Treatment methods for high-risk multiple myeloma

Abstract

The present invention provides a method for treating subjects with multiple myeloma, a method for achieving minimal residual disease (MRP) negativity in subjects with multiple myeloma, and a method for predicting the likelihood of relapse and / or disease progression in subjects with multiple myeloma, or for reducing the risk thereof. [Solution] A method is provided for achieving minimal residual disease (MRP) negativity in a subject with multiple myeloma, comprising administering to the subject therapeutically effective doses of an anti-CD38 antibody, a corticosteroid, and a non-corticosteroid chemotherapeutic agent for a period of time sufficient to achieve MRP negativity.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application was filed on 31 October 2017, and is incorporated in its entirety by reference herein. This asserts the benefits of the U.S. Provisional Application No. 62 / 579,234.

[0002] (Integration by referencing data in ASCII text files) This application is a distribution of the following ASCII text file submitted simultaneously with this application. Incorporate the table by reference. a) File name: 01482024002_SEQUENCELISTING.txt Created on October 31, 2018, size 20KB.

[0003] (Field of invention) Methods for treating patients with high-risk multiple myeloma, and in patients with multiple myeloma Methods to achieve a negative residual disease status. , and predict the likelihood of recurrence and / or disease progression in subjects with multiple myeloma. Methods for preventing or reducing such risks are disclosed. [Background technology]

[0004] Multiple myeloma (MM) is a secretory form in the bone marrow characterized by a low growth index and extended lifespan. This is a B-cell malignancy characterized by the latent accumulation of plasmoplasmic cells. This disease ultimately affects the bone and bone. It attacks the marrow and causes numerous tumors and lesions throughout the skeletal system. It accounts for approximately 1% of all cancers. % and slightly more than 10% of all hematological malignancies may be attributable to MM. The incidence of MM is increasing in the elderly population. The incidence increases, and the median age at diagnosis is approximately 61 years.

[0005] Currently available therapies for MM include chemotherapy regimens, stem cell transplantation, and THALOMI. D (registered trademark) (thalidomide), REVLIMID (registered trademark) (lenalidomide), P OMALYST (registered trademark) (pomaridomide), VELCADE (registered trademark) (vorteso MIBU, NINLARO (registered trademark), IXAZOMIBU, KYPROLIS (registered trademark) (Carfilzomib), FARADYK® (Panobinostat), AREDI A(registered trademark) (pamidronate), ZOMETA(registered trademark) (zoledronic acid), and Examples include DARZALEX® (daratumumab), vincristine, and calamin. Sutene (BCNU), melphalan (Alkeran®), cyclophosphamide Doxorubicin (Adriamycin), and prednisone or dexamethasone. Current treatment protocols, including any combination of chemotherapy agents, have a complete remission rate of only about 5%. Moreover, without any adverse effects, the median survival time is approximately 36-48 months from the time of diagnosis. Recent advances in autologous transplantation of bone marrow or peripheral blood mononuclear cells after chemotherapy have made complete treatment possible. This resulted in increased remission rates and remission duration. Nevertheless, overall survival was only slightly longer. However, the duration has only been extended, and there is still no evidence of a cure. Ultimately, interferon Even under maintenance therapy with IFN-α alone or in combination with steroids, all It is thought that MM patients are likely to experience a relapse.

[0006] The effectiveness of available drug treatment regimens for MM is low in cell proliferation rate and 90% It is limited by the acquisition of drug resistance in affected patients. Chromosomal translocations, oncogene mutations, anti- Dysregulation of signaling pathways such as apoptotic pathways and survival pathways, as well as bone marrow (BM) Niches have been suggested to contribute to drug resistance in MM (see A for an overview). Refer to bdi et al., Oncotarget 4:2186-2207, 2013. (Referring to the luminescence). The BM niche is involved in the proliferation, survival, differentiation, migration, and drug resistance of malignant plasma cells. (Manier et al., J Biomed Biotechnol 20) 12. Published online on October 3, 2012, doi:_10.1155 (2012 / 157496). [Overview of the Initiative] [Means for solving the problem]

[0007] A method for treating a patient with high-risk multiple myeloma, wherein the patient is given anti-CD38 The therapeutically effective doses of antibodies, corticosteroids, and non-corticosteroid chemotherapeutic agents are high-risk. The method involves administering the drug for a sufficient amount of time to treat multiple myeloma. This will be disclosed in the detailed document.

[0008] A method for achieving minimal residual disease negativity in subjects with multiple myeloma, The targets include anti-CD38 antibodies, corticosteroids, and non-corticosteroid chemotherapeutic agents. Administer a therapeutically effective dose for a sufficient amount of time to achieve minimal residual disease negativity. Methods including the above are also provided.

[0009] A method for predicting the likelihood of recurrence and / or disease progression in subjects with multiple myeloma. The procedure includes measuring the minimal residual disease status in the subject, and the subject is anti-CD. 38 antibodies, corticosteroids, and non-corticosteroid chemotherapeutic agents were administered in therapeutically effective doses. It is being observed that the positive minimal residual disease status is recurring. Methods are also provided to indicate the possibility of onset and / or disease progression.

[0010] A method to reduce the risk of relapse and / or disease progression in patients with multiple myeloma. The targets include anti-CD38 antibodies, corticosteroids, and non-corticosteroids. This includes administering a therapeutically effective dose of a chemotherapy agent to achieve a minimal residual disease-negative state, Further disclosures are made regarding how a lesion-negative state reduces the risk of recurrence and / or disease progression. . [Brief explanation of the drawing]

[0011] The summary of the invention and the embodiments for carrying out the invention described below should be read in conjunction with the attached drawings. This is further understood. For the purpose of illustrating the method of disclosure, the drawings include exemplary embodiments of the present disclosure. This is shown. However, this method is limited to the specific embodiments disclosed herein. It is not. The drawings are not necessarily to scale, and instead illustrate embodiments. This is considered important. The drawing is as follows. [Figure 1] The graph shows the percentage of multiple myeloma patients who survived progression-free based on their cytogenetic risk status in the POLLUX (MMY3003) trial. DRd: Combination of daratumumab with lenarinomide and dexamethasone. Rd: Lenarinomide and dexamethasone. High risk: Patients have at least one of the following chromosomal abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q23), or del17p. Standard risk: Patients have a confirmed absence of any of the aforementioned chromosomal abnormalities. [Figure 2] The graph shows the percentage of multiple myeloma patients who survived progression-free based on their cytogenetic risk status in the CASTOR (MMY3004) trial. DVd: combination of daratumumab, bortezomib, and dexamethasone; Vd: bortezomib and dexamethasone. High risk: Patients have at least one of the following chromosomal abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q23), or del17p. Standard risk: Patients have a confirmed absence of any of the aforementioned chromosomal abnormalities. [Figure 3] This shows the number of sCR / CR patients who achieved MRD-negative status at the indicated MRD-negative threshold in the POLLUX trial (MMY3003, top) and the CASTOR trial (MMY3004, bottom). [Figure 4A] The graph shows the percentage of multiple myeloma patients who remained progression-free over time (in days) in the POLLUX (MMY3003) trial, specifically those with MRD negativity at the 10⁻⁴ threshold, in the DRd and Rd treatment arms. [Figure 4B] The graph shows the percentage of multiple myeloma patients who remained progression-free over time (in days) in the POLLUX (MMY3003) trial, specifically those with MRD negativity at the 10⁻⁵ threshold, in the DRd and Rd treatment arms. [Figure 4C] The graph shows the percentage of multiple myeloma patients who remained progression-free over time (in days) in the POLLUX (MMY3003) trial, specifically those with MRD negativity at the 10⁻⁶ threshold, in the DRd and Rd treatment arms. [Figure 5A] The graph shows the percentage of multiple myeloma patients who remained progression-free over time (in days) in the CASTOR (MMY3004) trial, based on MRD negativity at the 10⁻⁴ threshold, in the DVd and Vd treatment arms. [Figure 5B] The graph shows the percentage of multiple myeloma patients who remained progression-free over time (in days) in the CASTOR (MMY3004) trial, based on MRD negativity at the 10⁻⁵ threshold, in the DVd and Vd treatment arms. [Figure 5C]The graph shows the percentage of multiple myeloma patients who remained progression-free over time (in days) in the CASTOR (MMY3004) trial, based on MRD negativity at the 10⁻⁶ threshold, in the DVd and Vd treatment arms. [Figure 6A] This shows the MRD profile of a responder who was MRD-negative (threshold 10⁻⁵) at the time of suspected complete response (CR) and remained MRD-negative after CR. The frequency of malignant clones at baseline (x=0) and over time is shown. The vertical numbers printed in black for each MRD sample indicate the MRD clone count. Vertical dotted lines indicate the clinical response call for that subject, with the label printed below. Two distinctly different malignant clones (triangular and circular) were identified in this patient. This subject was MRD-positive at baseline and MRD-negative at and after suspected CR. [Figure 6B] This shows the MRD profile of a responder who was MRD-negative (threshold 10⁻⁵) at the time of suspected sCR and remained MRD-negative after sCR. The frequency of malignant clones at baseline (x=0) and over time is shown. The vertical numbers printed in black for each MRD sample indicate the MRD clone count. The vertical dotted lines indicate the clinical response call for that subject, with the label printed below. Two distinctly different tumor clones (solid and dashed lines) were identified in this patient. This subject was MRD-positive at baseline and MRD-negative at and after suspected sCR. [Figure 7A] The time-course MRD profile of non-responders is shown. The frequency of malignant clones at baseline (x=0) and over time is indicated. Vertical dotted lines represent the clinical response calls of the subjects, with labels printed below. Two distinctly different tumor clones (solid and dashed lines) were identified in this patient. This subject was MRD-positive at each evaluation time (threshold 10⁻⁵). [Figure 7B]The time-course MRD profile of non-responders is shown. The frequency of malignant clones at baseline (x=0) and over time is indicated. Vertical dotted lines represent the clinical response calls of the subjects, with labels printed below. Two distinctly different tumor clones (solid and dashed lines) were identified in this patient. This subject was MRD-positive at each evaluation time (threshold 10⁻⁵). [Figure 7C] The time-course MRD profile of non-responders is shown. The frequency of malignant clones at baseline (x=0) and over time is indicated. Vertical dotted lines represent the clinical response calls of the subjects, with labels printed below. Two distinctly different tumor clones (solid and dashed lines) were identified in this patient. This subject was MRD-positive at each evaluation time (threshold 10⁻⁵). [Figure 7D] The time-course MRD profile of non-responders is shown. The frequency of malignant clones at baseline (x=0) and over time is indicated. Vertical dotted lines represent the clinical response calls of the subjects, with labels printed below. Two distinctly different tumor clones (solid and dashed lines) were identified in this patient. This subject was MRD-positive at each evaluation time (threshold 10⁻⁵). [Figure 8A] The MRD profiles of subjects who first demonstrated a clinical response and subsequently experienced progressive disease are shown. The frequency of malignant clones at baseline (x=0) and over time is indicated. Vertical dotted lines indicate the subject's clinical response call, with the label printed below. Three distinctly different tumor clones (solid, dashed, and dotted lines) were identified in this patient. This subject was MRD-positive at each evaluation time (threshold 10⁻⁵). [Figure 8B] The MRD profiles of subjects who first demonstrated a clinical response and subsequently experienced progressive disease are shown. The frequency of malignant clones at baseline (x=0) and over time is indicated. Vertical dotted lines indicate the clinical response call of a subject, with the label printed below. Two distinctly different tumor clones (solid and dashed lines) were identified in this patient. This subject was MRD-positive at each evaluation time (threshold 10⁻⁵). [Figure 9A]This shows the MRD profile of a subject who demonstrated a rapid clinical response but only achieved MRD negativity after a suspected complete response (CR). The frequency of malignant clones at baseline (x=0) and over time is shown. Vertical dotted lines indicate the clinical response call of that subject, with labels printed below. Two distinctly different tumor clones (solid and dashed lines) were identified in this patient. This subject was MRD-positive at baseline and suspected CR, and MRD-negative approximately 340 days after the start of treatment (threshold 10⁻⁵). [Figure 9B] This shows the MRD profile of a subject who demonstrated a rapid clinical response but only became MRD-negative after a suspected complete response (CR). The frequency of malignant clones at baseline (x=0) and over time is shown. Vertical dotted lines indicate the clinical response call for that subject, with labels printed below. Two distinctly different tumor clones (solid and dashed lines) were identified in this patient. This subject was MRD-positive at baseline, suspected CR, approximately 170 and 260 days after initiation of treatment, and MRD-negative approximately 360 days after initiation of treatment (threshold 10⁻⁵). [Figure 10A] This shows the MRD profile of a subject who exhibited a slow clinical response and remained MRD-positive after a suspected complete response (CR). The frequency of malignant clones at baseline (x=0) and over time is shown. Vertical dotted lines indicate the subject's clinical response call, with labels printed below. Two distinctly different tumor clones (solid and dashed lines) were identified in this patient. This subject was MRD-positive at each evaluation time (threshold 10⁻⁵). [Figure 10B] This shows the MRD profile of a subject who exhibited a slow clinical response and remained MRD-positive after a suspected complete response (CR). The frequency of malignant clones at baseline (x=0) and over time is shown. Vertical dotted lines indicate the subject's clinical response call, with labels printed below. Two distinctly different tumor clones (solid and dashed lines) were identified in this patient. This subject was MRD-positive at each evaluation time (threshold 10⁻⁵). [Figure 10C]This shows the MRD profile of a subject who exhibited a slow clinical response and remained MRD-positive after a suspected complete response (CR). The frequency of malignant clones at baseline (x=0) and over time is shown. Vertical dotted lines indicate the subject's clinical response call, with labels printed below. Two distinctly different tumor clones (solid and dashed lines) were identified in this patient. This subject was MRD-positive at each evaluation time (threshold 10⁻⁵). [Figure 10D] This shows the MRD profile of a subject who exhibited a slow clinical response and remained MRD-positive after a suspected complete response (CR). The frequency of malignant clones at baseline (x=0) and over time is shown. Vertical dotted lines indicate the subject's clinical response call, with labels printed below. Two distinctly different tumor clones (solid and dashed lines) were identified in this patient. This subject was MRD-positive at each evaluation time (threshold 10⁻⁵). [Figure 11A] This table shows the percentage of patients with MRD-negative outcomes (MRD) at the indicated MRD-negative threshold (10⁻⁴, 10⁻⁵, or 10⁻⁶) in standard-risk patients from the POLLUX (MMY3003) trial. Light bars: patients who received lenarinomide and dexamethasone alone (Rd), dark bars: patients who received daratumumab, lenarinomide, and dexamethasone (DRd). **p<0.005, ***p<0.0001 (between the indicated DRd group and the indicated Rd group). [Figure 11B] This chart shows the percentage of high-risk patients who were MRD-negative at the indicated MRD-negative threshold (10⁻⁴, 10⁻⁵, or 10⁻⁶) from the POLLUX (MMY3003) trial. Light bars: patients who received lenarinomide and dexamethasone alone (Rd), dark bars: patients who received daratumumab, lenarinomide, and dexamethasone (DRd). *p<0.05 (between the indicated DRd group and the indicated Rd group). [Figure 12A]This chart shows the percentage of patients with MRD-negative status at the indicated MRD-negative threshold (10⁻⁴, 10⁻⁵, or 10⁻⁶) in standard-risk patients from the CASTOR (MMY3004) trial. Light bars: patients who received bortezomib and dexamethasone (Vd), dark bars: patients who received daratumumab, bortezomib, and dexamethasone (DVd). *p<0.05, **p<0.005 (between the indicated DVd group and the indicated Vd group). [Figure 12B] This chart shows the percentage of high-risk patients who were MRD-negative at the indicated MRD-negative threshold (10⁻⁴, 10⁻⁵, or 10⁻⁶) from the CASTOR (MMY3004) trial. Light bars: patients who received bortezomib and dexamethasone (Vd), dark bars: patients who received daratumumab, bortezomib, and dexamethasone (DVd). *p<0.05 (DVd group vs. Vd group). [Modes for carrying out the invention]

[0012] The methods disclosed are those made in connection with the attached drawings, which form part of this disclosure. It can be more easily understood by referring to the detailed explanation. The disclosed method is: Not limited to the specific methods described and / or illustrated herein, and furthermore, used herein The terms used are intended solely to illustrate specific embodiments and are not used in the claims. Please understand that this is not intended to limit the method to this one.

[0013] Unless otherwise specified, this describes possible mechanisms or forms of operation, or reasons for improvement. The explanations provided are for illustrative purposes only. The method of this disclosure is the proposed method. It is not limited by the mechanism or form of the work, or by the validity of the reasons for improvement.

[0014] Where numerical ranges are enumerated or established herein, this range includes its endpoints and their This includes all individual integers and rational numbers within the range, and furthermore, their endpoints and internal integers and rational numbers. Each of the various possible combinations of numbers forms a narrower range within that range. This includes, and each of their narrower scopes is as if explicitly enumerated, the scope described The group of values ​​larger than the range within the specified range is formed into smaller subgroups. The range of numerical values ​​is as described herein. Where a value is described as greater than a given value, that range is finite and is not described herein. The upper limit is defined by a value that is operable within the context of the present invention. If a value is stated to be less than the value specified herein, the range is Nevertheless, its lower limit is defined by a non-zero value. The scope of the present invention is The range is not intended to be limited to the specific values ​​listed when defining the range. It is comprehensive and can be combined.

[0015] When a value is expressed as an approximation using the antecedent "approximately", that particular value is an approximation of another implementation. It is understood that the form is being formed. References to specific numerical values ​​are not otherwise specified in the context. To the extent of the limit, it shall include at least that specific value.

[0016] In this specification, for clarity, disclosures described in the context of separate embodiments are provided. Multiple features of the method may also be provided in combination in a single embodiment. Please understand this. Conversely, the disclosed which is described as a single embodiment for the sake of brevity. The various features of the law may also be provided separately or in any subordinate combination.

[0017] As used herein, the singular forms "a," "an," and "the" include plural forms. Let's assume that.

[0018] Throughout this specification and the claims, various terms are used with respect to the aspects of this specification. Unless otherwise specified, such terms are to be given their ordinary meanings in the relevant technical field. Other specifically defined terms are to be interpreted in a manner consistent with the definitions provided herein. As used herein, "about" is used in connection with a numerical range, cutoff, or specific value to indicate that the recited value can vary by up to 10% from the recited value. Since many of the numerical values used herein are determined experimentally, one of ordinary skill in the art should understand that such determinations can vary between different experiments and will often be different. The values used herein should not be considered unduly limited by this inherent variability. Thus, the term "about" is used to encompass variations of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from a defined value. Similarly, the term "comprising" is intended to include examples subsumed by the terms "consisting essentially of" and "consisting of". Similarly, the term "consisting essentially of" is intended to include examples subsumed by the term "consisting of". "CD38" refers to the human CD38 protein (UniProtKB accession number P28907) (synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP

[0019] As used herein, "about" is used in connection with a numerical range, cutoff, or specific value to indicate that the recited value can vary by up to 10% from the recited value. Since many of the numerical values used herein are determined experimentally, one of ordinary skill in the art should understand that such determinations can vary between different experiments and will often be different. The values used herein should not be considered unduly limited by this inherent variability. Thus, the term "about" is used to encompass variations of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from a defined value. As used herein, "about" is used in connection with a numerical range, cutoff, or specific value to indicate that the recited value can vary by up to 10% from the recited value. Since many of the numerical values used herein are determined experimentally, one of ordinary skill in the art should understand that such determinations can vary between different experiments and will often be different. The values used herein should not be considered unduly limited by this inherent variability. Thus, the term "about" is used to encompass variations of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from a defined value. As used herein, "about" is used in connection with a numerical range, cutoff, or specific value to indicate that the recited value can vary by up to 10% from the recited value. Since many of the numerical values used herein are determined experimentally, one of ordinary skill in the art should understand that such determinations can vary between different experiments and will often be different. The values used herein should not be considered unduly limited by this inherent variability. Thus, the term "about" is used to encompass variations of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from a defined value. As used herein, "about" is used in connection with a numerical range, cutoff, or specific value to indicate that the recited value can vary by up to 10% from the recited value. Since many of the numerical values used herein are determined experimentally, one of ordinary skill in the art should understand that such determinations can vary between different experiments and will often be different. The values used herein should not be considered unduly limited by this inherent variability. Thus, the term "about" is used to encompass variations of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from a defined value. As used herein, "about" is used in connection with a numerical range, cutoff, or specific value to indicate that the recited value can vary by up to 10% from the recited value. Since many of the numerical values used herein are determined experimentally, one of ordinary skill in the art should understand that such determinations can vary between different experiments and will often be different. The values used herein should not be considered unduly limited by this inherent variability. Thus, the term "about" is used to encompass variations of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from a defined value. As used herein, "about" is used in connection with a numerical range, cutoff, or specific value to indicate that the recited value can vary by up to 10% from the recited value. Since many of the numerical values used herein are determined experimentally, one of ordinary skill in the art should understand that such determinations can vary between different experiments and will often be different. The values used herein should not be considered unduly limited by this inherent variability. Thus, the term "about" is used to encompass variations of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from a defined value. As used herein, "about" is used in connection with a numerical range, cutoff, or specific value to indicate that the recited value can vary by up to 10% from the recited value. Since many of the numerical values used herein are determined experimentally, one of ordinary skill in the art should understand that such determinations can vary between different experiments and will often be different. The values used herein should not be considered unduly limited by this inherent variability. Thus, the term "about" is used to encompass variations of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from a defined value. As used herein, "about" is used in connection with a numerical range, cutoff, or specific value to indicate that the recited value can vary by up to 10% from the recited value. Since many of the numerical values used herein are determined experimentally, one of ordinary skill in the art should understand that such determinations can vary between different experiments and will often be different. The values used herein should not be considered unduly limited by this inherent variability. Thus, the term "about" is used to encompass variations of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from a defined value.

