Medication regimen

Abstract

This disclosure relates to a combination drug regimen comprising an anti-KMA antibody, IMiD / CELMoD, and a steroid. Such a combination may be used for the treatment of multiple myeloma.

Description

[Technical Field]

[0001] Related application data This application claims priority from Australian Patent Application No. 2023 / 900983, filed on April 4, 2023, entitled "A Dosing Regimen." The entire contents of this application are incorporated herein by reference.

[0002] Sequence List This application is filed together with an electronic sequence listing. The entire contents of the sequence listing are incorporated herein by reference.

[0003] This disclosure relates to a combination drug regimen comprising an anti-KMA antibody, IMiD / CELMoD, and a steroid. Such a combination may be used for the treatment of multiple myeloma. [Background technology]

[0004] Multiple myeloma represents the malignant proliferation of plasma cells originating from a single clone. The tumors of multiple myeloma, their products, and the patient's response to them can result in several organ dysfunctions, symptoms of bone pain or fractures, renal failure, increased susceptibility to infection, anemia, hypocalcemia, coagulation disorders, neurological symptoms, and hyperviscosity vascular symptoms.

[0005] Despite numerous treatment options, multiple myeloma remains an incurable disease for most patients, and there are currently no effective long-term treatments available for it. For example, in Australia and the United States, the current probability of surviving five years after initial diagnosis is 55%. Therefore, new treatment methods are needed. [Overview of the Initiative]

[0006] Monoclonal antibodies are considered to have a high potential for immunotoxicity, which can be dose-dependent. Therefore, when low doses of monoclonal antibodies are considered effective for therapeutic purposes, higher doses are often not considered.

[0007] Early clinical trials of anti-KMA antibodies suggested they were not subject to the phenomenon known as "antigen sink." Therefore, combined with the known potential for monoclonal antibody-induced immunotoxicity at higher doses, anti-KMA antibodies were considered candidates for lower dosages.

[0008] However, the Phase II trial surprisingly demonstrated that administration of anti-KMA antibodies at a dose of 10 mg / kg provided a favorable safety profile in human subjects. This favorable safety profile resulted from the anti-KMA antibody not unexpectedly depleting immune cells, either alone or more specifically in combination with immunomodulatory agents (IMiDs) or cereblon E3 ligase modulators (CELMoDs) and steroids. In addition, when kappaMab (KM) was administered in combination with IMiDs and steroids (e.g., lenalidomide / dexamethasone), the safety profile of this combination was comparable to the safety profile of lenalidomide / dexamethasone administered in the literature (e.g., no increased rates of thrombocytopenia, neutropenia, or infections in KM / lenalidomide / dexamethasone-treated patients compared to lenalidomide / dexamethasone alone).

[0009] The observed safety profile of other monoclonal antibodies in the treatment of multiple myeloma is surprising, as they typically result in immune cell depletion due to the presence of antigen targets on both malignant plasma cells and healthy immune cells (e.g., BCMA and CD38). Therefore, our findings support higher doses of anti-KMA antibodies, such as KM (e.g., above 10 mg / kg), particularly in combination with IMiD or CELMoD and steroids. This represents a significant advance in the art, as increased dosing of anti-KMA antibodies, particularly in combination with IMiD or CELMoD and steroids, may improve outcomes for patients with multiple myeloma, especially those with relapsed or refractory multiple myeloma.

[0010] Therefore, in one example, this disclosure relates to a method for treating multiple myeloma in a subject requiring treatment for multiple myeloma, wherein the method is applied to the subject. At least 30 mg / kg of anti-KMA antibody, IMiD or CELMoD, The present invention relates to methods, including administering treatment with steroids.

[0011] The method of this disclosure also, At least 30 mg / kg of anti-KMA antibody, IMiD or CELMoD, This relates to combination drug regimens, including steroids, for use in the treatment of multiple myeloma in the subject.

[0012] The method disclosed herein further relates to the treatment of multiple myeloma in the subject, A single or multiple dose of at least 30 mg / kg of anti-KMA antibody, Single-dose or multi-dose IMiD or CELMoD, Single-dose or multi-dose steroids, The kit includes instructions for using an anti-KMA antibody, IMiD or CELMoD, and a steroid.

