to 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, the corticosteroids are administered on days 1, 8, 15, and 22 of one treatment cycle, and one treatment cycle is 28 days. In one embodiment, the corticosteroids are administered on days 1, 8, 15, and 22 of each of two treatment cycles, and one treatment cycle is 28 days. In one embodiment, the corticosteroids are administered on days 1, 8, 15, and 22 of each of three treatment cycles, and one treatment cycle is 28 days. In one embodiment, the corticosteroids are administered on days 1, 8, 15, and 22 of each of four treatment cycles, and one treatment cycle is 28 days. In one embodiment, the corticosteroids are administered on days 1, 8, 15, and 22 of each of five treatment cycles, and one treatment cycle is 28 days. In one embodiment, the corticosteroids are administered on days 1, 8, 15, and 22 of each of six treatment cycles, and one treatment cycle is 28 days. In one embodiment, the corticosteroids are administered on days 1, 8, 15, and 22 of each of seven treatment cycles, and one treatment cycle is 28 days. In one embodiment, the corticosteroids are administered on days 1, 8, 15, and 22 of each of eight treatment cycles, and one treatment cycle is 28 days.

[0069] In one aspect, the administration of anti-CD38 antibody therapy results in an incidence of less than 60%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of one or more treatment-related adverse events (TRAE) or treatment-emergent adverse events (TEAE) selected from the group consisting of grade 3 or 4 anemia, hemolytic anemia, neutropenia, thrombocytopenia, fatigue, infusion-related reaction (IRR), leukopenia, and lymphopenia. TEAE are adverse events observed or diagnosed up to about 30 days after the final dose of the drug, regardless of cause. TEAE may have any underlying cause related to a disease or treatment not related to the anti-CD38 antibody, or TEAE may be specifically related to the anti-CD38 antibody. Preferably, the administration of the anti-CD38 antibody results in an incidence of less than 30% of one or more treatment-emergent adverse events (TEAE) selected from the group consisting of grade 3 or 4 anemia, hemolytic anemia, thrombocytopenia, fatigue, infusion-related reaction (IRR), leukopenia, and lymphopenia.

[0070] In one aspect, the administration of anti-CD38 antibody therapy results in depletion of RBC of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%.

[0071] In one aspect, the administration of anti-CD38 antibody therapy results in depletion of platelets of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%.

[0072] In one aspect, the VH chain region of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 10. Preferably, the VH chain region of the anti-CD38 antibody or its antigen-binding fragment may comprise an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or its antigen-binding fragment may comprise an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 10. Preferably, the VH chain region of the anti-CD38 antibody or its antigen-binding fragment may comprise an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or its antigen-binding fragment may comprise an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 10. Preferably, the VH chain region of the anti-CD38 antibody or its antigen-binding fragment may comprise an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or its antigen-binding fragment may comprise an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10. Preferably, the VH chain region of the anti-CD38 antibody or its antigen-binding fragment may comprise an amino acid sequence having at least 97% sequence identity to SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or its antigen-binding fragment may comprise an amino acid sequence having at least 97% sequence identity to SEQ ID NO: 10. Preferably, the VH chain region of the anti-CD38 antibody or its antigen-binding fragment may comprise an amino acid sequence having at least 99% sequence identity to SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or its antigen-binding fragment may comprise an amino acid sequence having at least 99% sequence identity to SEQ ID NO: 10.

[0073] Preferably, the VH chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence has at least 80% sequence identity to SEQ ID NO: 9. The VL chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the VH chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence has at least 85% sequence identity to SEQ ID NO: 9. The VL chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 85% sequence identity to SEQ ID NO: 10. Preferably, the VH chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence has at least 90% sequence identity to SEQ ID NO: 9. The VL chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 90% sequence identity to SEQ ID NO: 10. Preferably, the VH chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence has at least 95% sequence identity to SEQ ID NO: 9. The VL chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 95% sequence identity to SEQ ID NO: 10.Preferably, the VH chain of the anti-CD38 antibody or its antigen-binding fragment comprises CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence has at least 97% sequence identity to SEQ ID NO: 9. The VL chain of the anti-CD38 antibody or its antigen-binding fragment comprises CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 97% sequence identity to SEQ ID NO: 10. Preferably, the VH chain of the anti-CD38 antibody or its antigen-binding fragment comprises CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence has at least 99% sequence identity to SEQ ID NO: 9. The VL chain of the anti-CD38 antibody or its antigen-binding fragment comprises CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 99% sequence identity to SEQ ID NO: 10.

[0074] In one aspect, the VH chain region of the anti-CD38 antibody or its antigen-binding fragment has the amino acid sequence of SEQ ID NO: 9 or a variant thereof with up to three amino acid substitutions, and the VL chain region of the anti-CD38 antibody or its antigen-binding fragment has the amino acid sequence of SEQ ID NO: 10 or a variant thereof with up to three amino acid substitutions.

[0075] In one aspect, the VH chain region of the anti-CD38 antibody or its antigen-binding fragment has the amino acid sequence of SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or its antigen-binding fragment has the amino acid sequence of SEQ ID NO: 10.

[0076] In one aspect, the heavy chain of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 11, and the light chain of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 12. Preferably, the heavy chain of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 11, and the light chain of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 12. Preferably, the heavy chain of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 11, and the light chain of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 12. Preferably, the heavy chain of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 11, and the light chain of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 12. Preferably, the heavy chain of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 97% sequence identity to SEQ ID NO: 11, and the light chain of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 97% sequence identity to SEQ ID NO: 12. Preferably, the heavy chain of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 99% sequence identity to SEQ ID NO: 11, and the light chain of the anti-CD38 antibody or its antigen-binding fragment comprises an amino acid sequence having at least 99% sequence identity to SEQ ID NO: 12.

[0077] Preferably, the heavy chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain sequence has at least 80% sequence identity with SEQ ID NO: 11. The light chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain sequence may have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the heavy chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain sequence has at least 85% sequence identity with SEQ ID NO: 11. The light chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain sequence may have at least 85% sequence identity with SEQ ID NO: 12. Preferably, the heavy chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain sequence has at least 90% sequence identity with SEQ ID NO: 11. The light chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain sequence may have at least 90% sequence identity with SEQ ID NO: 12. Preferably, the heavy chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain sequence has at least 95% sequence identity with SEQ ID NO: 11. The light chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain sequence may have at least 95% sequence identity with SEQ ID NO: 12.Preferably, the heavy chain of the anti-CD38 antibody or its antigen-binding fragment comprises CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain sequence has at least 97% sequence identity to SEQ ID NO: 11. The light chain of the anti-CD38 antibody may comprise CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain sequence has at least 97% sequence identity to SEQ ID NO: 12. Preferably, the heavy chain of the anti-CD38 antibody or its antigen-binding fragment comprises CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain sequence has at least 99% sequence identity to SEQ ID NO: 11. The light chain of the anti-CD38 antibody or its antigen-binding fragment may comprise CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain sequence has at least 99% sequence identity to SEQ ID NO: 12.

[0078] In one aspect, the anti-CD38 antibody or its antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 11 or a variant thereof with up to three amino acid substitutions and the light chain amino acid sequence of SEQ ID NO: 12 or a variant thereof with up to three amino acid substitutions.

[0079] In one aspect, the anti-CD38 antibody or its antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 11 and the light chain amino acid sequence of SEQ ID NO: 12.

[0080] In one aspect, the anti-CD38 antibody or its antigen-binding fragment is fully human. In another aspect, the anti-CD38 antibody or its antigen-binding fragment is humanized. In another aspect, the anti-CD38 antibody or its antigen-binding fragment is affinity matured.

[0081] In one aspect, the anti-CD38 antibody or its antigen-binding fragment does not cause hemolytic anemia or thrombocytopenia.

[0082] In one embodiment, the blood cancer is multiple myeloma (MM). In one embodiment, the blood cancer is newly diagnosed multiple myeloma (NDMM) or untreated multiple myeloma. In one embodiment, the blood cancer is relapsed or refractory multiple myeloma (RRMM). In one embodiment, the method of the present invention effectively treats one or more underlying symptoms of MM, NDMM, or RRMM, or other CD38-related disorders that the patient is suffering from. In one embodiment, the blood cancer is NDMM and stem cell transplantation is not planned as an initial treatment for patients with NDMM.

[0083] In one aspect, the therapeutically effective amount of the anti-CD38 antibody or antigen-binding fragment thereof is a dosage of about 300 milligrams (mg). Preferably, the present invention provides a unit dosage form of 300 mg.

[0084] In one aspect, a unit dosage form is provided, wherein the VH chain region of the anti-CD38 antibody or an antigen-binding fragment thereof comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or an antigen-binding fragment thereof comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 10. Preferably, a unit dosage form is provided, wherein the VH chain region of the anti-CD38 antibody or an antigen-binding fragment thereof may comprise an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or an antigen-binding fragment thereof may comprise an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 10. Preferably, a unit dosage form is provided, wherein the VH chain region of the anti-CD38 antibody or an antigen-binding fragment thereof may comprise an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or an antigen-binding fragment thereof may comprise an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 10. Preferably, a unit dosage form is provided, wherein the VH chain region of the anti-CD38 antibody or an antigen-binding fragment thereof may comprise an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or an antigen-binding fragment thereof may comprise an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 10. Preferably, a unit dosage form is provided, wherein the VH chain region of the anti-CD38 antibody or an antigen-binding fragment thereof may comprise an amino acid sequence having at least 97% sequence identity to SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or an antigen-binding fragment thereof may comprise an amino acid sequence having at least 97% sequence identity to SEQ ID NO: 10. Preferably, a unit dosage form is provided, wherein the VH chain region of the anti-CD38 antibody or an antigen-binding fragment thereof may comprise an amino acid sequence having at least 99% sequence identity to SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or an antigen-binding fragment thereof may comprise an amino acid sequence having at least 99% sequence identity to SEQ ID NO: 10.

[0085] Preferably, the VH chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence has at least 80% sequence identity to SEQ ID NO: 9, and the VL chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 80% sequence identity to SEQ ID NO: 10, and a unit dosage form is provided. Preferably, the VH chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence has at least 85% sequence identity to SEQ ID NO: 9, and the VL chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 85% sequence identity to SEQ ID NO: 10, and a unit dosage form is provided. Preferably, the VH chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence has at least 90% sequence identity to SEQ ID NO: 9, and the VL chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 90% sequence identity to SEQ ID NO: 10, and a unit dosage form is provided. Preferably, the VH chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence has at least 95% sequence identity to SEQ ID NO: 9, and the VL chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 95% sequence identity to SEQ ID NO: 10, and a unit dosage form is provided.Preferably, the VH chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence has at least 97% sequence identity to SEQ ID NO: 9, and the VL chain of the anti-CD38 antibody comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 97% sequence identity to SEQ ID NO: 10, and a unit dosage form is provided. Preferably, the VH chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence has at least 99% sequence identity to SEQ ID NO: 9, and the VL chain of the anti-CD38 antibody or its antigen-binding fragment comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the VL sequence may have at least 99% sequence identity to SEQ ID NO: 10, and a unit dosage form is provided.

[0086] In one aspect, a unit dosage form is provided, wherein the VH chain region of the anti-CD38 antibody or its antigen-binding fragment has the amino acid sequence of SEQ ID NO: 9 or a variant thereof having a maximum of 3 amino acid substitutions, and the VL chain region of the anti-CD38 antibody or its antigen-binding fragment has the amino acid sequence of SEQ ID NO: 10 or a variant thereof having a maximum of 3 amino acid substitutions.

[0087] In one aspect, a unit dosage form is provided, wherein the VH chain region of the anti-CD38 antibody or its antigen-binding fragment has the amino acid sequence of SEQ ID NO: 9, and the VL chain region of the anti-CD38 antibody or its antigen-binding fragment has the amino acid sequence of SEQ ID NO: 10.

[0088] In one aspect, a unit dosage form is provided, wherein the heavy chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 11, and the light chain of the anti-CD38 antibody comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 12. Preferably, a unit dosage form is provided, wherein the heavy chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 11, and the light chain or an antigen-binding fragment thereof of the anti-CD38 antibody comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 12. Preferably, a unit dosage form is provided, wherein the heavy chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 11, and the light chain or an antigen-binding fragment thereof of the anti-CD38 antibody comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 12. Preferably, a unit dosage form is provided, wherein the heavy chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 11, and the light chain or an antigen-binding fragment thereof of the anti-CD38 antibody comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 12. Preferably, a unit dosage form is provided, wherein the heavy chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises an amino acid sequence having at least 97% sequence identity to SEQ ID NO: 11, and the light chain or an antigen-binding fragment thereof of the anti-CD38 antibody comprises an amino acid sequence having at least 97% sequence identity to SEQ ID NO: 12. Preferably, a unit dosage form is provided, wherein the heavy chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises an amino acid sequence having at least 99% sequence identity to SEQ ID NO: 11, and the light chain or an antigen-binding fragment thereof of the anti-CD38 antibody comprises an amino acid sequence having at least 99% sequence identity to SEQ ID NO: 12.

[0089] Preferably, a unit dosage form is provided wherein the heavy chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain sequence has at least 80% sequence identity to SEQ ID NO: 11, and the light chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain sequence may have at least 80% sequence identity to SEQ ID NO: 12. Preferably, a unit dosage form is provided wherein the heavy chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain sequence has at least 85% sequence identity to SEQ ID NO: 11, and the light chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain sequence may have at least 85% sequence identity to SEQ ID NO: 12. Preferably, a unit dosage form is provided wherein the heavy chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain sequence has at least 90% sequence identity to SEQ ID NO: 11, and the light chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain sequence may have at least 90% sequence identity to SEQ ID NO: 12. Preferably, a unit dosage form is provided wherein the heavy chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain sequence has at least 95% sequence identity to SEQ ID NO: 11, and the light chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain sequence may have at least 95% sequence identity to SEQ ID NO: 12.Preferably, a unit dosage form is provided wherein the heavy chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, and the remainder of the heavy chain sequence has at least 97% sequence identity to SEQ ID NO:11, and the light chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises CDR sequences defined by SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, and the remainder of the light chain sequence has at least 97% sequence identity to SEQ ID NO:12. Preferably, a unit dosage form is provided wherein the heavy chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, and the remainder of the heavy chain sequence has at least 99% sequence identity to SEQ ID NO:11, and the light chain of the anti-CD38 antibody or an antigen-binding fragment thereof comprises CDR sequences defined by SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, and the remainder of the light chain sequence has at least 99% sequence identity to SEQ ID NO:12.

[0090] In one aspect, a unit dosage form is provided wherein the anti-CD38 antibody or an antigen-binding fragment thereof comprises the heavy chain amino acid sequence of SEQ ID NO:11 or a variant thereof having up to 3 amino acid substitutions and the light chain amino acid sequence of SEQ ID NO:12 or a variant thereof having up to 3 amino acid substitutions.

[0091] In one aspect, a unit dosage form is provided wherein the anti-CD38 antibody or an antigen-binding fragment thereof comprises the heavy chain amino acid sequence of SEQ ID NO:11 and the light chain amino acid sequence of SEQ ID NO:12.

[0092] In one aspect, a unit dosage form is provided wherein a human anti-CD38 antibody or an antigen-binding fragment thereof is administered in the form of a pharmaceutically acceptable composition. Preferably, the pharmaceutically acceptable composition is suitable for subcutaneous administration.

[0093] In one aspect, the unit dosage form is formulated for subcutaneous administration of an antibody or an antigen-binding fragment thereof in the treatment of blood cancers selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, chronic lymphocytic leukemia, plasmacytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, and Burkitt lymphoma.

[0094] In one aspect, the blood cancer is multiple myeloma (MM). In one embodiment, the blood cancer is newly diagnosed multiple myeloma (NDMM) or untreated multiple myeloma. In one embodiment, the blood cancer is relapsed or refractory multiple myeloma (RRMM).

[0095] In one aspect, there is provided a human anti-CD38 antibody or an antigen-binding fragment thereof for use in a treatment method, wherein the antibody or the antigen-binding fragment thereof does not cause significant levels of erythrocyte depletion and / or platelet depletion after administration, and the human anti-CD38 antibody or the antigen-binding fragment thereof is administered subcutaneously at a dosage of about 300 milligrams. Preferably, the human anti-CD38 antibody or the antigen-binding fragment thereof that does not cause significant levels of erythrocyte depletion and / or platelet depletion after administration can be the anti-CD38 antibody or the antigen-binding fragment thereof as defined herein.

[0096] In one aspect, there is provided a unit dosage form comprising an isolated antibody or an antigen-binding fragment thereof, which does not cause significant levels of erythrocyte depletion and / or platelet depletion after administration, and the unit dosage form is formulated for subcutaneous administration of the antibody or the antigen-binding fragment thereof at a dosage of about 300 milligrams.

[0097] In one aspect, there is provided a human anti-CD38 antibody or an antigen-binding fragment thereof as defined herein for use in a treatment method, and the human anti-CD38 antibody or the antigen-binding fragment thereof is formulated for subcutaneous administration. Preferably, the human anti-CD38 antibody or the antigen-binding fragment thereof is administered subcutaneously.

[0098] In one aspect, there is provided a human anti-CD38 antibody or antigen-binding fragment thereof as defined herein for use in the treatment of diseases shown to bind to CD38, and the human anti-CD38 antibody or antigen-binding fragment thereof is formulated for subcutaneous administration. Preferably, the human anti-CD38 antibody or antigen-binding fragment thereof is administered subcutaneously.

[0099] In one aspect, the dosages of the anti-CD38 antibody or antigen-binding fragment thereof and dexamethasone administered are weekly dosages when used in combination with (a) lenolidomide, (b) lenolidomide and bortezomib, or (c) pomalidomide as described herein. In one aspect, the dosage of the administered anti-CD38 antibody or antigen-binding fragment thereof as described herein is a bi-weekly dosage. In one aspect, the dosage of the administered anti-CD38 antibody or antigen-binding fragment thereof as described herein is a once every four-week dosage.

[0100] Preferably, the human anti-CD38 antibody or antigen-binding fragment thereof can be administered at a dosage of about 300 milligrams of antibody. Preferably, the human anti-CD38 antibody or antigen-binding fragment thereof can be formulated for subcutaneous administration. Preferably, the human anti-CD38 antibody or antigen-binding fragment thereof can be formulated for subcutaneous administration at a dosage of about 300 milligrams of antibody.

[0101] In one aspect, there is provided a human anti-CD38 antibody or antigen-binding fragment thereof as defined herein for use in the treatment of hematological cancers, the human anti-CD38 antibody or antigen-binding fragment thereof is formulated for subcutaneous administration, and the human anti-CD38 antibody or antigen-binding fragment thereof is administered at a dosage of about 300 milligrams of antibody. Preferably, the human anti-CD38 antibody or antigen-binding fragment thereof can be administered subcutaneously.

[0102] Suitably, the blood cancer can be multiple myeloma, chronic lymphocytic leukemia, chronic lymphocytic leukemia, plasmacytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, B cell lymphoma, or Burkitt lymphoma.

[0103] In one embodiment, the blood cancer is multiple myeloma (MM). In one embodiment, the blood cancer is newly diagnosed multiple myeloma (NDMM) or untreated multiple myeloma. In one embodiment, the blood cancer is relapsed or refractory multiple myeloma (RRMM).

[0104] These and other embodiments, features, and possible advantages will become apparent with reference to the following description.

DETAILED DESCRIPTION OF THE INVENTION

[0105] Introduction In the blood vessels of patients with active disease, approximately 36-fold more CD38 molecules are expressed on RBCs than on myeloma cells. Thus, for example, off-target expression of CD38 may need to be saturated before unbound antibody can pass into the bone marrow and saturate the CD38 expressed on myeloma cells. This may explain why other anti-CD38 antibodies in the art that bind strongly to RBCs and platelets (such as daratumumab and isatuximab) require high-dose systemic administration to achieve efficacy.

[0106] AB79, daratumumab, isatuximab, and MOR202 are anti-CD38 IgG1 antibodies that kill tumors mainly by antibody-dependent cellular cytotoxicity (ADCC). This mechanism requires effector cells (such as NK cells) to bind to antibodies on target cells and secrete cytotoxic agents in a concentrated manner to form a lytic synapse. The frequency of these effector cells in the blood is many orders of magnitude lower than that of RBCs and platelets. For example, the ratio of RBCs to NK cells in the blood is 20,000:1. Therefore, since effector cells are mainly bound by anti-CD38 antibodies that bind to RBCs and platelets, the effector activity of daratumumab, isatuximab, and MOR202 is diverted from tumors, preventing the formation of lytic synapses with tumors, which results in low efficiency of ADCC.

[0107] Treatment of patients with anti-CD38 antibodies that bind to RBCs and platelets can result in life-threatening side effects. For example, in one study, treatment of relapsed or refractory multiple myeloma with MOR202 resulted in multiple severe treatment-related adverse events or TEAEs (see, e.g., Raab et al. (2015) Blood 126:3035). The most common TEAEs in any grade were anemia (15 patients, 34%), fatigue (14 patients, 32%), infusion-related reactions (IRR) and leukopenia (each 13 patients, 30%), lymphopenia and nausea (each 11 patients, 25%). Grade ≥3 TEAEs were reported in 28 patients (64%), and the most common ones included lymphopenia (8 patients, 18%), leukopenia (5 patients, 11%), and hypertension (4 patients, 9%). IRR occurred mainly during the first infusion and all were grade 1-2 except for one patient (grade 3). Infections were generally reported (26 patients, 59%) but were not judged to be treatment-related in the majority of cases. MOR202 is clinically used only via IV infusion.

[0108] Other Morphosys antibodies that target CD38 are known (see, e.g., WO2006 / 125640, which discloses four human antibodies: MOR03077, MOR03079, MOR03080, and MOR03100, as well as two mouse antibodies: OKT10 and IB4). These prior art antibodies are inferior to the antibodies (e.g., AB79) for use according to the present invention for various reasons. MOR03080 binds to human CD38 and cynomolgus CD38, but has low affinity for human CD38 (Biacore K D = 27.5 nm). OKT10 binds to human CD38 and cynomolgus CD38, but has low / moderate affinity for human CD38 (Biacore K D = 8.28 nm). MOR03079 binds to human CD38 with high affinity (Biacore K D = 2.4 nm), but does not bind to cynomolgus CD38. MOR03100 and MOR03077 bind to human CD38 with moderate or low affinity (Biacore K D = 10 nm and 56 nm, respectively). In comparison, the antibodies for use according to the present invention (e.g., AB79) bind to human and cynomolgus CD38 and have high affinity for human CD38 (Biacore K D = 5.4 nm). Furthermore, the prior art antibodies have insufficient ADCC and CDC activities.

[0109] The advantage of more efficient ADCC is the ability to deliver the anti-CD38 therapeutic as a low volume injection. If an antibody for use according to the present invention (e.g., AB79) is formulated at a concentration of 100 mg / mL, the effective dose for an 80 kg myeloma patient can be administered as a single subcutaneous injection of <1.0 mL. In contrast, an effective dose of daratumumab or isatuximab (i.e., 100 mg / mL) delivered to this patient in a comparable form would require 12.8 mL or 8 - 16 mL, respectively, to be administered.

[0110] Methods and unit dosages of anti-CD38 are provided herein by subcutaneously administering a therapeutically effective amount of an anti-CD38 antibody or antigen-binding fragment thereof in combination with (a) lenolidomide, (b) lenolidomide and bortezomib, or (c) pomalidomide, thereby providing unexpected benefits and preventing side effects, inconvenience, and costs of administration of high-dose systemic anti-CD38 antibody therapy.