[0020] Similarly, the term "comprising" is intended to include examples subsumed by the terms "consisting essentially of" and "consisting of". Similarly, the term "consisting essentially of" is intended to include examples subsumed by the term "consisting of". Similarly, the term "comprising" is intended to include examples subsumed by the terms "consisting essentially of" and "consisting of". Similarly, the term "consisting essentially of" is intended to include examples subsumed by the term "consisting of". Similarly, the term "comprising" is intended to include examples subsumed by the terms "consisting essentially of" and "consisting of". Similarly, the term "consisting essentially of" is intended to include examples subsumed by the term "consisting of".

[0021] "CD38" refers to the human CD38 protein (UniProtKB accession number P28907) (synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP 7)(synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP - Refers to ribose hydrolase 1). Human CD38 is an amino acid combination as shown in Sequence ID No. 1. It has a column. CD38 has amino acid residues 1-21 that represent the cytoplasmic domain, and amino acid residues Residues 22-42 represent the transmembrane domain, and residues 43-300 represent the extracellular domain. It is a type II transmembrane protein. Anti-CD38 antibodies are, for example, described in International Publication No. 2008. Publication No. / 037257, International Publication No. 2008 / 047242, and International Publication No. 2007 / 0 It is listed in issue 42309.

[0022] The term "antibody" and similar terms are intended to be used in a broad sense, including monoclonal antibodies. (Mouse, human, human-adapted, humanized, and chimeric monoclonal antibodies, etc.), antibody flag Menthols, bispecific or multispecific antibodies, dimers, tetramers, or multimers, and single-chain antibodies. Contains antibodies and immunoglobulin molecules.

[0023] Immunoglobulins are classified into five major classes based on the amino acid sequence of their heavy chain constant domain. In other words, they can be assigned to IgA, IgD, IgE, IgG, and IgM. IgA and IgG has isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. They are further classified as follows. The antibody light chains of any vertebrate species have their constant domains Based on the amino acid sequence, there are two distinctly different types: kappa (κ) and lambda It can be assigned to one of (λ).

[0024] An "antibody fragment" is an immunoglobulin component that retains the antigen-binding properties of a parent full-length antibody. It refers to a part of the child. An example antibody fragment is the heavy chain complementarity-determining region (HCDR)1. 2, and / or 3, Light chain complementarity determination region (LCDR) 1, 2, and / or 3, This is the chain variable region (VH) or light chain variable region (VL). Antibody fragments have VL, A monovalent fragment consisting of VH, a constant light chain (CL), and a (constant heavy chain 1)CH1 domain. The Fab fragment is connected to two other fragments by disulfide bridges in the hinge region. The F(ab)2 fragment is a divalent fragment containing the Fab fragment, and VH and an Fd fragment consisting of a CHI domain, and the VL and VH domains of a single arm of the antibody An Fv fragment consisting of a y-in domain and a domain antibody consisting of a VH domain or a VL domain. (dAb) Fragment (Ward et al., Nature 341:544-5) (46, 1989) and are included. The VH domain and VL domain are manipulated and synthetic phosphorus By linking them together via a KAR, various types of single-chain antibody designs can be formed, and here The VH / VL domains either pair up within the molecule, or the VH and VL domains are separate. When expressed by a single-chain antibody construct, it pairs with other molecules, resulting in single-chain Fv(scF v) Forms a monovalent antigen-binding site such as a diabody. For example, International Publication No. 199 Issues 8 / 44001, 1988 / 01649, 1994 / 13804, and the same These are described in publication No. 1992 / 01047. These antibody fragments are already known to those skilled in the art. Obtained using the techniques of knowledge, these fragments are processed in the same way as in the case of full-length antibodies. It will be screened for usefulness.

[0025] The phrase "isolated antibodies" substantially includes other antibodies with different antigen specificities. Refers to an antibody or antibody fragment that does not contain human CD38 (for example, an isolated anti-CD38 antibody does not contain human CD38). (It substantially does not contain antibodies that specifically bind to antigens other than 38). However, isolated The anti-CD38 antibody was found in cynomolgus monkeys (Macaca fascicularis). s)) CD38 and other antigens such as human CD38 orthologs exhibit cross-reactivity. It is possible. Furthermore, the isolated antibodies are substantially free of other cellular material and / or chemical substances. There are cases where this is the case.

[0026] The antibody variable region is a "framework" region interrupted by three "antigen-binding sites". It consists of the following. The antigen-binding site is defined using various terms: (i) Complementarity-determining region ( CDR) (3 in VH (HCDR1, HCDR2, HCDR3) and 3 in VL (L CDR1, LCDR2, LCDR3) are based on sequence variability (Wu and Kab). at, J Exp Med 132:211-50, 1970, Kabat et al. .Sequences of Proteins of Immunological Interest,5th Ed.Public Health Service,Na tional Institutes of Health,Bethesda,Md. (1991), (ii) "Hyper-Variable Region" ("HVR" or "HV") (3 within VH (H 1, H2, H3) and three within VL (L1, L2, L3) are Chothia and Lesk(Chothia and Lesk,Mol Biol 196:901- The region of the antibody variable domain that is hypervariable in the structure defined by 17,1987) It refers to the region. Another term is "IMGT-CDR" (Lefranc et al., Dev Comparat Immunol 27:55-77, 2003) and "Specificity Determination" Residue usage (SDRU) (Almagro Mol Recognit,17:132-4 Includes 3,2004). International ImMunoGeneTics ( The IMGT database (http: / / www_imgt_org) is a database of antigen-binding sites. Provides standard numbers and definitions for CDR, HV, and IMGT notations. For the response, see Lefranc et al., Dev.Comparat.Immun This is described in ol.27:55-77, 2003.

[0027] A "framework" or "framework sequence" is defined as an antigen-binding site. This is the remaining sequence of the variable region, excluding the specified part. The antigen-binding site is described by various terms as described above. Therefore, the exact amino acid sequence of the framework can be defined as how the antigen-binding site is It depends on how it's defined.

[0028] A "humanized antibody" is one in which the antigen-binding site is derived from a non-human species, and the framework region is derived from a human antibody. This refers to antibodies derived from the globulin sequence. Humanized antibodies have substitutions within the framework region. Because it may include expressed human immunoglobulins or It does not have to be a complete replica of the germline gene sequence. If the antibody has a constant region, That constant region also originates from a human sequence. The term "derived from" is used in relation to humanized antibodies. "The sequence of the region in question corresponds to the corresponding region of the species-derived immunoglobulin on which it is based." This means that the sequence is at least 80% homologous.

[0029] "Human-adapted" antibodies or "Human Framework-Adapted (HFA)" antibodies are published in the U.S. Patent Application Publication. This refers to humanized antibodies adapted according to the method described in Publication No. 2009 / 0118127. Human-adapted antibodies are most effective for the CDR1 and CDR2 loops and a portion of the light chain CDR3 loop. Based on the large CDR and FR similarity, length compatibility, and sequence similarity, acceptor human The framework becomes humanized by selecting it.

[0030] "Human antibodies" are those in which both the framework and antigen-binding site are derived from human sequences. This refers to antibodies that have a heavy chain variable region and a light chain variable region. If the antibody contains a constant region, The constant region also originates from a human sequence. Human antibodies have a variable region that is related to human germline immunity. Human when obtained from a system using globulin or rearranged immunoglobulin genes The origin sequence contains a heavy chain variable region or a light chain variable region "derived" from it. Such a system is The human immunoglobulin gene library presented on the page, and the human immunoglobulin gene library described herein. This includes transgenic non-human animals such as mice that possess the toimmunoglobulin gene locus. "Human antibodies" are, for example, naturally occurring antibodies within the framework or antigen-binding site. Intentional introduction of cytoplasmic mutations or substitutions can alter the human germline or reorganized immunoglobulin chain. This may include amino acid differences compared to the sequence. Typically, the amino acid sequence of a "human antibody" is different from that of a human antibody. The amino acid sequence encoded by germline or rearranged immunoglobulin genes and At least approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% %, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 They are 99% or 100% identical. In some cases, "human antibodies" are, for example, K nappik et al., J Mol Biol 296:57-86,2000) The consensus framework derived from human framework sequence analysis described below See column, or for example, Shi et al., J Mol Biol 397:385-96. As described in 2010 and International Publication No. 2009 / 085462, presented on phages It may contain synthetic HCDR3 incorporated into a human immunoglobulin gene library. Antibodies whose primary binding site originates from a non-human species are not included in the definition of "human antibodies."

[0031] Isolated humanized antibodies may be synthetic. Human antibodies are derived from human immunoglobulin sequences. However, phages incorporating synthetic CDRs and / or synthetic frameworks The antibody characteristics are generated using a system such as a display, or by performing in vitro mutagenesis. It can improve the in vivo human antibody germline repertoire, which is naturally present within the germline repertoire. Antibodies can be obtained.

[0032] "Recombinant antibodies" include all antibodies prepared, expressed, produced, or isolated by recombinant means. The body, for example, the human immunoglobulin gene or a hybridoma prepared therefrom Antibodies isolated from animals that are sgenic or transchromosomal (e.g., mice) Antibodies isolated from host cells transformed to express antibodies (as further described below) The body, antibodies isolated from recombinant combinatorial antibody libraries, and human immunoglobulins By any other means, including splicing the phosphorus gene sequence with another DNA sequence Antibodies produced, expressed, manufactured, or isolated, or those produced in vitro using Fab arm exchange. It contains the antibodies that were produced.

[0033] A "monoclonal antibody" refers to a preparation of an antibody molecule with a single molecular composition. The antibody composition exhibits a single binding specificity and affinity for a specific epitope, or two. In the case of heavily specific monoclonal antibodies, double binding specificity to two distinct epitopes It exhibits this property. Therefore, monoclonal antibodies are those which remove the C-terminal lysine from the antibody heavy chain. A population of antibodies in which the amino acid composition of each heavy chain and each light chain is monolithic, with the exception of any possible known modifications. This refers to the fact that monoclonal antibodies may exhibit heterogeneous glycosylation within the antibody population. Monoclonal antibodies can be monospecific or multispecific, or monovalent, bivalent, or polyvalent. This is possible. Bispecific antibodies are included in the term monoclonal antibodies.

[0034] An "epitope" refers to a part of an antigen to which an antibody specifically binds. Typically, the chemically active (polar, nonpolar, or hydrophobic) part of the amino acid or polysaccharide side chain is a part of the site. (d) Consists of surface groups and may have specific three-dimensional structural properties and specific charge properties. Epitope It is composed of continuous and / or discontinuous amino acids that form conformational spatial units. It is possible. In discontinuous epitopes, amino acids located in different parts of the linear sequence of the antigen can cause tanning. The folding of protein molecules brings them into very close proximity in three-dimensional space.

[0035] A "mutant" is defined as a reference polyparticle that has been modified in one or more ways, such as substitution, insertion, or deletion. This refers to a polypeptide or polynucleotide that is different from the reference polynucleotide or nucleotide.

[0036] "In combination" means that two or more therapeutic agents are used together in a mixture, or individually, on the target. This means that the drugs can be administered simultaneously as a group, or individually, in any order and sequence. do.

[0037] The terms "to treat," "treatment," and similar terms refer to therapeutic treatment and prophylactic treatment. It refers to both preventative measures and measures aimed at reducing the severity and / or frequency of symptoms. Elimination of the underlying cause of the condition and / or symptoms, the frequency or likelihood of the symptoms and / or the underlying cause of the symptoms Reducing the cause, improving or repairing damage directly or indirectly caused by multiple myeloma. Includes. "Treatment" extends survival time compared to the expected survival time of untreated subjects. This also includes causing [something]. Those who are treated include those with a condition or disease, as well as those with a condition This includes individuals who are prone to disease, or individuals for whom a condition or disease can be prevented.

[0038] "Therapeutic effective dose" refers to the amount of medication needed to achieve the desired treatment over the required period of time. This refers to the effective amount of disclosed combination therapy. The effective therapeutic dose depends on the patient's condition, age, sex, and body type. This can vary depending on factors such as severity, as well as the ability of the combination therapy to induce the desired response in the subject. Examples of indicators of therapeutic effectiveness include, for example, improvement in the patient's health status, reduction in tumor volume, and tumor growth. Examples include the cessation or delay of tumor growth, and / or the absence of metastasis of cancer cells to other parts of the body. It can be done.

[0039] "Inhibiting growth" (for example, when referring to cells such as tumor cells) means the absence of combination therapy. In vitro or in vivo cell growth in contact with combination therapy compared to the growth of the same cells shown below. This refers to a measurable decrease in [the relevant area]. Inhibition of cell growth in vitro or in vivo is less likely to occur. Approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, and 80% respectively. It can be %, approximately 90%, approximately 99%, or approximately 100%. Inhibition of cell growth occurs through various mechanisms. For example, antibody-mediated ADCC, ADCP, and / or CDC, apoptosis, necrosis This can be caused by inhibition of cell proliferation.

[0040] "Subject" includes any human or non-human animal. "Non-human animal" includes any vertebrate Vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, Cattle, chickens, amphibians, and reptiles are examples. The terms "subject" and "patient" are defined herein. They can be used interchangeably.

[0041] The following abbreviations will be used throughout this disclosure: bone marrow aspirate (BMA), complete response ( CR), daratumumab, bortezomib, and dexamethasone (DVd), daratumumab, Lenalinomide and dexamethasone (DRd), International Myeloma Working Group (IMW) G) International Staging System (ISS), Minimal Residual Disease (MRD), Multiple Myeloma (MM) ), partial response (PR), progression-free survival (PFS), overall response rate (ORR), overall survival ( OS), lenalinomide and dexamethasone (Rd), strict complete response (sCR), disease progression Time to treatment (TTP), bortezomib and dexamethasone (Vd), very good portion response (VGPR), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) ), bortezomib (Bort), complement-dependent cell-mediated cytotoxicity (CDC), complementarity-determining region (CD) R), steady-state light chain (CL), (steady-state heavy chain 1)CH1 domain, daratumumab (DARA), Heavy chain CDR (HCDR), heavy chain variable region (VH), lenalidomide (LEN), light chain CDR (LCDR), Light Chain Variable Region (VL), Patient (pts).

[0042] Treatment methods for patients with high-risk multiple myeloma. A method for treating a patient with high-risk multiple myeloma, wherein the patient is given anti-CD38 The therapeutically effective doses of antibodies, corticosteroids, and non-corticosteroid chemotherapeutic agents are high-risk. The method involves administering the drug for a sufficient amount of time to treat multiple myeloma. This will be disclosed in the detailed document.

[0043] Any anti-CD38 antibody may be used in the disclosed method. For example, any anti-CD38 antibody The variant region is obtained from an existing anti-CD38 antibody, and optionally, a full-length antibody is obtained using a standard method. It can be cloned as follows. The exemplary antibody variable region that can bind to CD38 and be used is International Publication Nos. 2005 / 103083, 2006 / 125640, and 2007 / 042309, 2008 / 047242, 2012 / 092612, same As described in Issues 2006 / 099875 and 2011 / 154453(A1) Yes, they are.

[0044] The anti-CD38 antibody contains human CD38, including SKRNIQFSCKNIYR (SEQ ID NO: 2). The region and the human CD38 region including EKVQTLEAWVIHGG (SEQ ID NO: 3) are linked. It may be compatible. The anti-CD38 antibody contains the human CD38 region including SEQ ID NO: 2 and SEQ ID NO: 3. The antibody binds to the human CD38 region, and at least 1, 2, 3, and 4 of SEQ ID NO: 2 , residues 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, and within SEQ ID NO: 3 at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 It binds to a number of residues. In some embodiments, the anti-CD38 antibody contains the HI of SEQ ID NO: 2. The region of human CD38 containing at least one amino acid within the CD38 region and SEQ ID NO: 3 It binds to at least one amino acid within the region. In some embodiments, an anti-CD38 antibody This includes at least two amino acids within the human CD38 region, including SEQ ID NO: 2, and SEQ ID NO: 3 It binds to at least two amino acids within the region of human CD38, including several implementations. In this state, the anti-CD38 antibody contains at least three cells within the human CD38 region, including SEQ ID NO: 2. It binds to at least three amino acids within the region of human CD38, including amino acids and SEQ ID NO: 3. To do so, in the region of human CD38 containing SEQ ID NO: 2 and the region of human CD38 containing SEQ ID NO: 3 The antibody to be bound is, for example, obtained using a standard method and as described herein. The mice were immunized with peptides having amino acid sequences including SEQ ID NOs: 2 and 3, for example, EL The obtained antibodies were characterized for binding to peptides using ISA or mutagenesis testing. It can be generated by doing so.

[0045] The human CD38 region containing SEQ ID NO: 2 and the human CD38 region containing SEQ ID NO: 3 are bound to this region. An exemplary anti-CD38 antibody is DARZALEX (trademark) (daratumumab), and That is, • Heavy chain amino acid sequence of SEQ ID NO: 12 and light chain amino acid sequence of SEQ ID NO: 13 • The heavy chain variable region (VH) of SEQ ID NO: 4 and the light chain variable region (VL) of SEQ ID NO: 5, / or • Heavy chain complementarity determination region (CDR) 1 of sequence numbers 6, 7, and 8, respectively, and heavy chain CDR Determination of the light chain complementarity of 2, and heavy chain CDR3, and sequence numbers 9, 10, and 11, respectively. Includes region (CDR)1, light chain CDR2, and light chain CDR3.

[0046] The anti-CD38 antibody contains the heavy chain CDR1, which includes the amino acid sequence of SEQ ID NO: 6, and the amino acid sequence of SEQ ID NO: 7. Heavy chain CDR2 containing the no-acid sequence, heavy chain CDR3 containing the amino acid sequence of SEQ ID NO 8, SEQ ID NO Light chain CDR1 contains the amino acid sequence of 9, and light chain CDR2 contains the amino acid sequence of sequence number 10. It may contain light chain CDR2 and light chain CDR3 containing the amino acid sequence of SEQ ID NO: 11. 38 antibodies have the amino acid sequence of SEQ ID NO: 4 and 95%, 96%, 97%, 98%, 99%, and VH contains 100% identical amino acid sequences, and the amino acid sequence of SEQ ID NO: 5 is 95% identical to that of 9 May contain VLs that have 6%, 97%, 98%, 99%, or 100% identical amino acid sequences. In some embodiments, the anti-CD38 antibody is VH and containing the amino acid sequence of SEQ ID NO: 4. The VL may contain the amino acid sequence of SEQ ID NO: 5. The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 12. It may include a heavy chain containing an amino acid sequence and a light chain containing the amino acid sequence of SEQ ID NO: 13.

[0047] The anti-CD38 antibody contains the VH heavy chain CDR1 and heavy chain CD, which are the amino acid sequences of SEQ ID NO: 14. R2, and heavy chain CDR3, and VL light chain CDR1 containing the amino acid sequence of SEQ ID NO: 15 It may include light chain CDR2 and light chain CDR3. The anti-CD38 antibody is the amine of SEQ ID NO: 15 Amino acid sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical to the no-acid sequence. VH containing, and the amino acid sequence of SEQ ID NO: 15 and 95%, 96%, 97%, 98%, 99% It may contain VLs that have %, or 100%, the same amino acid sequence. In some embodiments, The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 14 (VH) and SEQ ID NO: 15 (amino acids). It may include a VL containing a sequence. In some embodiments, for example, the anti-CD38 antibody is mA b003 (as described in U.S. Patent No. 7,829,693 incorporated herein by reference) It may include (reru).

[0048] The anti-CD38 antibody contains the VH heavy chain CDR1 and heavy chain CD, which are the amino acid sequences of SEQ ID NO: 16. R2, and heavy chain CDR3, and VL light chain CDR1 containing the amino acid sequence of SEQ ID NO: 17 It may include light chain CDR2 and light chain CDR3. The anti-CD38 antibody is the amine of SEQ ID NO: 16. Amino acid sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical to the no-acid sequence. VH, which includes the amino acid sequence of SEQ ID NO: 17, and 95%, 96%, 97%, 98%, 99% It may contain VLs that have %, or 100%, the same amino acid sequence. In some embodiments, The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 16 (VH) and SEQ ID NO: 17 (amino acids). It may include a VL containing a sequence. In some embodiments, for example, the anti-CD38 antibody is mA b024 (as described in U.S. Patent No. 7,829,693 incorporated herein by reference) It may include (reru).

[0049] The anti-CD38 antibody contains the VH heavy chain CDR1 and heavy chain CD, which are the amino acid sequences of SEQ ID NO: 18. R2, and heavy chain CDR3, and VL light chain CDR1 containing the amino acid sequence of SEQ ID NO: 19 It may include light chain CDR2 and light chain CDR3. The anti-CD38 antibody is the amine of SEQ ID NO: 18. Amino acid sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical to the no-acid sequence. VH containing, and the amino acid sequence of SEQ ID NO: 19 and 95%, 96%, 97%, 98%, 99% It may contain VLs that have %, or 100%, the same amino acid sequence. In some embodiments, The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 18 (VH) and SEQ ID NO: 19 (amino acids). It may include a VL containing a sequence. In some embodiments, for example, the anti-CD38 antibody is MO R-202 (MOR-03087) (as incorporated herein by reference, U.S. Act 8, This may include (as described in publications 088 and 896).