[0013] In the above example, the anti-KMA antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL). The VH comprises a complementarity-determining region (CDR) 1 containing the amino acid sequence shown in SEQ ID NO: 6, a CDR2 containing the amino acid sequence shown in SEQ ID NO: 7, and a CDR3 containing the sequence shown in SEQ ID NO: 8. The VL comprises a CDR1 containing the amino acid sequence shown in SEQ ID NO: 9, a CDR2 containing the amino acid sequence shown in SEQ ID NO: 10, and a CDR3 containing the sequence shown in SEQ ID NO: 11. In another example, the anti-KMA antibody has a VH containing the sequence described in SEQ ID NO: 1, and a VL containing the sequence described in SEQ ID NO: 2.

[0014] In one example, approximately 30 mg / kg to 60 mg / kg of anti-KMA antibody is administered to the subject. For example, 30 mg / kg to 60 mg / kg of anti-KMA antibody is administered to the subject. In another example, approximately 45 mg / kg of anti-KMA antibody is administered to the subject. For example, 45 mg / kg of anti-KMA antibody is administered to the subject. In yet another example, approximately 60 mg / kg of anti-KMA antibody is administered to the subject. For example, 60 mg / kg of anti-KMA antibody is administered to the subject.

[0015] In one example, IMiD is lenalidomide, pomalidomide, or thalidomide. For example, IMiD may be lenalidomide. In one example, CELMoD is iverdamide or CC-92480. For example, CELMoD is iverdamide. In one example, approximately 25 mg of IMiD or CELMoD is administered to the subject. In one example, 25 mg of IMiD or CELMoD is administered to the subject. For example, approximately 25 mg of lenalidomide is administered to the subject. In one example, 25 mg of lenalidomide is administered to the subject.

[0016] In one example, the steroid is dexamethasone or prednisone. For example, the steroid is dexamethasone. In one example, approximately 40 mg of the steroid is administered to the subject. In one example, 40 mg of the steroid is administered to the subject. For example, approximately 40 mg of dexamethasone is administered to the subject. In one example, 40 mg of dexamethasone is administered to the subject.

[0017] A method for treating multiple myeloma in patients requiring treatment for multiple myeloma, wherein this method is effective for patients. At least 30 mg / kg of anti-KMA antibody, 25mg IMiD or CELMoD, A method including administering treatment with 40 mg of steroids.

[0018] A method of treating multiple myeloma in a subject who requires treatment for multiple myeloma, the method comprising administering to the subject at least 30 mg / kg of an anti-KMA antibody having the CDR of KM, and 25 mg of lenalidomide, and 40 mg of dexamethasone, in a treatment.

[0019] In one example, the treatment comprises administering to the subject during the treatment phase once a week, at least 30 mg / kg of the anti-KMA antibody, and once a day, an IMiD or CELMoD, and once a week, a steroid.

[0020] In one example, the duration of the treatment phase is at least 6 weeks to at least 10 weeks. For example, the duration of the treatment phase is 6 weeks to 10 weeks. In one example, the duration of the treatment phase is at least 8 weeks. For example, the duration of the treatment phase is 8 weeks.

[0021] In one example, the method of the present disclosure further comprises administering an IMiD or CELMoD once a day to the subject for at least 3 weeks before the start of the treatment phase. For example, the method of the present disclosure further comprises administering an IMiD or CELMoD once a day to the subject for 3 weeks before the start of the treatment phase.

[0022] In one example, the method of the present disclosure further comprises administering a steroid to the subject at least 1 week before the start of the treatment phase. For example, the method of the present disclosure further comprises administering a steroid to the subject 1 week before the start of the treatment phase.

[0023] In one example, the immune cells of the subject are maintained at a level corresponding to the immune cells of the subject before administration of the anti-KMA antibody. In another example, the immune cells of the subject are maintained at a level corresponding to the immune cells of the subject after the treatment phase. In one example, the immune cells of the subject are one or more or all of red blood cells, white blood cells, and platelets.

[0024] For example, treatment is administered to the subject at the treatment stage. Once a week, at least 30 mg / kg of anti-KMA antibody, Once daily, take 25 mg of IMiD or CELMoD, This includes administering 40 mg of steroids once a week.