[0111] The present invention provides methods and unit dosage forms for treating a disease (including hematological cancers) in which binding to CD38 is demonstrated by subcutaneously administering a therapeutically effective amount of an isolated anti-CD38 antibody or antigen-binding fragment thereof to a patient in need thereof. In some embodiments, the antibody or antigen-binding fragment thereof for subcutaneous administration comprises a heavy chain variable region comprising SEQ ID NO: 9 (or a sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity thereto), and a light chain variable region comprising SEQ ID NO: 10 (or a sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity thereto). The anti-CD38 antibody or antigen-binding fragment thereof provided herein can be therapeutically effective when administered by subcutaneous administration.

[0112] Lenalidomide (LEN) is currently marketed by Celgene as Revlimid for the treatment of multiple myeloma. Lenalidomide is cytotoxic to tumor cells, activates natural killer (NK) cells, and upregulates CD38 expression on tumor cells. Lenalidomide is a thalidomide analog, and thus other thalidomide analogs (such as pomalidomide or thalidomide itself, etc.) are expected to be effective when used in combination with the anti-CD38 antibody or antigen-binding fragment thereof of the present invention.

[0113] Pomalidomide (POM) is currently marketed by Celgene as Pomalyst in the United States and as Imnovid by Celgene in the EU and Russia.

[0114] Dexamethasone (DEX) is a corticosteroid that inhibits MM tumor growth by showing synergistic effects with lenalidomide and pomalidomide. Dexamethasone is included as an anti-inflammatory and immunosuppressive agent and is used in the treatment of many conditions, and is used in cancer treatment to counteract certain side effects of anti-tumor treatment.

[0115] Bortezomib (originally PS-341; marketed as Velcade (VEL) by Takeda Oncology, Chemobort by Cytogen, and Bortecad by Cadila Healthcare) is a chemotherapeutic agent of the peptide boronate class that acts as a proteasome inhibitor. Multiple other classes of proteasome inhibitors are known. The peptide boronate is approved in the United States for the treatment of relapsed multiple myeloma. Another peptide boronate is CEP-18770. Other classes of proteasome inhibitors include peptide aldehydes (e.g., MG132), peptide vinyl sulfones, peptide epoxyketones (e.g., epoxomicin, carfilzomib), β-lactone inhibitors (e.g., lactacystin, MLN 519, NPI-0052, salinosporamide A), metals (e.g., disulfuram), and compounds that form dithiocarbamate complexes with the specific antioxidant catechin-3-gallate (e.g., epigallocatechin-3-gallate), as well as salinosporamide A. Another proteasome inhibitor (ixazomib) was approved by the FDA in 2015 for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma after at least one prior therapy.

[0116] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings commonly understood by those of ordinary skill in the art. The meanings and scopes of such terms will be apparent. However, in any event of potential ambiguity, the definitions provided herein shall prevail over any dictionary or external definition. Further, unless the context otherwise requires, singular terms shall include the plural, and plural terms shall include the singular. The term "or" includes "and / or" unless otherwise specified. Further, the use of the terms "including", "includes", or "included" is not limiting. Terms such as "element" and "component" encompass both elements and components that include one unit and elements and components that include two or more sub-units, unless specifically specified otherwise.

[0117] Generally, the nomenclature and techniques used in connection with cell and tissue culture, molecular biology, immunology, microbiology, genetics, and the chemistry and hybridization of proteins and nucleic acids described herein are well known and commonly used in the art. The methods and techniques of the present invention are generally carried out according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification, unless otherwise indicated. Enzyme reactions and purification techniques are carried out according to the manufacturer's specifications, as generally accomplished in the art or as described herein. The nomenclature used in connection with analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein, as well as their laboratory procedures and techniques, are well known and commonly used in the art. Standard techniques are used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, delivery, and treatment of patients.

[0118] All headings and section titles are used for clarity and reference purposes only and should not be construed as being in any way limiting. For example, one of ordinary skill in the art will recognize that it may be useful to combine various aspects of the disclosure from different headings and sections as appropriate, in accordance with the spirit and scope of the invention described herein.

[0119] Definitions Selected terms are defined below to facilitate understanding of the present invention.

[0120] The terms "human CD38" and "human CD38 antigen" refer to the amino acid sequence of SEQ ID NO:1 as defined herein, or a functional fraction thereof (such as an epitope, etc.) (Table 1). Generally, CD38 retains a short cytoplasmic tail, a transmembrane domain, and an extracellular domain. The terms "cynomolgus CD38" and "cynomolgus CD38 antigen" refer to the amino acid sequence of SEQ ID NO:2, which is 92% identical to the amino acid sequence of human CD38 (Table 1). Synonyms for CD38 include cyclic ADP ribose hydrolase; cyclic ADP ribose - hydrolase 1; ADP ribosyl cyclase; ADP - ribosyl cyclase 1; cADPr hydrolase 1; CD38 - rs1; I - 19; NIM - R5 antigen; 2'-phospho - cyclic - ADP - ribose transferase; 2'-phospho - ADP - ribosyl cyclase; 2'-phospho - cyclic - ADP - ribose transferase; 2'-phospho - ADP - ribosyl cyclase; T10.

[0121] [Table 1]

[0122] The terms "therapeutically effective amount" and "therapeutically effective dosage" refer to an amount of a therapeutic agent that, in an amount and for a period of time necessary to achieve the desired therapeutic result, reduces or alleviates the severity and / or duration of a disorder or one or more of its symptoms; prevents the progression of a disorder; causes regression of a disorder; prevents the recurrence, onset, or progression of one or more symptoms associated with a disorder; or is sufficient to enhance or improve the prophylactic or therapeutic effect(s) of another therapeutic modality (e.g., a prophylactic or therapeutic agent). A therapeutically effective amount can vary according to factors such as the individual's disease state, age, sex, and weight, as well as the ability of the pharmaceutical to elicit the desired response in the individual. A therapeutically effective amount of an antibody is one in which any toxic or damaging effects of the antibody or antibody portion are outweighed by therapeutically beneficial effects. A therapeutically effective amount of an antibody for the treatment of a tumor can be measured by its ability to stabilize the progression of the disease. The ability of a compound to inhibit cancer can be evaluated in animal model systems that predict effectiveness in human tumors. The term "unit dose" or "dosage form" refers to the amount of a pharmaceutical administered to a patient in a single dose. A dosage form is a pharmaceutical preparation in a form that is marketed for use and is apportioned into specific dosages by a specific admixture of an active ingredient and inactive components (excipients) in a particular outer form (e.g., a capsule shell, etc.).

[0123] The terms "patient" and "subject" include both humans and other animals (particularly mammals). Accordingly, the compositions, dosages, and methods disclosed herein are applicable to both human and veterinary therapeutic modalities. In one embodiment, the patient is a mammal, such as a human.

[0124] The term "disease shown to bind to CD38" means a disease in which binding of a binding partner to CD38 (e.g., an anti-CD38 antibody of the present invention) provides a prophylactic or therapeutic effect, including remission of one or more symptoms of the disease. Such binding can result in blocking of other factors or binding partners for CD38, neutralization of CD38, ADCC, CDC, complement activation, or some other mechanism by which the disease is prevented or treated. Factors and binding partners for CD38 include autoantibodies to CD38, which are blocked by the anti-CD38 antibodies or antigen-binding fragments thereof of the present invention. Such binding is shown as a result of expression of CD38 by a cell or subset of cells (e.g., MM cells), whereby the presentation of a CD38 binding partner to the target results in removal (e.g., lysis) of those cells, for example via hemolysis or apoptosis. Such expression of CD38 can be normal, overexpressed, inappropriately expressed, or a consequence of activation of CD38, compared to normal cells or compared to other cell types, either in a non-diseased state or between diseased states.

[0125] The term "blood cancer" refers to malignant neoplasms of hematopoietic tissue, encompassing leukemia, lymphoma, and multiple myeloma. Non-limiting examples of pathologies associated with abnormal CD38 expression include multiple myeloma; B-cell chronic lymphocytic leukemia (B-CLL); acute lymphoblastic leukemia; chronic myelogenous leukemia; acute myelogenous leukemia; chronic lymphocytic leukemia (CLL); chronic myelogenous leukemia or chronic myeloid leukemia (CML); acute myelogenous leukemia or acute myeloid leukemia (AML); acute lymphoblastic leukemia (ALL); hairy cell leukemia (HCL); myelodysplastic syndrome (MDS); and all subtypes and stages of these leukemias and other blood diseases (e.g., blast phase (BP), chronic phase (CP), or accelerated phase (AP) of CML), but are not limited to these, which are defined by morphological, histochemical, and immunological techniques well known to those skilled in the art.

[0126] The term "isolated antibody" refers to an antibody or an antigen-binding fragment thereof that is substantially free of other antibodies having different antigen specificities. For example, an isolated antibody that specifically binds to CD38 is substantially free of antibodies that specifically bind to antigens other than CD38. However, an isolated antibody that specifically binds to an epitope, isoform, or variant of human CD38 or cynomolgus CD38 may have cross-reactivity, for example, to other related antigens (such as CD38 homologs from other species). Further, an isolated antibody may be a homogeneous population of antibodies that is substantially free of other cellular materials and / or chemical substances, or that has been substantially separated and / or purified from other components (such as recombinant cells) of the system in which the antibody was produced.

[0127] The term "recombinant antibody" refers to an antibody that is prepared, expressed, produced, or isolated by recombinant means, such as an antibody isolated from a transgenic or chromosomally modified animal (such as a mouse) for a human immunoglobulin gene or a hybridoma prepared therefrom; an antibody isolated from a host cell transformed to express the antibody; an antibody isolated from a combinatorial antibody library; and an antibody produced by any other means involving splicing of a human immunoglobulin gene sequence to other DNA sequences, or an antibody produced in vitro, etc.

[0128] The terms "red blood cell", "RBC", and "erythrocyte" refer to bone marrow-derived hemoglobin-containing blood cells that carry oxygen to cells and tissues and return carbon dioxide to the respiratory system for transport. RBCs are also referred to as red cells, red blood corpuscles, haematids, and erythroid cells.

[0129] The term "over a period of time" refers to any period (e.g., minutes, hours, days, months, or years). For example, over a period of time can refer to at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 60 minutes, at least 75 minutes, at least 90 minutes, at least 105 minutes, at least 120 minutes, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, at least 22 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 1 month, at least 1 year, or any time in between. In other words, the antibody from the composition can be absorbed by an individual administered over a period of at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 60 minutes, at least 75 minutes, at least 90 minutes, at least 105 minutes, at least 120 minutes, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, at least 22 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 1 month, at least 1 year, or any time in between.

[0130] The term "treatment cycle" refers to a period of treatment with a drug or combination of drugs, followed by a period of rest (i.e., no treatment) for one or more of the drugs. A typical treatment cycle will be 28 days but can vary. The cycle can be repeated multiple times on a regular schedule to constitute the entire course of treatment. The course of treatment can be 4 to 8 cycles and can be truncated or extended depending on the patient's response.

[0131] A composition that "substantially" contains a component means that the composition contains more than about 80% by weight of the component. Preferably, the composition can contain more than about 90% by weight of the component. Preferably, the composition can contain more than about 95% by weight of the component. Preferably, the composition can contain more than about 97% by weight of the component. Preferably, the composition can contain more than about 98% by weight of the component. Preferably, the composition can contain more than about 99% by weight of the component.

[0132] The term "about" refers to the degree of proximity in numbers, degrees, volumes, times, etc. that have minor variations of up to 10% in magnitude. Thus, the term "about" is used to cover variations of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from the specified value.

[0133] The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle suitable for the administration of the compounds of the present invention to mammals. Carriers include liquid or solid filling substances, diluents, excipients, solvents, or encapsulating materials involved in transporting or delivering the subject compound from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. In one embodiment, the pharmaceutically acceptable carrier is suitable for intravenous administration. In another embodiment, the pharmaceutically acceptable carrier is suitable for injection into a local area. In another embodiment, the pharmaceutically acceptable carrier is suitable for subcutaneous administration. In another embodiment, the pharmaceutically acceptable carrier is suitable for subcutaneous injection.

[0134] The term "pharmaceutical composition" refers to a preparation suitable for administration to a subject and treatment of a disease. When the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered as a pharmaceutical to a mammal (e.g., human), they can be administered "as such" or in combination with a pharmaceutically acceptable carrier and / or other excipients as a pharmaceutical composition containing the anti-CD38 antibody or antigen-binding fragment thereof. The pharmaceutical composition can be in the form of a unit dosage form for administering a specific dosage of the anti-CD38 antibody or antigen-binding fragment thereof at a specific concentration, specific amount, or specific volume. The pharmaceutical composition containing the anti-CD38 antibody or antigen-binding fragment thereof is provided either alone or in combination with a prophylactic agent, therapeutic agent, and / or pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition can include a unit dosage form according to the present invention either alone or in combination with a prophylactic agent, therapeutic agent, and / or pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition can include the human anti-CD38 antibody or antigen-binding fragment thereof described herein either alone or in combination with a prophylactic agent, therapeutic agent, and / or pharmaceutically acceptable carrier.

[0135] "In combination with" means that two or more therapeutic substances can be administered to a subject together in a mixture, simultaneously as a single agent, or sequentially as a single agent in any order. The mode of administration of each therapeutic substance can vary; for example, in triple combination therapy, one therapeutic substance can be administered subcutaneously, one orally, and one intravenously.

[0136] Conventional antibody structural units typically contain a tetramer. Each tetramer is typically composed of two identical pairs of polypeptide chains, and each pair has one "light" chain (typically having a molecular weight of about 25 kDa) and one "heavy" chain (typically having a molecular weight of about 50 - 70 kDa). Human light chains are classified as κ light chains and λ light chains. Heavy chains are classified as μ, δ, γ, α, or ε, and define the antibody isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has multiple subclasses, including but not limited to IgG1, IgG2, IgG3, and IgG4. IgM has subclasses, including but not limited to IgM1 and IgM2. Thus, an "isotype" refers to any of the subclasses of immunoglobulins defined by the chemical and antigenic characteristics of their constant regions. Known human immunoglobulin isotypes are IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM1, IgM2, IgD, and IgE. Therapeutic antibodies can also include hybrids of isotypes and / or subclasses.

[0137] Each variable heavy (VH) region and variable light (VL) region (about 100 - 110 amino acids in length) consists of three hypervariable regions called "complementary determining regions" (CDRs) and four framework regions (FRs) (about 15 - 30 amino acids in length), arranged in the following order: FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4, from the amino terminus to the carboxy terminus. "Variable" refers to the fact that the CDRs vary extensively in sequence among antibodies, thereby determining a unique antigen-binding site.

[0138] The hypervariable regions generally encompass approximately amino acid residues 24 - 34 (LCDR1; "L" represents the light chain), 50 - 56 (LCDR2), and 89 - 97 (LCDR3) in the light chain variable region, and approximately 31 - 35B (HCDR1; "H" represents the heavy chain), 50 - 65 (HCDR2), and 95 - 102 (HCDR3) in the heavy chain variable region, near the amino acid residues from Kabat et al. (1991) Sequences Of Proteins Of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, and / or residues forming hypervariable loops (e.g., residues 26 - 32 (LCDR1), 50 - 52 (LCDR2), and 91 - 96 (LCDR3) in the light chain variable region, and 26 - 32 (HCDR1), 53 - 55 (HCDR2), and 96 - 101 (HCDR3) in the heavy chain variable region (Chothia and Lesk (1987) J. Mol. Biol. 196:901 - 917)).

[0139] The Kabat numbering system is generally used in conjunction with the EU numbering system for the Fc region when referring to residues in the variable domains (approximately residues 1 - 107 of the light chain variable region and residues 1 - 113 of the heavy chain variable region) (e.g., Kabat et al. (1991) Sequences Of Proteins Of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD).

[0140] The term "immunoglobulin (Ig) domain" refers to a region of an immunoglobulin that has a distinct tertiary structure. In addition to the variable domains, each heavy and light chain has constant domains: constant heavy chain (CH) domains; constant light chain (CL) domains, and a hinge domain. In the context of IgG antibodies, the IgG isotypes each have three CH regions. The carboxy-terminal portions of each HC and LC define constant regions that primarily serve effector functions. Thus, the "CH" domains in the context of IgG are as follows. "CH1" refers to positions 118 - 220 according to the Kabat EU index. "CH2" refers to positions 237 - 340 according to the Kabat EU index, and "CH3" refers to positions 341 - 447 according to the Kabat EU index.

[0141] The term "hinge region" refers to a flexible polypeptide that includes the amino acids between the first and second constant domains of an antibody. Structurally, the IgG CH1 domain ends at EU position 220 and the IgG CH2 domain begins at residue EU position 237. Thus, for IgG, the antibody hinge is defined herein to include positions 221 (D221 in IgG1) - 236 (G236 in IgG1), and the numbering follows the Kabat EU index. In some embodiments, for example in the context of the Fc region, a lower hinge is included and generally the "lower hinge" refers to positions 226 - 230.

[0142] The term "Fc region" 36 refers to a polypeptide that includes the constant region of an antibody, excluding the first constant region Ig domain and, in some cases, a portion of the hinge. Thus, Fc refers to the last two constant region Ig domains of IgA, IgD, and IgG, the last three constant region Ig domains of IgE and IgM, and the flexible hinge at the N-terminus of these domains. For IgA and IgM, Fc may include the J chain. For IgG, the Fc domain includes the Ig domains Cγ2 and Cγ3 (Cγ2 and Cγ3), and the lower hinge region between Cγ1 (Cγ1) and Cγ2 (Cγ2). The boundaries of the Fc region can vary, but the human IgG heavy chain Fc region is typically defined as including residue C226 or P230 (numbering according to the Kabat EU index) at its carboxyl terminus. In some embodiments, as described more fully below, amino acid modifications are made to the Fc region, for example, to alter binding to one or more FcγR or FcRn receptors.

[0143] The term "humanized antibody" refers to an antibody in which the antigen-binding site is derived from an antibody sequence from a non-human species and the framework and constant regions are derived from human antibody sequences. Since a humanized antibody may contain substitutions in the framework region, the framework need not be an exact copy of an expressed human antibody or germline gene sequence. The term "derived from" when referring to a humanized antibody means that the Ig domain in question is at least 80% identical to the sequence of an antibody from the species to which it is being referred.

[0144] The term "human antibody" refers to an antibody in which both the antigen-binding site (framework region) and the constant region are derived from human-origin sequences. For example, if the variable region of the antibody is obtained from a system using human germline immunoglobulin genes or rearranged immunoglobulin genes, they are "derived from" human-origin sequences. Such systems include human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals (such as mice carrying the human immunoglobulin locus described herein). A "human antibody" may contain amino acid differences due to, for example, naturally occurring somatic mutations or the introduction of intentional substitutions in the framework or antigen-binding site when compared to human germline immunoglobulin sequences or rearranged immunoglobulin sequences. Typically, a "human antibody" is at least 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 amino acid sequence to the amino acid sequence encoded by a human germline immunoglobulin gene or a rearranged immunoglobulin gene.

[0145] CD38 antibody Accordingly, the present invention provides isolated anti-CD38 antibodies and antigen-binding fragments thereof that specifically bind to human and primate CD38 proteins, which are found to be useful in subcutaneous administration methods and unit dosage forms. Particular ones used in the present invention are antibodies or antigen-binding fragments thereof that bind to both human CD38 protein and primate CD38 protein, especially those of primates used in clinical trials such as cynomolgus monkeys (Macaca fascicularis, Crab eating macaque, also referred to herein as "cyno").

[0146] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof of the invention interacts with CD38 via a number of amino acid residues, and based on human sequence numbering, include K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294. Preferably, the anti-CD38 antibody or antigen-binding fragment thereof of the invention interacts with CD38 via a number of amino acid residues, and based on human sequence numbering, may include K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294 of SEQ ID NO:1. Preferably, the anti-CD38 antibody or antigen-binding fragment thereof of the invention interacts with CD38 via a number of amino acid residues, and may include K121, F135, Q139, D141, M142, E239, W241, F274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294 of SEQ ID NO:2. Note that these residues are identical in both human and cynomolgus monkey, except for the exception that S274 is actually F274 in cynomolgus monkey. These residues may represent immunodominant epitopes and / or residues within the footprint of the specific antigen-binding peptide.

[0147] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof for use according to the present invention comprises a heavy chain comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4; HCDR2 AB79), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 AB79), or a variant of the sequence having a maximum of three amino acid changes. In some embodiments, the antibody or antigen-binding fragment thereof for use according to the present invention comprises a light chain comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 AB79), RDS (SEQ ID NO: 7; LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 AB79), or a variant of the sequence having a maximum of three amino acid changes. In some embodiments, the antibody or antigen-binding fragment thereof for use according to the present invention comprises a heavy chain comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4; HCDR2 AB79), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 AB79), or a variant of the sequence having a maximum of three amino acid changes, and a light chain comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 AB79), RDS (SEQ ID NO: 7; LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 AB79), or a variant of the sequence having a maximum of three amino acid changes. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof comprises a heavy chain comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4; HCDR2 AB79), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 AB79). In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 AB79), RDS (SEQ ID NO: 7; LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 AB79).In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4; HCDR2 AB79), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 AB79), and a light chain comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 AB79), RDS (SEQ ID NO: 7; LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 AB79). In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 9. Preferably, the VH chain comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence may have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the VH chain comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence may have at least 85% sequence identity to SEQ ID NO: 9. Preferably, the VH chain comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence may have at least 90% sequence identity to SEQ ID NO: 9. Preferably, the VH chain comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence may have at least 95% sequence identity to SEQ ID NO: 9. Preferably, the VH chain comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence may have at least 97% sequence identity to SEQ ID NO: 9. Preferably, the VH chain comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the sequence may have at least 99% sequence identity to SEQ ID NO: 9.

[0148] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the variable heavy (VH) chain amino acid sequence of SEQ ID NO: 9. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVSSASTKGPSVFPLA (SEQ ID NO: 9).

[0149] In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 10. Preferably, the VL chain comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the sequence may have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the VL chain comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the sequence may have at least 85% sequence identity to SEQ ID NO: 10. Preferably, the VL chain comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the sequence may have at least 90% sequence identity to SEQ ID NO: 10. Preferably, the VL chain comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the sequence may have at least 95% sequence identity to SEQ ID NO: 10. Preferably, the VL chain comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the sequence may have at least 97% sequence identity to SEQ ID NO: 10. Preferably, the VL chain comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the sequence may have at least 99% sequence identity to SEQ ID NO: 10.

[0150] In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain comprising the variable light (VL) chain amino acid sequence of SEQ ID NO: 10. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLFPPSSEEL (SEQ ID NO: 10).

[0151] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the VH chain amino acid sequence of SEQ ID NO: 9 described herein or a variant thereof, and a light chain comprising the VL chain amino acid sequence of SEQ ID NO: 10 described herein or a variant thereof.

[0152] As will be recognized by those of skill in the art, the variable heavy and variable light chains can be linked to human IgG constant domain sequences (generally IgG1, IgG2, or IgG4).

[0153] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 11. Preferably, the heavy chain comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain may have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the heavy chain comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain may have at least 85% sequence identity to SEQ ID NO: 11. Preferably, the heavy chain comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain may have at least 90% sequence identity to SEQ ID NO: 11. Preferably, the heavy chain comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain may have at least 95% sequence identity to SEQ ID NO: 11. Preferably, the heavy chain comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain may have at least 97% sequence identity to SEQ ID NO: 11. Preferably, the heavy chain comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain may have at least 99% sequence identity to SEQ ID NO: 11.