[0050] The anti-CD38 antibody contains the VH heavy chain CDR1 and heavy chain CD, which are the amino acid sequences of SEQ ID NO: 20. R2, and heavy chain CDR3, and VL light chain CDR1 containing the amino acid sequence of SEQ ID NO: 21 It may include light chain CDR2 and light chain CDR3. The anti-CD38 antibody is the amine of SEQ ID NO: 20 Amino acid sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical to the no-acid sequence. VH containing, and the amino acid sequence of SEQ ID NO: 21 and 95%, 96%, 97%, 98%, 99% It may contain VLs that have %, or 100%, the same amino acid sequence. In some embodiments, The anti-CD38 antibody contains the amino acid sequence of VH and SEQ ID NO: 20, which are the amino acids of SEQ ID NO: 21. It may include a VL containing a sequence. In some embodiments, for example, an anti-CD38 antibody is used. Tuximab (as described in U.S. Patent No. 8,153,765, incorporated herein by reference) (may include) In some embodiments, isatuximab VH and VL may include IgG1 It can be represented as / κ.

[0051] Substantially identical antibodies to those disclosed herein may be used in the manner disclosed. The term "substantially identical" means that the antibody heavy chain or lighter than the antibody disclosed herein. This means that the chain amino acid sequences are identical or have "very slight differences." The slight difference refers to 1, 2 in the antibody heavy or light chain that does not adversely affect the antibody's properties. , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids This is a substitution. The antibody sequence is, for example, Vector NTI v.9.0.0(Invi Using the initial configuration of the AlignX module from trogen, Carlsbad, CA) The protein sequences of the disclosed antibodies can be compared by pairwise alignment. It can be used as a matching sequence, for example, in a public database to verify related sequences or A search can be performed on the patent database. Used to perform such a search is... The example program uses default settings and is XBLAST or BLASTP The program (http: / / www.ncbi_nlm / nih_gov), or Geno meQuest(trademark)(GenomeQuest(Westborough, MA)) It is a suite. An antibody substantially identical to the disclosed antibody is, for example, an antibody of the disclosed antibody. It can be produced by making conservative modifications to the amino acid sequence. "Conservative modification" refers to the amino acid sequence. Amino acids that do not significantly affect or alter the binding properties of antibodies containing acid sequences. This refers to modifications. Conservative modifications include amino acid substitutions, additions, and deletions. "Spousal substitution" is a substitution in which an amino acid is replaced by an amino acid residue that has a similar side chain. The family of amino acid residues with similar side chains is well defined, and acidic side chains ( For example, aspartic acid, glutamic acid), basic side chains (for example, lysine, arginine, Histidine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, pro). Phosphorus, phenylalanine, methionine), non-loading side chains (e.g., glycine, asparagus) Gin, glutamine, cysteine, serine, threonine, tyrosine, tryptophan), fragrance Fragrance group side chains (e.g., phenylalanine, tryptophan, histidine, tyrosine), fats Group side chains (e.g., glycine, alanine, valine, leucine, isoleucine, serine, sulfate) Onine), amides (e.g., asparagine, glutamine), β-branched side chains (e.g., threon A (containing celine, valine, isoleucine), and sulfur-containing side chains (cysteine, methionine) It contains amino acids. Furthermore, as previously explained, alanine scanning mutagenesis (MacLennan et al., (1988) Acta Physiol Sc and Suppl 643:55-67, Sasaki et al., (1988) Adv Biophys 35:1-24), any native residue within the polypeptide is ara It may be substituted with nin. Exemplary examples may be performed on the anti-CD38 antibody used in the disclosed method. Substitutions include, for example, conservation with amino acids that have similar charge, hydrophobicity, or chemiometric properties. This includes conservative substitutions. Conservative substitutions modify the properties of an antibody, such as stability or affinity. It may also be done to improve or enhance antibody effector function. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid substitutions For example, this can be done on the heavy and / or light chains of an anti-CD38 antibody. Furthermore, Alanine Canyon As previously explained (MacLennan et al.), mutagenesis is a key factor. ,Acta Physiol Scand Suppl 643:55-67,1998 , Sasaki et al., Adv Biophys 35:1-24, 1998) Any native residue in the heavy chain and / or light chain may be substituted with alanine. Suitable amino acids The substitution can be determined by a person skilled in the art at the time such substitution is desired. Amino acid substitutions are, For example, this can be done by PCR mutagenesis (disclosed in U.S. Patent No. 4,683,195). It is possible. A library of mutants can be created using a well-known method, for example, by selecting 11 amino acids (A la, Cys, Asp, Glu, Gly, Lys, Asn, Arg, Ser, Tyr, T Random (NNK) codons or non-random codons (e.g., DVK codons) that encode rp. Using (DON), we can screen the library for mutants that possess the desired characteristics. It can be produced by and. The produced mutant is its C The ability to bind to D38 and induce ADCC can be tested.

[0052] Anti-CD38 antibodies are of the IgG1, IgG2, IgG3, or IgG4 isotype. This is possible. In some embodiments, the anti-CD38 antibody is of the IgG1 isotype. In some embodiments, the anti-CD38 antibody is of the IgG2 isotype. In some embodiments, the anti-CD38 antibody is of the IgG3 isotype. In some embodiments, the anti-CD38 antibody is of the IgG4 isotype.

[0053] The anti-CD38 antibody used in the disclosed method is, for example, a phage that is human immunoglobulin. or a part thereof, for example, Fab, single-chain antibody (scFv), or unpaired or paired Newly selected from phage display libraries manipulated to express antibody variable regions In some cases, it may be selected (Knappik et al., J Mol Biol 296: 57-86,2000, Krebs et al., J Immunol Meth 2 54:67-84, 2001, Vaughan et al., Nature Biot. echnology 14:309-314,1996, Sheets et al. PITAS(USA)95:6157-6162,1998, Hoogenboom a nd Winter, J Mol Biol 227:381, 1991, Marks et al., J Mol Biol 222:581, 1991). CD38 binding variable For example, the domain is Shi et al (2010) J.Mol.Biol.397: Bacteriophages described in 385-96 and International Publication No. 2009 / 085462 The antibody expresses its heavy and light chain variable regions as a fusion protein with a pIX coat protein. It can be isolated from a phage display library. The antibody library can be isolated from human CD38 cells. Screening was performed for binding to the extracellular domain, and the resulting positive clones were further characterized. After isolating Fab from the clone lysate, clone it as a full-length antibody. Such phage display methods for isolating human antibodies are available in the art. It is established in the United States Patent No. 5,223,409, U.S. Patent No. 5,403. ,484, U.S. Patent No. 5,571,698, U.S. Patent No. 5,427,908, United States Japanese Patent No. 5,580,717, U.S. Patent No. 5,969,108, U.S. Patent No. 6,172 ,197, U.S. Patent No. 5,885,793, U.S. Patent No. 6,521,404, United States Japanese Patent No. 6,544,731, U.S. Patent No. 6,555,313, U.S. Patent No. 6,582 See Patent No. 915 and U.S. Patent No. 6,593,081.

[0054] In some embodiments, the anti-CD38 antibody competes with the reference antibody for binding to CD38. In combination, this reference antibody is, a) Heavy chain CDR1 containing the amino acid sequence of SEQ ID NO: 6, and containing the amino acid sequence of SEQ ID NO: 7 Heavy chain CDR2 contains the amino acid sequence of SEQ ID NO: 8, and heavy chain CDR3 contains the amino acid sequence of SEQ ID NO: 9 Light chain CDR1 containing the sequence, light chain CDR2 containing the amino acid sequence of SEQ ID NO: 10, and SEQ ID NO: Light chain CDR3 containing 11 amino acid sequences, b) VH containing the amino acid sequence of SEQ ID NO: 4, and VL containing the amino acid sequence of SEQ ID NO: 5 , c) A heavy chain containing the amino acid sequence of SEQ ID NO: 12, and a heavy chain containing the amino acid sequence of SEQ ID NO: 13. Light chain, d) DARZALEX (trademark) (daratumumab), e) Heavy chain CDR1, heavy chain CDR2, and heavy chain of VH containing the amino acid sequence of SEQ ID NO: 14 CDR3, and the VL light chains CDR1 and CDR2, which contain the amino acid sequence of SEQ ID NO: 15. , and light chain CDR3, f) VH containing the amino acid sequence of SEQ ID NO: 14, and containing the amino acid sequence of SEQ ID NO: 15 VL, g)mAb003, h) Heavy chain CDR1, heavy chain CDR2, and heavy chain of VH containing the amino acid sequence of SEQ ID NO: 16 CDR3, and the VL light chains CDR1 and CDR2, which contain the amino acid sequence of SEQ ID NO: 17. , and light chain CDR3, i) VH containing the amino acid sequence of SEQ ID NO: 16, and containing the amino acid sequence of SEQ ID NO: 17 VL, j)mAb024, k) Heavy chain CDR1, heavy chain CDR2, and heavy chain of VH containing the amino acid sequence of SEQ ID NO: 18 CDR3, and the VL light chains CDR1 and CDR2, which contain the amino acid sequence of SEQ ID NO: 19. , and light chain CDR3, l) VH containing the amino acid sequence of SEQ ID NO: 18, and containing the amino acid sequence of SEQ ID NO: 19 VL, m)MOR-202 (MOR-03087), n) Heavy chain CDR1, heavy chain CDR2, and heavy chain of VH containing the amino acid sequence of SEQ ID NO: 20 CDR3, and the VL light chains CDR1 and CDR2, which contain the amino acid sequence of SEQ ID NO: 21. , and light chain CDR3, o) VH containing the amino acid sequence of SEQ ID NO: 20, and containing the amino acid sequence of SEQ ID NO: 21 VL, p) Isatuximab, or Includes any combination of q)a)~p).

[0055] The antibody was tested for binding to CD38 using a well-known in vitro method, using a reference antibody (above). Competition with reference antibodies, etc., as described in a) to q) below can be evaluated. In an exemplary method, C CHO cells expressing D38 by recombinant DNA were incubated with an unlabeled reference antibody at 4°C for 15 minutes. After incubation, the excess amount of fluorescently labeled test antibody can be incubated at 4°C for 45 minutes. After washing in PBS / BSA, fluorescence is measured by flow cytometry using a standard method. This can be done. In another exemplary method, the extracellular portion of human CD38 is ELISA-P The surface of the rate can be coated. An excess of unlabeled reference antibody is added over a period of approximately 15 minutes. Then, biotinylation antibody may be added. After washing in PBS / Tween, the test antibody The binding of otinized antibodies is controlled by horseradish peroxidase (HRP)-conjugated streptavidin. This can be detected using signals detected using standard methods. Therefore, the reference antibody may be labeled, while the test antibody may not be labeled. The body inhibits the binding of the test antibody, or the test antibody inhibits the binding of the reference antibody by at least approximately 90%. If the test antibody inhibits 95% or 100%, it competes with the reference antibody. Topics include, for example, peptide mapping using known methods or hydrogen / deuterium protection. It can be further defined by Sei or by the determination of its crystal structure.

[0056] Anti-CD38 antibody is effective against antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis. CD38 expression is mediated by ADCP, complement-dependent cell-mediated cytotoxicity (CDC), or apoptosis. It can induce cell killing. In some embodiments, the anti-CD38 antibody is used to treat AD CC induces the killing of CD38-expressing cells. In some embodiments, anti-CD38 The antibody induces the killing of CD38-expressing cells by ADCP. In some embodiments, Anti-CD38 antibodies induce the killing of CD38-expressing cells by the CDC. In terms of application, anti-CD38 antibodies induce the killing of CD38-expressing cells through apoptosis. In some embodiments, the anti-CD38 antibody is used against ADCC, ADCP, CDC, and Any combination of potosis induces the killing of CD38-expressing cells.

[0057] “Antibody-dependent cytotoxicity”, “antibody-dependent cell-mediated cytotoxicity”, or “ADCC” The Fc gamma receptor (FcγR) expressed in phenotypic cells affects antibody-coated target cells. , the lytic activity of natural killer (NK) cells, monocytes, macrophages, and neutrophils It is a mechanism that induces cell death, depending on the interaction with effector cells it possesses. NK cells express FcγRIIIa, while monocytes express FcγRI, FcγRII, and F It expresses cγRIIIa. Death of antibody-coated target cells such as CD38-expressing MM cells occurs at the membrane. As a result of effector cell activity through the secretion of pore-forming proteins and proteases. It occurs. To evaluate the ADCC activity of anti-CD38 antibodies, this antibody is used as an immunoeffector. - These can be added to CD38-expressing cells in combination with other cells, and these can form antigen / antibody complexes. This can be activated, leading to cell lysis of target cells. Cell lysis is then performed by lysing cells. By releasing a label (e.g., a radioactive substrate, fluorescent dye, or natural intracellular protein) It can be detected. Exemplary effector cells for such an assay include peripheral blood mononuclear cells. Examples include PBMCs and NK cells. CD38-expressing multiple myeloma cell lines or Primary MM cells can be used as target cells. In an exemplary assay, Lucifera MM cell lines modified to express the enzyme are incubated with an anti-CD38 antibody. PBMC effector cells isolated from the target were targeted in a target:effector cell ratio of 40:1. It is added. Four hours after the addition of PBMCs, luciferin is added and released from surviving MM cells. The resulting bioluminescent signal is measured by a luminometer (SpectraMax, M). It can be determined within 20 minutes using olecular devices, and the A of MM cells The DCC ratio is given by the formula: ADCC% = 1 - (average bioluminescence signal in the absence of PBMCs / P It can be calculated using (average bioluminescence signal in the presence of BMC) × 100%. The anti-CD38 antibody used in this method contains approximately 20%, 25%, 30%, and 35% of ADCC. , 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 90%, or 1 It can be induced 00%.

[0058] "Complement-dependent cell injury" or "CDC" refers to the Fc effector of target-binding antibodies. It binds to complement component C1q and activates it, and then activates the complement cascade to target This refers to the mechanism that induces cell death, which results in targeted cell death. Complement activation also involves targeting This can cause the deposition of complement components on the cell surface, leading to the deposition of complement receptors (e.g., CR3) on leukocytes. The binding promotes ADCC. In an exemplary assay, a B-cell malignant tumor is present. Primary BM-MNC cells isolated from patients were treated with anti-CD38 antibody and 10% pooled human serum. Complement derived from [unclear], treated at a concentration of 0.3-10 μg / mL for 1 hour, and primary CD38 + MM cell survival, van der Veer et al., Haematolog ica 96:284-290,2011, van der Veer et al., The technique described in Blood Cancer J 1(10):e41,2011 is used. The percentage of MM cells lysed can be determined by flow cytometry. The percentage of MM cells lysed is described herein. It can be determined with respect to the isotype control listed. Used in the disclosed method Anti-CD38 antibodies reduce CDC by approximately 20%, 25%, 30%, 35%, 40%, 45%, and 50%. %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or It can be 100% induced.

[0059] "Antibody-dependent cell phagocytosis" or "ADCP" refers to the action of macrophages or dendritic cells, etc. ADCP refers to a mechanism that eliminates antibody-coated target cells through uptake by phagocytic cells. Monocyte-derived macrophages are used as the phenotype cells, and GFP or other labeled molecules are used. Daudi cells (ATCC) expressing CD38 as target cells engineered to express it. (Registered Trademark) CCL-213 (Trademark), B-cell leukemia, or lymphoma cells are used. This can be evaluated by the following: The effector:target cell ratio may be, for example, 4:1. Effector cells were used with target cells for 4 hours, either with or without anti-CD38 antibody. They can be incubated with septic solution. After incubation, the cells are detached using actase. Yes, macrophages can react to fluorescently labeled anti-CD11b and anti-CD14 antibodies. Although it can be more clearly identified, the rate of phagocytosis can be determined using standard methods for CD11 + and CD1 4 + This can be determined based on the percentage of GFP fluorescence in macrophages. The anti-CD38 antibody used in this method reduces ADCP by approximately 20%, 25%, 30%, and 35%. 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, It can induce 90%, 95%, or 100% of cases.

[0060] The Fc portion of the anti-CD38 antibody is responsible for antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent Antibody effector devices for phagocytosis (ADCP) or complement-dependent cell-mediated cytotoxicity (CDC). It can mediate the function. Such functions are related to the food process of the Fc effector domain(s). By binding to Fc receptors on immune cells that have lytic or lytic activity, or by Fc This can be mediated by the binding of the component domain(s) to the components of the complement system. Typically, The effects mediated by Fc-binding cells or complement components are, for example, those of target cells. This leads to inhibition and / or depletion of CD38-expressing cells. Human IgG isotype, IgG1 IgG2, IgG3, and IgG4 exhibit different capabilities in terms of effector functions. ADCC can be mediated by IgG1 and IgG3, and ADCP can be mediated by IgG1, Ig It can be mediated by G2, IgG3, and IgG4, and the CDC has found that IgG1 and IgG3 Therefore, it can be mediated.

[0061] ADCC induced by anti-CD38 antibody is caused by a specific substitution within the antibody Fc. It can be enhanced. In some embodiments, the anti-CD38 antibody is amino acid 256, 290, 298th, 312th, 356th, 330th, 333rd, 334th, 360th, 378th, 430th place, or so This includes substitutions within the Fc region in any combination thereof, and this residue numbering is based on the EU index. In accordance with the provisions of U.S. Patent No. 6,737,056.

[0062] ADCC induced by anti-CD38 antibodies can be manipulated by controlling the antibody oligosaccharide component. It can also be enhanced. Human IgG1 or IgG3 is N-glycosylated with Asn297. Most glycans are bifid G0, G0F, G1, G1F, G2, or G2F. This is the morphology. Antibodies produced by unmanipulated CHO cells are typically small. At least 85% glycan fucose content (i.e., fucose within the sugar chain in Asn297) It has the amount of monosaccharides. Core fucoid from branched complex oligosaccharides attached to the Fc region. Removal of the compound modifies FcγRIIIa binding without altering antigen binding or CDC activity. The ADCC of the antibody is enhanced by good. Such modified antibodies control the osmotic pressure of the culture (Ko nno et al.,Cytotechnology 64:249-65,2012 Such modified antibodies control the osmotic pressure of cultures (Konno et al., Cytot Application as a host cell line for the variant CHO cell line Lec13 (Shields et al., J Biol Chem 27 7:26733-26740, 2002), application as a host cell line for the variant CHO cell line EB66 (Olivier et al., MAbs 2(4), 2010; prior to printing electronic publication, PMID: 20562582), application as a host cell line for the rat hybridoma cell line YB2 / 0 (Shinkawa et al., J Biol Chem 2 78:3466-3473, 2003), particularly the introduction of small interfering RNA against the α1,6-fucosyltransferase (FUT8) gene (Mori et al., Biot echnol Bioeng 88:901-908, 2004), or β-1,4-N -acetylglucosaminyltransferase III and Golgi α-mannosidase II or a potent α-mannosidase I inhibitor, such as kifunensine (Ferrara et al., J Biol Chem 281:5032-5036, 2006, Ferrara et al., Biotechnol Bioeng 93:851 -861, 2006, Xhou et al., Biotechnol Bioeng 99:652-65, 2008), etc., various methods that have been reported to successfully express a relatively highly defucosylated antibody with a bisected complex-type Fc oligosaccharide can be used to obtain. In some embodiments, the anti-CD38 antibody is between about 0% and about 15%, for example, 15% , 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3

[0063] ​​It may have a branched glycan structure with a fucose content of 3%, 2%, 1%, or 0%. In some embodiments, the anti-CD38 antibody is about 50%, 45%, 40%, 35%, 30% , 25%, 20%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7 %, 6%, 5%, 4%, 3%, 2%, 1%, or 0% fucose content and contains a branched gly can structure. Substitutions within the Fc region and reduced fucose content can enhance the ADCC activity of the anti-CD38 antibody.

[0064] The fucose content can be characterized and quantified by a plurality of methods, for example, 1) use of MALDI-TOF of N-glycosidase F-treated samples (e.g., conjugates, hybrids, as well as oligomannose structures and high-mannose structures) described in WO 2008 / 0775462, 2) enzymatic release of Asn 297 glycans, subsequent derivatization, and detection / quantification by HPLC (UPLC ) and / or HPLC-MS (UPLC-MS) with fluorescence detection, 3) treatment of Asn297 glycans with Endo S or other enzymes that cleave between the first Glc NAc monosaccharide and the second GlcNAc monosaccharide and leave fucose attached to the first GlcNA c, with or without this treatment, intact protein analysis of native or reduced mAb, 4) digestion of the antibody into constituent peptides by enzymatic digestion (e.g., trypsin or endopeptidase Lys-C), followed by separation, detection, and quantification by HPLC-MS (UPLC-MS), 5) separation of antibody oligosaccharides from antibody proteins by specific enzymatic deglycosylation with PNGase F at Asn297 and can be characterized and quantified. The oligosaccharides released in this way are labeled with a fluorophore, and the experimental mass and theoretical mass are compared, and the fucose content can be determined by HPLC-MS (UPLC-MS). The oligosaccharides released in this way are labeled with a fluorophore, and the experimental mass and theoretical mass are compared, and the fucose content can be determined by HPLC-MS (UPLC-MS). The oligosaccharides released in this way are labeled with a fluorophore, and the experimental mass and theoretical mass are compared, and the fucose content can be determined by HPLC-MS (UPLC-MS). The oligosaccharides released in this way are labeled with a fluorophore, and the experimental mass and theoretical mass are compared, and the fucose content can be determined by HPLC-MS (UPLC-MS). Matrix-assisted laser desorption ionization (MALDI) mass spectrometry by comparison with mass for fine characterization of glycan structures, determination of sialylation degree by ion-exchange HPLC (GlycoSep C), separation and quantification of oligosaccharide forms according to hydrophilicity criteria by normal-phase HPLC (GlycoSep N), and separation and quantification of oligosaccharides by various complementary techniques enabling separation and identification by high-performance capillary electrophoresis laser-induced fluorescence ( HPCE-LIF).