[0025] For example, treatment is administered to the subject at the treatment stage. Once a week, administer at least 30 mg / kg of anti-KMA antibody with KM CDR, Once a day, 25 mg of lenalidomide, This includes administering 40 mg of dexamethasone once a week.

[0026] For example, the method of this disclosure applies to the subject, Once a month, at least 30 mg / kg of anti-KMA antibody, Once a day, take IMiD or CELMoD, This further includes a maintenance phase, which involves administering steroids once a week.

[0027] For example, the method of this disclosure applies to the subject, Once a month, at least 30 mg / kg of anti-KMA antibody, Once daily, take 25 mg of IMiD or CELMoD, This further includes a maintenance phase, which involves administering 40 mg of steroids once a week.

[0028] For example, the method of this disclosure applies to the subject, Once a week, administer at least 30 mg / kg of anti-KMA antibody with KM CDR, Once a day, 25 mg of lenalidomide, The treatment further includes a maintenance phase, which involves administering 40 mg of dexamethasone once a week.

[0029] In one example, the maintenance phase follows the treatment phase. In another example, the maintenance phase lasts for at least 12 weeks. For example, the maintenance phase lasts for 12 weeks. In yet another example, the maintenance phase continues until the disease progresses.

[0030] Once the patient's disease has progressed, they are removed from therapy. In one case, the patient is switched to a different anti-multiple myeloma therapy. In another case, the maintenance phase is discontinued.

[0031] In one example, an anti-KMA antibody is formulated for intravenous infusion. In another example, IMiD or CELMoD is formulated for oral delivery. In yet another example, a steroid is formulated for oral delivery or intravenous infusion.

[0032] In one example, the subject has received at least one, at least two, at least three, at least four, at least five, or at least six prior treatment lines.

[0033] In one example, the subject achieved at least a minimal response (e.g., a 25% reduction in M ​​protein) to their most recent line of therapy.

[0034] In one example, the subject is refractory to at least one, at least two, at least three, or at least four prior therapy lines. In another example, the subject is refractory to at least one proteasome inhibitor, IMiD, CELMoD, or autologous stem cell transplantation.

[0035] In one case, the subject has relapsed myeloma. In another case, the subject's multiple myeloma is relapsed and refractory to at least one proteasome inhibitor, IMiD, CELMoD, or autologous stem cell transplantation.

[0036] For example, the subjects have no prior exposure to IMiD or CELMoD. For instance, the subjects have no prior exposure to lenalidomide.

[0037] Any example in this disclosure shall apply mutatis mutandis to any other example unless otherwise specified.

[0038] The present invention is intended for illustrative purposes only and should not be limited in scope by the specific examples described herein. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention as described herein.

[0039] Throughout this specification, unless otherwise specifically stated or the context requires, any reference to a single step, composition of a substance, group of steps, or group of compositions of a substance shall be construed as encompassing one or more (i.e., one or more) of those steps, compositions of a substance, groups of steps, or groups of compositions of a substance.

[0040] The present invention is described below by the following non-limiting embodiments and with reference to the accompanying drawings. Key for sequence listing Sequence ID 1: Amino acid sequence of KappaMab variable heavy chain (VH) Sequence ID 2: Amino acid sequence of the variable light chain (VL) of KappaMab Sequence ID 3: Amino acid sequence of the KMA switch region in the kappa light chain Sequence ID 4: Amino acid sequence of the KappaMab epitope Sequence ID 5: Amino acid sequence of KappaMab epitope 2 (improved binding) Sequence ID 6: Amino acid sequence of KappaMab VH CDR1 Sequence ID 7: Amino acid sequence of KappaMab VH CDR2 Sequence ID 8: Amino acid sequence of KappaMab VH CDR3 Sequence ID 9: Amino acid sequence of KappaMab VL CDR1 Sequence ID 10: Amino acid sequence of KappaMab VL CDR2 Sequence ID 11: Amino acid sequence of KappaMab VL CDR3 Amino acid sequence of SEQ ID NO: 12:K121 VH SEQ ID NO: 13: Amino acid sequence of K121 VC [Brief explanation of the drawing]