[0154] In some embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain (HC) amino acid sequence of SEQ ID NO: 11. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11).

[0155] In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 12. Preferably, the light chain comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain may have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the light chain comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain may have at least 85% sequence identity to SEQ ID NO: 12. Preferably, the light chain comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain may have at least 90% sequence identity to SEQ ID NO: 12. Preferably, the light chain comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain may have at least 95% sequence identity to SEQ ID NO: 12. Preferably, the light chain comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain may have at least 97% sequence identity to SEQ ID NO: 12. Preferably, the light chain comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain may have at least 99% sequence identity to SEQ ID NO: 12.

[0156] In some embodiments, the antibody or antigen-binding fragment thereof comprises the light chain (LC) amino acid sequence of SEQ ID NO: 12. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 12).

[0157] In some embodiments, the antibody or antigen-binding fragment thereof comprises the HC amino acid sequence of SEQ ID NO: 11 described herein or a variant thereof, and the LC amino acid sequence of SEQ ID NO: 12 described herein or a variant thereof.

[0158] The present invention encompasses antibodies or antigen-binding fragments thereof that bind to both human CD38 and cynomolgus CD38, and based on human numbering, interact with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the following amino acid residues: K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294 of SEQ ID NO: 1 and SEQ ID NO: 2. Preferably, the antibody or antigen-binding fragment thereof can interact with at least 90% of these amino acid residues. Preferably, the antibody or antigen-binding fragment thereof can interact with at least 95% of these amino acid residues. Preferably, the antibody or antigen-binding fragment thereof can interact with at least 97% of these amino acid residues. Preferably, the antibody or antigen-binding fragment thereof can interact with at least 98% of these amino acid residues. Preferably, the antibody or antigen-binding fragment thereof can interact with at least 99% of these amino acid residues. Preferably, the antibody or antigen-binding fragment thereof can interact with at least 14 (e.g., at least 15 or at least 16) of the following amino acids: K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294 of SEQ ID NO: 1 and SEQ ID NO: 2 based on human numbering.

[0159] In some embodiments, the antibody is full-length. As used herein, "full-length antibody" means the structure that constitutes the native biological form of an antibody, including variable and constant regions, including one or more modifications as outlined herein.

[0160] Alternatively, the antibody can have various structures and includes, but is not limited to, antibody fragments, antigen-binding fragments, monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimetics"), chimeric antibodies, humanized antibodies, antibody fusions (sometimes referred to as "antibody conjugates"), and fragments of each of these. Specific antibody fragments include: (i) Fab fragments consisting of VL, VH, CL, and CH1 domains; (ii) Fd fragments consisting of VH and CH1 domains; (iii) Fv fragments consisting of VL and VH domains of a single antibody; (iv) dAb fragments consisting of a single variable region (Ward et al. (1989) Nature 341:544-546); (v) isolated CDR regions; (vi) F(ab')2 fragments (bivalent fragments containing two linked Fab fragments); (vii) single-chain Fv molecules (scFv) in which the VH and VL domains are linked by a peptide linker that allows the two domains to associate to form an antigen-binding site (Bird et al. (1988) Science 242:423-426, Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883); (viii) bispecific single-chain Fv (WO03 / 11161); and (ix) "diabodies" or "triabodies" (multivalent or multispecific fragments constructed by gene fusion) (Tomlinson et al. (2000) Methods Enzymol. 326:461-479; WO94 / 13804; Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448), but are not limited to these.

[0161] Preferably, the antibody can be a Fab fragment. Preferably, the antibody can be an Fv fragment. Preferably, the antibody can be an Fd fragment. Preferably, the antibody structure can be an isolated CDR region. Preferably, the antibody can be an F(ab')2 fragment. Preferably, the antibody can be an scFv fragment.

[0162] In some embodiments, the antibody or an antibody fragment thereof, or an antigen-binding fragment thereof, does not cause a significant level of erythrocyte depletion and / or platelet depletion on days 1, 2, 4, 8, 10, 15, 20, 25, and / or 30 after administration.

[0163] The term "significant level of cell depletion" can relate to a level of cell depletion that has a detrimental outcome for the subject.

[0164] In some embodiments, the antibody or an antigen-binding fragment thereof does not cause a significant level of erythrocyte depletion and / or platelet depletion on day 1 after administration.

[0165] In some embodiments, the antibody or an antigen-binding fragment thereof does not cause a significant level of erythrocyte depletion and / or platelet depletion on day 2 after administration.

[0166] In some embodiments, the antibody or an antigen-binding fragment thereof does not cause a significant level of erythrocyte depletion and / or platelet depletion on day 4 after administration.

[0167] In some embodiments, the antibody or an antigen-binding fragment thereof does not cause a significant level of erythrocyte depletion and / or platelet depletion on day 8 after administration.

[0168] In some embodiments, the antibody or an antigen-binding fragment thereof does not cause a significant level of erythrocyte depletion and / or platelet depletion on day 10 after administration.

[0169] In some embodiments, the antibody or an antigen-binding fragment thereof does not cause a significant level of erythrocyte depletion and / or platelet depletion on day 15 after administration.

[0170] In some embodiments, the antibody or an antigen-binding fragment thereof does not cause a significant level of erythrocyte depletion and / or platelet depletion on day 20 after administration.

[0171] In some embodiments, the antibody or antigen-binding fragment thereof does not cause significant levels of erythrocyte depletion and / or platelet depletion 25 days after administration.

[0172] In some embodiments, the antibody or antigen-binding fragment thereof does not cause significant levels of erythrocyte depletion and / or platelet depletion 30 days after administration.

[0173] Preferably, the antibody or antigen-binding fragment thereof for use according to the invention may result in less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% depletion of RBCs after treatment. Preferably, the antibody or antigen-binding fragment thereof for use according to the invention may result in less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% depletion of platelets after treatment.

[0174] Antibody modification The present invention further provides variant anti-CD38 antibodies or antigen-binding fragments thereof. That is, there are a number of modifications made to the antibodies or antigen-binding fragments thereof of the present invention, including but not limited to amino acid modifications (affinity maturation) in the CDRs, amino acid modifications in the Fc region, glycan addition variants, other types of covalent modifications, and the like.

[0175] The term "variant" means a polypeptide that is different from that of the parent polypeptide. Amino acid variants can include amino acid substitutions, insertions, and deletions. Generally, as described herein, a variant can include any number of modifications as long as the function of the protein still exists. That is, in the case of amino acid variants generated in the CDRs of AB79, for example, an antibody or antigen-binding fragment, or an antibody variant thereof, should still specifically bind to both human CD38 and cynomolgus CD38. The term "variant Fc region" means an Fc sequence that is different from that of the wild-type or parent Fc sequence by at least one amino acid modification. An Fc variant can refer to the Fc polypeptide itself, a composition comprising the Fc variant polypeptide, or an amino acid sequence. If an amino acid variant is generated in the Fc region, for example, a variant antibody should maintain the functions required for a particular application or indication of the antibody. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions (e.g., substitutions of 1-10, 1-5, 1-4, 1-3, and 1-2) can be utilized. Suitable modifications can be made at one or more positions, as generally outlined in, for example, U.S. Patent Publication No. 2004013210; as well as U.S. Patents Nos. 6,086,875; 6,737,056; 7,317,091; 7,670,600; 8,084,582; 8,188,231; 8,367,805; and 8,937,158 (all of which are hereby expressly incorporated herein by reference in their entirety), and particularly for specific amino acid substitutions that increase binding to Fc receptors.

[0176] Preferably, the antibody variant or its antigen-binding fragment maintains the function of the parent sequence, i.e., the variant or fragment is a functional variant or fragment. Preferably, the antibody variant comprising the variant sequence maintains the function of the parent antibody, i.e., the antibody comprising the variant sequence or its antigen-binding fragment is capable of binding to human CD38 and / or cynomolgus CD38. Preferably, treatment with the variant or fragment can result in depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% of RBCs. Preferably, treatment with the variant or fragment can result in depletion of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% of platelets.

[0177] Variants can be considered with respect to similarity (i.e., amino acid residues having similar chemical properties / functions), and preferably variants are expressed with respect to sequence identity.

[0178] Sequence comparisons can be carried out with the aid of readily available sequence comparison programs or usually by visual inspection. These publicly and commercially available computer programs can calculate the sequence identity between two or more sequences.

[0179] It may be desired to have 1 to 5 modifications in the Fc region of a wild-type protein or a modified protein, and for example 1 to 5 modifications in the Fv region. The variant polypeptide sequence will preferably retain at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the parent sequence (e.g., the variable region, constant region, and / or heavy chain and light chain sequences for AB79). Preferably, the variant can have at least 80% sequence identity to the parent sequence. Preferably, the variant can have at least 85% sequence identity to the parent sequence. Preferably, the variant can have at least 90% sequence identity to the parent sequence. Preferably, the variant can have at least 92% sequence identity to the parent sequence. Preferably, the variant can have at least 95% sequence identity to the parent sequence. Preferably, the variant can have at least 97% sequence identity to the parent sequence. Preferably, the variant can have at least 98% sequence identity to the parent sequence. Preferably, the variant can have at least 99% sequence identity to the parent sequence.

[0180] In one embodiment, sequence identity is determined over the entire length of the sequence. In one embodiment, sequence identity is determined over the entire length of the candidate sequence as compared to the sequences recited herein.

[0181] Inhibition of CD38 activity and reduction of side effects The disclosed anti-CD38 antibodies or antigen-binding fragments thereof can inhibit cell proliferation. The term "inhibit proliferation" refers to any measurable decrease in cell proliferation, e.g., inhibition of cell culture proliferation by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100%, as compared to the proliferation of the same cells not contacted with the anti-CD38 antibody when contacted with the anti-CD38 antibody. Preferably, the inhibition of proliferation can be at least about 70%. Preferably, the inhibition of proliferation can be at least about 80%. Preferably, the inhibition of proliferation can be at least about 90%.

[0182] In some embodiments, the disclosed anti-CD38 antibody or antigen-binding fragment thereof can deplete activated lymphocytes and plasma cells. The term "depletion" in this context means a measurable decrease in the serum levels of activated lymphocytes and / or plasma cells in a subject as compared to an untreated subject. Generally, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100% depletion is observed. Preferably, the depletion can be at least 50%. Preferably, the depletion can be at least 60%. Preferably, the depletion can be at least 70%. Preferably, the depletion can be at least 80%. Preferably, the depletion can be at least 90%. Preferably, the depletion can be 100%. As shown below in the Examples, one particular advantage exhibited by the antibodies or antigen-binding fragments thereof of the present invention is the recoverability of these cells after dosing. That is, as is known for some treatments (such as by anti-CD20 antibodies), cell depletion can persist for extended periods and cause unwanted side effects. As shown herein, the effects on activated lymphocytes and / or plasma cells are recoverable.

[0183] The anti-CD38 antibodies or antigen-binding fragments thereof of the present invention allow for reduced side effects as compared to prior art anti-CD38 antibodies. In some embodiments, the antibodies or antigen-binding fragments thereof (e.g., AB79) for use according to the present invention do not induce TEAE. In some embodiments, the antibodies or antigen-binding fragments thereof (e.g., AB79) for use according to the present invention allow for a reduction in the incidence of TEAE in the patient population as compared to other anti-CD38 antibodies (such as MOR202, etc.). TEAE are typically referenced by Grades 1, 2, 3, 4, and 5, where Grade 1 is the lowest severity and Grade 5 is the highest severity of TEAE. Based on the FDA and other guidelines for the Common Terminology Criteria for Adverse Events (CTCAE) criteria for oncology drugs (e.g., see https: / / evs.nci.nih.gov / ftp1 / CTCAE / CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf; and https: / / ctep.cancer.gov / protocoldevelopment / electronic_applications / ctc.htm; and Nilsson and Koke (2001) Drug Inform. J. 35:1289-1299), the following is generally how such grades are determined. Grade 1 is mild, with no symptoms or mild symptoms; only clinical or diagnostic findings; no intervention is indicated. Grade 2 is moderate, with at least minimal, local, or non-invasive intervention indicated; activities of daily living (「ADL」) other than age-appropriate self-care are restricted. Grade 3 is severe or medically important but not immediately life-threatening, with hospitalization or extended hospitalization indicated; immobility; self-care activities of daily living are restricted. Grade 4 is a life-threatening prognosis, with urgent intervention indicated. Grade 5 is death related to the AE.

[0184] In some embodiments, the antibody or antigen-binding fragment thereof (e.g., AB79) for use according to the present invention enables a reduction in the grade of TEAE in a patient population as compared to other anti-CD38 antibodies (such as MOR202). In some embodiments, the antibody or antigen-binding fragment thereof (e.g., AB79) for use according to the present invention enables a reduction in the grade of TEAE from grade 5 to grade 4 as compared to other anti-CD38 antibodies (such as MOR202). In some embodiments, the antibody or antigen-binding fragment thereof (e.g., AB79) for use according to the present invention enables a reduction in the grade of TEAE from grade 4 to grade 3 as compared to other anti-CD38 antibodies (such as MOR202). In some embodiments, the antibody or antigen-binding fragment thereof (e.g., AB79) for use according to the present invention enables a reduction in the grade of TEAE from grade 3 to grade 2 as compared to other anti-CD38 antibodies (such as MOR202). In some embodiments, the antibody or antigen-binding fragment thereof (e.g., AB79) for use according to the present invention enables a reduction in the grade of TEAE from grade 2 to grade 1 as compared to other anti-CD38 antibodies (such as MOR202).

[0185] In some embodiments, the antibody or antigen-binding fragment thereof (e.g., AB79) for use according to the present invention enables a reduction in the grade of one or more TEAEs selected from the group consisting of anemia (including hemolytic anemia), thrombocytopenia, fatigue, infusion-related reaction (IRR), leukopenia, lymphopenia, and nausea. In some embodiments, the antibody or antigen-binding fragment thereof (e.g., AB79) for use according to the present invention enables a reduction in the occurrence of one or more TEAEs selected from the group consisting of anemia (including hemolytic anemia), thrombocytopenia, fatigue, infusion-related reaction (IRR), leukopenia, lymphopenia, and nausea.

[0186] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof results in depletion of less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of RBCs. In some embodiments, the AB79 antibody results in depletion of less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of RBCs. In some embodiments, the AB79 antibody or antigen-binding fragment thereof results in depletion of less than 10% of RBCs.

[0187] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof results in depletion of less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of platelets. In some embodiments, the AB79 antibody or antigen-binding fragment thereof results in depletion of less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of platelets. In some embodiments, the AB79 antibody or antigen-binding fragment thereof results in depletion of less than 10% of platelets.

[0188] In some embodiments, diagnostic tests are used to determine the presence and / or grade of anemia (including hemolytic anemia). Diagnostic tests for anemia (including hemolytic anemia) include measuring hemoglobin levels. Generally, hemoglobin levels are interpreted as follows. (i) Very mild anemia / no anemia: ≥ 12.0 g / dL, (ii) Mild: 10 - 12 g / dL, (iii) Moderate: 8 - 10 g / dL, (iv) Severe: 6 - 8 g / dL, and (v) Very severe: ≤ 6 g / dL. Other diagnostic tests for anemia (including hemolytic anemia) include measuring haptoglobin levels. Generally, a haptoglobin value ≤ 25 mg / dL indicates the presence of anemia (including hemolytic anemia). Other diagnostic tests include the direct antiglobulin test (DAT) (also referred to as the direct Coombs test), which is used to determine whether RBCs are coated in vivo with immunoglobulins, complement, or both.

[0189] In some embodiments, diagnostic tests are used to determine the presence and / or grade of thrombocytopenia. Generally, diagnostic tests for thrombocytopenia include measuring the number of platelets per microliter (μL) of blood. Normally, there are 150×10 3 ~450×10 3 platelets per μL of blood. Generally, thrombocytopenia is diagnosed when there are < 150×10 3 platelets per μL of blood. If there are 70 - 150×10 3 per μL of blood, it is generally diagnosed as mild thrombocytopenia. If there are 20 - 70×10 3 per μL, it is generally diagnosed as moderate thrombocytopenia. If there are < 20×10 3 per μL of blood, it is generally diagnosed as severe thrombocytopenia.

[0190] Disease indications The antibodies, methods, and dosage units of the present invention find use in a variety of applications, including the treatment or alleviation of CD38-related diseases. The therapeutic anti-CD38 antibodies or antigen-binding fragments thereof of the present invention bind to CD38-positive cells and result in the depletion of these cells via multiple mechanisms of action, including both the CDC pathway and the ADCC pathway.

[0191] It is known in the art that certain pathologies are associated with cells expressing CD38, and that certain pathologies are associated with overexpression, high-density expression, or upregulated expression of CD38 on the surface of cells. Whether a cell population expresses CD38 can generally be determined by methods known in the art (e.g., flow cytometry determination of the percentage of cells in a given population labeled with an antibody that specifically binds CD38, or immunohistochemical assays) as described below for diagnostic applications. For example, a cell population in which CD38 expression is detected in about 10-30% of the cells is considered to have a weak positive for CD38, and a cell population in which CD38 expression is detected in more than about 30% of the cells can be considered a defined positive for CD38 (Jackson et al. (1988) Clin. Exp. Immunol. 72:351-356), although other criteria can be used to determine whether a cell population expresses CD38. The density of expression on the surface of cells can be determined using methods known in the art (e.g., flow cytometry measurement of the mean fluorescence intensity of fluorescently labeled cells using an antibody that specifically binds CD38, etc.).

[0192] In one aspect, the present invention provides a method for treating a condition associated with the proliferation of cells expressing CD38, comprising administering to a patient a pharmaceutically effective amount of the disclosed antibody or antigen-binding fragment thereof in combination with (a) lenalidomide, (b) lenalidomide and bortezomib, or (c) pomalidomide. In some embodiments, the condition is cancer, and in certain embodiments, the cancer is a blood cancer. In some embodiments, the condition is multiple myeloma, chronic lymphocytic leukemia, chronic lymphocytic leukemia, plasmacytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, or Burkitt lymphoma. In a particular embodiment, the condition is multiple myeloma.

[0193] In some embodiments of the present invention, the blood cancer is selected from the group consisting of chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, and acute lymphocytic leukemia. In some embodiments of the present invention, the blood cancer is chronic lymphocytic leukemia. In some embodiments of the present invention, the blood cancer is chronic myeloid leukemia. In some embodiments of the present invention, the blood cancer is acute myeloid leukemia. In some embodiments of the present invention, the blood cancer is acute lymphocytic leukemia.

[0194] In some embodiments, the condition is multiple myeloma.

[0195] Multiple myeloma (MM) Multiple myeloma (MM) is a malignant disease of the B-cell lineage characterized by neoplastic clonal expansion of plasma cells in the bone marrow. Pharmacological findings in healthy volunteers have supported further investigation in MM (Fedyk et al. (2018) Blood 132:3249, which is hereby incorporated by reference in its entirety). The clonal expansion of myeloma cells causes various effects, including lytic lesions (holes) in the bone, decreased red blood cell count, production of abnormal proteins (due to damage associated with the kidneys, nerves, and other organs), reduced immune system function, and elevated blood calcium levels (hypercalcemia). Currently, treatment options include chemotherapy, preferably accompanied by autologous stem cell transplantation (ASCT) when possible. These treatment regimens show moderate efficacy. However, only a slight change in overall survival is observed, and the median survival is approximately 3 years. Therefore, there is an important unmet medical need for the treatment of multiple myeloma. In some embodiments, methods of treating multiple myeloma using the disclosed antibodies or antigen-binding fragments thereof are provided.

[0196] Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic pre-malignant diseases characterized by the absence of clonal expansion of monoclonal plasma cells in the bone marrow and end-organ damage.

[0197] Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell proliferative disorder with a high risk of progression to symptomatic or active multiple myeloma (Kyle et al. (2007) N. Engl. J. Med. 356(25):2582-2590). The international consensus criteria defining SMM were adopted in 2003 and require that the patient's M protein level be >30 g / L and / or the bone marrow clonal plasma cells be >10% (Internat. Myeloma Working Group (2003) Br. J. Haematol. 121:749-757). The patient must not have organ or related tissue dysfunction (such as bone lesions or symptoms). Recent studies have identified two subsets of SMM: i) patients with progressive disease and ii) patients with non-progressive disease (Internat. Myeloma Working Group (2003) Br. J. Haematol. 121:749-757).

[0198] Since there is no end-organ damage, SMM resembles monoclonal gammopathy of undetermined significance (MGUS) (Kyle et al. (2007) N. Engl. J. Med. 356(25):2582-2590). Clinically, however, SMM is much more likely to progress to active multiple myeloma or amyloidosis in 20 years (78% probability for SMM vs. 21% probability for MGUS) (Kyle et al. (2007) N. Engl. J. Med. 356(25):2582-2590).

[0199] The international consensus criteria defining MGUS require that the patient's M protein level be <30 g / L, the bone marrow plasma cells be <10%, and there be no organ or related tissue dysfunction (including bone lesions or symptoms) (Internat. Myeloma Working Group (2003) Br. J. Haematol. 121:749-757).

[0200] Systemic light chain amyloidosis Amyloidosis refers to a family of protein misfolding diseases in which different types of proteins aggregate as extracellular insoluble fibers. These are complex, multi-systemic diseases. A common type of systemic amyloidosis is systemic light chain (AL) amyloidosis (Gertz et al. (2004) Am. Soc. Hematol. 2004:257-82). Similar to multiple myeloma, AL amyloidosis is a plasma cell neoplasm. AL amyloidosis is a rare, progressive, and fatal disease in older adults caused by a small clonal population of plasma cells in the bone marrow that produce excessive amounts of free light chains of monoclonal immunoglobulins. Once in circulation, these pathologic light chains misfold and aggregate as fibrous material and deposit in the viscera. The deposits of amyloid fibers are the same free light chain proteins secreted by the clonal plasma cells (Cohen and Comenzo (2010) Am. J. Hematol. 2010:287-94; Merlini and Bellotti (2003) New England J. Med. 349(6):583-96; Murray et al. (2010) Blood (ASH Annual Meeting Abstracts) 116(21):abstr 1909). End-organ damage and ultimately death are caused as a result of this amyloid fiber deposition. Treatment methods that suppress clonal plasma cells can remit the AL amyloidosis disease by removing the source that produces the circulating toxic free light chains, which can then improve organ function and survival. There is no regulatory-approved treatment for systemic AL amyloidosis. The drugs used are those used in the treatment of multiple myeloma. Therefore, there is an important unmet medical need for the treatment of patients with AL amyloidosis, and targeting CD38 on plasma cells is a meaningful treatment strategy.

[0201] The use of the antibody or antigen-binding fragment thereof in the diagnosis and / or treatment of a number of diseases, including but not limited to autoimmune diseases (such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ulcerative colitis, systemic light chain amyloidosis, and graft-versus-host disease). In one aspect, the disease is systemic lupus erythematosus (SLE). In one aspect, the disease is rheumatoid arthritis (RA). In one aspect, the disease is inflammatory bowel disease (IBD). In one aspect, the disease is ulcerative colitis. In one aspect, the disease is graft-versus-host disease. In one aspect, the disease is systemic light chain amyloidosis.

[0202] Thus, for example, patients with a high content of plasma cells (SLE patients showing high levels of plasma cells, RA patients shown to be unresponsive to CD20-based therapies, etc.) can be treated.