[0065] Anti-CD38 antibodies can bind to human CD38 with a range of affinities (K D ). For example, anti-CD38 antibodies can bind to CD38 with a K of about 1×10 -8 M or less, such as 5×10 -9 M, 1×10 -9 M, 5×10 -10 M, 1×10 -10 M, 5×10 -11 M, 1×10 -11 M, 5×10 -12 M, 1×10 -12 M, 5×10 -13 M, 1×10 -13 M, 5×10 -14 M 1×10 -14 M, 5×10 -15 M, or any range or value of K D and can bind to C D38. In some embodiments, the anti-CD38 antibody can bind to CD38 with an affinity of 1×10 -8 M or less. In some embodiments, the anti-CD38 antibody can bind to CD38 with an affinity of 1×1 0 -9 M or less.

[0066] Antibody affinity is determined by KinExA instruments, ELISA, or competitive binding assays known to those skilled in the art. It can be measured using (I). The measured affinity of a particular antibody / CD38 interaction differs. It may differ when measured under different conditions (e.g., osmotic pressure, pH). Therefore, affinity and other binding parameters (e.g., K D , K on , K off The measurement of ) is typically, This is carried out using standardization conditions and standardized buffer solutions. Those skilled in the art can use, for example, Biacore. The internal error (standard deviation (SD)) of affinity measurement using 3000 or ProteOn is defined as follows: (Measured by) but typically within the range of 5-33% of typical detection limits. They will understand that it is possible. Therefore, K D In relation to this, the term "approximately" is This reflects the typical standard deviation in the assay. For example, K D is 1 x 10 -9 In the case of M A typical standard deviation (SD) is ±0.33 × 10⁻⁶. -9 It is M or less.

[0067] The dose of anti-CD38 antibody administered to patients with multiple myeloma is used to slow the disease being treated. A sufficient amount to neutralize or at least partially block it ("therapeutic effective dose") The range is approximately 0.005 mg to 100 mg / kg, for example, approximately 0.05 mg to 30 mg / kg. g or approximately 5 mg to approximately 25 mg / kg, or approximately 4 mg / kg, approximately 8 mg / kg, approximately 16 Contains mg / kg, or approximately 24 mg / kg. A suitable dose is, for example, approximately 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 15, 16, 17, 18, 19, 20, 21, 2 2, 23, 24, 25, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg was mentioned.

[0068] A fixed unit dose of the anti-CD38 antibody, for example, 50, 100, 200, 500, or 1 000 mg may be administered, or this dose may be, for example, based on the patient's surface area , 500, 400, 300, 250, 200, or 100 mg / m 2 and may be. Usually, doses between 1 and 8 times (for example, 1, 2, 3, 4, 5, 6, 7, or 8 times) may be administered to treat MM, but doses of 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, or more may be administered.

[0069] Administration of the anti-CD38 antibody may be repeated 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, or more later. The treatment course may be repeated, and long-term administration is also possible. Repeated administration may be at the same dose or at different doses. For example, the anti-CD38 antibody may be administered intravenously at 8 mg / kg or 16 mg / kg every 1 week for 8 weeks, and then at 8 mg / kg or 16 mg / kg every 2 weeks for an additional 16 weeks, and then at 8 mg / kg or 16 mg / kg every 4 weeks

[0070] The anti-CD38 antibody may be administered, for example, by maintenance therapy such as once a week over a period of 6 months or more. For example, the anti-CD38 antibody may be administered using single-dose or divided-dose administration every 24, 12, 8, 6, 4, or 2 hours, or a combination of these, as a daily dosage of about 0.1 mg / kg to 100 mg / kg, for example, 0.5, 0.9 per day​​ , 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / In kg, after the start of treatment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 2 7, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or On at least one day out of the 40 days, or on days 1, 2, 3, 4, 5, 6, 7, 8, 9, Among weeks 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 They may be offered at least once a week, or in combination of these.

[0071] Anti-CD38 antibodies reduce the risk of developing multiple myeloma and inhibit its progression. It delays the onset of the event and / or the relapse when multiple myeloma enters remission. It may also be administered prophylactically to reduce risk.

[0072] Exemplary corticosteroids include, for example, glucocorticoids (e.g., corticosteroids). Examples include sole, prednisone, or dexamethasone. In some embodiments, The corticosteroid is dexamethasone. Therefore, these methods target the subject, The therapeutically effective dose of anti-CD38 antibody, dexamethasone, and non-corticosteroid chemotherapeutic agents This may include administering the drug for a sufficient amount of time to treat high-risk multiple myeloma.

[0073] In some embodiments, corticosteroids are administered once a week at a dose of approximately 80 mg. In some embodiments, corticosteroids are administered once a week at a dose of approximately 40 mg. In one embodiment, corticosteroids are administered twice a week. In some embodiments, Corticosteroids are administered four times a week. In some embodiments, corticosteroids are administered four times a week. The id is administered once a week. In some embodiments, the corticosteroid is administered orally. In some embodiments, corticosteroids are administered intravenously. In this embodiment, the corticosteroid is dexamethasone.

[0074] Examples of non-corticosteroid chemotherapeutic agents include glutamate derivatives or protea Some examples include chromosome inhibitors. Exemplary glutamate derivatives include thalidomide (Th alomid (registered trademark) or thalidomide analogs, for example, CC-5013 (lenali Domido, Revlimid (trademark), pomalidomide, or CC4047 (Actimi d(trademark)) is an example. In some embodiments, the glutamic acid derivative is lenalide It is mid. Therefore, these methods target anti-CD38 antibody, corticosterone. A therapeutically effective dose of lenalidomide, and enough time to treat high-risk multiple myeloma. This may include administering the drug over a period of time.

[0075] In some embodiments, lenalinomide is administered once daily at a dose between approximately 10 mg and approximately 25 mg. In some embodiments, lenalinomide is administered once daily at a dose of approximately 25 mg. .

[0076] An example of a proteasome inhibitor is bortezomib (Velcade®). Examples include carfilzomib or ixazomib. In some embodiments, pro The theasome inhibitor is bortezomib. Therefore, these methods target anti-C Effective doses of D38 antibody, corticosteroids, and bortezomib for high-risk multiple bone disease This may include administering the drug for a sufficient amount of time to treat the myeloma.

[0077] In some embodiments, bortezomib is administered at approximately 1.5 mg / m². 2 It is administered once a week. In some embodiments, bortezomib is administered at approximately 1.3 mg / m². 2 It is administered once a week. In some embodiments, bortezomib is administered at approximately 1.3 mg / m². 2 ~about 1.5mg / m 2 weekly It is administered as a single dose. In some embodiments, bortezomib is administered at approximately 1.3 mg / m². 2 2 times a week It is administered as a single dose. In some embodiments, bortezomib is administered by subcutaneous injection. .

[0078] In some embodiments, these methods target an anti-CD38 antibody and dexamethasone. , and a therapeutically effective dose of lenalidomide, given in a sufficient amount of time to treat high-risk multiple myeloma. This may include administering over time. In some embodiments, these methods target, Therapeutic doses of anti-CD38 antibody, dexamethasone, and bortezomib for high-risk multiple bone marrow This may include administering the medication for a sufficient amount of time to treat the myeloma. So, these methods target anti-CD38 antibodies, dexamethasone, lenalidomide, and The therapeutically effective dose of bortezomib is administered for a sufficient amount of time to treat high-risk multiple myeloma. This may include administering the drug.

[0079] The target cytogenetic abnormalities are: t(4;14)(p16;q32), t(14;1 6) If you have one or more of the following: (q32;q23, or del17p, you are considered "high risk" It can be classified as such. Therefore, subjects with high-risk multiple myeloma are at(4;14)(p16;q32), bt(14;16)(q32;q23), c.del17p, dt(4;14)(p16;q32) and t(14;16)(q32;q23), et(4;14)(p16;q32) and del17p, ft(14;16)(q32;q23) and del17p, or gt(4;14)(p16;q32), t(14;16)(q32;q23), and It may have one or more chromosomal abnormalities, including del17p.

[0080] The target cytogenetic abnormalities are: t(4;14)(p16;q32), t(14;1 6) If none of (q32;q23, or del17p) are present, then it is considered "standard risk". It can be classified as follows.

[0081] Cytogenetic abnormalities can be detected by fluorescence in situ hybridization (FISH). It can be detected. In both chromosomal translocations, the oncogene is IgH on chromosome 14q32. Translocation occurs in the region, leading to dysregulation of these genes. t(4;14)(p16; q32) is fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain This involves the translocation of the protein containing MMSET (also known as WHSC1 / NSD2), t(1 4;16)(q32;q23) involves a translocation of the MAF transcription factor C-MAF. 17p deletion. (del17p) involves the loss of the p53 locus.

[0082] The target group includes individuals with untreated multiple myeloma, relapsed multiple myeloma, or refractory multiple myeloma. In some embodiments, the subject is high-risk refractory and / or relapsed multiple myeloma. It has.

[0083] Treatment methods include treatment with corticosteroid and non-corticosteroid chemotherapy agents. Compared to elephants, it is possible to improve one or more outcome measurements of the target. Examples of endpoints include progression-free survival, overall response rate, very good partial response, or More than that (very good partial response or better), complete response or better (comp This includes a let's response (or better), or any combination thereof.

[0084] These methods result in minimal residual disease in the subjects. -Negativity) can be achieved. A minimal residual disease-negative state is 0.01% (10 - 4 ), 0.001% (10 -5 ), 0.0001%(10 -6 ), or a combination thereof This can be determined by the sensitivity of the test. Negative minimal residual disease. This can be detected by evaluating the amount of myeloma cells in a bone marrow aspirate sample derived from the target organism. .

[0085] Anti-CD38 antibodies, corticosteroids, and non-corticosteroid chemotherapeutic agents are optional. It can be administered over a convenient time frame. In some embodiments, an anti-CD38 antibody, Corticosteroids and non-corticosteroid chemotherapy agents are administered simultaneously. In one embodiment, an anti-CD38 antibody, a corticosteroid, and a non-corticosteroid are used. The chemotherapy agents are administered sequentially in any order. An example administration schedule is as follows: The following can be listed. • Daratumumab is administered once a week (on days 1, 8, and 15) during cycles 1-3. Between stages 4 and 8, once every 4 weeks (on day 1), and thereafter, once every 4 weeks, at a dose of 16 mg / kg. It can be administered as an intravenous infusion. Bortezomib is administered in cycles 1-8, 1, 4, 8, and On day 11, 1.3 mg / m² 2 It can be administered subcutaneously (SC) at the following doses. Dexamethasone is 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12, for a total of 160 mg per cycle. It can be administered orally in total doses. Daratumumab is administered once a week (1, 8, 15) for 8 weeks during cycles 1 and 2. (and day 22), once every two weeks for 16 weeks (days 1 and 15) (cycles 3-6) ), thereafter, it may be administered intravenously at a dose of 16 mg / kg once every four weeks. If creatinine clearance exceeds 60 mL / min, nalidomide is administered once per cycle. ~On day 21, administer a dose of 25 mg (or when creatinine clearance is 30-60 mL / min) In some cases, it may be administered orally at a dose of 10 mg per day, while dexamethasone may be administered at a dose of 40 mg per day. It can be administered once a week. In the daratumumab group, even if the dose of dexamethasone is divided... Dexamethasone is often administered at a dose of 20 mg before infusion as a preventative measure against infusion-related reactions. It is also acceptable to administer 20 mg the following day.

[0086] Anti-CD38 antibodies, corticosteroids, and non-corticosteroid chemotherapeutic agents are optional. Forms of radiotherapy, such as external beam radiation therapy, intensity-modulated radiation therapy (IMRT), and optional Forms of radiosurgery, such as Gamma Knife, CyberKnife, Linac, and intra-tissue radiosurgery. Irradiation (e.g., implantation of radioactive seeds, GliaSite balloons), and / or external It may be administered in conjunction with surgery.

[0087] Anti-CD38 antibodies, corticosteroids, and non-corticosteroid chemotherapeutic agents are autologous It can be administered in conjunction with hematopoietic stem cell transplantation (AHSC).

[0088] Methods for achieving minimal residual disease-negative status in the target population. A method for achieving minimal residual disease negativity in subjects with multiple myeloma, The targets include anti-CD38 antibodies, corticosteroids, and non-corticosteroid chemotherapeutic agents. Administer a therapeutically effective dose for a sufficient amount of time to achieve minimal residual disease negativity. Methods including the above are also provided.

[0089] The percentage of those with minimal residual disease (MILG) is 0.01% (10 -4 ), 0.001% (10 -5 ), 0. 0001%(10 -6 ), or the sensitivity of a combination thereof, can be determined by several actual In terms of administration methods, a negative result for minimal residual disease (MILP) evaluates the amount of myeloma cells in the bone marrow aspirate sample derived from the subject. It is detected by doing so.

[0090] In addition to achieving minimal residual disease (MPD) negativity, this method also reduces progression-free survival. Let it.

[0091] The target group includes individuals with untreated multiple myeloma, relapsed multiple myeloma, or refractory multiple myeloma. In some embodiments, the subject is high-risk refractory and / or relapsed multiple myeloma. Patients with high-risk multiple myeloma have a high risk of early relapse and a poor prognosis and outcome. It is known that this is the case.

[0092] In some embodiments, the subjects have high-risk multiple myeloma. The subjects are as follows: Cytogenetic abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q2 If you have one or more of the following: 3. or del17p, you may be classified as "high risk". Therefore, subjects with high-risk multiple myeloma are, at(4;14)(p16;q32), bt(14;16)(q32;q23), c.del17p, dt(4;14)(p16;q32) and t(14;16)(q32;q23), et(4;14)(p16;q32) and del17p, ft(14;16)(q32;q23) and del17p, or gt(4;14)(p16;q32), t(14;16)(q32;q23), and It may have one or more chromosomal abnormalities, including del17p.

[0093] Regarding treatment methods, none of the anti-CD38 antibodies disclosed above are suitable for patients with multiple myeloma. It can be used in methods to achieve minimal residual disease negativity in elephants.

[0094] The anti-CD38 antibody contains human CD38, including SKRNIQFSCKNIYR (SEQ ID NO: 2). The region and the human CD38 region including EKVQTLEAWVIHGG (SEQ ID NO: 3) are linked. It is possible to match.

[0095] The anti-CD38 antibody contains the heavy chain CDR1, which includes the amino acid sequence of SEQ ID NO: 6, and the amino acid sequence of SEQ ID NO: 7. Heavy chain CDR2 containing the no-acid sequence, heavy chain CDR3 containing the amino acid sequence of SEQ ID NO 8, SEQ ID NO Light chain CDR1 contains the amino acid sequence of 9, and light chain CDR2 contains the amino acid sequence of sequence number 10. It may contain light chain CDR2 and light chain CDR3 containing the amino acid sequence of SEQ ID NO: 11. 38 antibodies have the amino acid sequence of SEQ ID NO: 4 and 95%, 96%, 97%, 98%, 99%, and VH contains 100% identical amino acid sequences, and the amino acid sequence of SEQ ID NO: 5 is 95% identical to that of 9 May contain VLs that have 6%, 97%, 98%, 99%, or 100% identical amino acid sequences. In some embodiments, the anti-CD38 antibody is VH and containing the amino acid sequence of SEQ ID NO: 4. The VL may contain the amino acid sequence of SEQ ID NO: 5. The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 12. It may include a heavy chain containing an amino acid sequence and a light chain containing the amino acid sequence of SEQ ID NO: 13.

[0096] The anti-CD38 antibody contains the VH heavy chain CDR1 and heavy chain CD, which are the amino acid sequences of SEQ ID NO: 14. R2, and heavy chain CDR3, and VL light chain CDR1 containing the amino acid sequence of SEQ ID NO: 15 It may include light chain CDR2 and light chain CDR3. The anti-CD38 antibody is the amine of SEQ ID NO: 15 Amino acid sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical to the no-acid sequence. VH containing, and the amino acid sequence of SEQ ID NO: 15 and 95%, 96%, 97%, 98%, 99% It may contain VLs that have %, or 100%, the same amino acid sequence. In some embodiments, The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 14 (VH) and SEQ ID NO: 15 (amino acids). It may include a VL containing a sequence. In some embodiments, for example, the anti-CD38 antibody is mA b003 (as described in U.S. Patent No. 7,829,693 incorporated herein by reference) It may include (reru).

[0097] The anti-CD38 antibody contains the VH heavy chain CDR1 and heavy chain CD, which are the amino acid sequences of SEQ ID NO: 16. R2, and heavy chain CDR3, and VL light chain CDR1 containing the amino acid sequence of SEQ ID NO: 17 It may include light chain CDR2 and light chain CDR3. The anti-CD38 antibody is the amine of SEQ ID NO: 16. Amino acid sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical to the no-acid sequence. VH, which includes the amino acid sequence of SEQ ID NO: 17, and 95%, 96%, 97%, 98%, 99% It may contain VLs that have %, or 100%, the same amino acid sequence. In some embodiments, The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 16 (VH) and SEQ ID NO: 17 (amino acids). It may include a VL containing a sequence. In some embodiments, for example, the anti-CD38 antibody is mA b024 (as described in U.S. Patent No. 7,829,693 incorporated herein by reference) It may include (reru).

[0098] The anti-CD38 antibody contains the VH heavy chain CDR1 and heavy chain CD, which are the amino acid sequences of SEQ ID NO: 18. R2, and heavy chain CDR3, and VL light chain CDR1 containing the amino acid sequence of SEQ ID NO: 19 It may include light chain CDR2 and light chain CDR3. The anti-CD38 antibody is the amine of SEQ ID NO: 18. Amino acid sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical to the no-acid sequence. VH containing, and the amino acid sequence of SEQ ID NO: 19 and 95%, 96%, 97%, 98%, 99% It may contain VLs that have %, or 100%, the same amino acid sequence. In some embodiments, The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 18 (VH) and SEQ ID NO: 19 (amino acids). It may include a VL containing a sequence. In some embodiments, for example, the anti-CD38 antibody is MO R-202 (MOR-03087) (as incorporated herein by reference, U.S. Act 8, This may include (as described in publications 088 and 896).

[0099] The anti-CD38 antibody contains the VH heavy chain CDR1 and heavy chain CD, which are the amino acid sequences of SEQ ID NO: 20. R2, and heavy chain CDR3, and VL light chain CDR1 containing the amino acid sequence of SEQ ID NO: 21 It may include light chain CDR2 and light chain CDR3. The anti-CD38 antibody is the amine of SEQ ID NO: 20 Amino acid sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical to the no-acid sequence. VH containing, and the amino acid sequence of SEQ ID NO: 21 and 95%, 96%, 97%, 98%, 99% It may contain VLs that have %, or 100%, the same amino acid sequence. In some embodiments, The anti-CD38 antibody contains the amino acid sequence of VH and SEQ ID NO: 20, which are the amino acids of SEQ ID NO: 21. It may include a VL containing a sequence. In some embodiments, for example, an anti-CD38 antibody is used. Tuximab (as described in U.S. Patent No. 8,153,765, incorporated herein by reference) (may include) In some embodiments, isatuximab VH and VL may include IgG1 It can be represented as / κ.

[0100] The treatment methods disclosed above include corticosteroid and non-corticosteroid chemotherapy. All of these methods are for patients with multiple myeloma who are aiming to achieve minimal residual disease (RAM) negativity. It may be used in law. Suitable corticosteroids include, for example, glucocorticoids. Examples include cortisol, prednisone, or dexamethasone. In this embodiment, the corticosteroid is dexamethasone. Suitable non-corticosteroids Examples of iodide chemotherapeutic agents include glutamate derivatives or proteasome inhibitors. An example of a glutamic acid derivative is thalidomide (Thalomid®). Or thalidomide analogs, for example, CC-5013 (lenalidomide, Revlimid( Examples include the trademarks Pomalidomide, or CC4047 (Actimid (trademark)). In some embodiments, the glutamic acid derivative is lenalidomide. Preferred protea Examples of somnocyte inhibitors include bortezomib (Velcade®) and carfilzomib. Examples include ib or ixazomib. In some embodiments, the proteasome inhibitor is , bortezomib.

[0101] Methods for predicting the likelihood of recurrence and / or disease progression, or for reducing the risk thereof. A method for predicting the likelihood of recurrence and / or disease progression in subjects with multiple myeloma. Furthermore, it reduces the risk of relapse and / or disease progression in patients with multiple myeloma. A method is provided.

[0102] Methods for predicting the likelihood of relapse and / or disease progression in patients with multiple myeloma , This includes measuring the minimal residual disease status in subjects, and the subjects undergoing treatment with anti-CD38 antibodies. He is receiving an effective dose, A positive minimal residual disease (MILI) status indicates the possibility of recurrence and / or disease progression.

[0103] Methods for predicting the likelihood of relapse and / or disease progression in patients with multiple myeloma , This includes measuring the minimal residual disease status in the subjects, and the subjects are tested for anti-CD38 antibody, col. The patient is receiving therapeutically effective doses of tycosteroids and non-corticosteroid chemotherapy agents. A positive minimal residual disease (MILI) status indicates the possibility of recurrence and / or disease progression.

[0104] A method to reduce the risk of relapse and / or disease progression in patients with multiple myeloma. teeth, The targets include anti-CD38 antibodies, corticosteroids, and non-corticosteroid chemotherapeutic agents. This includes administering a therapeutically effective dose to achieve a minimal residual disease-negative state. This indicates a reduced risk of recurrence and / or disease progression.

[0105] The target population includes untreated multiple myeloma, relapsed multiple myeloma, refractory multiple myeloma, or relapsed multiple myeloma. It may have sexual and refractory multiple myeloma. In some embodiments, the subject is high-risk refractory The patient has multiple myeloma, recurrent myeloma, or recurrent and refractory multiple myeloma.

[0106] In some embodiments, the subjects have high-risk multiple myeloma. The subjects are as follows: Cytogenetic abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q2 If you have one or more of the following: 3. or del17p, you may be classified as "high risk". Therefore, subjects with high-risk multiple myeloma are, at(4;14)(p16;q32), bt(14;16)(q32;q23), c.del17p, dt(4;14)(p16;q32) and t(14;16)(q32;q23), et(4;14)(p16;q32) and del17p, ft(14;16)(q32;q23) and del17p, or gt(4;14)(p16;q32), t(14;16)(q32;q23), and It may have one or more chromosomal abnormalities, including del17p.

[0107] Regarding treatment methods, none of the anti-CD38 antibodies disclosed above are suitable for patients with multiple myeloma. A method for predicting the likelihood of recurrence and / or disease progression in elephants, and for those with multiple myeloma It may be used in a manner that reduces the risk of recurrence and / or disease progression in the subject.

[0108] The anti-CD38 antibody contains human CD38, including SKRNIQFSCKNIYR (SEQ ID NO: 2). The region and the human CD38 region including EKVQTLEAWVIHGG (SEQ ID NO: 3) are linked. It is possible to match.

[0109] The anti-CD38 antibody contains the heavy chain CDR1, which includes the amino acid sequence of SEQ ID NO: 6, and the amino acid sequence of SEQ ID NO: 7. Heavy chain CDR2 containing the no-acid sequence, heavy chain CDR3 containing the amino acid sequence of SEQ ID NO 8, SEQ ID NO Light chain CDR1 contains the amino acid sequence of 9, and light chain CDR2 contains the amino acid sequence of sequence number 10. It may contain light chain CDR2 and light chain CDR3 containing the amino acid sequence of SEQ ID NO: 11. 38 antibodies have the amino acid sequence of SEQ ID NO: 4 and 95%, 96%, 97%, 98%, 99%, and VH contains 100% identical amino acid sequences, and the amino acid sequence of SEQ ID NO: 5 is 95% identical to that of 9 May contain VLs that have 6%, 97%, 98%, 99%, or 100% identical amino acid sequences. In some embodiments, the anti-CD38 antibody is VH and containing the amino acid sequence of SEQ ID NO: 4. The VL may contain the amino acid sequence of SEQ ID NO: 5. The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 12. It may include a heavy chain containing an amino acid sequence and a light chain containing the amino acid sequence of SEQ ID NO: 13.

[0110] The anti-CD38 antibody contains the VH heavy chain CDR1 and heavy chain CD, which are the amino acid sequences of SEQ ID NO: 14. R2, and heavy chain CDR3, and VL light chain CDR1 containing the amino acid sequence of SEQ ID NO: 15 It may include light chain CDR2 and light chain CDR3. The anti-CD38 antibody is the amine of SEQ ID NO: 15 Amino acid sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical to the no-acid sequence. VH containing, and the amino acid sequence of SEQ ID NO: 15 and 95%, 96%, 97%, 98%, 99% It may contain VLs that have %, or 100%, the same amino acid sequence. In some embodiments, The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 14 (VH) and SEQ ID NO: 15 (amino acids). It may include a VL containing a sequence. In some embodiments, for example, the anti-CD38 antibody is mA b003 (as described in U.S. Patent No. 7,829,693 incorporated herein by reference) It may include (reru).

[0111] The anti-CD38 antibody contains the VH heavy chain CDR1 and heavy chain CD, which are the amino acid sequences of SEQ ID NO: 16. R2, and heavy chain CDR3, and VL light chain CDR1 containing the amino acid sequence of SEQ ID NO: 17 It may include light chain CDR2 and light chain CDR3. The anti-CD38 antibody is the amine of SEQ ID NO: 16. Amino acid sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical to the no-acid sequence. VH, which includes the amino acid sequence of SEQ ID NO: 17, and 95%, 96%, 97%, 98%, 99% It may contain VLs that have %, or 100%, the same amino acid sequence. In some embodiments, The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 16 (VH) and SEQ ID NO: 17 (amino acids). It may include a VL containing a sequence. In some embodiments, for example, the anti-CD38 antibody is mA b024 (as described in U.S. Patent No. 7,829,693 incorporated herein by reference) It may include (reru).

[0112] The anti-CD38 antibody contains the VH heavy chain CDR1 and heavy chain CD, which are the amino acid sequences of SEQ ID NO: 18. R2, and heavy chain CDR3, and VL light chain CDR1 containing the amino acid sequence of SEQ ID NO: 19 It may include light chain CDR2 and light chain CDR3. The anti-CD38 antibody is the amine of SEQ ID NO: 18. Amino acid sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical to the no-acid sequence. VH containing, and the amino acid sequence of SEQ ID NO: 19 and 95%, 96%, 97%, 98%, 99% It may contain VLs that have %, or 100%, the same amino acid sequence. In some embodiments, The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 18 (VH) and SEQ ID NO: 19 (amino acids). It may include a VL containing a sequence. In some embodiments, for example, the anti-CD38 antibody is MO R-202 (MOR-03087) (as incorporated herein by reference, U.S. Act 8, This may include (as described in publications 088 and 896).

[0113] The anti-CD38 antibody contains the VH heavy chain CDR1 and heavy chain CD, which are the amino acid sequences of SEQ ID NO: 20. R2, and heavy chain CDR3, and VL light chain CDR1 containing the amino acid sequence of SEQ ID NO: 21 It may include light chain CDR2 and light chain CDR3. The anti-CD38 antibody is the amine of SEQ ID NO: 20 Amino acid sequences that are 95%, 96%, 97%, 98%, 99%, or 100% identical to the no-acid sequence. VH containing, and the amino acid sequence of SEQ ID NO: 21 and 95%, 96%, 97%, 98%, 99% It may contain VLs that have %, or 100%, the same amino acid sequence. In some embodiments, The anti-CD38 antibody contains the amino acid sequence of VH and SEQ ID NO: 20, which are the amino acids of SEQ ID NO: 21. It may include a VL containing a sequence. In some embodiments, for example, an anti-CD38 antibody is used. Tuximab (as described in U.S. Patent No. 8,153,765, incorporated herein by reference) (may include) In some embodiments, isatuximab VH and VL may include IgG1 It can be represented as / κ.

[0114] The treatment methods disclosed above include corticosteroid and non-corticosteroid chemotherapy. All of these drugs reduce the likelihood of relapse and / or disease progression in patients with multiple myeloma. Methods for predicting recurrence and / or disease progression in subjects with multiple myeloma, and the risk of relapse and / or disease progression. It can be used in a way that lowers the blood sugar. Suitable corticosteroids include, for example, glucosulfamethoxazole. Examples include cocorticoids (e.g., cortisol), prednisone, or dexamethasone. In some embodiments, the corticosteroid is dexamethasone. Non-corticosteroid chemotherapeutic agents include glutamate derivatives or proteasome inhibitors. Examples of such drugs include thalidomide. An example of a glutamic acid derivative is thalidomide. d(registered trademark)) or thalidomide analogs, for example, CC-5013 (lenalidomide, R evlimid (trademark), pomalidomide, or CC4047 (Actimid (trademark)) ) are examples. In some embodiments, the glutamic acid derivative is lenalidomide. A suitable proteasome inhibitor is bortezomib (Velcade®). Examples include carfilzomib or ixazomib. In some embodiments, prote The asome inhibitor is bortezomib.

[0115] Examples of embodiments are described below.

[0116] Embodiment 1. Method for achieving minimal residual disease (MILI) in a subject with multiple myeloma. The target is an anti-CD38 antibody, a corticosteroid, and a non-corticosteroid. The therapeutically effective dose of the therapeutic agent is administered for a sufficient amount of time to achieve minimal residual disease negativity. A method that includes giving in to something.

[0117] Embodiment 2. The anti-CD38 antibody is a heavy chain CDR1 containing the amino acid sequence of SEQ ID NO: 6, sequence Heavy chain CDR2 containing amino acid sequence number 7, heavy chain CDR containing amino acid sequence number 8 3. Light chain CDR1 containing the amino acid sequence of SEQ ID NO: 9, and containing the amino acid sequence of SEQ ID NO: 10 Embodiment 1 includes a light chain CDR2 and a light chain CDR3 containing the amino acid sequence of SEQ ID NO: 11. Methods used.

[0118] Embodiment 3. The corticosteroid is dexamethasone, as in Embodiments 1-2. method.

[0119] Embodiment 4. The non-corticosteroid chemotherapeutic agent is a glutamate derivative or proteaso The method according to Embodiments 1 to 3, which is a serotonin inhibitor.

[0120] Embodiment 5. The method according to Embodiment 4, wherein the glutamic acid derivative is lenalidomide.

[0121] Embodiment 6. The method according to Embodiment 4, wherein the proteasome inhibitor is bortezomib. .

[0122] Embodiment 7. Anti-CD38 antibody is administered once a week in a 28-day cycle, on days 1, 8, and 15 of cycles 1 and 2. On the 22nd day, once every two weeks in a 28-day cycle, on the 1st and 15th days between cycles 3 and 6. Subsequently, it is administered intravenously once every four weeks at a dose of approximately 16 mg / kg. Lenalidomide is administered in doses of approximately 10 mg to 25 mg on days 1 to 21 of a 28-day cycle. It is administered orally, Dexamethasone is administered once a week in doses ranging from approximately 20 mg to 40 mg. The method described in state 5.

[0123] Embodiment 8. Anti-CD38 antibody is administered once a week in a 21-day cycle, on days 1, 8, and 15 of cycles 1-3. Then, once every three weeks in a 21-day cycle, on the first day of cycles 4-8, and then once every four weeks thereafter. It is administered intravenously at a dose of approximately 16 mg / kg. Bortezomib is administered in a 21-day cycle, on days 1, 4, 8, and 11 of cycles 1-8, approximately It is administered subcutaneously (SC) at a dose of 1.3 mg / m2. Dexamethasone is administered once a week in doses ranging from approximately 20 mg to 40 mg. The method described in state 6.

[0124] Embodiment 9. Dexamethasone is administered at 20 doses on days 1, 2, 4, 5, 8, 9, 11, and 12. The total dose is 160 mg per cycle, administered intravenously or by post-oxygenation, as described in Embodiment 7. Method of loading.

[0125] Embodiment 10. Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, and 12. Embodiment 8 is administered intravenously or by partogen at a total dose of 0 mg and 160 mg per cycle. Method of description.

[0126] Embodiment 11. The subject has relapsed or refractory multiple myeloma, as in Embodiments 1-10. Method of description.

[0127] Embodiment 12. The subject is a person described in Embodiments 1 to 11 who has high-risk multiple myeloma. Law.

[0128] Embodiment 13. A subject with high-risk multiple myeloma, t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23), and de The method according to Embodiment 12, which has one or more chromosomal abnormalities including l17p.

[0129] Embodiment 14. Negative status of minimal residual lesions: 0.01%, 0.001%, 0.0001% The method according to Embodiments 1 to 13, determined by the sensitivity of, or a combination thereof.

[0130] Embodiment 15. An anti-CD38 antibody comprises the human CD38 region including SEQ ID NO: 2 and SEQ ID NO: 2. The method according to Embodiments 1 to 14, wherein the binding is to a region of human CD38 containing 3.

[0131] Embodiment 16. The anti-CD38 antibody comprises a heavy chain variable region including the amino acid sequence of SEQ ID NO: 4 and The method according to Embodiments 1 to 15, comprising a light chain variable region containing the amino acid sequence of SEQ ID NO: 5.

[0132] Embodiment 17. The anti-CD38 antibody comprises a heavy chain and sequence number containing the amino acid sequence of SEQ ID NO: 12. The method according to Embodiments 1 to 16, comprising a light chain containing the amino acid sequence of No. 13.

[0133] Embodiment 18. The anti-CD38 antibody VH containing the amino acid sequence of SEQ ID NO: 14, and VL containing the amino acid sequence of SEQ ID NO: 15 , VH containing the amino acid sequence of SEQ ID NO: 16, and VL containing the amino acid sequence of SEQ ID NO: 17. , VH containing the amino acid sequence of SEQ ID NO: 18, and VL containing the amino acid sequence of SEQ ID NO: 19. , or VH containing the amino acid sequence of SEQ ID NO: 20, and VL containing the amino acid sequence of SEQ ID NO: 21. The heavy chain CDR1, heavy chain CDR2, heavy chain CDR3, light chain CDR1, light chain CDR2, and light The method according to Embodiments 1 to 13, comprising chain CDR3.

[0134] Embodiment 19. The anti-CD38 antibody is VH containing the amino acid sequence of SEQ ID NO: 14, and VL containing the amino acid sequence of SEQ ID NO: 15 , VH containing the amino acid sequence of SEQ ID NO: 16, and VL containing the amino acid sequence of SEQ ID NO: 17. , VH containing the amino acid sequence of SEQ ID NO: 18, and VL containing the amino acid sequence of SEQ ID NO: 19. , or VH containing the amino acid sequence of SEQ ID NO: 20, and VL containing the amino acid sequence of SEQ ID NO: 21. The method according to Embodiment 18, including the method described in Embodiment 18.

[0135] Embodiment 20. The corticosteroid is dexamethasone or prednisone. The method described in Forms 1-2.

[0136] Embodiment 21. A negative result for minimal residual disease indicates the amount of myeloma cells in the bone marrow aspirate sample derived from the target. The method according to Embodiments 1 to 20, which is detected by evaluation.

[0137] Embodiment 22. The method according to Embodiments 1-21, wherein the method also reduces progression-free survival events. .

[0138] Embodiment 23. The glutamic acid derivative is lenalidomide, thalidomide, or pomalidomide. The method according to Embodiment 4.

[0139] Embodiment 24. The proteasome inhibitor is bortezomib, carfilzomib, or i The method according to Embodiment 4, wherein sazomib is used.

[0140] Embodiment 25. A method for treating a subject with high-risk multiple myeloma, wherein the patient, Anti-CD38 antibodies, corticosteroids, and non-corticosteroid chemotherapeutic agents are effective in treatment. This includes administering the dose for a sufficient amount of time to treat high-risk multiple myeloma. method.

[0141] Embodiment 26. The anti-CD38 antibody comprises a heavy chain CDR1 containing the amino acid sequence of SEQ ID NO: 6, Heavy chain CDR2 containing the amino acid sequence of sequence number 7, and heavy chain CD containing the amino acid sequence of sequence number 8. R3 contains the amino acid sequence of SEQ ID NO: 9, and CDR1 contains the amino acid sequence of SEQ ID NO: 10. Embodiments comprising a light chain CDR2 and a light chain CDR3 containing the amino acid sequence of SEQ ID NO: 11 Method 25.

[0142] Embodiment 27. The corticosteroid is dexamethasone, as in Embodiments 25-26. Method of description.

[0143] Embodiment 28. The non-corticosteroid chemotherapeutic agent is a glutamate derivative or protea The method according to embodiments 25-27, which is a chromosome inhibitor.

[0144] Embodiment 29. The embodiment according to Embodiment 28, wherein the glutamic acid derivative is lenalidomide. Law.

[0145] Embodiment 30. The proteasome inhibitor is bortezomib, as described in Embodiment 28. method.

[0146] Embodiment 31. Anti-CD38 antibody is administered once a week in a 28-day cycle, on days 1, 8, and 15 of cycles 1 and 2. On the 22nd day, once every two weeks in a 28-day cycle, on the 1st and 15th days between cycles 3 and 6. Subsequently, it is administered intravenously once every four weeks at a dose of approximately 16 mg / kg. Lenalidomide is administered in doses of approximately 10 mg to 25 mg on days 1 to 21 of a 28-day cycle. It is administered orally, Dexamethasone is administered once a week in doses ranging from approximately 20 mg to 40 mg. The method described in condition 29.

[0147] Embodiment 32. Anti-CD38 antibody is administered once a week in a 21-day cycle, on days 1, 8, and 15 of cycles 1-3. Then, once every three weeks in a 21-day cycle, on the first day of cycles 4-8, and then once every four weeks thereafter. It is administered intravenously at a dose of approximately 16 mg / kg. Bortezomib is administered in a 21-day cycle, on days 1, 4, 8, and 11 of cycles 1-8, approximately It is administered subcutaneously (SC) at a dose of 1.3 mg / m2. Dexamethasone is administered once a week in doses ranging from approximately 20 mg to 40 mg. The method described in condition 30.

[0148] Embodiment 33. Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, and 12. Embodiment 31: Administered intravenously or by particulate injection at a total dose of 0 mg and 160 mg per cycle. Methods used.

[0149] Embodiment 34. Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, and 12. Embodiment 32: Administered intravenously or by partogen (PO) at a total dose of 0 mg and 160 mg per cycle. Methods used.

[0150] Embodiment 35. An anti-CD38 antibody comprises the human CD38 region including SEQ ID NO: 2 and SEQ ID NO: 2. The method according to embodiments 25 to 34, wherein the binding is to a region of human CD38 containing 3.

[0151] Embodiment 36. The anti-CD38 antibody comprises a heavy chain variable region including the amino acid sequence of SEQ ID NO: 4 and The method according to Embodiments 25-35, which includes a light chain variable region containing the amino acid sequence of SEQ ID NO: 5. .

[0152] Embodiment 37. The anti-CD38 antibody comprises a heavy chain and sequence number containing the amino acid sequence of SEQ ID NO: 12. The method according to Embodiments 25 to 36, comprising a light chain containing the amino acid sequence of No. 13.

[0153] Embodiment 38. The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: VH and sequence number 14. VL containing the amino acid sequence of sequence number 15, VH containing the amino acid sequence of sequence number 16, and sequence number VL containing the amino acid sequence of sequence number 17, VH containing the amino acid sequence of sequence number 18, and sequence number VL containing the amino acid sequence of sequence number 19, or VH containing the amino acid sequence of sequence number 20, and The VL containing the amino acid sequence of column number 21, heavy chain CDR1, heavy chain CDR2, heavy chain CDR3, The method according to Embodiment 25, comprising light chain CDR1, light chain CDR2, and light chain CDR3.

[0154] Embodiment 39. The anti-CD38 antibody is VH containing the amino acid sequence of SEQ ID NO: 14, and VL containing the amino acid sequence of SEQ ID NO: 15 , VH containing the amino acid sequence of SEQ ID NO: 16, and VL containing the amino acid sequence of SEQ ID NO: 17. , VH containing the amino acid sequence of SEQ ID NO: 18, and VL containing the amino acid sequence of SEQ ID NO: 19. , or VH containing the amino acid sequence of SEQ ID NO: 20, and VL containing the amino acid sequence of SEQ ID NO: 21. The method according to embodiment 38, including the method described in embodiment 38.

[0155] Embodiment 40. The corticosteroid is dexamethasone or prednisone. The method described in Form 25.

[0156] Embodiment 41. The corticosteroid is dexamethasone, as in Embodiment 25. method.

[0157] Embodiment 42. The non-corticosteroid chemotherapeutic agent is a glutamate derivative or protea The method according to Embodiment 25, which is a chromosome inhibitor.

[0158] Embodiment 43. The glutamic acid derivative is lenalidomide, thalidomide, or pomalidomide. The method described in Embodiment 42.

[0159] Embodiment 44. The embodiment according to Embodiment 42, wherein the glutamic acid derivative is lenalidomide. Law.

[0160] Embodiment 45. The proteasome inhibitor is bortezomib, carfilzomib, or i The method according to embodiment 42, wherein sazomib is used.

[0161] Embodiment 46. The proteasome inhibitor is bortezomib, as described in Embodiment 42. method.

[0162] Embodiment 47. A subject with high-risk multiple myeloma, t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23), and de The method according to Embodiment 25, which has one or more chromosomal abnormalities including l17p.

[0163] Embodiment 48. Embodiment 2, in which the subject has high-risk refractory or relapsed multiple myeloma. The method described in 5.

[0164] Embodiment 49. A method in which corticosteroids and non-corticosteroid chemotherapeutic agents are administered. Embodiment 25 describes improving one or more evaluation items of the target compared to the target being evaluated. method.

[0165] Embodiment 50. One or more evaluation items are progression-free survival, overall response rate, very good partial survival. This includes a response or better, a complete response or better, or any combination thereof. The method described in Embodiment 49.

[0166] Embodiment 51. The method described in Embodiment 25, wherein the method achieves minimal residual disease negativity in the subject. Method of loading.

[0167] Embodiment 52. Risk of relapse and / or disease progression in subjects with multiple myeloma. A method to reduce The targets include anti-CD38 antibodies, corticosteroids, and non-corticosteroid chemotherapeutic agents. This includes administering a therapeutically effective dose to achieve a minimal residual disease-negative state. A method that demonstrates a reduced risk of recurrence and / or disease progression.

[0168] Embodiment 53. The possibility of recurrence and / or disease progression in subjects with multiple myeloma. A method of prediction, This includes measuring the minimal residual disease status in the subjects, and the subjects are tested for anti-CD38 antibody, col. The patient is receiving therapeutically effective doses of tycosteroids and non-corticosteroid chemotherapy agents. A method in which a positive minimal residual disease status indicates the possibility of recurrence and / or disease progression.

[0169] Embodiment 54. The anti-CD38 antibody is a heavy chain CDR1 containing the amino acid sequence of SEQ ID NO: 6, Heavy chain CDR2 containing the amino acid sequence of sequence number 7, and heavy chain CD containing the amino acid sequence of sequence number 8. R3 contains the amino acid sequence of SEQ ID NO: 9, and CDR1 contains the amino acid sequence of SEQ ID NO: 10. Embodiments comprising a light chain CDR2 and a light chain CDR3 containing the amino acid sequence of SEQ ID NO: 11 The method described in one of sections 52-53.