[0203] Antibody composition for in vivo administration The formulation of the antibody or antigen-binding fragment thereof used according to the present invention is prepared in the form of a lyophilized formulation or an aqueous solution for storage by mixing an antibody or antigen-binding fragment thereof having the desired purity with an optional pharmaceutically acceptable carrier, excipient, or stabilizing substance (Remington’s Pharmaceutical Sciences 16th edition (1980) Osol, A. Ed.).

[0204] The formulations herein may also contain two or more active compounds, preferably those having complementary activities that do not adversely affect each other, as required for the particular indication being treated. For example, it may be desirable to provide other specificities to the antibody or antigen-binding fragment thereof. Alternatively or additionally, the composition may contain cytotoxic agents, cytokines, growth inhibitors, and / or small molecule antagonists. Such molecules are preferably present in combination in an amount effective for the intended purpose.

[0205] Subcutaneous administration The anti-CD38 antibodies or antigen-binding fragments thereof (such as AB79) described herein can be administered at therapeutically effective and sufficient dosages, thereby enabling subcutaneous administration. Subcutaneous administration is the least invasive mode of administration and is the most versatile and thus the desired mode of administration that can be used for both short-term and long-term treatment regimens. In some embodiments, subcutaneous administration can be accomplished by injection. In some embodiments, when multiple injections or devices are required, the site of injection or device can be rotated.

[0206] Thus, particularly since the formulation must be taken regularly throughout the patient's lifetime (e.g., starting as early as the first year of life in children), subcutaneous formulations are much easier for the patient to self-administer. Additionally, the ease and speed of subcutaneous delivery allow for increased patient compliance and more rapid access to the medicament when needed. Thus, the subcutaneous formulations of the anti-CD38 antibodies or antigen-binding fragments thereof provided herein offer a significant advantage over the prior art and address certain unmet needs.

[0207] In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention are administered to a subject according to known methods via the subcutaneous route. In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention can be administered by subcutaneous injection. In a specific embodiment, the subcutaneous formulation is subcutaneously injected into the same site of the patient (e.g., administered to the upper arm, the front of the thigh, the lower part of the abdomen, or the upper back) for repeated or continuous injection. In other embodiments, the subcutaneous formulation is subcutaneously injected into different sites or rotation sites of the patient. Single or multiple administrations of the formulation can be used.

[0208] In some embodiments, the subcutaneous unit dosage forms described herein can be used for the treatment of cancer. In some embodiments, the subcutaneous unit dosage forms described herein can be used for the treatment of blood cancer. In some embodiments, the subcutaneous unit dosage forms described herein can be used for the treatment of multiple myeloma.

[0209] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention has an increased bioavailability as compared to prior art antibodies. In some embodiments, the bioavailability of the antibody or antigen-binding fragment thereof of the present invention is increased by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or more as compared to prior art antibodies that bind to human RBCs. In some embodiments, the bioavailability of the antibody or antigen-binding fragment thereof of the present invention is 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, or 300% or more as compared to prior art antibodies that bind to human RBCs. Preferably, the bioavailability can be increased by 50%. Preferably, the bioavailability can be increased by 60%. Preferably, the bioavailability can be increased by 70%. Preferably, the bioavailability can be increased by 80%. Preferably, the bioavailability can be increased by 90%.

[0210] In some embodiments, the increased bioavailability enables subcutaneous administration.

[0211] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention induces depletion of NK cells, B cells, and / or T cells. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention enables an increase in depletion of NK cells as compared to depletion of B cells or T cells. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention enables an increase in depletion of NK cells as compared to B cells and an increase in depletion of NK cells as compared to T cells. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention enables an increase in depletion of NK cells as compared to B cells and an increase in depletion of B cells as compared to T cells. In some embodiments, the antibody or antigen-binding fragment thereof of the present invention enables an increase in depletion of NK cells as compared to B cells and an increase in depletion of B cells as compared to T cells. Preferably, the antibody or antigen-binding fragment thereof of the present invention is CD38 - cells as compared to CD38 + cells may enable an increase in depletion.

[0212] In certain embodiments, the bioavailability of the anti-CD38 antibodies or antigen-binding fragments thereof described herein after subcutaneous administration is between at least 50% and at least 80% compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies or antigen-binding fragments thereof described herein after subcutaneous administration is between at least 60% and at least 80% compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies or antigen-binding fragments thereof described herein after subcutaneous administration is between at least 50% and 70% compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies or antigen-binding fragments thereof described herein after subcutaneous administration is between at least 55% and 65% compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies or antigen-binding fragments thereof described herein after subcutaneous administration is between at least 55% and 70% compared to intravenous administration normalized for the same dose.

[0213] In certain embodiments, the bioavailability of the anti-CD38 antibody or antigen-binding fragment thereof described herein after subcutaneous administration is at least 40%, at least 45%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, or at least 85% compared to intravenous administration normalized for the same dose. Preferably, the bioavailability can be at least 50% compared to intravenous administration normalized for the same dose. Preferably, the bioavailability can be at least 60% compared to intravenous administration normalized for the same dose. Preferably, the bioavailability can be at least 70% compared to intravenous administration normalized for the same dose. Preferably, the bioavailability can be at least 80% compared to intravenous administration normalized for the same dose. Preferably, the bioavailability can be at least 90% compared to intravenous administration normalized for the same dose.

[0214] In some embodiments, the disclosure provides a method wherein the bioavailability of the antibody or antigen-binding fragment thereof of the invention after subcutaneous administration is 50% - 80% compared to intravenous administration normalized for the same dose.

[0215] In some embodiments, the disclosure provides a method wherein the bioavailability of the antibody or antigen-binding fragment thereof of the invention after subcutaneous administration is at least 50% compared to intravenous administration normalized for the same dose.

[0216] In some embodiments, the present disclosure provides a method in which the bioavailability of an antibody of the invention or an antigen-binding fragment thereof after subcutaneous administration is at least 55% compared to intravenous administration normalized for the same dose.

[0217] In some embodiments, the present disclosure provides a method in which the bioavailability of an antibody of the invention or an antigen-binding fragment thereof after subcutaneous administration is at least 60% compared to intravenous administration normalized for the same dose.

[0218] In some embodiments, the present disclosure provides a method in which the bioavailability of an antibody of the invention or an antigen-binding fragment thereof after subcutaneous administration is at least 65% compared to intravenous administration normalized for the same dose.

[0219] In some embodiments, the present disclosure provides a method in which the bioavailability of an antibody of the invention or an antigen-binding fragment thereof after subcutaneous administration is at least 70% compared to intravenous administration normalized for the same dose.

[0220] In some embodiments, the present disclosure provides a method in which the bioavailability of an antibody of the invention or an antigen-binding fragment thereof after subcutaneous administration is at least 75% compared to intravenous administration normalized for the same dose.

[0221] In some embodiments, the present disclosure provides a method in which the bioavailability of an antibody of the invention or an antigen-binding fragment thereof after subcutaneous administration is at least 80% compared to intravenous administration normalized for the same dose.

[0222] In some embodiments, the present disclosure provides a unit dosage form comprising an anti-CD38 antibody or an antigen-binding fragment thereof described herein, wherein the anti-CD38 antibody results in less than 10% depletion of RBCs.

[0223] In some embodiments, the present disclosure provides a unit dosage form comprising an anti-CD38 antibody or antigen-binding fragment thereof described herein, wherein the anti-CD38 antibody results in less than 10% platelet depletion.

[0224] In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered subcutaneously as a single bolus injection. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered subcutaneously monthly. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered subcutaneously every two weeks. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered subcutaneously weekly. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered subcutaneously twice a week. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered subcutaneously daily. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered subcutaneously every 12 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered subcutaneously every 8 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered subcutaneously every 6 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered subcutaneously every 4 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered subcutaneously every 2 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is administered subcutaneously hourly.

[0225] In some embodiments, the therapeutic anti-CD38 antibody or antigen-binding fragment thereof is formulated as part of a unit dosage form. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof comprises a heavy chain comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4; HCDR2 AB79), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 AB79), or a variant of the sequence having up to three amino acid changes. In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 AB79), RDS (SEQ ID NO: 7; LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 AB79), or a variant of the sequence having up to three amino acid changes. In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4; HCDR2 AB79), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 AB79), or a variant of the sequence having up to three amino acid changes, and a light chain comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 AB79), RDS (SEQ ID NO: 7; LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 AB79), or a variant of the sequence having up to three amino acid changes. In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4; HCDR2 AB79), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 AB79). In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 AB79), RDS (SEQ ID NO: 7; LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 AB79).In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4; HCDR2 AB79), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 AB79), and a light chain having the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 AB79), RDS (SEQ ID NO: 7; LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 AB79). In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 9. Preferably, the heavy chain comprises the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 AB79), ISWNGGKT (SEQ ID NO: 4; HCDR2 AB79), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 AB79), and the remainder of the heavy chain may have at least 80% sequence identity to SEQ ID NO: 9. In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the variable heavy (VH) chain amino acid sequence of SEQ ID NO: 9. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVSSASTKGPSVFPLA (SEQ ID NO: 9).

[0226] In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 10. Preferably, the light chain comprises the following CDR sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 AB79), RDS (SEQ ID NO: 7; LCDR2 AB79), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 AB79), and the remainder of the light chain may have at least 80% sequence identity to SEQ ID NO: 10. In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain comprising the variable light (VL) chain amino acid sequence of SEQ ID NO: 10. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLFPPSSEEL (SEQ ID NO: 10).

[0227] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the VH region amino acid sequence of SEQ ID NO: 9 described herein or a variant thereof, and a light chain comprising the VL region amino acid sequence of SEQ ID NO: 10 described herein or a variant thereof.

[0228] As will be recognized by those skilled in the art, the variable heavy and variable light chains can be linked to human IgG constant domain sequences (generally IgG1, IgG2, or IgG4). In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain (HC) having an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 11. Preferably, the heavy chain comprises the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the heavy chain can have at least 80% sequence identity to SEQ ID NO: 11. In some embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain (HC) amino acid sequence of SEQ ID NO: 11. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO: 11).

[0229] In some embodiments, the antibody or antigen-binding fragment thereof comprises a light chain (LC) having an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 12. Preferably, the light chain comprises the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and the remainder of the light chain may have at least 80% sequence identity to SEQ ID NO: 12. In some embodiments, the antibody or antigen-binding fragment thereof comprises the light chain (LC) amino acid sequence of SEQ ID NO: 12. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS(SEQ ID NO: 12).

[0230] In some embodiments, the antibody or antigen-binding fragment thereof comprises the HC amino acid sequence of SEQ ID NO: 11 described herein or a variant thereof, and the LC amino acid sequence of SEQ ID NO: 12 described herein or a variant thereof.

[0231] In some embodiments, a formulation comprising an anti-CD38 antibody or antigen-binding fragment thereof is in unit dosage form. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 45 mg to about 1,800 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 45 mg to about 300 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 135 mg to about 1,800 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 135 mg to about 300 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 600 mg to about 1,800 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 1200 mg to about 1,800 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 45 mg to about 1,200 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 135 mg to about 1,200 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 300 mg to about 600 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 600 mg to about 1,200 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 600 mg to about 1,200 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 45 mg to about 135 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 45 mg to about 600 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 135 mg to about 600 mg.

[0232] In some embodiments, the dosage is in mg per kilogram body weight. In some embodiments, the dosage is a daily dosage. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 300 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage of about 600 mg.

[0233] In some embodiments, the unit dosage form of the anti-CD38 antibody or antigen-binding fragment thereof provided herein may further comprise one or more pharmaceutically acceptable excipients, carriers, and / or diluent substances. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is provided as a pharmaceutical composition comprising a unit dosage form according to the invention. Preferably, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients, carriers, and / or diluent substances.

[0234] The dosing regimen is adjusted to provide the optimal desired response (e.g., therapeutic response). For example, a single bolus can be administered, multiple divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the requirements of the treatment situation. The composition can be formulated in unit dosage forms for ease of administration and uniformity of dosage. As used herein, unit dosage forms refer, in some embodiments, to physically discrete units suitable as a single dosage for the subject to be treated, each unit containing a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0235] The specifications for the unit dosage forms of the present invention are determined by and directly depend on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the unique limitations in the art with respect to the formulation of such active compounds for the treatment of individuals.

[0236] The effective dosage and dosage regimen for the anti-CD38 antibody or antigen-binding fragment thereof used in the present invention depend on the type and severity of the disease or condition being treated and can be determined by those skilled in the art.

[0237] In one embodiment, the therapeutic antibody or antigen-binding fragment thereof is formulated at a concentration of 100 mg / ml. In some embodiments, volumes of 1.75 mL, 2.0 mL, 2.25 mL, or 2.5 mL are injected into the thigh, abdomen, or mid-upper arm. In some embodiments, volumes of 1.75 mL, 2.0 mL, 2.25 mL, or 2.5 mL are injected into the thigh or abdomen. In some embodiments, a volume of 2.25 mL is injected into the thigh or abdomen. In some embodiments, the dose is administered over a period of 4, 6, 8, or 10 hours. In some embodiments, the dose is administered over an 8-hour period. In some embodiments, 2, 4, 6, or 8 doses are administered. In some embodiments, 2 doses are administered. In some embodiments, 4 doses are administered. In some embodiments, 6 doses are administered. In some embodiments, 8 doses are administered. In some embodiments, the dose is administered every 2 hours.

[0238] In a further embodiment, the anti-CD38 antibody or antigen-binding fragment thereof is administered once every two weeks for 2 to 12 weeks. Preferably, the antibody or antigen-binding fragment thereof can be administered once every two weeks for, for example, 3 to 10 weeks. Preferably, the antibody or antigen-binding fragment thereof can be administered once every two weeks for, for example, 4 to 8 weeks. Preferably, the antibody or antigen-binding fragment thereof can be administered once every two weeks for, for example, 5 to 7 weeks.

[0239] In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof is administered subcutaneously at a frequency that changes over time. Preferably, the antibody or antigen-binding fragment thereof is administered once a week for 8 weeks, then once every 2 weeks for 16 weeks, and then once every 4 weeks in a 28-day treatment cycle until unacceptable toxicity is observed or the subject drops out for other reasons.

[0240] In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof is administered by maintenance therapy once a week for a period of, for example, 6 months or longer.

[0241] In one embodiment, the present disclosure provides a unit dosage form comprising the anti-CD38 antibody or antigen-binding fragment thereof described herein, wherein the anti-CD38 antibody results in less than 10% depletion of RBCs.

[0242] In one embodiment, the present disclosure provides a unit dosage form comprising an anti-CD38 antibody or antigen-binding fragment thereof, (a) lenalidomide, (b) lenalidomide and bortezomib, or (c) pomalidomide as described herein, wherein the anti-CD38 antibody or antigen-binding fragment thereof results in less than 10% depletion of platelets when used in combination with (a) lenalidomide, (b) lenalidomide and bortezomib, or (c) pomalidomide.

[0243] In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide and dexamethasone over the course of a 28-day treatment cycle of 1 to 8. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide and dexamethasone over the course of one 28-day treatment cycle. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide and dexamethasone over the course of two 28-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide and dexamethasone over the course of three 28-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide and dexamethasone over the course of four 28-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide and dexamethasone over the course of five 28-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide and dexamethasone over the course of six 28-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide and dexamethasone over the course of seven 28-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide and dexamethasone over the course of eight 28-day treatment cycles.

[0244] In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof is administered on days 1, 8, 15, and 22 of the first two treatment cycles, days 1 and 15 of the subsequent four treatment cycles, and day 1 of any additional treatment cycles; b) lenalidomide is administered on days 1 to 21 of each treatment cycle; c) dexamethasone is administered on days 1, 8, 15, and 22 of each of the first 8 treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of one treatment cycle. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of two treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of three treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of four treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of five treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of six treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of seven treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of eight treatment cycles.

[0245] In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide, dexamethasone, and bortezomib over the course of 1 to 8 twenty-eight-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide, dexamethasone, and bortezomib over the course of one twenty-eight-day treatment cycle. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide, dexamethasone, and bortezomib over the course of two twenty-eight-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide, dexamethasone, and bortezomib over the course of three twenty-eight-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide, dexamethasone, and bortezomib over the course of four twenty-eight-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide, dexamethasone, and bortezomib over the course of five twenty-eight-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide, dexamethasone, and bortezomib over the course of six twenty-eight-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide, dexamethasone, and bortezomib over the course of seven twenty-eight-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with lenalidomide, dexamethasone, and bortezomib over the course of eight twenty-eight-day treatment cycles.

[0246] In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof is administered on days 1, 8, 15, and 22 of the first two treatment cycles, on days 1 and 15 of the subsequent four treatment cycles, and on day 1 of any additional treatment cycles; b) lenalidomide is administered on days 1 to 21 of each treatment cycle; c) dexamethasone is administered on days 1, 8, 15, and 22 of each of the first 1 to 8 treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of each of the first 1 to 8 treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of one treatment cycle, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of two treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of three treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of four treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of five treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of six treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of seven treatment cycles, and one treatment cycle is 28 days. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of eight treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of 1, 2, 3, 4, 5, 6, 7, or 8 treatment cycles, and one treatment cycle is 28 days.In one embodiment, bortezomib is administered on days 1, 8, and 15 of one treatment cycle, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of two treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of three treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of four treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of five treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of six treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of seven treatment cycles, and one treatment cycle is 28 days. In one embodiment, bortezomib is administered on days 1, 8, and 15 of each of eight treatment cycles, and one treatment cycle is 28 days. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of one treatment cycle; d) bortezomib is administered on days 1, 8, and 15 of one treatment cycle, and one treatment cycle is 28 days. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of two treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of two treatment cycles, and one treatment cycle is 28 days. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of three treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of three treatment cycles, and one treatment cycle is 28 days. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of four treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of four treatment cycles, and one treatment cycle is 28 days.In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of five treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of five treatment cycles, and one treatment cycle is 28 days long. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of six treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of six treatment cycles, and one treatment cycle is 28 days long. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of seven treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of seven treatment cycles, and one treatment cycle is 28 days long. In one embodiment, c) dexamethasone is administered on days 1, 8, 15, and 22 of eight treatment cycles; d) bortezomib is administered on days 1, 8, and 15 of eight treatment cycles, and one treatment cycle is 28 days long.

[0247] In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with pomalidomide and dexamethasone over the course of 1 to 8 treatment cycles of 28 days. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with pomalidomide and dexamethasone over the course of one 28-day treatment cycle. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with pomalidomide and dexamethasone over the course of two 28-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with pomalidomide and dexamethasone over the course of three 28-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with pomalidomide and dexamethasone over the course of four 28-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with pomalidomide and dexamethasone over the course of five 28-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with pomalidomide and dexamethasone over the course of six 28-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with pomalidomide and dexamethasone over the course of seven 28-day treatment cycles. In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof of the present invention is administered in combination with pomalidomide and dexamethasone over the course of eight 28-day treatment cycles.

[0248] In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof is administered on days 1, 8, 15, and 22 of the first two treatment cycles, on days 1 and 15 of the subsequent four treatment cycles, and on day 1 of any additional treatment cycles; b) pomalidomide is administered on days 1 to 21 of each treatment cycle; c) dexamethasone is administered on days 1, 8, 15, and 22 of each of the first 1 to 8 treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of one treatment cycle. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of two treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of three treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of four treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of five treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of six treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of seven treatment cycles. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of each of eight treatment cycles.

[0249] Treatment modality In the methods of the invention, the treatment regimens are used to provide a positive treatment response with respect to a disease or condition. The term "positive treatment response" refers to an improvement in the disease or condition and / or an improvement in the symptoms associated with the disease or condition. For example, a positive treatment response can be an improvement in a disease such as: (1) a reduction in the number of neoplastic cells; (2) an increase in neoplastic cell death; (3) an inhibition of neoplastic cell survival; (5) an inhibition of tumor growth (i.e., a slowdown to some extent, preferably an interruption); (6) an increase in patient survival rate; and (7) some relief from one or more symptoms associated with the disease or condition, among one or more of these.

[0250] A positive treatment response in any given disease or condition can be determined by standardized response criteria specific to that disease or condition. Tumor response can be assessed for changes in tumor morphology (i.e., overall tumor burden, tumor size, and the like) using screening techniques such as magnetic resonance imaging (MRI) scans, radiologic imaging, computed tomography (CT) scans, bone scan imaging, endoscopy, and tumor biopsy sampling (including bone marrow aspiration (BMA) and circulating tumor cell counts).

[0251] In addition to these positive treatment responses, subjects undergoing treatment may experience beneficial effects of improvement in symptoms associated with the disease. For B cell tumors, the subject may experience a decrease in so-called B symptoms (e.g., night sweats, fever, weight loss, and / or urticaria). For pre-malignant conditions, treatment with anti-CD38 therapeutic antibodies can block the development of related malignancies (e.g., the development of multiple myeloma in subjects with monoclonal gammopathy of undetermined significance (MGUS)) and / or extend the time prior to it.

[0252] Improvement of the disease can be characterized as complete remission. The term "complete remission" refers to the absence of clinically detectable disease and normalization of any previously abnormal radiologic studies, bone marrow fluid and cerebrospinal fluid (CSF), or abnormal monoclonal protein in the case of myeloma.

[0253] Such remission can persist for at least 4 to 8 weeks, or at least 6 to 8 weeks following treatment according to the method of the invention. Alternatively, improvement of the disease can be classified as partial remission. The term "partial remission" can refer to a reduction of at least about 50% in all measurable tumor burden (i.e., the number of malignant cells present in the subject, the measured volume of the tumor mass, or the amount of abnormal monoclonal protein) in the absence of new lesions, which can persist for 4 to 8 weeks, or 6 to 8 weeks.

[0254] Treatment according to the present invention includes a "therapeutically effective amount" of the pharmaceutical used.

[0255] The terms "therapeutically effective amount" and "therapeutically effective dosage" refer to the dosage and period necessary to achieve the desired therapeutic result, and reduce or alleviate the severity and / or duration of the disorder or one or more of its symptoms; prevent the progression of the disorder; cause regression of the disorder; prevent the recurrence, onset, or progression of one or more symptoms associated with the disorder; or are sufficient to promote or improve the prophylactic and / or therapeutic effect(s) of another treatment (e.g., prophylactic or therapeutic agent). The therapeutically effective amount can vary according to factors such as the individual's disease state, age, gender, and weight, as well as the ability of the pharmaceutical to elicit the desired response in the individual. The therapeutically effective amount is also one in which any toxic or damaging effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects. The "therapeutically effective amount" of an antibody for tumor treatment can be measured by its ability to stabilize the progression of the disease. The ability of a compound to inhibit cancer can be evaluated in animal model systems predictive of efficacy in human tumors.

[0256] Alternatively, this property of the composition can be evaluated by investigating the ability of the compound to inhibit cell proliferation or induce apoptosis by in vitro assays known to those skilled in the art. The therapeutically effective amount of a therapeutic compound can reduce the tumor size or otherwise alleviate the symptoms of the subject. Those skilled in the art will be able to determine such amount based on such factors as the size of the subject, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0257] Anti-CD38 antibody kit In another aspect of the invention, there is provided a kit for the treatment of a disease or condition associated with blood cancer. In one embodiment, the kit comprises a dose of an anti-CD38 antibody or antigen-binding fragment thereof (such as AB79) described herein, in combination with (a) lenolidomide, (b) lenolidomide and bortezomib, or (c) pomalidomide. In some embodiments, the kit provided herein may contain one or more doses of a liquid or lyophilized formulation provided herein. When the kit contains a lyophilized formulation of an anti-CD38 antibody or antigen-binding fragment thereof (such as AB79) described herein, generally the kit will also contain a liquid (such as sterile water or a pharmaceutically acceptable buffer) suitable for reconstitution of the liquid formulation. In some embodiments, the kit may contain a formulation of an anti-CD38 antibody or antigen-binding fragment thereof described herein, pre-packaged in a syringe for subcutaneous administration by a healthcare professional or for home use. In some embodiments, the kit may contain lenolidomide and dexamethasone for oral, intravenous, or subcutaneous administration in a suitable dosage form. In some embodiments, the kit may contain lenolidomide, dexamethasone, and bortezomib for oral, intravenous, or subcutaneous administration in a suitable dosage form. In one embodiment, lenolidomide is in an oral dosage form. In certain embodiments, dexamethasone is in an oral or intravenous dosage form. In one embodiment, bortezomib is in a subcutaneous dosage form.

[0258] In certain embodiments, the kit will be for single administration or for a dosage of an anti-CD38 antibody or antigen-binding fragment thereof (such as AB79) described herein in combination with (a) lenalidomide, (b) lenalidomide and bortezomib, or (c) pomalidomide. In other embodiments, the kit may contain multiple dosages of an anti-CD38 antibody or antigen-binding fragment thereof (such as AB79) described herein for subcutaneous administration. In one embodiment, the kit may include a formulation of an anti-CD38 antibody or antigen-binding fragment thereof described herein pre-packaged in a syringe for subcutaneous administration by a healthcare professional or for home use.

[0259] In certain embodiments, the kit will be for single administration or for a dosage of an anti-CD38 antibody or antigen-binding fragment thereof (such as AB79) described herein in combination with lenalidomide and dexamethasone. In other embodiments, the kit may contain multiple dosages of an anti-CD38 antibody or antigen-binding fragment thereof (such as AB79) described herein for subcutaneous administration, and multiple dosages of lenalidomide for oral administration and dexamethasone for oral or intravenous administration. In one embodiment, the kit may include a formulation of an anti-CD38 antibody or antigen-binding fragment thereof described herein pre-packaged in a syringe for subcutaneous administration by a healthcare professional or for home use.

[0260] In certain embodiments, the kit may be for single administration, or for doses of an anti-CD38 antibody or antigen-binding fragment thereof (such as AB79) described herein in combination with lenalidomide, dexamethasone, and bortezomib. In other embodiments, the kit may contain an anti-CD38 antibody or antigen-binding fragment thereof (such as AB79) described herein for subcutaneous administration, and multiple doses of lenalidomide for oral administration, dexamethasone for oral or intravenous administration, and bortezomib for subcutaneous administration. In one embodiment, the kit may include a formulation of an anti-CD38 antibody or antigen-binding fragment thereof described herein pre-packaged in a syringe for subcutaneous administration by a healthcare professional or for home use. In one embodiment, the kit may include bortezomib described herein pre-packaged in a syringe for subcutaneous administration by a healthcare professional or for home use.

[0261] In certain embodiments, the kit may be for single administration, or for doses of an anti-CD38 antibody or antigen-binding fragment thereof (such as AB79) described herein in combination with pomalidomide and dexamethasone. In other embodiments, the kit may contain an anti-CD38 antibody or antigen-binding fragment thereof (such as AB79) described herein for subcutaneous administration, and multiple doses of pomalidomide for oral administration and dexamethasone for oral or intravenous administration. In one embodiment, the kit may include a formulation of an anti-CD38 antibody or antigen-binding fragment thereof described herein pre-packaged in a syringe for subcutaneous administration by a healthcare professional or for home use.

[0262] Manufactured product In other embodiments, a manufactured article containing a material useful for the treatment of the disorders described above is provided. The manufactured article includes a container and a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container can be formed from a variety of materials (such as glass or plastic). The container holds a composition effective for treating the condition and can have a sterile access port (e.g., the container can be an intravenous fluid bag or vial having a stopper pierceable by a hypodermic needle). The active agent in the composition is an antibody. The label on or associated with the container indicates that the composition is to be used for treating the selected condition. The manufactured article can further include a second container containing a pharmaceutically acceptable buffer (such as phosphate buffered saline, Ringer's solution, or dextrose solution). The manufactured article can further include other materials desired from a commercial and user perspective, including other buffers, diluting substances, filters, needles, syringes, and package inserts with instructions for use.

Example

[0263] Example 1: Summary of Previous Clinical Trials of Anti-CD38 Antibody AB79 Table 2 provides a summary of previous clinical trials for anti-CD38 antibody AB79.

[0264]

Table 2

[0265] In a human first-in-human (FIH) study, a Phase 1, double-blind, placebo-controlled, dose-escalation study (AB79-101) was conducted in 74 healthy subjects, and AB79 was shown to be safe with no serious adverse events (SAEs) and with the expected pharmacodynamic effects. The IV of AB79 was a single intravenous dose of 0.06 mg / kg (0.1 μg / mL of C max) The levels of peripheral blood NK cells in all subjects receiving ) it were reduced by >90% from baseline levels. SC-administered AB79 also ) decreased the levels of blasts in peripheral blood in a dose- ) dependent manner. As a potent and convenient second-generation ) anti-CD38 monoclonal antibody, SC of AB79 warranted the ) development of a treatment for the treatment of multiple ) myeloma (MM).

[0266] The AB79-1501 study was a Phase 1b / 2a, multi-center, open-label, dose-escalation, single-arm study in patients with relapsed and refractory multiple myeloma (RRMM) who had been previously treated with at least a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), an alkylating agent, and steroids. Patients eligible for study enrollment were refractory or intolerant to at least one PI and at least one IMiD, and had received either three or more prior treatments or two or more prior treatments if one of these treatments included a combination of PI and IMiD. In the dose-escalation part of the Phase 1b of the study, patients previously exposed to an anti-CD38 agent were eligible, but this criterion was not required. In the expanded Phase 2a of the study, patients were refractory to at least one anti-CD38 monoclonal therapy at any time during previous treatment. The study was designed to evaluate the safety and tolerability of SC-administered AB79 monotherapy in patients with RRMM (including patients refractory to daratumumab), to determine the recommended Phase 2 dose (RP2D), and to provide a preliminary assessment of its monotherapy activity against RRMM. Parameters such as safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and disease response were assessed.

[0267] Clinical safety data include those from patients receiving a single dose and from patients receiving multiple doses in multiple cycles followed by a period without treatment. Based on the mechanism of action (MOA) of AB79 and the subcutaneous (SC) route of administration, potential adverse events (AEs) include systemic reactions (such as cytokine release syndrome (CRS) and hypersensitivity reactions), hematological effects (such as reduction in platelet, lymphocyte, neutrophil, and RBC counts), infections (such as bacterial and / or viral infections secondary to immunosuppression), and injection site reactions (i.e., erythema or tenderness).

[0268] Results AB79-1501 trial (single-agent AB79 for RRMM) At the time of data cut-off, 19 (19) patients were treated in the dose-escalation part of an ongoing trial in patients with RRMM and had completed at least one cycle. Four patients were in the first cohort (45 mg); three patients were in the second cohort (135 mg); six patients were in the third cohort (300 mg); and six patients were in the fourth cohort (600 mg). The most common TEAE (≥ 10% of patients) in the population at this timepoint, regardless of causality, were fatigue and upper respiratory tract infection (27% each), insomnia (22%), diarrhea and nausea (17% each), headache and anemia (15% each), neutropenia, abdominal distension, back pain, and hypertension (12% each), cough and pneumonia (10% each). There were no systemic reactions. Injection site reactions were rare (< 0.25%). Overall, the majority of AEs (55%) were grade 1 or 2. In the monotherapy cohort, no DLTs were reported and no MTD was identified. The RP2D was determined to be 600 mg for AB79 monotherapy. One drug-related SAE (MedDRA PT: diverticulitis) was reported in a patient with a history of diverticulitis. Two AEs leading to trial discontinuation were reported and both were reported to be not related to AB79. At the time of data cut-off, the preliminary objective response rate (ORR) at the RP2D in anti-CD38 naive patients who had received at least cycle 1 of AB79 was 36%, the clinical utility rate (defined as more than minimal response) was 73% and the disease control rate (defined as more than stable disease) was 91%. The duration of response was not estimable.

[0269] AB79-2001 Trial (AB79 Alone for the Treatment of SLE) AB79-2001 is a double-blind, placebo-controlled phase 1b trial in patients with moderate to severe SLE. At the time of the clinical data cut-off, a total of 15 patients had received at least one dose of AB79 or placebo. For this trial, the data are still blinded. No new safety concerns were identified. There were no patients with grade 3 or higher TEAEs or AEs leading to discontinuation of the study drug, regardless of randomization to placebo or AB79.

[0270] Example 2: A non-blinded, multi-center, Phase 1b trial (AB79-1002) to investigate the safety of AB79 in combination with a backbone regimen for the treatment of patients newly diagnosed with multiple myeloma (NDMM) who are not planned to receive stem cell transplantation as an initial treatment The primary objective of this trial is to determine the recommended Phase 2 dose (RP2D) of AB79 when administered in combination with a backbone treatment regimen to patients with newly diagnosed multiple myeloma (NDMM). Secondary objectives are to determine the overall response rate (ORR) and to assess safety by the assessment of the incidence of adverse events (AE).

[0271] This is a Phase 1b, multi-center, non-blinded trial to evaluate the safety, efficacy, tolerability, and pharmacokinetics (PK) of AB79 when added to one of two standard backbone regimens (lenalidomide + dexamethasone [LenDex], or bortezomib [Velcade] + lenalidomide and dexamethasone [VRd]) in adult patients with newly diagnosed multiple myeloma (NDMM) in whom stem cell transplantation (SCT) is not planned as an initial treatment. Doses and schedules for the backbone regimens (LenDex and VRd) are given according to product labels or standard medical practice. Treatment cycles are 28 days until disease progression (PD) or unacceptable toxicity occurs. Treatment may be discontinued for other reasons listed below. AB79 is supplied by the sponsor of the trial. Bortezomib, dexamethasone, and lenalidomide are standard therapeutic agents supplied from commercial sources. Approximately 18 adult patients with NDMM in whom SCT is not planned as an initial treatment will be enrolled in each group of the trial (approximately 36 patients in total).

[0272] Patient participation includes a screening phase, a treatment phase, and a follow-up phase. The screening phase is up to approximately 28 days before Day 1 of Cycle 1. The treatment phase continues from Day 1 of Cycle 1 until the patient experiences disease progression or unacceptable toxicity, or meets any other stopping criteria. Once the patient discontinues the investigational treatment and completes the End of Treatment (EOT) visit, the follow-up phase of the trial begins and continues until the trial ends or the patient completes the Overall Survival (OS) follow-up.

[0273] Once a patient is registered in the trial, they are assigned to the treatment regimen in a non-randomized manner. First, 6 patients are treated with AB79 in combination with the backbone treatment regimen. After giving one cycle of the treatment regimen to the 6 patients, a Dose-Limiting Toxicity (DLT) assessment is conducted. After the first cycle, if (1) the patient has not experienced DLT, (2) does not show signs of disease progression, and (3) in the opinion of the study physician, the benefit from the additional AB79 added to the backbone regimen continues, the patient may receive additional treatment cycles. After treating 6 patients for 2 and 3 treatment cycles respectively in a given treatment regimen, an additional safety review is performed. If safety data from Cycle 1 is available for all 6 patients in the initial cohort, the important safety data is reviewed and evaluated by the study request team. Then, an additional 12 patients are registered.

[0274] If it is determined that DLT has been reported in 2 of the 6 patients and it is necessary to evaluate either a more conservative dose or schedule, the study sponsor may register additional patients to meet the trial objectives. For example, the study sponsor could register 6 patients at a more conservative dose or schedule to monitor safety and subsequently register up to an additional 12 patients to confirm safety and anti-myeloma activity.

[0275] Patients are followed until 30 days after the last dose of AB79 or until the start of subsequent alternative anticancer therapy to allow for detection of any delayed treatment-related AEs (EOT visit). For patients who discontinue the investigational drug before PD, disease evaluations are continued. After documenting PD, subsequent anticancer treatments and responses to treatment are recorded, and survival status is obtained. If the patient dies, the date and cause of death are collected and documented. Follow-up continues until the end of the trial.

[0276] After all patients enrolled in the trial have had the opportunity to complete 2 years of treatment, an analysis of the clinical trial report is conducted. The trial is designed to last 36 months (including the periods of enrollment, treatment, and follow-up).

[0277] Trial Design Administer 300 mg of AB79 subcutaneously once every other week for 8 weeks (8 doses), once every 2 weeks for 16 weeks (8 doses), and then once every 4 weeks until PD (in combination with the backbone therapy). Administer the backbone therapy (LenDex or VRd) according to the practice at the product label / regional institution. VRd administers bortezomib once a week for 3 weeks, and LenDex is given in a standard 28-day cycle. The treatment schedule is shown in Table 3. Evaluate patients from the first dose of AB79 until 30 days after PD or until the treatment discontinuation criteria defined in the trial protocol are met.

[0278]

Table 3

[0279] The strength of the AB79 formulation for SC is 100 mg of AB79 in 1 mL (100 mg / mL). After the patient has received premedication treatment, the AB79 dose is administered by syringe as an SC injection up to a maximum volume of approximately 2 mL per injection (i.e., 200 mg / 2 mL). The injection sites are rotated using the abdomen, thighs, arms, and upper buttock regions.

[0280] Lenalidomide-Dexamethasone Regimen (LenDex) Administer lenalidomide orally daily at 25 mg for 21 days according to the product label. Administer dexamethasone intravenously (IV) or orally at 40 mg once a week or 20 mg once a week if the patient is >75 years old according to the product label. Dexamethasone is taken before AB79 dosing as premedication for at least cycle 1, and if there is no systemic IRR, the timing of dexamethasone dosing can be adjusted by standard medical judgment. Dexamethasone is dosed after cycle 8 according to the tolerance associated with dexamethasone and the medical judgment of the physician. One treatment cycle is 28 days according to the product label until disease progression or unacceptable toxicity. Lenalidomide and dexamethasone are obtained from commercial sources.

[0281] Bortezomib-Lenalidomide-Dexamethasone Regimen (VRd) Administer bortezomib subcutaneously (SC) at 1.3 mg / m 2 once a week (on days 1, 8, and 15) for up to 8 cycles according to the product label. Administer lenalidomide orally daily at 25 mg for 21 days according to the product label. Administer dexamethasone intravenously or orally at 40 mg once a week or 20 mg once a week if the patient is >75 years old according to the product label. Dexamethasone is taken before AB79 dosing as premedication for at least cycle 1, and if there is no systemic IRR, the timing of dexamethasone dosing can be adjusted by standard medical judgment. Dexamethasone is dosed after cycle 8 according to the tolerance associated with dexamethasone and the medical judgment of the physician. One treatment cycle is 28 days according to the product label until disease progression or unacceptable toxicity (note that for bortezomib it is up to 8 cycles). Bortezomib, lenalidomide, and dexamethasone are obtained from commercial sources.

[0282] Premedication Before each injection, the patient receives the following premedication on each dosing day approximately 1 to 3 hours before the AB79 injection: oral acetaminophen (650 - 1000 mg) and oral or IV diphenhydramine (25 - 50 mg, or equivalent). Any patient with a history of COPD may receive premedication with 10 mg of montelukast (or equivalent leukotriene inhibitor). Post-injection medications (short-acting and long-acting bronchodilators, inhaled corticosteroids, etc.) can be administered. After the first 4 injections, these additional inhaled post-injection medications can be discontinued if the patient does not experience a major injection reaction. After the first 4 injections, if the patient does not experience a major injection reaction, the study physician can reduce the pre-dose and post-dose medications.

[0283] Post-dose medications Apply corticosteroid cream topically to the injection site(s) and apply ice topically for approximately 10 - 15 minutes. The patient may receive low-dose methylprednisolone (<20 mg) for prevention of reactions associated with delayed injection as clinically indicated after injection.

[0284] Main criteria for inclusion Each patient must meet all of the following inclusion criteria to be registered in the trial: (1) previously untreated MM as defined by the International Myeloma Working Group (IMWG) criteria, which requires treatment according to the treating physician; (2) the patient is an appropriate candidate for either VRd or LenDex backbone anti-myeloma therapy according to the treating physician; (3) the patient has measurable disease defined by at least one of the following: (a) serum M protein ≥ 1 g / dL (≥ 10 g / L); (b) urinary M protein ≥ 200 mg / 24 hours; and (c) serum free light chain (FLC) assay: if the serum FLC ratio is abnormal, the involved FLC level ≥ 10 mg / dL (≥ 100 mg / L); (4) adult male or female patients over 18 years of age who are not expected to receive SCT as initial therapy. Stem cell collection and mobilization regimens are permitted if clinically indicated but must be confirmed first by the clinician / nominee. Stem cell mobilization and collection can occur at any time after the 4th treatment cycle according to institutional clinical practice; (5) the patient meets the following clinical laboratory criteria: (a) hemoglobin > 7.5 g / dL; (b) absolute neutrophil count (ANC) ≥ 1000 / mm 3 (Granulocyte colony-stimulating factor (G-CSF) or other growth factors that assist the patient in meeting eligibility criteria are not permitted); (c) platelet count ≥ 75,000 / mm 3(Platelet transfusions that assist the patient in meeting the eligibility criteria are not permitted); (d) Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) (except for Gilbert syndrome: direct bilirubin ≤ 2 times ULN); (e) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times ULN; (f) Creatinine clearance (by calculated creatinine clearance) ≥ 50 mL / min; (6) The patient practices contraception or abstinence; (7) For patients receiving lenalidomide: Prophylactic anticoagulation must be possible by standard clinical practice as directed by the investigator; (8) Life expectancy is > 3 months; (9) Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2; (10) Informed consent based on a fully explained, voluntarily written document must be provided prior to the performance of any study-related procedures that are not part of standard medical care, with the understanding that consent may be withdrawn at any time without detriment to future medical care; (11) Patients who scrupulously adhere to and are able to comply with the requirements of standard medical procedures for multiple myeloma, the study visit schedule, and other study implementation protocols.

[0285] Main criteria for evaluation and analysis: The primary evaluation item is the recommended dose of the combination of AB79 and the backbone regimen, based on the number of patients with DLT in cycle 1 according to the Medical Dictionary for Regulatory Activities (MedDRA). The secondary evaluation items are (a) the objective response rate (ORR, response of partial response (PR) or better) for each regimen, based on the investigator's assessment according to the IMWG criteria; (b) the incidence of adverse events (AEs) according to the MedDRA System Organ Class and Preferred Term (including grade 3 or higher events, serious adverse events (SAEs), AEs leading to discontinuation of AB79, and AEs resulting in death during the study).

[0286] Statistical considerations: Adverse events are summarized for each treatment group and overall. Categorical variables (such as ORR) are tabulated for each treatment group and overall. Time-to-event variables (such as DOR, PFS, and OS) are analyzed using Kaplan-Meier survival curves, and Kaplan-Meier medians (if estimable) are provided. PK parameters are summarized as needed.

[0287] Sample size justification: The sample size is not determined based on a formal hypothesis test, but rather on the evaluation of DLT and safety outcomes. Therefore, each regimen of AB79 and the backbone therapy specified in the clinical trial protocol are evaluated individually for DLT determination and safety. First, 6 patients evaluable for DLT are evaluated for safety and DLT before additional patients are enrolled. The cohort is expanded by enrollment of additional patients to obtain a more comprehensive assessment of safety, PK, pharmacodynamics, or disease response, which can further inform the selection of the RP2D. Once the RP2D is determined, up to an additional 12 patients (for a total of approximately 18 patients for each regimen of AB79 and the backbone therapy) are enrolled. A forward calculation of statistical power is not performed, but Table 4 shows the width of the 80% confidence interval for the range of observed response rates based on the ORR observed in the 18-patient cohort size.

[0288]

Table 4

[0289] Definition of DLT Toxicity is evaluated according to NCI CTCAE (version 4.03, effective June 14, 2010; US Department of Health and Human Services, 2010). DLT is evaluated at the end of cycle 1. Only toxicities occurring during the DLT evaluation period are used for the purpose of defining DLT and for subsequent cohort expansion or dose modification decisions. DLT is based on AB79-related toxicity. Toxicities resulting from non-compliance with requirements specified in the trial protocol (e.g., antiviral prophylaxis) are not eligible as DLTs if they result in ≥ grade 3 toxicity. TEAE clearly attributable to external causes will not be defined as DLTs. DLT is defined as any of the following events, at least probably considered by the investigator to be related to AB79: (1) Hematologic toxicities not clearly related to underlying disease, defined as follows: (a) Grade 4 thrombocytopenia lasting for more than 7 consecutive days (platelet count < 25,000 / mm 3 ), or ≥ grade 3 low platelet count with significant bleeding (clinically significant bleeding is defined as a blood loss of 100 mL or the need for red blood cell transfusion); (b) platelet count < 10,000 / mm 3 ; (c) Grade 4 neutropenia lasting for more than 7 consecutive days (ANC < 500 cells / mm 3 ), (d) Grade 3 neutropenia with infection and / or fever (fever is defined as a single temperature > 38.5°C or a persistent temperature > 38°C for > 1 hour) (ANC < 1000 cells / mm 3); and (e) hemolysis of grade ≥ 3 (excluding events clearly due to external causes (e.g., direct Coombs test is negative)), are included in the DLT definition; (2) non-hematological toxicities of grade 3 or higher that are clearly not related to the underlying disease, excluding the following: (a) grade 3 injection-associated (systemic) reactions (IAR) without recurrence of grade 3 symptoms that respond to symptomatic therapy (e.g., antihistamines, non-steroidal anti-inflammatory drugs, narcotics, IV fluids); (b) grade 3 fatigue or weakness lasting < 7 days after the last dose of AB79; (c) grade 3 nausea or grade 3 vomiting that responds to antiemetic treatment. Optimal antiemetic prophylaxis is defined as an antiemetic regimen using a 5-hydroxytryptamine type 3 antagonist (5-HT3) given at standard dose and according to the standard schedule; (d) grade 3 diarrhea that responds to antidiarrheal treatment; and (e) isolated elevations of ALT or AST of grade 3 or higher that resolve to grade ≤ 1 or baseline within 7 days.

[0290] Incomplete recovery from treatment-related toxicities resulting in a delay of > 2 weeks in the next scheduled AB79 injection before the start of cycle 2 is considered a DLT. The inability to administer at least 80% of the planned dose of an individual agent in the backbone regimen due to drug-related AEs is evaluated based on all available safety data as a potential DLT prior to cohort expansion decisions.

[0291] Dose escalation rules First, six patients are treated with the initial dose of AB79 in combination with the backbone treatment regimen: LenDex or VRd. The determination of DLT and safety assessment will be performed after one complete cycle has been completed by six evaluable patients receiving a given AB79 regimen with the backbone treatment. If safety data are available for all six patients in the cohort, critical safety data are reviewed and evaluated before enrolling additional patients. If DLT is observed in one or fewer patients during the treatment regimen, at least 12 additional patients are enrolled in that treatment regimen to verify the safety of the AB79 dose. If DLT is observed in two or more of the six patients, the dose of AB79 is tapered to the dose and / or schedule determined by the sponsor of the clinical trial and then expanded to 12 additional patients after six additional patients. A more conservative dosing schedule can also be implemented as a means of providing an overall lower dose. Each AB79 regimen + backbone regimen is evaluated separately for DLT determination and safety.