[0170] Embodiment 55. The corticosteroid is dexamethasone, as in Embodiments 52-54. Method of description.

[0171] Embodiment 56. The non-corticosteroid chemotherapeutic agent is a glutamate derivative or protea The method according to embodiments 52 to 55, which is a chromosome inhibitor.

[0172] Embodiment 57. The embodiment according to Embodiment 56, wherein the glutamic acid derivative is lenalidomide. Law.

[0173] Embodiment 58. The proteasome inhibitor is bortezomib, as described in Embodiment 56. method.

[0174] Embodiment 59. Anti-CD38 antibody is administered once a week in a 28-day cycle, on days 1, 8, and 15 of cycles 1 and 2. On the 22nd day, once every two weeks in a 28-day cycle, on the 1st and 15th days between cycles 3 and 6. Subsequently, it is administered intravenously once every four weeks at a dose of approximately 16 mg / kg. Lenalidomide is administered in doses of approximately 10 mg to 25 mg on days 1 to 21 of a 28-day cycle. It is administered orally, Dexamethasone is administered once a week in doses ranging from approximately 20 mg to 40 mg. The method described in form 57.

[0175] Embodiment 60. Anti-CD38 antibody is administered once a week in a 21-day cycle, on days 1, 8, and 15 of cycles 1-3. Then, once every three weeks in a 21-day cycle, on the first day of cycles 4-8, and then once every four weeks thereafter. It is administered intravenously at a dose of approximately 16 mg / kg. Bortezomib is administered in a 21-day cycle, on days 1, 4, 8, and 11 of cycles 1-8, approximately It is administered subcutaneously (SC) at a dose of 1.3 mg / m2. Dexamethasone is administered once a week in doses ranging from approximately 20 mg to 40 mg. The method described in condition 58.

[0176] Embodiment 61. Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, and 12. Embodiment 55: Administered intravenously or by topical administration at a total dose of 0 mg and 160 mg per cycle. Methods described in ~60.

[0177] Embodiment 62. The subject has relapsed or refractory multiple myeloma, as in Embodiments 52-61. Methods used.

[0178] Embodiment 63. The embodiment described in Embodiments 52 to 62, wherein the subject has high-risk multiple myeloma. method.

[0179] Embodiment 64. A subject with high-risk multiple myeloma, t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23), and de The method according to Embodiment 63, which has one or more chromosomal abnormalities including l17p.

[0180] Embodiment 65. An anti-CD38 antibody comprises the human CD38 region including SEQ ID NO: 2 and SEQ ID NO: 2. The method according to embodiments 52 to 64, wherein the binding is to a region of human CD38 containing 3.

[0181] Embodiment 66. The anti-CD38 antibody comprises a heavy chain variable region including the amino acid sequence of SEQ ID NO: 4 and The method according to Embodiments 52 to 65, which includes a light chain variable region containing the amino acid sequence of SEQ ID NO: 5. .

[0182] Embodiment 67. The anti-CD38 antibody comprises a heavy chain and sequence number containing the amino acid sequence of SEQ ID NO: 12. The method according to Embodiments 52 to 66, comprising a light chain containing the amino acid sequence of No. 13.

[0183] Embodiment 68. The anti-CD38 antibody VH containing the amino acid sequence of SEQ ID NO: 14, and VL containing the amino acid sequence of SEQ ID NO: 15 , VH containing the amino acid sequence of SEQ ID NO: 16, and VL containing the amino acid sequence of SEQ ID NO: 17. , VH containing the amino acid sequence of SEQ ID NO: 18, and VL containing the amino acid sequence of SEQ ID NO: 19. , or VH containing the amino acid sequence of SEQ ID NO: 20, and VL containing the amino acid sequence of SEQ ID NO: 21. The heavy chain CDR1, heavy chain CDR2, heavy chain CDR3, light chain CDR1, light chain CDR2, and light The method according to embodiments 52 to 64, including chain CDR3.

[0184] Embodiment 69. The anti-CD38 antibody is VH containing the amino acid sequence of SEQ ID NO: 14, and VL containing the amino acid sequence of SEQ ID NO: 15 , VH containing the amino acid sequence of SEQ ID NO: 16, and VL containing the amino acid sequence of SEQ ID NO: 17. , VH containing the amino acid sequence of SEQ ID NO: 18, and VL containing the amino acid sequence of SEQ ID NO: 19. , or VH containing the amino acid sequence of SEQ ID NO: 20, and VL containing the amino acid sequence of SEQ ID NO: 21. The method according to embodiment 68, including the method described above.

[0185] Embodiment 70. The corticosteroid is dexamethasone or prednisone. The method described in Forms 52-54.

[0186] Embodiment 71. The glutamic acid derivative is lenalidomide, thalidomide, or pomalidomide. The method according to embodiment 56.

[0187] Embodiment 72. The proteasome inhibitor is bortezomib, carfilzomib, or i The method according to embodiment 56, wherein sazomib is used. [Examples]

[0188] To further illustrate some of the embodiments disclosed herein, the following examples are provided. These embodiments are for illustrative purposes only and do not limit the embodiments of the present disclosure. No.

[0189] Example 1. Study Design NCT02136134 (CASTOR) The purpose of this study is to compare VELCADE® (bortezomib) and dexamethasone. Compared to VELCADE(registered trademark) (bortezomib) and dexamethasone, For participants with relapsed or refractory multiple myeloma who receive daratumumab in combination with other medications. The objective is to evaluate the effects of [the drug]. This study is a multicenter, randomized, open-label, active-controlled phase 3 trial. For the prior identification interim analysis, see Palumpo et al., NEJM 375. This is described in 754-66, 2016. The clinical trial number for this study is NCT0213. The number is 6134.

[0190] Eligibility Having received at least one prior treatment for multiple myeloma, and at least one of those treatments Confirmed progressive multiple myeloma (International Myeloma Virus) that showed at least a partial response to prior treatment. Patients who met the criteria of the IMWG (Medical Information Working Group) were eligible.

[0191] Exclusion criteria Patients who have previously received daratumumab or other anti-CD38 therapy, or who are refractory to bortezomib. Patients who are either or have experienced unacceptable side effects from bortezomib, 1000 cells / mm³ 3 Neutrophil count less than 7.5 g / dL, hemoglobin less than 7.5 g / dL, 75,000 / mm³ 3 Blood size less than Number of boards, 1.73m 2 Creatinine clearance of less than 20 mL / min per body surface area is normal. Alanine aminotransferase or asparagus at 2.5 times or more of the upper limit of the range aminotransferase levels and 1.5 times or more above the upper limit of the normal range Patients with rilbin levels, patients with diseases refractory to other proteasome inhibitors, Alternatively, patients with Grade 2 or higher peripheral neuropathy or neuropathic pain are treated at this research institute. It was excluded from the investigation.

[0192] Experimental treatment 498 patients were randomly assigned in a 1:1 ratio to receive daratumumab, bortezomib, and Dexamethasone (DVd, "daratumumab group") or bortezomib and dexamethasone (Vd, "control group") was given. Randomization was based on the International Staging System (ISS) and prior treatment. The number of programs (1:2 or more than 3:3), and previous VELCADE® treatments ( The results were stratified by "no" versus "yes".

[0193] Daratumumab is administered once a week (on days 1, 8, and 15) during cycles 1-3. From ages 4 to 8, once every 3 weeks (on day 1), and then once every 4 weeks thereafter, at a dose of 16 mg / kg. It was administered by intravenous infusion. VELCADE® was administered in cycles 1-8, steps 1 and 4. On days 8 and 11, 1.3 mg / m² 2 Dexamethasone was administered subcutaneously (SC) at the following dose. 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12, 160 per cycle. The total dose of mg was administered orally.

[0194] Primary evaluation items From the date of randomization until the date of disease progression or death (whichever occurs first) Progression-free survival (PFS) is defined as the period of time during which progression occurs.

[0195] Secondary evaluation items Time to disease progression (TTP), overall response rate (ORR), and very good partial response (VGP) The percentage of patients showing R) or better, duration of response, time to response, and overall survival ( OS). TTP is defined by the International Myeloma Working Group (IMWG) criteria as being inactive. This is defined as the period from the day the treatment was initiated to the day the first signs of progression were observed. Overall response rate This is defined by the IMWG criteria as follows: strict complete response (sCR), complete response, and very good partial response. Defined as (VGPR), or partial response (PR). Duration of response is defined according to IMWG standards. The period is defined as the period from the date on which the response was first observed to the date on which signs of progressive disease were first observed. The calculation is performed by first confirming the response from the first administration of the research treatment. This is defined as until the day. VGPR is used to reduce blood myeloma stool by less than 100 mg per 24 hours. It is defined as a decrease of more than 90% in protein (M-protein) and urinary myeloma protein. OS is measured from the day of randomization to the day the participant's death occurred.

[0196] In addition, among participants who achieved VGPR or better, there were participants with minimal residual disease (MRD). The proportion of individuals will be evaluated by analyzing bone marrow aspiration specimens.

[0197] Safety evaluation Safety assessment includes evaluation of adverse events, clinical laboratory tests, vital signs, and electrocardiogram records. This includes the definition of adverse events in the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Therefore, we classified them into grades.

[0198] Statistical data Using a group sequential design with one pre-specified interim analysis, the primary endpoint The endpoint was evaluated. O'Brien-Flem at the interim analysis of the primary endpoint. The ing termination boundary value is determined based on the number of events observed on the data cutoff date, Lan-D The calculation was performed using the eMets alpha consumption function. The efficacy analysis included all randomized participants. Based on the treatment intention population, including patients. Secondary endpoints were stratified to loa The NK test was used to compare DVd and Vd. Hazard ratios and corresponding 95% confidence levels were also used. The regression interval was estimated using a stratified Cox regression model and treated as the sole explanatory variable. The distribution was estimated using the Rund-Meier method. Stratified Cochran-Mantel-H We used the Aenszel chi-squared test to examine the differences between groups.

[0199] Interim results as of the data cutoff date of January 11, 2016 As of the data cutoff date, there were 243 patients in the DVd group and 237 patients in the Vd group. 74 patients in the DVd group and 10 patients in the Vd group had received at least one dose of the experimental treatment. Four patients had discontinued treatment due to progressive disease or adverse events. These two groups Table 1 shows the demographics, disease, and clinical characteristics of patients receiving treatment. International stage The Classification System (ISS) disease staging is based on the combination of serum β2-microglobulin and albumin. This was derived based on the combination. The ISS consists of three stages, namely, Stage I (Serum less than 3.5 mg per liter (300 nmol per liter)) β2-microglobulin levels and 3.5 g or more of alcohol per deciliter Bumin level), Stage II (not Stage I or Stage III), and Stage Di-III (5.5 mg per liter (470 nmol per liter) or more It consists of serum β2-microglobulin (shown above). Higher stages indicate more severe disease. show.

[0200] Effectiveness The overall response rate was 82.9% in the DVd group and 63.2% in the Vd group (p<0). 001). Table 2 shows a summary of patient responses for which response could be evaluated.

[0201] [Table 1]

[0202] [Table 2]

[0203] safety Most patients in the DVd group and the majority of patients in the Vd group experienced at least one adverse event after the start of treatment. (98.8% and 95.4%, respectively). Grade 3 or 4 adverse events occurred in the DVd group. This was observed at a higher rate in the DVd group than in the Vd group (76.1% vs. 62.4%). Three of the most common grade 3 or 4 adverse events reported were thrombocytopenia (each These were 45.3% and 32.9%, anemia (14.4% and 16.0%, respectively), and Neutropenia was observed in 12.8% and 4.2% of patients, respectively.

[0204] The proportion of patients who discontinued treatment due to at least one adverse event was different in the DVd group and the Vd group. The percentages were similar (7.4% and 9.3%, respectively). The most common adverse events leading to treatment discontinuation were... The event (occurring in at least 1% of patients in either group) is peripheral sensory neuropathy (each The causes were 0.4% and 2.5%, and pneumonia (1.2% and 0.4%, respectively). Adverse events occurred in 13 patients (5.3%) in the DVd group and 14 patients ( These events were reported in 5.9% of cases, and were primarily a result of a general deterioration in the patient's physical health. (0.4% and 1.3%, respectively). Two or more patients in either treatment group. Other fatal adverse events reported included pneumonia (1 patient in the DVd group, 2 patients in the Vd group). (number of patients), ischemic stroke (2 patients and 0 patients, respectively), and respiratory failure ( There were 2 patients and 0 patients, respectively. No immunogenic cases were reported in the DVd group. Furthermore, no cases of hemolysis were reported in any of the treatment groups. Infusion-related reactions of that grade were reported in 45.3% of patients, and 98.2% of these patients Therefore, the event occurred during the initial infusion. Infusion-related reactions are mainly limited to grade 1 or 2 events. Furthermore, at least one Grade 3 event was reported in 21 patients (8.6%), and Grade No 4 events were reported. The most common infusion-related reaction confirmed by the principal investigator was... Common adverse events include dyspnea (10.7%), bronchospasm (9.1%), and cough (7%). The figure was 0%. Two patients discontinued treatment due to infusion-related reactions, one of whom had a tracheal reaction. One patient developed bronchospasm, while the other developed bronchospasm, laryngeal hydrops, and a rash.

[0205] Example 2. Study Design NCT02076009 (POLLUX) The purpose of this study is to compare lenalinomide and dexamethasone alone with lenalinomide and dexamethasone alone. The administration of daratumumab in combination with dexamethasone for relapsed or refractory multiple bone disease The objective was to evaluate the effects on participants with myeloma. This study was a multicenter, randomized, open-label study. This was an active-controlled Phase 3 trial. For the pre-existing specific interim analysis, Dimopolos e This is described in t al., NEJM 375:1319-312016. The floor test number is NCT02076009.

[0206] Eligibility Having received at least one prior treatment for multiple myeloma, and at least one of those treatments Confirmed progressive multiple myeloma (International Myeloma Virus) that showed at least a partial response to prior treatment. Patients who met the criteria of the IMWG (Medical Information Working Group) were eligible.

[0207] Exclusion criteria Patients who have previously received daratumumab or other anti-CD38 therapy, or who are refractory to lenarinomide. or patients who have experienced unacceptable side effects from lenalinomide, 1000 cells / mm 3 Neutrophil count less than 7.5 g / dL, hemoglobin less than 7.5 g / dL, 75,000 / mm³ 3 Blood size less than Number of boards, 1.73m 2 Creatinine clearance of less than 20 mL / min per body surface area is normal. Alanine aminotransferase or asparagus at 2.5 times or more of the upper limit of the range aminotransferase levels and 1.5 times or more above the upper limit of the normal range Patients with lilbin levels or creatinine clearance less than 30 mL / min were excluded. did.

[0208] Experimental treatment Patients were randomly assigned in a 1:1 ratio to receive daratumumab, lenarinomide, and dexamethoxazole. Dazone (DRd, "daratumumab group") or lenalinomide and dexamethasone (Rd, A control group was given. Randomization was performed according to the International Staging System (ISS) and prior treatment program. The number (more than 1:2 or 3:3), and the previous lenarinomide treatment ("no" vs "yes") Therefore, we stratified the data.

[0209] Daratumumab is administered once a week (1, 8, 15, and ) for 8 weeks during cycles 1 and 2. (Day 22), once every two weeks for 16 weeks (Days 1 and 15) (Cycles 3-6) Subsequently, it was administered intravenously at a dose of 16 mg / kg once every four weeks. In both groups, If creatinine clearance exceeds 60 mL / min, lenalidomide should be administered once per cycle. ~On day 21, administer a dose of 25 mg (or when creatinine clearance is 30-60 mL / min) In some cases, it is administered orally at a dose of 10 mg per day, and dexamethasone is taken once a week at a dose of 40 mg. The drug was administered once. For the DRd group, the dose of dexamethasone was divided and administered by infusion. As a preventative measure against related reactions, a 20 mg dose was administered before infusion, and another 20 mg dose was administered the following day.

[0210] Primary evaluation items From the date of randomization until the date of disease progression or death (whichever occurs first) Progression-free survival (PFS) is defined as the period of time during which progression occurs.

[0211] Secondary evaluation items Time to disease progression (TTP), overall response rate (ORR), and very good partial response (VGP) The percentage of patients showing R) or better, duration of response, time to response, and overall survival ( OS). TTP is defined by the International Myeloma Working Group (IMWG) criteria as being inactive. This is defined as the period from the day the treatment was initiated to the day the first signs of progression were observed. Overall response rate This is defined by the IMWG criteria as follows: strict complete response (sCR), complete response, and very good partial response. Defined as (VGPR), or partial response (PR). Duration of response is defined according to IMWG standards. The period is defined as the period from the date on which the response was first observed to the date on which signs of progressive disease were first observed. The calculation is performed by first confirming the response from the first administration of the research treatment. This is defined as until the day. VGPR is used to reduce blood myeloma stool by less than 100 mg per 24 hours. It is defined as a decrease of more than 90% in protein (M-protein) and urinary myeloma protein. OS is measured from the day of randomization to the day the participant's death occurred.

[0212] In addition, among participants who achieved VGPR or better, there were participants with minimal residual disease (MRD). The proportion of individuals will be evaluated by analyzing bone marrow aspiration specimens.

[0213] Statistical data Using a group sequential design with one pre-specified interim analysis, the primary endpoint The endpoint was evaluated. O'Brien-Flem at the interim analysis of the primary endpoint. The ing termination boundary value is determined based on the number of events observed on the data cutoff date, Lan-De The calculation was performed using the Mets alpha consumption function. The efficacy analysis included all randomized participants. Based on the treatment intention population, including patients. Secondary endpoints were stratified using Loran. The k-test was used to compare DRd and Rd. Hazard ratios and corresponding 95% confidence levels were obtained. The interval was estimated using a stratified Cox regression model and treated as the sole explanatory variable. The distribution was estimated using the n'Meyer method. Stratified Cochran-Mantel-Ha We used the Enszel chi-squared test to examine the differences between groups.

[0214] Interim results as of the data cutoff date of March 7, 2016 As of the data cutoff date, there were 286 patients in the DRd group and 283 patients in the Rd group. 66 patients in the DRd group and 13 patients in the Rd group had received at least one dose of the experimental treatment. Two patients had discontinued treatment, primarily due to progressive disease or adverse events. Table 3 shows the demographics, disease, and clinical characteristics of patients in the treatment-seeking group. The staging system (ISS) is based on serum β2-microglobulin and albumin levels. This was derived based on the combination of the following: The ISS has three stages, namely Stage I (less than 3.5 mg per liter (300 nmol per liter)) Serum β2-microglobulin levels and 3.5 g or more per deciliter Albumin level), Stage II (neither Stage I nor Stage III), and Stage III (5.5 mg per liter (470 nmol per liter) or It consists of more than this amount of serum β2-microglobulin. Higher stages indicate more severe disease. It shows signs of illness.

[0215] [Table 3]

[0216] Effectiveness At a median follow-up of 13.5 months, a total of 169 events occurred, including disease progression or death (D In the Rd group, there were 53 patients [18.5%], compared to 116 patients [41.0%] in the Rd group. It was reported that the hazard ratio for disease progression or death in the DRd group versus the Rd group was 0.37. (95% confidence interval [CI], 0.27~0.52, P<0.001 (stratified log-rank) (According to the test)). The Kaplan-Meier progression-free survival rate at 12 months was 8 in the DRd group. 3.2% (95% CI, 78.3-87.2), 60.1% (95% CI, 5) in the Rd group. The range was 4.0-65.7. The median progression-free survival was 18.4 months (95%) in the Rd group. Compared to the CI (13.9 - not estimable), this was not achieved in the DRd group (95% CI, (Unable to estimate). Similarly, in the analysis of the time to disease progression events, a total of 148 events occurred (DRd group). In the Rd group, there were 44 patients [15.4%], compared to 104 patients [36.7%]. ) Observed (hazard ratio: 0.34, 95% CI, 0.23~0.48, P<0.00) 1) The progression-free survival rate at 12 months was 63.2% (95% CI, 57.1%) in the Rd group. In comparison to the 68.8% group, the DRd group showed 85.7% (95% CI, 80.9-89.4). Yes, there was. Table 4 shows a summary of patient responses for which response could be evaluated.

[0217] [Table 4]

[0218] safety For the safety population, the most common adverse event of any grade during treatment (any grade) (More than 15% of patients in the group) and Grade 3 or 4 adverse events (more than 5% of patients in either group) neutropenia, anemia, thrombocytopenia, febrile neutropenia, lymphopenia, diarrhea Fatigue, upper respiratory tract infection, constipation, cough, muscle cramps, nasopharyngitis, nausea, fever, insomnia, difficulty breathing, The symptoms included back pain, vomiting, asthenia, peripheral edema, and pneumonia. 10% of the DRd group compared to the Rd group. Adverse events that occurred more frequently than those mentioned above included neutropenia, diarrhea, upper respiratory tract infection, and cough. Most of these were attributed to longer-term exposure to treatment in the DRd group. Deep vein thrombosis It was reported in 1.8% of patients in the DRd group and 3.9% of patients in the Rd group. 37.0 in the Rd group In comparison, 51.9% of patients in the DRd group had grade 3 or 4 neutropenia. Grade 3 or 4 thrombocytopenia was present in 12.7% and 13.5% of patients, respectively. The percentage of patients who experienced adverse events leading to treatment discontinuation was similar in both groups. The rate was 6.7% in the DRd group and 7.8% in the Rd group. Adverse events leading to death. Elephants were found in 11 patients (3.9%) in the DRd group and 15 patients (5.3%) in the Rd group. It occurred. The most common adverse event leading to death was acute kidney injury (0.4% of patients in the DRd group). In the Rd group, 1.1% of patients experienced septic shock (1.1% and 0.4%, respectively). The most common side effects were pneumonia (0.7% in each group).