[0292] Patients who have not received all doses of AB79 in cycle 1 for reasons other than DLT are replaced within the cohort. Patients who receive all doses of AB79 but in whom recovery from toxicity is not effective in an unexpected situation and in whom the safety of cycle 1 cannot be fully evaluated should be replaced within the cohort. Patients who have experienced DLT should not be replaced.

[0293] For all patients, after treating six patients in a given backbone regimen for two and three treatment cycles respectively, an additional ongoing safety review is performed. Evaluation of doses up to intermediate doses or those determined to be safe as evaluated in the RRMM trial, alternative dosing schedules (inter-dose intervals), and expansion of existing dose levels are all acceptable following consideration between the sponsor of the clinical trial and the investigator if such measures are required for patient safety or for a better understanding of the dose-related toxicity, exposure, or pharmacodynamics of AB79.

[0294] Safety and Disease Assessment Safety assessment includes monitoring TEAE according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. Clinically significant changes in clinical laboratory parameters (standard hematology and chemistry), vital signs, electrocardiogram (ECG) monitoring, and Eastern Cooperative Oncology Group (ECOG) performance status, as judged by the investigator, are recorded as AEs in both the source documents and the electronic case report (eCRF). Toxicities occurring during the DLT evaluation period are used for the purpose of defining DLT and for subsequent cohort expansion or dose modification decisions. DLT is based on AB79-related toxicity.

[0295] Efficacy assessment of tumor response and disease progression is performed according to IMWG criteria. Efficacy evaluation includes measurement of myeloma protein in serum and urine. Bone marrow examination, bone survey, computed tomography (CT) or magnetic resonance imaging (MRI) to evaluate lytic and / or plasmacytoma, and serum calcium corrected for albumin are evaluated as needed based on the patient's baseline disease state.

[0296] PK, Pharmacodynamics, and Immunogenicity Assessment Blood samples for PK, pharmacodynamics, and immunogenicity (including anti-drug antibody (ADA)) testing are collected at specific time points.

[0297] Primary Endpoints The primary endpoint is the recommended dose of the combination of AB79 and the backbone regimen, based on the number of patients with dose-limiting toxicity (DLT) according to the Medical Dictionary for Regulatory Activities (MedDRA) in cycle 1.

[0298] Secondary Endpoints The secondary evaluation items are: (a) the ORR (response of at least partial response [PR]) for each regimen, based on the assessment by the treating physicians according to the IMWG criteria; and (b) the incidence of AEs according to the MedDRA System Organ Class and Preferred Term (including grade 3 or higher events, serious adverse events (SAEs), AEs leading to discontinuation of AB79, and AEs resulting in death during the trial).

[0299] Exploratory evaluation items The exploratory evaluation items are: (1) the estimated value of 1-year PFS (defined as the Kaplan-Meier estimate of patients without progression or death at 1 year from the date of the first dose); (2) the duration of response (defined as the time from the date of the first response report to the date of the first PD report); (3) the time to response (defined as the time from the date of the first dose to the date of the first report of response (PR or above)); (4) the estimated value of 1-year overall survival (defined as the probability of patient survival 1 year after the date of the first dose of treatment); (5) OS (defined as the time from the date of the first dose of treatment to the date of death); (6) determination of minimal residual disease in bone marrow aspirate (BMA) samples obtained by a suspicious VGPR or higher assessment (using next-generation flow cytometry); (7) the PK of AB79 in combination with the backbone treatment regimen. As PK parameters, C max , the time after administration when the maximum plasma concentration is reached (T max) and area under the curve (AUC), among others; (8) changes in CD38 expression on MM cells and other immune cells in BMA and peripheral blood before, during, and at the end of the treatment; (9) pharmacodynamic analysis of the presence and changes of immune cells in BMA and peripheral blood before, during, and at the end of the treatment; (10) evaluation of the exploration of biomarkers capable of predicting efficacy and / or resistance (including, but not limited to, changes in cytokines / chemokines); (11) comparison of changes in overall health status (as measured by the overall health scale, function, and symptoms of EORTC QLQ-C30 and EORTC QLQ-MY20) between baseline assessment and each post-baseline assessment; and (12) the incidence and characteristics of anti-AB79 antibodies.

[0300] Criteria for dose modification of standard backbone agents Patients receiving bortezomib and lenalidomide can modify each drug according to the prescribing information. Table 5 shows the dose reduction steps along the backbone regimens of VRd and LenDex. Patients experiencing an AE attributable to one of these agents should reduce by one dose level as indicated in the prescribing information. If dose reduction of one of these agents is required due to toxicity, dose re-escalation is not approved.

[0301]

Table 5

[0302] Modification of dexamethasone treatment (both groups) Patients experiencing an AE attributable to dexamethasone can reduce the dose of dexamethasone according to standard medical judgment. If dose reduction is required due to toxicity, dose re-escalation is not approved.

[0303] Tables 6 - 9 provide a list of clinical and research tests for standard treatment.

[0304]

Table 6

[0305]

Table 7

[0306]

Table 8

[0307] For the estimation of creatinine clearance, the following Cockcroft-Gault formula: Estimated creatinine clearance = [(140 - age) × weight](kg) / 72 × serum creatinine (mg / dL)] is used. For female patients, multiply the result of the above formula by 0.85.

[0308] Disease assessment The patient is assessed for disease response according to the IMWG criteria.

[0309]

Table 9

[0310] Clinical laboratory evaluation for disease assessment For the determination of the disease stage according to the International Staging System, blood samples are collected during screening for the measurement of serum β2-microglobulin and albumin. Obtain clinical laboratory evaluations for disease assessment, serum protein electrophoresis (SPEP), 24-hour urine collection for urine protein electrophoresis (UPEP), serum FLC, serum and urine immunofixation tests, and total immunoglobulin levels. If the patient has measurable M protein restricted to the urine, the quantification of the M protein component can be determined by UPEP only. Patients measurable by SPEP have only 24-hour urine collections at screening and EOT, documenting PR, VGPR, CR, or PD. Perform immunofixation to confirm CR.

[0311] Interference test Since AB79 is a monoclonal IgGκ antibody similar to daratumumab, SPEP and serum immunofixation can be positive due to the anti-CD38 monoclonal antibody. Therefore, if the SPEP value reaches ≤ 0.2 g / dL in two consecutive disease evaluations, CR is always suspected and the need for an interference test is triggered. Currently, if the interference test result is positive, the assay is then determined to be positive for endogenous protein, and thus the disease still exists. If the interference test result is negative, the assay is then determined to be negative for endogenous protein, and thus the remaining protein is probably the CD38 monoclonal antibody. A confirmatory bone marrow aspirate (BMA) evaluation can be performed for the possibility of CR, but has not yet been done.

[0312] Blood samples for IgM, IgG, and IgA are obtained at screening and at certain time points throughout the study. Quantification of IgD and IgE is performed only at screening. For rare patients in whom MM of IgD or IgE is reported, a quantitative test for that antibody is followed at the same time points as IgG and IgA.

[0313] Bone marrow biopsy and / or bone marrow aspirate Results of BMA and / or biopsy for morphological, clinical staging, and cytogenetic evaluation (from bone marrow performed within 8 weeks of study participation) must be available at screening; if not, BMA and / or biopsy are obtained at screening. If not previously assayed, perform BMA for at least the following cytogenetic abnormalities: chromosome deletion 17 [del(17)], chromosome translocation 4:14 [t(4:14)], and chromosome translocation 14:16 [t(14:16)]. If BMA is performed during screening, examine samples for baseline CD38 expression, baseline receptor occupancy, pharmacodynamic measurements, and immunoprofiling.

[0314] Patients suspected of achieving CR should have a BMA collected at any time and document the CR according to IMWG criteria. Suspected CR (sCR) is defined independent of the results of immunofixation. Perform BMA when M protein measurements in SPEP (for heavy chain patients) or UPEP (for light chain patients) are below the detection limit or not quantifiable. Evaluate BMA samples for analysis of CR and minimal residual disease. Determine the κ / λ ratio by immunohistochemistry or immunofluorescence to assess sCR.

[0315] Cytogenetics / Fluorescence in situ hybridization Patients without a historically reported cytogenetic result for high-risk abnormalities of del(17), t(4:14), and t(14:16) should have a cytogenetic evaluation performed on the BMA sample at screening. If historically reported cytogenetics are available, the BMA sample at screening is not required as long as results are available for the minimal cytogenetic markers mentioned here. Cytogenetic evaluation using fluorescence in situ hybridization or conventional cytogenetics (karyotype) is acceptable. However, at a minimum, the cytogenetic markers must include the three high-risk abnormalities of del(17), t(4:14), and t(14:16). Additional abnormalities [ampl 1q, del(13), or del(1p)] can also be tested.

[0316] Radiologic assessment of the disease Perform imaging to evaluate extramedullary disease at least at screening and at the time of the EOT visit. The choice of imaging method (e.g., bone survey, CT, MRI, positron emission tomography - computed tomography [PET-CT]) is at the discretion of the treating physician. However, all treatment phases and follow-up scans should use the same imaging method used at screening to facilitate consistent disease assessment. Perform the imaging examination at screening (within 8 weeks of the first dose of the investigational drug). If extramedullary disease of soft tissue is reported, repeated imaging should be performed upon request to document response or progression according to the IMWG criteria.

[0317] Biomarkers, pharmacodynamics, and PK samples Table 10 provides a list of patient samples collected for the study.

[0318]

Table 10

[0319] Collect serum samples for the measurement of the concentration of AB79 at multiple time points. If it is determined that a change in the sampling scheme is necessary to better characterize the PK profile of AB79, the timing of the samples, rather than the total number of samples, can be modified during the study based on the new PK data.

[0320] Assay multiple biomarkers for safety, PK, and, if possible, correlation with efficacy. These biomarkers are used to identify patients with a higher probability of response or adverse reactions to AB79. Perform biomarker sample analysis if required or when requested. Since new techniques are continuously being developed, the methods recommended for biomarker analysis cannot be predicted.

[0321] BMA samples are collected for the assessment of minimal residual disease and for profiling tumor and immune cells present in the bone marrow. BMA samples are also collected during and at the end of treatment to analyze CD38 expression by flow cytometry and monitor changes in immune cells.

[0322] For example, serum samples for cytokine / chemokine levels are collected before, during, and at the end of treatment to assist in identifying patients with a higher probability of experiencing response or adverse reactions to AB79.

[0323] Blood samples are collected before, during, and at the end of treatment to analyze CD38 expression by flow cytometry and monitor changes in immune cells. Blood samples are also collected before, during, and at the end of treatment to profile immune cells and analyzed for the presence and changes of immune cells by flow cytometry or mass cytometry. Blood samples for the assessment of ADA are collected at various time points. Samples must be collected before the investigational drug is administered on the dosing day and, optionally, at unscheduled visits of subjects who experience an AE determined by the investigator to coincide with an allergy or other IRR. If ADA is detected as positive, the sample can be further characterized.

[0324] Discontinuation of treatment with the investigational drug and patient replacement For patients who meet any of the following criteria: dropout by the subject; pregnancy; AE / SAE; PD; inadequate treatment response; initiation of hematopoietic SCT; deviation from the study implementation plan; study terminated by the sponsor; loss of follow-up; and physician's decision, the study treatment is permanently discontinued. Once the study treatment has been discontinued, all of the outlined study procedures for the EOT visit are completed.

[0325] It should be noted that some patients may discontinue the investigational therapy for reasons other than PD before completing the entire treatment course. These patients will remain in the trial for PFS follow-up assessment until PD occurs. PFS and / or OS follow-up assessments will continue to be performed as long as the patient does not withdraw consent for follow-up.

[0326] Patients remaining on investigational therapy at the end of the trial (whether the trial is completed or for any other reason) will be provided continued access to AB79 either through commercial supply (if available and reimbursable) or through continued treatment in another extension or rollover trial.

[0327] Withdrawal of patients from the trial Patients may withdraw from the trial for any of the following reasons: death; trial terminated by the sponsor; withdrawal by the subject; and loss to follow-up.

[0328] Adverse events Definition of pretreatment events Pretreatment events are any unfavorable medical occurrences in a patient or subject before the administration of any investigational medicinal product, who has signed consent based on adequate information to participate in the trial, which do not necessarily have a causal relationship with trial participation.

[0329] Definition of adverse events (AE) AE means any adverse medical event in a patient or subject administered a pharmaceutical product, and the adverse medical event need not necessarily have a causal relationship with this treatment. Thus, an AE can be any adverse, unintended sign (including abnormal clinical laboratory findings), symptom, or disease that temporarily accompanies the use of a pharmaceutical (research) product, whether or not it is related to the pharmaceutical product. This includes any newly occurring event or previous condition that has an increased severity or frequency since the administration of the investigational drug. Abnormal clinical laboratory values will not be assessed as an AE unless the value leads to discontinuation or delay in treatment, dose modification, does not lead to treatment intervention, or is determined by the investigator to be a clinically significant change from baseline.

[0330] Definition of Serious Adverse Event (SAE) SAE means any adverse medical event that, at any dose, (1) results in death; (2) is life-threatening (refers to an AE where the patient was at risk of death at the time of the event. It does not refer to an event that might have caused death if it had been more severe); (3) requires hospitalization of an inpatient or prolongation of an existing hospitalization; (4) results in persistent or significant disability (defined as substantial disruption of the ability of a person to perform normal life functions) or incapacity; (5) is a congenital anomaly / birth defect; (6) is a medically important event. An AE that does not result in death is considered serious if it immediately threatens life or requires hospitalization and either it can cause harm to the patient or requires medical or surgical intervention to prevent one of the outcomes listed above, or is judged to be serious when it is suspected of transmission via a pharmaceutical product of an infectious agent. Examples of such medical events include anaphylactic bronchospasm requiring intensive treatment in the emergency room or at home, a blood disorder or convulsion that does not result in hospitalization of an inpatient, or the onset of drug dependence or drug abuse. Any organism, virus, or infectious particle (e.g., prion protein that transmits transmissible spongiform encephalopathy), whether pathogenic or non-pathogenic, is considered an infectious agent.

[0331] For each AE that includes any clinical examination abnormality, the degree is determined using the NCI CTCAE (version 4.03, effective June 14, 2010). Since the terms "severe" and "serious" are not synonyms, clarification should be made between SAEs and AEs that are determined to be serious (grade 3 or 4). The general term "serious" is often used to describe the degree (severity) of a specific event, although the event may have relatively minor medical significance in itself (such as grade 3 headache, etc.). This is not the same as "severe", which is usually associated with an event that threatens the patient's life or ability to function, based on the patient / event outcome or activity criteria described above. A serious AE (grade 3 or 4) does not necessarily have to be determined to be severe. For example, a white blood cell count of 1000 / mm 3 ~2000 / mm 3 is less than and is determined to be grade 3 (severe), but does not have to be determined to be severe. Severity (not degree) is provided as a guide for the definition of regulatory reporting obligations.

[0332] Period for Monitoring and Observation of AE Monitor AE (both non-serious and serious) through the study as follows: (1) Report AE from the signing of consent based on sufficient explanation for 30 days after the administration of the final dose of the investigational drug. Monitor ongoing AE at the end of the study until either the AE resolves (returns to baseline), it is clearly determined that the AE is due to the patient's stable or chronic condition or concurrent illness(es), the second-choice alternative therapy is initiated, or 6 months after the occurrence of PD, whichever is earlier; (2) Report SAE from the signing of consent based on sufficient explanation for 30 days after the administration of the final dose of the investigational drug. After this period, only report SAE related to Takeda drugs (AB79 and Velcade) to the Takeda Global Pharmacovigilance department or designee. Monitor SAE until either the SAE resolves or it is clearly determined that it is due to the patient's stable or chronic condition or concurrent illness(es). In addition, since there is an increased risk of new primary malignancies with lenalidomide, report all cases of new primary malignancies from the first dose of the study treatment regimen until death (including the follow-up period) regardless of causality to the study treatment regimen until either the end of the study by the study sponsor or at least 3 years after the final dose of any of the drugs in the study treatment regimen, whichever is earlier.

[0333] PK analysis Estimate PK parameters using non-compartmental analysis. Calculate the parameters using the concentration-time data of AB79 for individual patients included in the PK analysis set. Calculated PK parameters may include, but are not limited to, C max , t max , and AUC last .

[0334] Summarize the PK parameters using descriptive statistics. Present the individual AB79 concentration-time data and the individual PK parameters in a list and aggregate them using summary statistics by dose cohort. Plot the individual and mean concentration-time profiles by dose cohort. The PK data collected in this study may also contribute to future population PK analyses of AB79. These population PK analyses may include data collected in other AB79 clinical trials. The analysis plans for the population PK analyses are defined separately and the results of these analyses are reported separately. Similarly, the time-matched PK and triple ECG data collected in this study may contribute to future concentration-QT intervals corrected for heart rate (QTc) analysis. These analyses may include data collected in other AB79 clinical trials. The analysis plans for the concentration-QTc analyses are defined separately and the results are reported separately.

[0335] Pharmacodynamic analysis During the clinical development of AB79, multiple biomarkers are examined and evaluated for their correlation with safety and, if possible, efficacy. The markers studied are those linked to either the drug itself or the disease being treated. Summarize the markers that indicate changes in tumor burden (i.e., changes in immune cells or soluble biomarkers) using descriptive statistics. List the individual data. Provide summaries separately for each study phase and for each dose, if applicable.

[0336] PK / Pharmacodynamic analysis Attempt to evaluate the potential relationships between the dose of AB79 and the serum exposure of AB79 vs multiple biomarkers (such as CD38 expression levels and changes in immune cells, etc.). These analyses are essentially exploratory and all results are essentially descriptive.

[0337] Immunogenicity analysis Analyze and summarize the AB79 immunogenicity status (ADA negative, transient, and persistent positive, and ADA titers), using descriptive statistics (based on SAP) when applicable. Explore the effect of immunogenicity on PK, safety, and efficacy. The immunogenicity analysis is based on available data from patients who had a baseline assessment and at least one post-baseline immunogenicity assessment.

[0338] QOL analysis Assess QOL by the EORTC 30-item QLQ-C30 questionnaire and by the EORTC QLQ-MY20 (20-item assessment) specifically designed to address QOL in MM patients (http: / / groups.eortc.be / qol / questionnaires, accessed March 19, 2019). The main scales constructed from the EORTC QLC-C30 are overall health status / QOL, physical function, role function in daily life, emotional function, cognitive function, and social life function. Nine additional scales: fatigue, nausea and vomiting, pain, dyspnea, insomnia, anorexia, constipation, diarrhea, and financial difficulty, may be derived. Conduct both surveys before day 1 of cycle 1, then every 3 months in year 1, and then every 6 months until PD thereafter.

[0339] Use the QOL measurement values on day 1 of cycle 1 as the baseline. Conduct the analysis for the summary scores and for the subscales and individual symptoms. The changes between the baseline and each post-baseline assessment are described overall. The QOL assessment items are the overall health status and the remaining EORTC QLQ-C30 and EORTC QLQ-MY20 subscales and individual item scores. Present the change in scores using a cumulative frequency distribution plot.

[0340] Safety analysis Assess safety by the frequency, severity and type of AEs, as well as by changes from baseline in the patient's vital signs, body weight, and the results of clinical laboratory tests using the safety analysis set. Tabulate the exposure to the investigational drug and the reasons for discontinuation. Tabulate the TEAEs occurring from after the administration of the first dose of the study through 30 days after the last dose of the investigational drug.

[0341] Tabulate AEs according to MedDRA and include the following categories: (1) TEAEs; (2) drug-related TEAEs; (3) TEAEs of grade 3 or higher; (4) drug-related TEAEs of grade 3 or higher; (5) the most commonly reported TEAEs (i.e., those reported in ≥ 10% of all patients); (6) SAEs (related and unrelated); (7) TEAEs leading to modification and discontinuation of the investigational drug.

[0342] Results Study AB79-1002, (a) lenalidomide and dexamethasone (LenDex), and (b) AB79 in combination with lenalidomide, dexamethasone, and bortezomib (VRd) AB79-1002 is an open-label, multi-center, Phase 1b trial investigating the safety and tolerability of AB79 in combination with a backbone regimen ((a) lenalidomide and dexamethasone, or (b) lenalidomide, dexamethasone, and bortezomib) for the treatment of patients with newly diagnosed multiple myeloma (NDMM) in whom stem cell transplantation is not planned as an upfront therapy. Eligible patients for trial enrollment have previously untreated NDMM and stem cell transplantation is not planned as first-line therapy. The trial was designed to determine the Phase 2 recommended Phase 2 dose (RP2D) and provide a preliminary assessment of AB79 in combination for NDMM. Parameters such as safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and disease response were evaluated. Ten patients were enrolled. In this ongoing trial, clinical safety data include those from patients who received at least 1 dose at a dose of 300 or 600 mg, or at least 1 cycle if exposed to multiple doses (but not multiple cycles) in combination with standard doses of the backbone regimen. Regardless of the AB79 dose of the combination partner and regardless of causality in the population, the most common treatment-emergent adverse events (TEAEs) (≥2 patients) at this date are lymphopenia (5 patients), diarrhea (3 patients), and abdominal pain, chills, dysgeusia, fatigue, muscle spasm, nausea, neutropenia, peripheral edema, and rhinitis (2 patients each). No dose-limiting toxicities (DLTs) were reported. There were no drug-related serious AEs, AEs that led to any drug discontinuation, or deaths during the trial. The TEAEs in this combination trial are consistent with the reported safety profiles of the individual agents in the combination regimen and are generally as expected based on clinical experience with the single agent AB79 (Study AB79-1501) and the backbone regimens of VRD and RD.

[0343] At the data cut-off, the preliminary objective response rate (ORR) (including both backbone regimens) for the population was 100%, including deep responses (stringent CR and VGPR) and durable responses (data cut-off exposure range from 1 to 11 cycles). At the present time, the determination of objective response for 1 patient is pending.

[0344] Example 3: A multi-center, dose-escalating, open-label, single-arm, Phase 1 / 2a study (AB79-1501) to investigate the safety, tolerability, efficacy, pharmacokinetics, and immunogenicity of AB79 administered subcutaneously as a single agent and in combination with pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (RRMM) This is a multi-center, dose-escalating, open-label, single-arm, Phase 1 / 2a study designed to provide a preliminary assessment of activity against MM to determine the safety, tolerability, efficacy, PK, and immunogenicity of AB79 monotherapy in patients with RRMM. This study is an amendment to the Phase 1 / 2a study of RRMM described in Example 1 and enables (a) an increase in the number of patients enrolled in the Phase 1 study; and (b) the addition of a cohort of patients to evaluate AB79 in combination with the backbone regimen of pomalidomide and dexamethasone (PomDex) in patients with RRMM who have received at least two prior treatments and are refractory to their last therapy prior to study entry. PomDex is approved for this patient population, and the addition of an anti-CD38 monoclonal antibody (especially those administered subcutaneously (SC)) to PomDex may be beneficial and convenient for patients.

[0345] Accordingly, the primary objective of the Phase 1 portion of this study is to determine the safety and tolerability of (a) AB79 monotherapy and (b) AB79 in combination with the backbone regimen of PomDex in patients with RRMM. The primary objective of the Phase 2a portion of this study is to provide a preliminary assessment of the clinical activity of AB79 monotherapy in patients with RRMM.

[0346] The secondary objectives of the first part of the trial are to investigate the possible maximum tolerated dose / phase 2 recommended dose (MTD / RP2D) of AB79 (a) as a single agent and (b) when added to the backbone regimen of PomDex. The secondary objectives of the 2a part of the trial are: (a) to further evaluate safety at the MTD / RP2D; (b) to provide a preliminary assessment of time-to-event measurements; (c) to further evaluate the immunogenicity of AB79; and (d) to further characterize the PK of AB79.

[0347] The exploratory objective of this trial is to explore biomarkers that can be tested for correlation with clinical efficacy and safety parameters, including, but not limited to: (a) characterizing the pharmacodynamic profile of AB79 on immune cells (including CD38 occupancy); (b) determining CD38 expression on MM cells and other immune cells before and during treatment; (c) immunophenotyping bone marrow aspirates (BMA) and whole blood cells containing CD38+ immune cells at baseline and at different time intervals during treatment; and (d) identifying pharmacodynamic biomarkers (including, but not limited to, B cell receptor (BCR) and T cell receptor (TCR) clonality, cytokines, chemokines, and complement proteins) at baseline and at different time intervals during treatment.

[0348] The first part of the trial evaluates the administration of the single agent AB79 for dose-limiting toxicity (DLT) to determine the MTD or RP2D for further assessment in the Phase 2a. The recommended dose below the MTD is identified based on the scrutiny of safety, PK, PD (e.g., CD38 occupancy), and clinical data from the first part of the trial. The safety and tolerability of AB79 are assessed by recording and analyzing TEAE, dose modifications, treatment discontinuation, vital signs, physical examinations, serum chemistry and hematology, urine tests, ECG, and concomitant medications. In Phase 1, approximately 6 doses of AB79 are evaluated in ascending cohorts of 3 - 6 patients per cohort. The cohorts can be expanded by enrolling additional patients to further clarify the selection of the RP2D before enrolling in the second part of the trial. In the second part of this trial, grade 4 or higher non-hematological toxicities are monitored starting from the first 10 enrolled patients and then every 10 patients thereafter. Additionally, patient cohorts receive AB79 in combination with the backbone regimen of pomalidomide and dexamethasone (PomDex) in patients with RRMM who have received at least two prior treatments and are refractory to their last pre-study therapy.

[0349] Approximately 100 patients are enrolled in the trial (approximately 55 patients in Phase 1 and 45 patients in Phase 2a). The maximum duration of treatment is expected to be 12 months for patients receiving monotherapy and approximately 18 months for patients in the combination cohorts. However, patients with clinical benefit (as determined by the investigator and approved by the sponsor's medical monitor) may continue treatment with the explicit approval of the sponsor's medical monitor.

[0350] Increase the AB79 injection in the first phase as follows: 45 mg, 135 mg, 300 mg, 600 mg, 1200 mg, and 1800 mg incrementally. After the patient has received premedication treatment, administer the dose by syringe as an SC injection up to a maximum of 200 mg of AB79 in 2 mL per injection. For multiple SC injections due to the dose levels required to administer the total prescribed dose (i.e., 300 mg dose and above), administer the dose on Day 1 of Cycle 1 by giving each SC injection at 30-minute intervals until the total planned dose has been administered. On all drug administration days after Day 1 of Cycle 1, if the patient does not have IR, give the SC injections simultaneously without a waiting period. For the first phase, administer each dose of AB79 subcutaneously in each 28-day treatment cycle as once every other week for 8 weeks (8 doses), then once every 2 weeks for 16 weeks (8 doses), and then once every 4 weeks until PD or unacceptable toxicity occurs. The patient receives ongoing treatment with AB79 until PD, unacceptable toxicity, or dropout due to other reasons. Administer PomDex only in the first phase combination cohort according to the package insert. See Table 3.

[0351] For the second part of the second phase (2a), select the dose based on a review of the available safety, efficacy, PK, and PD information from the first phase of the trial in the absence of DLT. Premedication is mandatory in the first and second parts of the second phase (2a).

[0352] The trial provides a confirmation cohort and a combination cohort. In each cohort, a dose of 300 mg of AB79 is administered subcutaneously once every other week for 8 weeks (8 doses) between Cycles 1 and 2, once a week for 16 weeks (8 doses) between Cycles 3 - 6, and then once every 4 weeks until PD in subsequent cycles. At least 6 patients in each subgroup are examined for safety, available efficacy, PK, and pharmacodynamics after receiving one cycle of treatment and then based on what is ongoing. Additionally, approximately 12 patients with RRMM disease who have not received an anti - CD38 agent are enrolled in this cohort. The combination cohort also receives pomalidomide and dexamethasone (PomDex) and is given according to the product label (Pomalyst USPI). Dexamethasone is administered IV or orally at 40 mg / day on Days 1, 8, 15, and 22, or for patients over 75 years old, given at 20 mg / day on Days 1, 8, 15, and 22 (Pomalyst USPI, Section 14.1). In the combination cohort, up to 6 patients are initially enrolled and the safety in Cycle 1 is examined. If DLT occurs in 0 out of 6 or 1 out of 6 patients, an additional 12 patients [6 patients who have not previously received an anti - CD38 agent and 6 patients who have previously been exposed to an anti - CD38 agent] are tested at the initial dose of AB79 for a total of 18 patients. If DLT occurs in 2 out of 6 patients, an additional cohort of 6 patients is tested at a tapered dose. Intermediate or more conservative dosing schedules can also be implemented as a means to provide an overall lower dose. Lower doses of pomalidomide are also determined based on available safety data. If AB79 - related DLT occurs at a revised dose in 0 out of 6 or 1 out of 6 patients, an additional cohort of up to 12 patients (eligible as described above for anti - CD38 naive or exposed) is tested at this dose level (i.e., a lower dose than the initial dose, intermediate, or more conservative than the initial dose) or a conservative dosing schedule, and a total of 18 patients are tested at a lower dose / conservative dosing schedule.If DLT occurs at a lower dose in 2 out of 6 patients, this cohort is stopped for further evaluation.

[0353] Patients in the Phase 1 dose-escalation cohort consist of adult patients with RRMM who have been previously treated with at least PI, IMiD, and steroids. Patients have either a refractory disease or are intolerant to at least 1 PI and at least 1 IMiD, and if one of these therapies included a combination of PI and IMiD, the patient should have received either 3 or more prior treatments or 2 or more prior treatments. Patients who have previously undergone autologous stem cell transplantation will be additionally exposed to alkylating agents, while patients who have not previously undergone autologous stem cell transplantation may not be exposed to alkylating agents according to standard practice. Up to 6 patients are refractory to anti-CD38 agents, and approximately 12 patients in this cohort are anti-CD38 naive.

[0354] Patients in the Phase 1 combination cohort consist of adult patients with RRMM who have received at least 2 prior treatments including lenalidomide and a proteasome inhibitor and demonstrated PD at or within 60 days of completion of the last therapy. The first 6 patients enrolled have not previously received or may have been previously exposed to an anti-CD38 antibody. Once safety data have been reviewed, the following patients enrolled at the RP2D / MTD are patients who have not previously received (approximately 6 patients) or have been previously exposed to (approximately 6 patients) an anti-CD38 monoclonal antibody.

[0355] Pre-dose medications: Phase 1 dose-escalation and dose-confirmation cohorts Patients will receive the following premedication 1 to 3 hours before the start of AB79 administration on each dosing day. Dexamethasone: an IV dose of approximately 20 mg for the first injection. Oral dexamethasone (approximately 20 mg) or an equivalent long-acting corticosteroid can be used before subsequent injections. Antipyretic: oral acetaminophen (650 - 1000 mg); antihistamine: oral or IV diphenhydramine (25 - 50 mg, or equivalent); montelukast 10 mg (or an equivalent leukotriene inhibitor). For patients with a history of COPD, post-injection medications (such as short-acting and long-acting bronchodilators and inhaled corticosteroids) can be prescribed. After the first 4 injections, if the patient does not experience a major IR, these additional inhaled post-injection medications can be discontinued.

[0356] Premedication: only in the first combination cohort (AB79-PomDex) Patients will receive the following premedication 1 to 3 hours before the start of AB79 administration on each dosing day. Antipyretic: oral acetaminophen (650 - 1000 mg); antihistamine: oral or IV diphenhydramine (25 - 50 mg, or equivalent); montelukast 10 mg (or an equivalent leukotriene inhibitor). For patients with a history of COPD, post-injection medications (such as short-acting and long-acting bronchodilators and inhaled corticosteroids) can be prescribed. After the first 4 injections, if the patient does not experience a major IR, these additional inhaled post-injection medications can be discontinued.

[0357] Post-administration medications Apply corticosteroid cream topically to the injection site(s), and apply ice topically for approximately 10 - 15 minutes. Patients can receive low-dose methylprednisolone (<20 mg) for the prevention of reactions associated with delayed injection as clinically indicated after injection.

[0358] Main criteria for inclusion The main criteria for inclusion are as follows. Male and female patients with an ECOG performance status of ≤ 2, aged 18 years or older, who require additional therapy as determined by the investigator. Patients must have received the final dose of the following treatments / procedures within the specified minimum interval prior to the first dose of AB79: 180 days for antibody therapy (including anti-CD38); 90 days for autologous transplantation; 14 days for chemotherapy, radiotherapy, and major surgery; and 7 days for corticosteroid therapy (up to the systemic equivalent of 10 mg of prednisone per day). Patients must have the following clinical laboratory values: absolute neutrophil count ≥ 1.0 × 10 9 / L; platelets ≥ 75,000 / mm 3 (≥ 75 × 10 9 / L); Hemoglobin ≥ 7.5 g / dL; Creatinine clearance ≥ 30 mL / min (Cockcroft-Gault formula); Total bilirubin ≤ 1.5 times the upper limit of the normal range (ULN); and Alanine aminotransferase / Aspartate aminotransferase ≤ 2.5 × ULN, must have appropriate organ function as determined. Patients must have RRMM documented according to the IMWG criteria and have a measurable disease defined as one of the following: Serum M protein ≥ 0.5 g / dL (≥ 5 g / L) and Urine M protein ≥ 200 mg / 24 hours. Patients without measurable M protein on serum protein electrophoresis or urine protein electrophoresis must have serum free light chain (FLC) assay results with an abnormal serum FLC ratio and an involved FLC level ≥ 10 mg / dL (≥ 100 mg / L). Patients must have evidence of RRMM as defined by the IMWG criteria. For patients in the escalation cohort and the confirmation cohort, they must have received prior myeloma therapy including proteasome inhibitors (PI), immunomodulatory drugs (IMiD), and steroids; be refractory or intolerant to at least one PI and at least one IMiD; and have received either ≥ 3 regimens of prior treatment or, if one of those prior treatments included the combination of PI and IMiD, then received at least 2 regimens of prior treatment; In the first phase, prior exposure to anti-CD38 agents as a single agent or in combination is possible but not required for patients in the escalation cohort. Patients in the combination cohort only must have received prior treatment with ≥ 2 anti-myeloma pre-therapies; have either relapsed disease or relapsed and refractory disease; progressed at the completion of the last anti-myeloma therapy or within 60 days of it; Patients may have either not received an anti-CD38 monoclonal antibody or been previously exposed to it; There are cohorts of patients refractory to at least one anti-CD38 mAb therapy at any time during treatment and patients who have never received an anti-CD38 mAb before.In the second part of the Phase 2a trial, the two largest cohorts of RRMM patients can be enrolled: a cohort refractory to at least one anti-CD38 mAb therapy at any time during treatment, and a cohort that has never received an anti-CD38 mAb previously.

[0359] Primary and secondary endpoints: In Phase 2a, treat approximately 48 additional patients (up to 24 patients with untreated anti-CD38 RRMM and up to 24 patients with RRMM refractory to anti-CD38 therapy) to provide a preliminary prediction of the ORR in two expanded cohorts of RRMM patients. The Phase 2a of the trial will also provide a more reliable prediction of the safety profile at the MTD / RP2D.

[0360] A forward calculation of statistical power has not been performed, but the following table shows the width of the 80% CI for the range of observed response rates based on the ORR observed in a cohort size of 24 patients.

[0361] [Table 11]

[0362] Definition of DLT Toxicity is evaluated according to NCI CTCAE (version 4.03, effective June 14, 2010). DLT is defined as any of the following events, regardless of relevance, except for events clearly attributable to external causes. Grade 4 clinical laboratory abnormalities, except for those clearly attributable to external causes; NCI CTCAE grade ≥ 3 non-hematological TEAE (excluding grade 3 nausea / vomiting that can be subsequently managed with anti-emetics (grade 3 nausea or vomiting that persists for more than 48 hours with or without appropriate medical intervention); grade 3 fatigue lasting less than 3 days (approximately 72 hours); grade 3 elevation of alanine aminotransferase or aspartate aminotransferase that resolves to grade ≤ 1 or baseline within 7 days; grade 3 IR without recurrence of symptoms that responds to symptomatic treatment (e.g., antihistamines, non-steroidal anti-inflammatory drugs (NSAIDs), narcotics, IV fluids), except for events clearly attributable to external causes and occurring during the first cycle; NCI CTCAE grade ≥ 4 hematological TEAE (excluding grade ≥ 3 hemolysis, excluding events clearly attributable to external causes (e.g., negative direct Coombs test); grade ≥ 3 low platelet count accompanied by clinically significant bleeding defined as > 100 cc of blood loss or the need for transfusion); incomplete recovery from treatment-related toxicity resulting in a delay of > 2 weeks in the next scheduled injection before the start of cycle 2.

[0363] For the purpose of dose escalation, a DLT occurring before the administration on day 1 of cycle 2 is an event that meets the above criteria. A TEAE that meets the DLT definition occurring in a subsequent cycle determines the suitability of the MTD as the RP2D.

[0364] Patients who experience a DLT will drop out of the study treatment unless the study sponsor approves subsequent treatment in a lower dose cohort, and such patients will not be counted as patients in that lower dose cohort for the escalation decision.

[0365] In the first phase, for patients who do not receive all four doses of AB79 within the 28-day (±2) treatment window or on day 29 (i.e., cycle 2, day 1) due to assessment for reasons other than DLT, they will be replaced. Patients who experience DLT will not be replaced.

[0366] Use a 3+3 dose escalation schema to explain dose escalation decisions and MTD / RP2D estimation. First, enroll 3 patients at the starting dose level. If none of the patients in the cohort of 3 patients show DLT during the 28-day cycle, then the dose can be escalated for the next cohort of 3 patients. If 1 patient in the cohort of 3 patients shows DLT, then expand this cohort to a total of 6 patients. If ≤1 of the 6 patients experiences DLT, continue the escalation to the next higher dose level and enroll 3 patients there. If 2 or more patients (2 or more out of 3 or 2 or more out of 6) experience DLT, taper the dosing to the next lower dose level and, if 3 patients were being treated at that dose level, enroll 3 additional patients there. If 6 patients are enrolled at a lower level of DLT of ≤1 out of 6, stop the dosing and this dose level can be judged as the MTD. The MTD is defined as the highest dose in a cohort of 6 patients with ≤1 DLT patient.

[0367] For all cohorts, treatment uses a 28-day cycle length. For a new cycle of treatment to start, the patient must meet the following criteria. (a) The absolute neutrophil count must be ≥1000 / mm 3 and must be; the platelet count must be ≥75,000 / mm 3It must be; (c) To resume treatment, the toxicity determined to be related to the treatment with AB79 must heal to Grade ≤ 1 or baseline, or to a level determined to be acceptable by the physician. If the patient does not meet the criteria cited for retreatment, delay the start of the next treatment cycle by one week. At the end of that week, re-evaluate the patient to determine whether the criteria for retreatment have been met. If a subsequent cycle delay longer than 28 days is due to drug-related AE, the patient may be withdrawn from the treatment by agreement of the sponsor's medical monitor, unless there is a clinical benefit as assessed by the investigator. And (d) For AB79 injections within the same cycle, the decision to withhold treatment is left to the discretion of the investigator, based on clinical data and analytical data, and also based on the toxicity experienced by the patient from previous injections during the same cycle. The investigator should distinguish between acute toxicity (such as IR) from which the patient has recovered at the time of the next injection and subacute toxicity (such as neutropenia) which may worsen during another injection when there is no clear recovery. If the dose cannot be administered on the scheduled day, the investigator may, at their discretion, examine the patient within 48 hours. If AB79 cannot be administered within the cycle during this 48-hour window, skip the dose and schedule the next dose for the patient.

[0368] Patients who experience AE due to AB79 may continue the test treatment with the same dose, withhold the AB79 treatment, or permanently discontinue the trial. Patients who withhold the test drug due to treatment-related AE or AE that may be treatment-related may resume test drug treatment after the AE has healed at the same dose level or at a reduced dose, depending on the nature and severity of the AE and whether it is a first occurrence or recurrent.

[0369] Safety and disease assessment In the second part of this Phase 2a trial, non-hematological toxicities of grade 4 or higher are monitored starting from the first 10 registered patients, and then every 10 patients. If the stopping boundaries of ≥4 / 10 and ≥6 / 20 are reached, accrual to the trial is put on hold to enable investigation. After consideration by the study team, a decision is made as to whether accrual can be resumed. The boundaries are based on the Bayes method for monitoring outcomes in clinical trials. If the stopping rules are met, the parameters for the toxicity rate of the binomial distribution are given by the prior beta distribution with parameters 0.4 and 1.6, such that the probability that the true toxicity rate exceeds 18% is 80%.

[0370] Primary evaluation items For Phase 1, the primary evaluation items in order of importance are: the number of patients with TEAE overall and per dose level; patients with DLT at each dose level; patients with TEAE of grade ≥3; patients with SAE; patients discontinued due to TEAE; and patients with dose modification (delay, interruption, dose reduction).

[0371] The primary evaluation item for Phase 2a is the ORR, defined as the proportion of patients who achieved at least a partial response (PR) during the trial, as defined by the IMWG Uniform Response Criteria.

[0372] The primary evaluation items for Phase 1 are the RP2D based on both safety and efficacy outcomes as a single agent and when added to the backbone regimen of PomDex; summary statistics for the following PK parameters as a single agent and when added to the backbone regimen of PomDex (measured maximum concentration (C max ); C max at the time (t max when it first occurs); area under the concentration-time curve (AUC last));The ORR, defined as the proportion of patients with MM who were evaluated and achieved ≥ PR (≥ 50% tumor reduction) during the trial as defined by the IMWG Uniform Response Criteria), while receiving AB79 as a single agent and in combination with PomDex; the proportion of patients who achieved a minimal response (MR) defined as a 25% tumor reduction (including patients with measurable disease by serum FLC); and the incidence and characteristics of anti-AB79 antibodies.

[0373] The primary endpoints for the Phase 2a were the frequency of DLT-like and other TEAEs occurring over the course of extended treatment with AB79 (including dose modification, treatment discontinuation, and information on vital signs); the following PK parameters: C max , t max , and AUC last summarized statistics; the incidence and characteristics of anti-AB79 antibodies; assessment of the proportion of patients who achieved an MR defined as a 25% tumor reduction; duration of response (DOR) (defined as the time from the date of the first response report to the date of the first PD report); progression-free survival (PFS) (defined as the time from the date of the first dose to the earliest date of PD (as defined by the IMWG criteria) or the date of death from any cause); overall survival (OS) (defined as the time from the date of the first dose to the date of death from any cause); and time to response (defined as the time from the date of the first dose to the date of the first response (≥ PR) report).

[0374] The exploratory evaluation items in the first phase and part 2a of the trial are to explore biomarkers that can examine the correlation with clinical efficacy and safety parameters, including CD38 expression on MM cells and other immune cells before and during the treatment; the pharmacodynamic profile of AB79 on immune cells (including CD38 occupancy); immunophenotypic analysis of BMA and / or whole blood cells containing CD38+ immune cells at baseline and at different time intervals during treatment; and pharmacodynamic biomarkers (including but not limited to BCR and TCR clonality, cytokines, chemokines, and complement proteins) at baseline and at different time intervals during treatment.

[0375] Primary specimen collection for PK, pharmacodynamic, and biomarker assessment Blood samples are collected (except for BMA) via venipuncture or indwelling catheter at various time points for measurement of the serum concentration of AB79 and biomarker assessment.

[0376] Measurement of PK Serum samples for measurement of the concentration of AB79 are collected at multiple time points. If it is determined that a change in the sampling scheme is necessary to better characterize the PK profile of AB79, the timing of the samples, rather than the total number of samples, can be modified during the trial based on the new PK data.

[0377] Biomarker and pharmacodynamic measurement Multiple biomarkers are assayed and examined for correlation with safety, PK, and, if possible, efficacy. These biomarkers are used to identify patients with a higher probability of response or adverse reactions to AB79. The markers under study are markers associated with either the drug itself or the disease being treated. Markers of immune system activation are summarized using descriptive statistics.

[0378] Pharmacodynamic and CD38 occupancy measurement BMA samples are collected at the start of cycles 2, 4, 7, and 13 for analysis of CD38 expression on the surface of MM cells at screening. The assessment of CD38 occupancy on MM cells in BMA is performed during treatment. The BMA samples collected at the start of cycles 2, 4, 7, and 13 are also used for analysis of CD38 occupancy on MM cells. The assessment of occupancy is performed monolithically. Residual cells from these samples are used for molecular characterization, including but not limited to the impact of Fcγ receptor polymorphisms on efficacy, and the safety of AB79, and genotyping of the binding epitope of AB79.

[0379] The assessment of CD38 occupancy measures the extent of CD38 occupancy by AB79 on the surface of circulating CD38-expressing surrogate cells (e.g., PB, NK cells, and monocytes).

[0380] Blood samples for flow cytometry are drawn on day 1 of all cycles and at follow-up visits. These blood samples are analyzed by flow cytometry for the presence and changes of immune cells (such as B lymphocytes and T lymphocytes, monocytes, and NK cells, etc.). Blood samples are collected before dosing and 24 hours after the first injection in cycles 1 and 2, and then before dosing at each subsequent indicated clinic visit. Residual cells from these samples are used for molecular characterization, which will include but not be limited to the impact of Fcγ receptor polymorphisms on efficacy, and the safety of AB79, and genotyping of the binding epitope of AB79.

[0381] Assessment of ADA Serum samples for the assessment of anti-AB79 immunogenicity are collected at various time points. Blood samples are collected before the administration of AB79 (i.e., before dosing on Day 1; baseline value), then subsequently before each designated clinic visit for AB79 dosing (post-baseline value), and at the clinic visit of any patient who experiences a TEAE determined by the investigator to be consistent with hypersensitivity / IR. Samples are first screened for ADA titer. If a sample is detected as ADA positive, it can be assayed for neutralizing activity.

[0382] Direct Coombs test and indirect Coombs test Serum samples for the direct Coombs test and indirect Coombs test are collected at various time points.

[0383] Completion of the investigational treatment (for individual patients) Patients receive AB79 until they experience PD, unacceptable toxicity, withdrawal of consent, death, or termination of the study by the sponsor. Patients have a follow-up clinic visit 30 days after the last dose of the investigational drug or prior to the initiation of subsequent alternative anticancer therapy to enable detection of any delayed AEs. Patients who discontinue investigational treatment for reasons other than PD continue PFS follow-up every 4 weeks from EOT until either PD occurs, death, initiation of subsequent anticancer therapy, study termination, or 12 months after discontinuation of investigational treatment, whichever occurs first. Patients are followed up for OS every 12 weeks until death, loss to follow-up, withdrawal of consent, or study termination. The duration of the study is approximately 42 months (3.5 years).