[0219] The incidence of daratumumab injection-related reactions of any grade was 47.7%, and this reaction 92% of the reactions occurred during the initial injection. These reactions were mainly of grade 1 or 2. Of these, a total of 15 patients (5.3%) had a grade 3 infusion reaction, and grade 4 or 5... No patients experienced any events. The most common infusion-related reaction was cough (8.5% of patients). Dyspnea (8.5%) and vomiting (5.7%) were reported. One patient received a grade 3 infusion. Daratumumab was discontinued due to related events, but the patient recovered, and treatment with lenalidomide and dexamethasone was terminated. I continued to receive treatment.

[0220] Example 3. In patients with relapsed or refractory multiple myeloma (RRMM) in high-risk patients Lenalidomide and dexamethasone or bortezomib and dexamethasone in combination The effectiveness of daratumumab method The analysis set is from the POLLUX trial, which included patients who received 1-3 lines of prior treatment (1-3PL subgroups). This includes subgroup analysis of patients from Example 2) and the CASTOR study (Example 1). Academic abnormalities were assessed at the pre-randomization screening visit based on on-site laboratory evaluation using fluorescent iB. Determined by cytogenetic hybridization (FISH). High-risk cytogenetics Patients with the following abnormalities: t(4;14)(p16;q32), t(14; 16) This included patients who had one or more of the following: (q32;q23, or del17p). Standard-risk patients were defined as those who underwent cytogenetic testing and did not meet the high-risk criteria. He was right.

[0221] Result: POLLUX In subgroups 1-3PL (DRd: n=272, Rd: n=264), PFS is greater than Rd. DRd showed significant improvement (median: not reached [NR] vs. 18.4 months, HR, 0.36 (95% CI, 0.25-0.50, P<0.0001), 12-month PFS rates are as follows: The estimated rates were 83.2% versus 60.4%. The time to progression was also significantly shorter in DRd compared to Rd. Longer (median: NR vs. 18.4 months, HR: 0.32, 95% CI, 0.22-0.4) 6. P<0.0001). ORR (94% vs 77%), very good partial response (VGPR). ) or higher rates (76% vs. 45%), and complete response (CR) or higher rates (44%) % vs. 20% were also significantly higher in DRd than in Rd (all P<0.0001). ). The median time to VGPR or higher among responders was 2.8 in the DRd group. In contrast to the Rd group, the median time to CR or better was 2.9 months. The average durations were 6.7 months versus 7.5 months, respectively.

[0222] For patients in subgroups 1-3PL with high-risk cytogenetic abnormalities (n in each treatment group) (=33) A significantly longer PFS was observed in DRd compared to Rd (median: NR vs. 8.3 months). Month, HR: 0.30, 95% CI, 0.14~0.67, P=0.0019). Significantly higher. ORR (91% vs 69%, P=0.0267), VGPR or better (73% vs 28%, P=0.0004), and CR or better rates (36% vs. 9%, P=0.01 04) In patients with high-risk cytogenetic conditions treated with DRd, It was achieved in that case.

[0223] Figure 1 shows the proportion of subjects surviving without progression in each subgroup over time.

[0224] Result: CASTOR The median follow-up period was 7.4 months. Prior treatment (1-3PL) was sub- In the group (DVd: n=229, Vd: n=219), PFS was higher in DVd than in Vd. Longer than expected (median: not reached [NR] vs. 7.3 months, HR: 0.39, 95% CI, 0.2) (8-0.55, P<0.0001), 12-month PFS rates were 62.2% vs. 29%, respectively. It was estimated at 0.3%. The median time to progression (TTP) between 1-3PL patients was, respectively, NR was 7.4 months (HR: 0.29, 95% CI, 0.20-0.43, P< (0.0001). The overall response rate (ORR) was significantly higher in DVd than in Vd (84% vs. 67%). %, P<0.0001), very good partial response (VGPR) or higher rate. Related to (62% vs. 32%, P<0.0001).

[0225] Among 1-3PL patients with standard risk cytogenetic status, PFS was greater in DVd than in Vd. The interval was also significantly longer (HR: 0.38, 95% CI, 0.25-0.58, P<0.0001). The estimated 12-month PFS rates were 58.7% and 27.0%, respectively. In patients with high-risk cytogenetic abnormalities who received Vd, the results were significantly longer than with Vd. (HR: 0.46, 95% CI, 0.22~0.97, P=0.0367), 12 months The estimated PFS rates were 63.2% and 26.7%, respectively. Finally, MRD-negative patients The rate is across all evaluation thresholds (10) between subgroups 1-3PL. -4 , 10 -5 , and 10 -6 )in It was significantly higher (4 times or more).

[0226] Figure 2 shows the proportion of subjects surviving without progression in each subgroup over time.

[0227] conclusion The addition of DARA to Rd will enable the treatment of RRMM patients with high-risk cytogenetic abnormalities. Outcomes were significantly improved, and the addition of DARA to Vd was found to improve PFS and in these patients. It showed a promising trend toward improved response rates. Notably, high-risk patients treated with DRd showed significant improvement. The PFS outcome in patients is the PFS outcome in standard-risk patients treated with Rd alone. These results were at least comparable to targeting CD38 in combination with Rd. However, this suggests that it may help overcome poor outcomes associated with high-risk cytogenetic conditions. ru.

[0228] Example 4. MRD analysis MRD sample collection and processing In the POLLUX study, MRD status was defined as a suspected C in subjects who maintained this response. Evaluation was performed at the time of R, and at 3 and 6 months after suspected CR (in the treatment cohort) (Blinded). In the CASTOR study, MRD was evaluated at the time of suspected CR (treatment cohort). (Blinded against the target), if the subject reaches MRD negative, additional analysis is performed on the Vd background. At the end of the Vd therapy (6 months after the start of the research therapy), and finally at the end of the Vd background therapy. The MRD assay was performed 6 months later (12 months after the start of the research therapy). The assay is performed using a solution (BMA) and the ClonoSEQ (trademark) assay (Adaptive Evaluated by Biotechnologies, Seattle, WA, USA. In short, bone marrow mononuclear cells are collected within 48 hours of being sent to Covance Central. Laboratory Services(Indianapolis,IN,US) Lymphop (A, Geneva, Switzerland, Singapore) Cells were isolated from 2-3 mL of BMA by rep(Ficoll) separation. Stored as a pack at -70°C. Lymphoprep isolation typically involves granulocytes in the sample. It removes over 95%, but when this sample is treated with red blood cell (RBC) lysis, Note that these cells are retained. In normal bone marrow, granulocytes make up 25% of the cell fraction. Lymphoprep isolation accounts for 50% of the total number of cells in the sample being analyzed, disproportionately reducing the total number of cells. This is because other studies using RBC lysis have twice as many commonalities as POLLU. These studies are less rigorous than the MRD determination in the X study and the CASTOR study. This could lead to differences in MRD negativity rates.

[0229] Genomic DNA was isolated into IGH-complete (IGH-VDJH) and IGH-incomplete (IGH-D JH), and a pair of multiplexed locus-specific ply of the immunoglobulin κ locus (IGK) Amplification was performed using a marset. The amplified products were subjected to sequencing to determine different clone types in the sample. The sequence and frequency were obtained. Myeloma clones for gene rearrangement in the sample obtained at the time of diagnosis were identified. To clarify, a 5% frequency threshold (i.e., any clone type that existed at a frequency greater than 5%) The treatment was applied to patients with high-frequency myeloma clones. MRD in floor samples is classified as IGH-VDJH, IGH-DJH, and / or previously described The IGK assay (Vij R, Mazumder A, Klinger M, e t al.Deep sequencing reveals myeloma cel ls in peripheral blood in majority of mu ltiple myeloma patients.Clin Lymphoma My Evaluation was performed using eloma (Leuk.2014;14:131-139). The myeloma-derived sequences identified were analyzed in follow-up samples for each subject, and the MRD (Myeloma Reduction) was determined. It was used as a target to assess the presence of MRD. Multiple sequencing algorithms were used for MRD quantification. The amount of cancer-derived molecules in the sample was evaluated for each rearranged B cell in the reactant. Once determined, the final MRD measurement is calculated, and the amount of cancer-derived molecules per million cell equivalents is calculated. The number was obtained. If two or more tumor clones existed, the clone with the highest MRD value was selected. I reported the matter.

[0230] Data Analysis Methods Clinical data Input datasets from the clinical cutoff date of the POLLUX study and CASTOR study This analysis was performed using only R software. All data analysis and related graph generation were done using R software. The analysis was conducted using the following method. The analysis population was an ITT population, which included all randomized subjects. The best response reported in the analysis was determined by a computer algorithm following the IMWG response and disease progression criteria. The best confirmed effectiveness was achieved through Zoom.

[0231] MRD data Technical aspects of MRD data Using baseline diagnostic samples from each subject, myeloma clonates were found to be present at a frequency of more than 5%. The clone was characterized. If a high-frequency myeloma clone could not be identified, the sample was Calibration failed. This occurred in both the POLLUX and CASTOR studies, with a 75% failure rate. And a calibration rate of 77% was achieved by BMA samples collected during screening in these MM subjects. This was observed in MRD assays using the sample (Table 5). These samples were found to be relapsed or refractory MRD. The fact that it originated from an M target is based on the calibration rate observed in newly diagnosed MM target samples. This also contributed to a high calibration rate. In addition, these studies showed that relapsed or refractory MM Because this corresponds to the first prospective assessment of MRD in the global study of the subject, this calibration rate is used by the academic This could reflect the application of technology in the real world, based on the state of technological research.

[0232] [Table 5]

[0233] MRD status 10 -4 , 10 -5 , and 10 -6 This was determined by the sensitivity threshold. Importantly, Each of these has at least 10,000, 100,000, and 1,000,000 details. Strict criteria for vesicular input equivalents are necessary to determine the MRD status at each threshold. For subsets of samples in both UX and CASTOR studies, the input details... The number of cells is 10 -5 or 10 -6 The required threshold was not reached, and therefore the MRD call was "M Defined as "RD ambiguity," samples at the evaluated threshold are counted as MRD positive. (Table 6)

[0234] MRD Data Processing MRD status call, total input cell equivalents, and clone count data are clinical data. Data obtained from the cutoff date. Total input cell equivalents, clone count data, and clone count data. MRD data for individual receptors, including their frequency, is provided by the supplier (Adaptive B). This was provided by iotechnologies, and is used by Cyberlab. Saved to the repository.

[0235] The clone count and frequency provided by the supplier were calculated as follows:

[0236]

number

[0237]

number

[0238] The data from the retested samples were averaged by frequency according to the supplier's instructions, and then cross-referenced. The data was summarized by totaling the counts.

[0239] For each MRD evaluation sample, the MRD status call is one of three different sample detection thresholds. 10 -4 , 10 -5 , or 10 -6 ) For each instance, "MRD negative", "MRD positive", or "M It was determined to be either "RD ambiguity" or "the number of detected clones is less than 1 and Input cell count is the detection limit threshold (10 -4 , 10 -5 , or 10 -6 (one of the following) If the above conditions were met, a "negative MRD" test result was obtained. If the number of detected clones was 1 or more, If MRD assessment was not performed in the ITT population, the test result was "MRD positive". The result was obtained. Although the number of detected clones was less than 1, the total input cell equivalent was (10 -4 , 10 -5 , or 10 -6 If the required sensitivity level (either of the following) is not reached, "MRD We obtained the test results for "ambiguity".

[0240] When comparing MRD-negative counts between subgroups, MRD calls should be either MRD-negative or MRD-positive. Divided into two categories, MRD positive is defined as being tested and positive at all time points, or ambiguous. This includes approved subjects and controls that were not tested.

[0241] [Table 6]

[0242] result Primary MRD results In short, in the ITT population, the DRd group had a higher MRD-negative rate compared to the Rd group. The birth rate was shown. 29 percent (29%) of the subjects in the DRd group died in 10 -4 MRD negative at the threshold In contrast to the Rd group, only 7.8% achieved sexual status (Mantel-Haens). Zel odds ratio = 4.88, 95% CI: 2.94, 8.08, p = < 0.0001). Similarly, in the CASTOR study, the subjects treated with DVd were the same as the subjects treated with Vd (3%). Compared to (Mantel-Haen), it showed a higher incidence of MRD negativity (14%). Szel odds ratio estimate = 5.56, 95% CI: 2.37, 13.04, p = < 0.0 001). As an exploratory analysis, the MRD rate was set to two more stringent thresholds, 10 -5 and 10 -6 But it was evaluated. In the POLLUX study, the MRD negativity rate was lower in the Rd group at both lower thresholds. The Drd group showed significantly higher levels compared to the control group. In the CASTOR study, DVd While it showed an increased MRD negativity rate compared to Vd at both lower thresholds, 10 -5 threshold It was significant only in [specific location].

[0243] All best confirmed response call and MRD status In the POLLUX study, subjects treated with DRd showed a higher C In the ASTOR study, compared to subjects treated with Vd, subjects treated with Vd showed a higher response rate. A statistically significant improvement was observed.

[0244] Higher rates in the daratumumab combination group in the POLLUX and CASTOR studies In addition to ORR (data not shown), a higher incidence of MRD-negative status was observed in both studies. It was detected in the latumumab combination group (Figure 3). In the POLLUX study, the group treated with DRd In that case, 75 subjects (26% of ITT) showed the best-confirming clinical response of sCR or CR. (38 and 37 participants respectively) -4 The MRD-negative state was reached at the threshold. In the d treatment group, 20 subjects who showed the best confirmatory clinical response of sCR or CR (ITT) 7% (10 people each) -4 MRD became negative (Table 7).

[0245] The CASTOR study showed that treatment with DVd resulted in sCR or the best-confirming clinical response of CR. The 25 subjects shown (10% of ITT) (5 and 20, respectively) -4 M RD-negative status was achieved. If treated with Vd, 10 -4 A negative MRD at the threshold, or sCR or These were 7 subjects (3% of ITT) who showed the best confirmed clinical response to complete response (CR) (3 and 4, respectively). Observed in (name of subjects) (Table 7). In both studies, 10 -5 and 10 -6 At the sensitivity threshold, M RD-negative counts decreased. Regimens including daratumumab were used as background therapy. Nevertheless, it consistently showed a three-fold or greater increase in the MRD negativity rate compared to the control group. .

[0246] [Table 7]

[0247] Minimal residual disease over time In the POLLUX study, MRD assessment was used for subjects who maintained this response, with questionable C The procedure was performed at the time of R, and at 3 and 6 months after suspected CR (for the treatment cohort). (Blinded). In the CASTOR study, MRD in the ITT population was compared to suspected CR. At the time point (blinded for the treatment cohort), at the end of Vd background therapy (6 months from the start of the study) Evaluation will be conducted 12 months after the start of the study, and 6 months after Vd background therapy. The depth and duration of the MRD response were evaluated over time. The experiment became possible (data not shown).

[0248] As seen in both studies, MRD was evaluated in subjects who showed a suspected CR, and these In the treatment group, MRD negativity occurred simultaneously with a change in the clinical response to CR or sCR, and the patient's condition worsened. Observed in half of the cases: partial response (PR), stable disease (SD), or minimal response (MR). Bone marrow samples from a limited number of subjects that showed a clinical response were inadvertently used to obtain responses of VGPR or higher. The samples were sent for MRD analysis targeting the subjects that showed the following characteristics. As expected, these subjects Although one patient tested positive for MRD, there was one patient in each of the daratumumab combination groups (DRd and DVd). One sample derived from the subject was an exception.

[0249] In the POLLUX study, patients who showed MRD-negative status but whose best clinical response was less than VGPR (Very Good Clinical Response) This one subject had baseline plasmacytoma and experienced a maximum reduction of 36%. Achieved. Despite the VGPR response being evaluated by the principal investigator (data shown) The best response according to the central algorithm was MR. The lower threshold for MRD negativity (1 0 -5 and 10 -6 In this case, the subject was MRD-positive (data not shown).

[0250] Further evaluation of this one subject in the CASTOR study who achieved MRD-negative status Furthermore, the index clones identified during screening decreased to an MRD-negative state. From 81.9% to 0.4% of bone marrow cells, non- It was revealed that the related myeloma clone became dominant at the time of testing (7%). The subjects were those with progressive disease as a result of the current response according to the principal investigator and the central algorithm. However, 10 -4 This explains why it is counted as MRD-negative at the hierarchical threshold (data shown). (Not sure). Lower threshold for MRD negativity (10 -5 and 10 -6 ) In this case, the subject is MRD The result was positive (data not shown).

[0251] MRD status and progression-free survival Subjects who achieved MRD-negative status in either treatment group were considered to have MR at all three thresholds tested. Compared to D-positive subjects, fewer PFS events were experienced (in the case of POLLUX, Figure 4A). Figures 4B and 4C, and in the case of CASTOR, Figures 5A, 5B, and 5C). MRD positive. Among the subjects whose condition remained unchanged, both studies compared them to the standard treatment regimen, Rd, and Vd. An improvement in PFS was observed in the daratumumab combination group.

[0252] MRD status and prior treatment line In the POLLUX study, subjects treated with DRd who had received up to four lines of prior treatment were: 10 -4 The highest rate of achieving MRD negativity was observed in subjects who had received one line of prior treatment. (n=41, 14.3% ITT, Table 8). When treated with Rd, each of the prior treatment lines A lower rate of MRD negativity was achieved, and the subjects were those who had received 1 or 2 lines of prior treatment, totaling 2 patients. Only those who met the criteria (0.7% of ITT) received 4+ lines of prior treatment. The subjects did not reach an MRD-negative state. Detection threshold 10-5 and 10 -6 And the same A turn was observed.

[0253] In the CASTOR study, when treated with DVD, 10 -4 This achieved the highest MRD negativity rate. (n=20, 8%). Subjects who received 2 or 3 lines of prior treatment had lower MRD negativity. The rates are shown (4% of ITT for n=10, and 1.6% of ITT for n=4, respectively). In treatment group d, only subjects who received one or two lines of prior treatment achieved MRD-negative status. The percentages were n=4, 1.6%, and n=3, 1.2%, respectively. A similar trend was observed in 10 -5 Observed . 10 -6 Therefore, the subjects who received 3+ line prior treatment in the DVd treatment group and the Vd treatment group In this study, subjects who received 2+ line prior treatment did not achieve MRD-negative status.

[0254] [Table 8]

[0255] MRD case study example These studies identified many MRD case studies, and each tumor clone sequence was individually... ClonoSEQ (trademark) is used in clinical trials to investigate how it behaves during treatment in the target population. This demonstrated that the assay could be used.

[0256] MRD-negative responders who maintain an MRD-negative state. In the POLLUX study, MRD was evaluated in patients who maintained this response, and multiple factors at the time of treatment were considered. At the time of suspected complete remission (CR), and at 3 and 6 months after suspected CR. The evaluation was conducted at the point when a large number of subjects (the majority of whom were in the DRd group) showed a suspected complete response. An MRD-negative state was achieved and maintained over time. Figures 6A and 6B show two such pairs. This shows the MRD profile of an elephant.

[0257] MRD positivity in partial and non-responders A limited number of samples from subjects showing a clinical response of PR, SD, or MR were inadvertently selected by V Only subjects showing a response of GPR or higher were sent for MRD analysis. Clinically As expected, these subjects, as well as other subjects that could be identified, showed MRD negative symptoms. The condition did not reach a state of equilibrium, and the frequency of these clonal receptors remained high. (Figures 7A, 7B, 7C) Figure 7D shows the MRD profiles of four such subjects.

[0258] MRD during treatment for relapse Clonal response, followed by proliferation, initially shows a clinical response, and then progresses to disease. This was observed in some subjects. Figures 8A and 8B show the MRD profiles of two such subjects. This indicates that in these subjects, the MRD diagnostic clone decreased at the time of CR, and subsequently... The clonal frequency increased, and progressive disease was later clinically detected. These cases were MR. The D test can be used as a highly sensitive measure of disease response, including early signs of relapse and progression. This suggests that it has come.

[0259] Increased depth of response Some subjects showed a rapid clinical response and a significant reduction in clonal frequency, but the results were questionable. At the time of CR, MRD negativity was not achieved during the initial evaluation. These subjects did not reach MRD negativity. It took more time to complete, but eventually the MRD test became negative at that point. (Figure) Figures 9A and 9B show the MRD profiles of two such subjects.

[0260] Slow responder Individual MRD clone receptors were clearly reduced, and interestingly, some reached the clinical response state of CR or sCR reduced at different rates but many remained MRD positive. Figures 10A, 10B, 10C, and 10D show the MRD profiles of four such subjects identified.

[0261] MRD negativity in high - risk and standard - risk subjects The analysis set included a subset analysis of subjects from the POLLUX trial (Example 2) and the CASTOR trial (Example 1) classified as high - risk subjects or standard - risk subjects based on cytogenetic abnormalities as described herein. MRD negativity was evaluated separately at thresholds of 10 -4 10 -5 and 10 -6 .

[0262] In POLLUX, a significantly higher proportion of standard - risk subjects reached MRD negativity at the 10 -4 MRD threshold (p < 0 .0001, 48 patients (DRd) vs. 14 patients (Rd)) and the 10 -5 MRD threshold (p < 0.005, 34 patients (DRd) vs. 8 patients (Rd)) (Figure 11A). At the 10 MRD threshold in standard - risk subjects, statistical significance was not reached -6 (15 patients (DRd) vs. 5 patients (Rd)). A significantly higher proportion of high - risk subjects reached MRD negativity at the 10 MRD threshold (p < 0.05, 6 patients (DRd) vs. 0 patients (Rd -4 )) and the 10 MRD threshold (p < 0.05, 5 patients (DRd) vs. 0 patients (Rd -5 )) (Figure 11B). At the 10 MRD threshold in standard - risk subjects -6 ​​​​ did not reach statistical significance (4 patients (DRd) vs. 0 patients (Rd)).