[0384] Discontinuation of treatment with the investigational drug and patient replacement The following criteria: a patient experiences an AE, or other medical condition indicating to the treating investigator that continued participation is not in the patient's best interest; patient withdrawal; and confirmation of pregnancy in a female patient; for any patient meeting any of these, permanently discontinue the investigational drug. Treatment with the investigational drug may also be discontinued for the following reasons: AE / SAE; deviation from the trial implementation protocol; PD; symptom exacerbation; inadequate treatment response; trial terminated by the sponsor; loss of follow-up; or other; for any of these.

[0385] Prior to completing the entire treatment course, some patients may discontinue the investigational drug for reasons other than PD. These patients will remain in the trial for post-treatment PFS assessment until PD occurs.

[0386] Adverse event Definition of pre-treatment event A pre-treatment event is any unfavorable medical occurrence in a patient or subject prior to the administration of any investigational medicinal product, for which consent has been signed based on a sufficient explanation for participating in the trial, and which does not necessarily have a causal relationship with trial participation.

[0387] Definition of adverse event (AE) An AE means any unfavorable medical occurrence in a patient or subject to whom a medicinal product has been administered, and an unfavorable medical occurrence does not necessarily have a causal relationship with this treatment. Thus, an AE can be any adverse, unintended sign (including abnormal clinical laboratory findings), symptom, or disease that is temporarily associated with the use of a medicinal (investigational) product, whether or not it is related to the medicinal product. This includes any newly occurring event, or an existing condition, with an increase in severity or frequency after administration of the investigational drug. Abnormal clinical laboratory values will not be assessed as AEs unless the value leads to discontinuation or delay in treatment, dose modification, treatment intervention, or is judged by the treating investigator to be a clinically significant change from baseline.

[0388] Definition of serious adverse event (SAE) SAE means any adverse medical event that, at any dose, (a) results in death; (b) is life-threatening (referring to an AE where the patient was at risk of death at the time of the event. It does not refer to an event that would have caused death if it had been more severe); (c) requires hospitalization of an inpatient or prolongation of an existing hospitalization; (d) results in persistent or significant disability (defined as substantial disruption of the ability of a person to perform normal life functions) or incapacity; (e) is a congenital anomaly / birth defect; or (f) is a medically important event. (f) refers to an AE that does not result in death, that is not immediately life-threatening or require hospitalization, but that, based on appropriate medical judgment, may endanger the patient, require medical or surgical intervention to prevent one of the outcomes listed above, or is judged to be serious when there is suspicion of transmission via a pharmaceutical product of an infectious agent. Examples of such medical events include allergic bronchospasm requiring intensive treatment in the emergency room or at home, blood disorders or convulsions that do not result in hospitalization of an inpatient, or the onset of drug dependence or drug abuse. Any organism, virus, or infectious particle (e.g., prion protein that transmits transmissible spongiform encephalopathy), whether pathogenic or non-pathogenic, is considered an infectious agent.

[0389] In this study, the severity of each AE, including any clinical laboratory abnormalities, was determined using NCI CTCAE (version 4.03, effective June 14, 2010). Since the terms severe and serious are not synonyms, clarification is made between SAEs and AEs that are determined to be severe (grade 3 or 4). The general term serious is often used to describe the severity of a specific event, but the event may itself have relatively minor medical significance (e.g., grade 3 headache, etc.). This is not the same as serious, which is usually associated with an event that threatens the patient's life or ability to function, based on the patient / event outcome or activity criteria described above. A severe AE (grade 3 or 4) does not necessarily need to be judged as serious. For example, 1000 / mm 3 ~<2000 / mm3 The white blood cell count is determined to be Grade 3 (severe), but it may not be determined to be severe. The severity (not the degree) is provided as a guide for the definition of the regulatory reporting obligation.

[0390] Potential risk Based on the mechanism of action of AB79, potential AEs may include injection or injection site reactions (IR), cytokine release syndrome (CRS), hematological effects, and infections.

[0391] IR is potentially a dose-limiting AE and is often associated with the IV administration of biological agents targeted at the treatment of hematological malignancies. The frequency of IR associated with SC injection of these therapies is lower. Antibody-mediated "true" clinical hypersensitivity reactions occur after repeated exposure. The symptoms of hypersensitivity range from mild skin rashes to more severe reactions, wheezing, hypotension, inadequate perfusion, respiratory arrest, and rarely death. Non-anaphylactic clinical hypersensitivity occurs within the first hour, but delayed responses have been reported. The symptoms of anaphylaxis, a potentially life-threatening condition, range from swelling, angioedema, bronchospasm, dyspnea, and shock.

[0392] CRS represents a significant IR often associated with the use of monoclonal antibodies used in anti-inflammatory drugs and anti-tumor therapies. CRS can occur early in the course of treatment and is often caused by the involvement and proliferation of T cells, which can lead to high levels of activation of the immune system and an increase in cytokine release. It can occur in many cases after the first injection of the drug. The characteristic feature of CRS is fever. CRS also presents with rash, urticaria, headache, chills, fatigue, nausea, and / or vomiting. Severe cytokine release syndrome (SCRS) is characterized by severe dyspnea and is often accompanied by fever, chills, rigors, urticaria, and angioedema in addition to bronchospasm and hypoxia. This syndrome is accompanied by some features of tumor lysis syndrome (such as hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, and elevated lactate dehydrogenase, etc.) and can be accompanied by acute respiratory failure and death. Acute respiratory failure can be accompanied by events such as interstitial lung infiltration or interstitial pulmonary edema that can be seen on chest X-ray. The syndrome frequently appears within 1 to 2 hours of the start of the first infusion. Patients with a history of lung dysfunction or those with lung tumor infiltration are at high risk of poor outcomes and are treated with great care. Patients who develop SCRS should immediately discontinue the medication and receive aggressive symptomatic treatment.

[0393] Hematological effects may include reduction of platelets, lymphocytes, and RBCs.

[0394] Bacterial and / or viral infections secondary to immunosuppression (such as nasopharyngitis or upper respiratory tract infections, etc.) may be observed.

[0395] PK Analysis PK parameters are estimated using non-compartmental analysis methods. The parameters are calculated using the concentration-time data of AB79 for individual patients included in the PK analysis set. The calculated PK parameters include C max , t max , and AUC lastThese may include, but are not limited to (as permitted by the data). Summarize the PK parameters using descriptive statistics. Present the individual AB79 concentration-time data and individual PK parameters in a list and aggregate them using summary statistics by dose cohort. Plot the individual and mean concentration-time profiles by dose cohort. The PK data collected in this study may also contribute to future population PK analyses of AB79. These population PK analyses may include data collected in other AB79 clinical trials. The analysis plans for the population PK analyses are defined separately, and the results of these analyses are reported separately. Similarly, the time-matched PK and triple ECG data collected in this study may contribute to future concentration-QT intervals corrected for heart rate (QTc) analysis. These analyses may include data collected in other AB79 clinical trials. The analysis plans for the concentration-QTc analysis are defined separately, and the results are reported separately.

[0396] Measurement of Biomarkers Collect serum samples to monitor changes in circulating biomarkers (biomarkers including, but not limited to, cytokines, chemokines, and complement proteins) during treatment. These biomarkers may be used to identify patients with a higher probability of experiencing efficacy or adverse reactions to AB79. Perform biomarker sample analysis if required or when requested. Since new techniques are continuously being developed, the methods and clinical assays recommended for biomarker analysis cannot be predicted.

[0397] Collect serum samples for the assessment of circulating biomarkers at the time of the study visit. Collect blood samples as follows. · Day 1 of Cycle 1: Before dosing and approximately 24 hours after the first injection. · Days 8, 15, and 22 of Cycle 1: Before dosing. · Day 1 of Cycle 2: Before dosing and approximately 24 hours after the first injection. · Days 8, 15, and 22 of Cycle 2: Before dosing. · Day 1 of Cycle 3 and Day 1 of each subsequent cycle: Before dosing. · Visit at EOT.

[0398] Immunogenicity analysis AB79 immunogenicity is analyzed using the immunogenicity analysis set by determination of the proportion, incidence, and characteristics (e.g., titer, transient and persistent nature of ADA; and potential of neutralizing activity) of patients with positive ADA (transient and persistent), as well as the proportion of patients in Phase 2a with positive neutralizing ADA. NAB is also assayed in patients. The analysis is based on data available from patients with baseline assessment and at least one post-baseline immunogenicity assessment. If possible, the impact of anti-AB79 antibodies on PK profile, drug efficacy, and clinical safety is evaluated.

[0399] Efficacy analysis The preliminary efficacy of AB79 for MM is evaluated by ORR (defined as the proportion of patients achieving PR or better during the trial), as well as measurement of the components of sCR, CR, VGPR, and PR, as defined by the IMWG Uniform Response Criteria. MR will also be analyzed. In addition, the efficacy of AB79 is assayed in patients by measurement of DOR, PFS, and 1-year OS. TTR will also be measured.

[0400] IMWG criteria IMWG definition of MM: Clonal plasma cells ≥ 10% * or plasmacytoma or extramedullary plasmacytoma proven by biopsy *(Clonality is established by demonstrating kappa lambda light chain restriction by flow cytometry, immunohistochemistry, or immunofluorescence. The bone marrow plasmacyte percentage should preferably be estimated from a core biopsy sample; in cases where there is a discrepancy between aspirate and core biopsy, the highest value is used) and any one or more of the following events that define multiple myeloma. (a) Evidence of end-organ damage that can be specifically attributed to an underlying plasma cell proliferative disorder; (b) Hypercalcemia: Serum calcium > 0.25 mmol / L (> 1 mg / dL) higher than the upper limit of the normal range, or > 2.75 mmol / L (> 11 mg / dL); (c) Renal insufficiency: Creatinine clearance < 40 mL per minute or serum creatinine > 177 μmol / L (> 2 mg / dL); anemia: Hemoglobin value > 20 g / L below the lower limit of the normal value, or hemoglobin value < 100 g / L; (d) Bone lesions: One or more osteolytic lesions on skeletal radiography, CT, or PET CT (if there are < 10% clonal plasma cells in the bone marrow, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal bone marrow involvement); (e) Any one or more of the following biomarkers of malignancy: (i) Clonal bone marrow plasmacyte percentage ≥ 60%; (ii) Tumoral (involved) serum free light chain:Ratio of non-tumoral (uninvolved) serum free light chain § (FLC) ≥ 100; (iii) > 1 focal lesion on MRI study (these values are based on the serum Freelite assay (Binding Site Group, Birmingham, UK). Tumoral FLC must be ≥ 100 mg / L. Each focal lesion must be ≥ 5 mm in size). See Table 12.

[0401] [Table 12-1]

[0402] [Table 12-2]

[0403] PD is defined as an increase of ≥ 25% from the low response value of any of the following: (a) serum M protein (absolute increase must be ≥ 0.5 g / dL); if the starting M component is ≥ 5 g / dL, an increase in serum M component of ≥ 1 g / dL is sufficient to define recurrence, and / or (b) urinary M protein (absolute increase must be ≥ 200 mg / 24 h), and / or (c) for patients with no measurable serum and urinary M protein levels only: the difference between the neoplastic and non-neoplastic FLC levels (absolute increase must be > 10 mg / dL); (d) percentage of bone marrow plasma cells (absolute percentage must be ≥ 10%) only in patients with no measurable serum and urinary M protein levels and no measurable disease by FLC levels. Alternatively, PD is defined as an increase of ≥ 25% from the low response value of any of the following: (a) clear onset of new bone lesions or soft tissue plasmacytomas, or clear increase in size of existing bone lesions or soft tissue plasmacytomas, or (b) onset of hypercalcemia (corrected serum calcium > 11.5 mg / dL) attributable solely to a plasma cell proliferative disorder.

[0404] Clarification of the IMWG criteria for coding PD: The bone marrow criteria for PD should be used only for patients with no measurable disease by M protein and FLC levels. "25% increase" refers to M protein, FLC, and bone marrow results and not to bone lesions, soft tissue plasmacytomas, or hypercalcemia, and the "lowest response value" need not be a confirmed value.

[0405] The ECOG scale for performance status is provided in Table 13.

[0406]

Table 13

[0407] Clinical chemistry, hematology, and urinalysis Clinical chemistry and blood parameters for blood sample analysis, as well as parameters for urine sample analysis, are shown below in the table.

[0408] For patients in the cohort receiving AB79 monotherapy, perform the following tests shown in Tables 14 and 15.

[0409] [Table 14]

[0410] [Table 15]

[0411] For the estimation of creatinine clearance, use the following Cockcroft-Gault formula: Estimated creatinine clearance = [(140 - age) × weight](kg) / 72 × serum creatinine (mg / dL)]. For female patients, multiply the result of the above formula by 0.85.

[0412] Perform the following tests shown in Tables 16, 17, and 18 only for patients in the Phase 1 combination cohort (AB79-PomDex) cohort.

[0413] [Table 16]

[0414] [Table 17]

[0415] [Table 18]

[0416] Pre-treatment prognostic risk assessment Collect a blood sample for serum β2-microglobulin at screening to assess the patient's disease state.

[0417] Assessment of disease response Assess the patient for disease response according to the IMWG criteria. In addition, in patients with multiple myeloma measurable by serum free light chain, MR is defined as a reduction of 25% or more and 49% or less in the difference between the neoplastic FLC level and the non-neoplastic FLC level.

[0418] For patients in the Phase 1 combination cohort (AB79-PomDex), perform the following assessments shown in Table 19.

[0419]

Table 19

[0420] Computed tomography / magnetic resonance imaging Perform scans at least at screening and at the time of the EOT visit. All treatment phases and follow-up scans should use the same imaging method used at screening.

[0421] For patients with reported extramedullary disease, perform a whole-body X-ray, a positron emission tomography-computed tomography (PET-CT) scan, a computed tomography (CT) scan (including low-dose CT), or a magnetic resonance imaging (MRI) scan. The screening scan can be performed up to 21 days before the first dose of AB79. However, if the patient undergoes an appropriate imaging examination within 5 weeks from the planned first dose of the investigational drug, that image can be used as the baseline and does not need to be repeated as part of the screening. If disease is reported, then repeat the PET-CT scan, CT scan, or MRI scan as required to report response or PD.

[0422] Additional investigations (X-ray, CT, or MRI) can also be performed at the discretion of the investigator in cases such as bone pain, for example.

[0423] Blood samples for the quantification of Ig (IgM, IgG, and IgA) are obtained at screening, before dosing on Day 1 of all cycles, and at all visits.

[0424] Blood and 24-hour urine samples before dosing are obtained at screening, on Day 1 of all cycles, and at all visits.

[0425] Serum samples are obtained before dosing on Day 1 of all cycles and at all visits for serum FLC assay (including quantification of κ and λ chains and ratio).

[0426] Serum and urine samples are obtained at screening, before dosing on Day 1 of all cycles for CR confirmation, and at all visits for efficacy assessment for serum and urine immunofixation tests.

[0427] BMA is collected during the screening period and at the start of the designated study visits for Cycles 2, 4, 7, and Cycle 13. BMA is obtained at screening for disease assessment (if standard BMA was collected within 5 weeks prior to consent, that BMA can be used as baseline and need not be repeated as part of screening, except if cytogenetic evaluation is not available). BMA will be obtained at any time to assess CR or to investigate suspected PD as needed.

[0428] Patients who do not have a historically reported cytogenetic result for high-risk abnormalities of del(17), t(4:14), and t(14:16) will have a cytogenetic evaluation performed on the BMA sample at screening. The cytogenetic evaluation can be performed using fluorescence in situ hybridization or conventional cytogenetics (karyotype). At a minimum, the cytogenetic markers must include the three high-risk abnormalities of del(17), t(4:14), and t(14:16). Additional abnormalities (ampl 1q, del13, or del1p) can also be tested. Cytogenetics is analyzed locally according to local criteria.

[0429] Results: AB79-1501 trial, AB79 alone, or in combination with pomalidomide and dexamethasone (PomDex) At the data cutoff point, 5 patients were being treated with the combination of AB79+PomDex. At this date, the most common TEAE (≥2 patients), regardless of causality, was neutropenia and cough (2 patients each). There were no systemic reactions or injection site reactions were rare. In the AB79+PomDex cohort, there was 1 DLT (neutropenia) and the evaluation of the MTD is ongoing. No drug-related SAE or AE leading to discontinuation of the study drug or death during the study was reported in combination.

[0430] AB79 demonstrated early signs of antitumor activity, as demonstrated by a minimum response defined as at least a 50% reduction in disease burden in some patients and a 25% - 49% reduction in disease burden in other patients. At the data cutoff point, the preliminary objective response rate (ORR) was 40% and the clinical utility rate (defined as a minor response or greater) was 100%. The duration of response was not estimable.

[0431] Incorporation by reference The content of all cited references (including reference documents, patents, patent applications, and websites) that may be cited through this application is hereby expressly incorporated herein by reference in its entirety for any purpose to the same extent as if each individual reference were specifically and individually indicated to be incorporated by reference in its entirety for any purpose, as is the case with the references cited therein.

[0432] Equivalents The present disclosure may be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the foregoing embodiments are not intended to limit the present disclosure, but should be regarded as illustrative in all respects. Thus, the scope of the present disclosure is indicated not by the foregoing description, but by the appended claims, and it is intended that all changes that come within the meaning and range of equivalence of the claims be embraced within this specification. Modifications for the practice of the invention that are obvious to those skilled in the art are intended to be within the scope of the appended claims.

Claims

**Claim 1** A combination for treating a subject having multiple myeloma, comprising: a) an anti-CD38 antibody or an antigen-binding fragment thereof, b) lenalidomide, and c) dexamethasone, and administered to the subject for a time sufficient to treat multiple myeloma, wherein the anti-CD38 antibody comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8, and wherein the anti-CD38 antibody or its antigen-binding fragment is administered subcutaneously at a dose of about 2 mL or less. **Claim 2** A combination for treating a subject having multiple myeloma, comprising: a) an anti-CD38 antibody or an antigen-binding fragment thereof, b) pomalidomide, and c) dexamethasone, and administered to the subject for a time sufficient to treat multiple myeloma, wherein the anti-CD38 antibody comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light (VL) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8, and wherein the anti-CD38 antibody or its antigen-binding fragment is administered subcutaneously at a dose of about 2 mL or less. **Claim 3** The combination according to claim 1 or 2, wherein the VH chain region has the amino acid sequence of SEQ ID NO: 9 and the VL chain region has the amino acid sequence of SEQ ID NO:

10. **Claim 4** The combination according to claim 1 or 2, wherein the anti-CD38 antibody or its antigen-binding fragment comprises the heavy chain amino acid sequence of SEQ ID NO: 11 and the light chain amino acid sequence of SEQ ID NO:

12. **Claim 5** The combination according to any one of claims 1 to 3, wherein the anti-CD38 antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype. **Claim 6** The combination according to claim 5, wherein the anti-CD38 antibody is of the IgG1 isotype. **Claim 7** The combination according to claim 1 or 2, wherein the anti-CD38 antibody or antigen-binding fragment thereof is fully human.

8. The combination according to claim 1, wherein the multiple myeloma is newly diagnosed multiple myeloma (NDMM) or untreated multiple myeloma.

9. The combination according to claim 8, wherein the CD38-positive blood cancer is newly diagnosed multiple myeloma (NDMM), and the subject is a patient in whom stem cell transplantation is not planned as an initial treatment method.

10. The combination according to claim 1 or 2, wherein the multiple myeloma has not been previously treated with multiple myeloma drugs.

11. The combination according to claim 1, wherein the subject has refractory or relapsed multiple myeloma (RRMM).

12. The combination according to claim 1 or 2, wherein the anti-CD38 antibody or antigen-binding fragment thereof is administered once a week at a dose of about 300 mg for two treatment cycles, once every two weeks at a dose of about 300 mg for the subsequent four treatment cycles, and once every four weeks at a dose of about 300 mg for any subsequent treatment cycles, and one treatment cycle is 28 days.

13. The combination according to claim 1 or 2, wherein the anti-CD38 antibody or antigen-binding fragment thereof is administered in the absence of hyaluronidase.

14. The combination according to claim 1, wherein the lenalidomide is administered daily at a dose of about 2.5 to about 25 mg for 21 days of each treatment cycle for up to eight treatment cycles, and one treatment cycle is 28 days.

15. The combination according to claim 1 or 14, wherein the lenalidomide is administered orally.

16. The combination according to claim 2, wherein the pomalidomide is administered daily at a therapeutically effective dose for 21 days of each treatment cycle for up to eight treatment cycles, and one treatment cycle is 28 days.

17. The combination according to claim 1 or 16, wherein the pomalidomide is administered orally.

18. The combination according to claim 1 or 2, wherein the dexamethasone is administered once a week at a dose of about 20 to 40 mg for 1 to 8 treatment cycles, and one treatment cycle is 28 days.

19. The combination according to claim 18, wherein the dexamethasone is administered once a week at a dose of about 40 mg for 1 to 8 treatment cycles, and one treatment cycle is 28 days.

20. The combination according to any one of claims 18 or 19, wherein the dexamethasone is administered orally or intravenously.

21. The combination according to claim 1, further comprising administering a therapeutically effective amount of bortezomib.

22. The bortezomib is administered once a week at a dose of about 0.7 to 1.3 mg / m ２ for 3 weeks out of 1 to 8 treatment cycles, and the one treatment cycle is 28 days, the combination according to claim 21.

23. The combination according to claim 21 or 22, wherein the bortezomib is administered subcutaneously.

24. a) the anti-CD38 antibody or antigen-binding fragment thereof is administered on days 1, 8, 15, and 22 of the first two treatment cycles, days 1 and 15 of the subsequent four treatment cycles, and day 1 of any additional treatment cycles; b) lenalidomide is administered on days 1 to 21 of each treatment cycle; and c) the dexamethasone is administered on days 1, 8, 15, and 22 of each of the 1 to 8 treatment cycles, wherein one treatment cycle is 28 days, the combination according to claim 1.

25. a) the anti-CD38 antibody or antigen-binding fragment thereof is administered on days 1, 8, 15, and 22 of the first two treatment cycles, days 1 and 15 of the subsequent four treatment cycles, and day 1 of any additional treatment cycles; b) pomalidomide is administered on days 1 to 21 of each treatment cycle; and c) the dexamethasone is administered on days 1, 8, 15, and 22 of each of the 1 to 8 treatment cycles, wherein one treatment cycle is 28 days, the combination according to claim 2.

26. The combination according to claim 24, further comprising administering a therapeutically effective amount of bortezomib.

27. The bortezomib is administered once a week at a dose of about 0.7 to 1.3 mg / m ２ for 3 weeks out of 1 to 8 treatment cycles, and the one treatment cycle is 28 days, the combination according to claim 26.

28. The combination according to claim 27, wherein the bortezomib is administered on days 1, 8, and 15 of each treatment cycle.

29. The combination according to claim 20, wherein the dexamethasone is administered on days 1, 8, 15, and 22 of each treatment cycle.

30. The combination according to any one of the preceding claims, wherein the subject receives premedication 1 to 3 hours before the start of anti-CD38 antibody administration on each dosing day, and the premedication comprises an antipyretic and an antihistamine.

31. The antipyretic substance is acetaminophen and is administered orally in a dose of about 650 to about 1000 mg The combination according to claim 30, which is administered.

32. The combination according to claim 30 or claim 31, wherein the antihistamine substance is diphenhydramine or an equivalent, and is administered orally or intravenously at a dose of about 25 mg to about 50 mg.

33. The combination according to any one of claims 30 to 32, wherein the premedication further comprises montelukast or an equivalent leukotriene inhibitor.

34. The combination according to claim 33, wherein the montelukast or an equivalent leukotriene inhibitor is administered at a dose of about 10 mg.

Images