[0263] In CASTOR, a significantly higher proportion of standard-risk subjects achieved -4 MRD negativity at the 10 -5 MRD threshold (p < 0.005, 4 patients (DVd) vs. 4 patients (Vd)) and at the 10 -6 MRD threshold (p < 0.05, 1 patient (DVd) vs. 1 patient (Vd)) (Figure 12A). At the 10 -5 MRD threshold, statistical significance was not reached (1 patient (DVd) vs. 1 patient (Vd)). A significantly higher proportion of high-risk subjects achieved -4 MRD negativity at the 10 -6 MRD threshold (p < 0.05, 5 patients (DVd) vs. 0 patients (Vd)) (Figure 12B). In high-risk subjects (4 patients (DRd) vs. 0 patients (Rd)), statistical significance was not reached at the 10

[0264] MRD Case Type: Conclusion These plots further categorize responses and highlight the potential utility of longitudinal MR D analysis to avoid phenotypes. Additionally, patients can be identified as to which ones will worsen during treatment, enabling earlier therapeutic intervention in subsequent treatment.

[0265] Conclusion Regardless of background therapy or threshold, the minimal residual disease negativity rate was significantly higher in regimens containing daratumumab compared to the control group at the predefined hierarchical threshold of 10 (PO -4 LLUX study: DRd: 29% vs. Rd: 7.8%, CASTOR study: DVd: 14 % vs. Vd: 3.0%), and the MRD negativity rate was at least three-fold higher. Also, at more stringent thresholds ​ 10 -5 Further evaluation showed that the regimen including daratumumab was significantly more effective compared to the control group. It was shown that a high MRD negativity rate could be achieved. Furthermore, these MRD data demonstrate that this difficult This highlights the ability of regimens containing daratumumab to enhance the depth of response in the patient population. Also, 10 -6 Therefore, DVd caused an increase in the MRD negativity rate compared to Vd, The results did not reach statistical significance.

[0266] In summary, these two studies are in the Phase 3 clinical research setting for relapsed or refractory mammary gland disease. This corresponds to the first randomized controlled predictive evaluation of MRD, and therapies including daratumumab are being evaluated for MM. It demonstrated that it can significantly elicit deep-level clinical responses. Regardless of the type of therapy, regimens containing daratumumab were evaluated in all aspects compared to the control group. The valence threshold consistently showed a three-fold or greater increase in the MRD negativity rate. Importantly, M Because subjects who achieved RD-negative status showed a low PFS event rate, the addition of daratumumab... The deep clinical response induced by this may lead to improved long-term outcomes.

[0267] Those skilled in the art will be able to make numerous changes and modifications to the preferred embodiments of the present invention. It is possible to do so, and such changes and modifications can be made without departing from the spirit of the present invention. They will understand that this is possible. Therefore, the attached claims are true to the spirit of the present invention. And it is intended to cover all such equivalent transformations that fall within the range.

[0268] Each patent, patent application, and publication disclosure cited or referenced herein is subject to change in full. This is incorporated herein by reference.

[0269] Table 9-1

[0270] Table 9-2

Claims

1. A method for achieving minimal residual disease negativity in subjects with multiple myeloma, The subjects listed are anti-CD38 antibodies, corticosteroids, and non-corticosteroid chemotherapeutic agents. Administer a therapeutically effective dose for a sufficient amount of time to achieve minimal residual disease negativity. A method that includes [this].

2. The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 6, heavy chain CDR1, and SEQ ID NO:

7. Heavy chain CDR2 containing the amino acid sequence, heavy chain CDR3 containing the amino acid sequence of SEQ ID NO: 8, sequence Light chain CDR1 containing amino acid sequence number 9, and light chain CD containing amino acid sequence number 10. The method according to claim 1, comprising a light chain CDR3 containing R2 and the amino acid sequence of SEQ ID NO:

11. Law.

3. The method according to claims 1 to 2, wherein the corticosteroid is dexamethasone.

4. The non-corticosteroid chemotherapeutic agent is a glutamate derivative or proteasome inhibitor. The method according to claims 1 to 3, which is an agent.

5. The method according to claim 4, wherein the glutamic acid derivative is lenalidomide.

6. The method according to claim 4, wherein the proteasome inhibitor is bortezomib.

7. a) The anti-CD38 antibody is administered once a week in a 28-day cycle, in cycles 1 and 2, 1, 8, and 1.

5. On the 22nd day, once every two weeks in a 28-day cycle, on the 1st and 1st day between cycles 3 and 6. On the fifth day, it was administered intravenously at a dose of approximately 16 mg / kg once every four weeks thereafter. 、 b) Lenalidomide is administered in doses of approximately 10 mg to 25 mg between days 1 and 21 of a 28-day cycle. It is administered orally in the prescribed dose. c) Dexamethasone is administered once a week at a dose between approximately 20 mg and 40 mg. The method described in item 5.

8. a) The anti-CD38 antibody is administered once a week in a 21-day cycle, in cycles 1-3, 1, 8 and On the 15th day, once every three weeks in a 21-day cycle, on the first day of cycles 4-8, and then for four weeks thereafter. It is administered once in between as an intravenous infusion at a dose of approximately 16 mg / kg. b) Bortezomib is administered on days 1, 4, 8, and 11 of cycles 1-8 in a 21-day cycle. , about 1.3mg / m ２ It is administered subcutaneously (SC) at the following doses: c) Dexamethasone is administered once a week at a dose between approximately 20 mg and 40 mg. The method described in item 6.

9. Dexamethasone is administered at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. The method according to claim 7, wherein the total dose is 160 mg per cru, administered IV or PO.

10. Dexamethasone is administered at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. The method according to claim 8, wherein the total dose is 160 mg per cru, administered IV or PO.

11. The method according to claims 1 to 10, wherein the subject has relapsed or refractory multiple myeloma.

12. The method according to claims 1 to 11, wherein the subject has high-risk multiple myeloma.

13. The subject with the aforementioned high-risk multiple myeloma, a) t(4;14)(p16;q32), b) t(14;16)(q32;q23), c) del17p, d) t(4;14)(p16;q32) and t(14;16)(q32;q23), e) t(4;14)(p16;q32) and del17p, f) t(14;16)(q32;q23) and del17p, or g) t(4;14)(p16;q32), t(14;16)(q32;q23), and del17p The method according to claim 12, wherein the chromosomal abnormality includes one or more chromosomal abnormalities.

14. The percentage of those with minimal residual lesions who have a negative result is 0.01%, 0.001%, 0.0001%, or less. The method according to claims 1 to 13, determined by the sensitivity of the combination thereof.

15. The anti-CD38 antibody comprises the human CD38 region including SEQ ID NO: 2 and the human CD38 region including SEQ ID NO:

3. The method according to claims 1 to 14, wherein the region of CD38 is coupled.

16. The anti-CD38 antibody includes the heavy chain variable region containing the amino acid sequence of SEQ ID NO: 4 and SEQ ID NO: 5 The method according to claims 1 to 15, comprising a light chain variable region containing the amino acid sequence.

17. The anti-CD38 antibody contains a heavy chain containing the amino acid sequence of SEQ ID NO: 12 and the amino acid sequence of SEQ ID NO:

13. The method according to claims 1 to 16, comprising a light chain containing a mino acid sequence.

18. The aforementioned anti-CD38 antibody, a) VH containing the amino acid sequence of SEQ ID NO: 14 and V containing the amino acid sequence of SEQ ID NO: 15 L, b) VH containing the amino acid sequence of SEQ ID NO: 16 and V containing the amino acid sequence of SEQ ID NO: 17 L, c) VH containing the amino acid sequence of SEQ ID NO: 18 and V containing the amino acid sequence of SEQ ID NO: 19 L, or d) VH containing the amino acid sequence of SEQ ID NO: 20 and V containing the amino acid sequence of SEQ ID NO: 21 L's Heavy chain CDR1, heavy chain CDR2, heavy chain CDR3, light chain CDR1, light chain CDR2, and light chain C The method according to claims 1 to 13, including DR3.

19. The aforementioned anti-CD38 antibody, a) VH containing the amino acid sequence of SEQ ID NO: 14 and V containing the amino acid sequence of SEQ ID NO: 15 L, b) VH containing the amino acid sequence of SEQ ID NO: 16 and V containing the amino acid sequence of SEQ ID NO: 17 L, c) VH containing the amino acid sequence of SEQ ID NO: 18 and V containing the amino acid sequence of SEQ ID NO: 19 L, or d) VH containing the amino acid sequence of SEQ ID NO: 20 and V containing the amino acid sequence of SEQ ID NO: 21 The method according to claim 18, comprising L.

20. The corticosteroid is dexamethasone or prednisone, according to claims 1 to 2. Method of description.

21. The aforementioned negative minimal residual lesions allow us to evaluate the amount of myeloma cells in the bone marrow aspirate sample derived from the subject. The method according to claims 1 to 20, which is detected by doing so.

22. The method according to claims 1 to 21, wherein the method also reduces progression-free survival events.

23. The glutamic acid derivative is lenalidomide, thalidomide, or pomalidomide. The method according to claim 4.

24. The proteasome inhibitor is bortezomib, carfilzomib, or ixazomib. A method according to claim 4.

25. A method for treating a subject with high-risk multiple myeloma, wherein the patient is given anti-CD38 The therapeutically effective amounts of antibodies, corticosteroids, and non-corticosteroid chemotherapeutic agents are as described above. A method comprising administering an agent for a sufficient period of time to treat high-risk multiple myeloma.

26. The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 6, heavy chain CDR1, and SEQ ID NO:

7. Heavy chain CDR2 containing the amino acid sequence, heavy chain CDR3 containing the amino acid sequence of SEQ ID NO: 8, sequence Light chain CDR1 containing amino acid sequence number 9, and light chain CD containing amino acid sequence number 10. The claim 25 includes a light chain CDR3 comprising R2 and the amino acid sequence of SEQ ID NO:

11. method.

27. The method according to claims 25 to 26, wherein the corticosteroid is dexamethasone.

28. The non-corticosteroid chemotherapeutic agent is a glutamate derivative or proteasome inhibitor. The method according to claims 25 to 27, which is an agent.

29. The method according to claim 28, wherein the glutamic acid derivative is lenalidomide.

30. The method according to claim 28, wherein the proteasome inhibitor is bortezomib.

31. a) The anti-CD38 antibody is administered once a week in a 28-day cycle, in cycles 1 and 2, 1, 8, and 1.

5. On the 22nd day, once every two weeks in a 28-day cycle, on the 1st and 1st day between cycles 3 and 6. On the fifth day, it was administered intravenously at a dose of approximately 16 mg / kg once every four weeks thereafter. 、 b) Lenalidomide is administered in doses of approximately 10 mg to 25 mg between days 1 and 21 of a 28-day cycle. It is administered orally in the prescribed dose. c) Dexamethasone is administered once a week at a dose between approximately 20 mg and 40 mg. The method described in item 29.

32. a) The anti-CD38 antibody is administered once a week in a 21-day cycle, in cycles 1-3, 1, 8 and On the 15th day, once every three weeks in a 21-day cycle, on the first day of cycles 4-8, and then for four weeks thereafter. It is administered once in between as an intravenous infusion at a dose of approximately 16 mg / kg. b) Bortezomib is administered on days 1, 4, 8, and 11 of cycles 1-8 in a 21-day cycle. , about 1.3mg / m ２ It is administered subcutaneously (SC) at the following doses: c) Dexamethasone is administered once a week at a dose between approximately 20 mg and 40 mg. The method described in item 30.

33. Dexamethasone is administered at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. The method according to claim 31, wherein the total dose is 160 mg per cru, administered IV or PO.

34. Dexamethasone is administered at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. The method according to claim 32, wherein the total dose is 160 mg per cru, administered IV or PO.

35. The anti-CD38 antibody comprises the human CD38 region including SEQ ID NO: 2 and the human CD38 region including SEQ ID NO:

3. The method according to claims 25 to 34, wherein the region of CD38 is coupled.

36. The anti-CD38 antibody includes the heavy chain variable region containing the amino acid sequence of SEQ ID NO: 4 and SEQ ID NO: 5 The method according to claims 25 to 35, comprising a light chain variable region containing the amino acid sequence.

37. The anti-CD38 antibody contains a heavy chain containing the amino acid sequence of SEQ ID NO: 12 and the amino acid sequence of SEQ ID NO:

13. The method according to claims 25 to 36, comprising a light chain containing a mino acid sequence.

38. The aforementioned anti-CD38 antibody, a) VH containing the amino acid sequence of SEQ ID NO: 14 and V containing the amino acid sequence of SEQ ID NO: 15 L, b) VH containing the amino acid sequence of SEQ ID NO: 16 and V containing the amino acid sequence of SEQ ID NO: 17 L, c) VH containing the amino acid sequence of SEQ ID NO: 18 and V containing the amino acid sequence of SEQ ID NO: 19 L, or d) VH containing the amino acid sequence of SEQ ID NO: 20 and V containing the amino acid sequence of SEQ ID NO: 21 L's Heavy chain CDR1, heavy chain CDR2, heavy chain CDR3, light chain CDR1, light chain CDR2, and light chain C The method according to claim 25, including DR3.

39. The aforementioned anti-CD38 antibody, a) VH containing the amino acid sequence of SEQ ID NO: 14 and V containing the amino acid sequence of SEQ ID NO: 15 L, b) VH containing the amino acid sequence of SEQ ID NO: 16 and V containing the amino acid sequence of SEQ ID NO: 17 L, c) VH containing the amino acid sequence of SEQ ID NO: 18 and V containing the amino acid sequence of SEQ ID NO: 19 L, or d) VH containing the amino acid sequence of SEQ ID NO: 20 and V containing the amino acid sequence of SEQ ID NO: 21 The method according to claim 38, comprising L.

40. Claim 25 states that the corticosteroid is dexamethasone or prednisone. Method of loading.

41. The method according to claim 25, wherein the corticosteroid is dexamethasone.

42. The non-corticosteroid chemotherapeutic agent is a glutamate derivative or proteasome inhibitor. The method according to claim 25, which is an agent.

43. The glutamic acid derivative is lenalidomide, thalidomide, or pomalidomide. The method according to claim 42.

44. The method according to claim 42, wherein the glutamic acid derivative is lenalidomide.

45. The proteasome inhibitor is bortezomib, carfilzomib, or ixazomib. A method according to claim 42.

46. The method according to claim 42, wherein the proteasome inhibitor is bortezomib.

47. The subject with the aforementioned high-risk multiple myeloma, a) t(4;14)(p16;q32), b) t(14;16)(q32;q23), c) del17p, d) t(4;14)(p16;q32) and t(14;16)(q32;q23), e) t(4;14)(p16;q32) and del17p, f) t(14;16)(q32;q23) and del17p, or g) t(4;14)(p16;q32), t(14;16)(q32;q23), and del17p The method according to claim 25, wherein the chromosomal abnormality includes one or more chromosomal abnormalities.

48. The person described in claim 25, wherein the subject has high-risk, refractory or relapsed multiple myeloma. Law.

49. The above method involves receiving the corticosteroid and the non-corticosteroid chemotherapeutic agent. Compared to the target, the method described in claim 25 improves one or more evaluation items of the target. method.

50. One or more of the above evaluation items are progression-free survival, overall response rate, very good partial response, or Claims include more than, complete response or more, or any combination thereof. Method 49.

51. The method according to claim 25, wherein the method achieves minimal residual disease negativity in the subject. 。

52. A method for reducing the risk of relapse and / or disease progression in patients with multiple myeloma. And, The aforementioned subjects received anti-CD38 antibodies, corticosteroids, and non-corticosteroid chemotherapy. The procedure involves administering a therapeutically effective dose of the drug to achieve a minimal residual disease-negative state, and the residual disease A method in which a change in the negative state indicates a reduced risk of relapse and / or disease progression.

53. A method for predicting the likelihood of recurrence and / or disease progression in subjects with multiple myeloma. There is, This includes measuring the minimal residual disease status in the subject, wherein the subject is anti-CD38 anti The body receives therapeutically effective doses of corticosteroids and non-corticosteroid chemotherapy agents. the law of nature, A method in which a positive minimal residual disease status indicates the possibility of recurrence and / or disease progression.

54. The anti-CD38 antibody contains the amino acid sequence of SEQ ID NO: 6, heavy chain CDR1, and SEQ ID NO:

7. Heavy chain CDR2 containing the amino acid sequence, heavy chain CDR3 containing the amino acid sequence of SEQ ID NO: 8, sequence Light chain CDR1 containing amino acid sequence number 9, and light chain CD containing amino acid sequence number 10. Claims 52 to 53, comprising a light chain CDR3 containing R2 and the amino acid sequence of SEQ ID NO:

11. One of the methods described above.

55. The corticosteroid is dexamethasone, as described in any one of claims 52 to 54. Method of loading.

56. The non-corticosteroid chemotherapeutic agent is a glutamate derivative or proteasome inhibitor. The method according to any one of claims 52 to 55, which is an agent.

57. The method according to claim 56, wherein the glutamic acid derivative is lenalidomide.

58. The method according to claim 56, wherein the proteasome inhibitor is bortezomib.

59. a) The anti-CD38 antibody is administered once a week in a 28-day cycle, in cycles 1 and 2, 1, 8, and 1.

5. On the 22nd day, once every two weeks in a 28-day cycle, on the 1st and 1st day between cycles 3 and 6. On the fifth day, it was administered intravenously at a dose of approximately 16 mg / kg once every four weeks thereafter. 、 b) Lenalidomide is administered in doses of approximately 10 mg to 25 mg between days 1 and 21 of a 28-day cycle. It is administered orally in the prescribed dose. c) Dexamethasone is administered once a week at a dose between approximately 20 mg and 40 mg. The method described in item 57.

60. a) The anti-CD38 antibody is administered once a week in a 21-day cycle, in cycles 1-3, 1, 8 and On the 15th day, once every three weeks in a 21-day cycle, on the first day of cycles 4-8, and then for four weeks thereafter. It is administered once in between as an intravenous infusion at a dose of approximately 16 mg / kg. b) Bortezomib is administered on days 1, 4, 8, and 11 of cycles 1-8 in a 21-day cycle. It is administered subcutaneously (SC) at a dose of approximately 1.3 mg / m2. c) Dexamethasone is administered once a week at a dose between approximately 20 mg and 40 mg. The method described in claim 58.

61. Dexamethasone is administered at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. The person according to claims 55 to 60, who is administered IV or PO in a total dose of 160 mg per crust. Law.

62. The subject is having relapsed or refractory multiple myeloma, according to any one of claims 52 to 61. Method of description.

63. The subject is a high-risk multiple myeloma, as described in any one of claims 52 to 62. The method.

64. The subject with the aforementioned high-risk multiple myeloma, a) t(4;14)(p16;q32), b) t(14;16)(q32;q23), c) del17p, d) t(4;14)(p16;q32) and t(14;16)(q32;q23), e) t(4;14)(p16;q32) and del17p, f) t(14;16)(q32;q23) and del17p, or g) t(4;14)(p16;q32), t(14;16)(q32;q23), and del17p The method according to claim 63, wherein the chromosomal abnormality includes one or more chromosomal abnormalities.

65. The anti-CD38 antibody comprises the human CD38 region including SEQ ID NO: 2 and the human CD38 region including SEQ ID NO:

3. The method according to any one of claims 52 to 64, wherein the region of CD38 is coupled.

66. The anti-CD38 antibody includes the heavy chain variable region containing the amino acid sequence of SEQ ID NO: 4 and SEQ ID NO: 5 The method according to any one of claims 52 to 65, comprising a light chain variable region containing the amino acid sequence. Law.

67. The anti-CD38 antibody contains a heavy chain containing the amino acid sequence of SEQ ID NO: 12 and the amino acid sequence of SEQ ID NO:

13. The method according to any one of claims 52 to 66, comprising a light chain containing a mino acid sequence.

68. The aforementioned anti-CD38 antibody, a) VH containing the amino acid sequence of SEQ ID NO: 14 and V containing the amino acid sequence of SEQ ID NO: 15 L, b) VH containing the amino acid sequence of SEQ ID NO: 16 and V containing the amino acid sequence of SEQ ID NO: 17 L, c) VH containing the amino acid sequence of SEQ ID NO: 18 and V containing the amino acid sequence of SEQ ID NO: 19 L, or d) VH containing the amino acid sequence of SEQ ID NO: 20 and V containing the amino acid sequence of SEQ ID NO: 21 L's Heavy chain CDR1, heavy chain CDR2, heavy chain CDR3, light chain CDR1, light chain CDR2, and light chain C The method according to any one of claims 52 to 64, including DR3.

69. The aforementioned anti-CD38 antibody, a) VH containing the amino acid sequence of SEQ ID NO: 14 and V containing the amino acid sequence of SEQ ID NO: 15 L, b) VH containing the amino acid sequence of SEQ ID NO: 16 and V containing the amino acid sequence of SEQ ID NO: 17 L, c) VH containing the amino acid sequence of SEQ ID NO: 18 and V containing the amino acid sequence of SEQ ID NO: 19 L, or d) VH containing the amino acid sequence of SEQ ID NO: 20 and V containing the amino acid sequence of SEQ ID NO: 21 The method according to claim 68, comprising L.

70. Claims 52-5, wherein the corticosteroid is dexamethasone or prednisone. The method described in any of the four methods.

71. The glutamic acid derivative is lenalidomide, thalidomide, or pomalidomide. The method according to claim 56.

72. The proteasome inhibitor is bortezomib, carfilzomib, or ixazomib. A method according to claim 56.

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