[0041] [Figure 1] Study schema Stage 1 consisted of eight weekly doses of 10 mg / kg of KappaMab, followed by monthly doses until progression. Stage 2 consisted of eight weekly doses of 10 mg / kg of KappaMab plus 25 mg of lenalidomide and 40 mg of dexamethasone, followed by monthly doses of KappaMab plus lenalidomide and dexamethasone until progression. In Stage 2, Cycle 1 was 35 days, with LEN and DEX administered for one week prior to the first dose of KappaMab. The remaining cycles were 28 days, with KappaMab administered on day 1 of each cycle. [Figure 2] Duration of response in patients treated with stage KM-Rd. Shaded areas indicate the 95% confidence interval for the probability of a response remaining at each time point. [Figure 3] Cumulative incidence of the occurrence of the next treatment or competing events prior to the next treatment. The shaded area indicates the 95% confidence interval for each type of event at each time point. [Figure 4] A comparison of overall response rate (ORR) and best clinical response rate between stage 2 KM-Rd patients and Rd-MRDR patients. Comparing the best clinical response in the Rd-MRDR group to that of stage 2 patients, the overall percentage of best clinical responses was higher in stage 2 patients, accompanied by more responses and improved response quality. In addition, stage 2 patients (KM-Rd patients) had an ORR of 83% and a CBR of 93%, compared to a matched control group from the Australian and New Zealand Myeloma and Related Diseases registry (Rd-MRDR group) with an ORR of 45%. [Figure 5]A comparison of the overall survival endpoint in terms of time to event was performed between the KM-Rd group and the Rd-MRDR group. The log-rank test showed significance at p=0.0163, with a hazard ratio (HR) of 0.46 and a 95% CI (0.2466, 0.8679) with a 95% confidence interval. The median OS in the Rd-MRDR group was 27.8 months, while the median OS was not reached in the KM-Rd group. Regarding mortality data, in the KM-Rd cohort (n=40), 9 patients had evaluable data and 31 patients were censored, while in the Rd-MRDR group (n=77), 32 patients had evaluable data and 45 patients were censored. [Figure 6] Sequential M protein levels and FLC levels for Stage 1 (Panels A and B) and Stage 2 (Panels C and D). In Stage 1, in one patient, M protein levels decreased below baseline (Panel A, open inverted triangle), but FLC increased in this patient (Panel B). In Stage 1, one MM patient with only FLC showed a decrease in sFLC levels ranging from -36% to -80% from baseline during 31 cycles of treatment (Panel B, open dotted circle). In Stage 2, the majority of patients responded to KM-Rd (Panel C). The median % change from baseline in FLC increased in cycle 3 (i.e., after 9 KM doses), then decreased and remained below baseline (red line in Panel D). This was not observed in patients in Stage 1, where the median FLC dropped between cycles 3 and 4, then generally increased after cycle 4 (red line in Panel B). The median is the white line marked with the arrow in the figure. [Modes for carrying out the invention]

[0042] General techniques and selected definitions Unless otherwise specifically defined, all technical and scientific terms used herein shall be construed to have the same meaning as those generally understood by those skilled in the art (e.g., molecular biology, biochemistry, oncology, and clinical research).

[0043] Unless otherwise indicated, the molecular techniques and statistical methods used in this disclosure are standard procedures well known to those skilled in the art. Such techniques are described in J. Perbal, A Practical Guide to Molecular Cloning, John Wiley and Sons (1984), J. Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbour Laboratory Press (1989), TA Brown (editor), Essential Molecular Biology: A Practical Approach, Vol. 1 and 2, IRL Press (1991), DMGlover and BDHames (editors), DNA Cloning: A Practical Approach, Vols. 1-4, IRL Press (1995 and 1996), and FMAusubel et al. (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience (1988, including all updates to date), Ed Harlow and David Lane (editors), Antibodies: A Laboratory Manual, Cold Spring Harbour Laboratory, (1988), and JEColigan et al. (editors), Current This is described and explained through literature in sources such as Protocols in Immunology, John Wiley & Sons (including all updates to date).

[0044] Those skilled in the art will know that an "antibody" is generally composed of multiple polypeptide chains, for example, V L polypeptides and V HIt will be recognized that antibodies are thought to be proteins containing a variable region consisting of polypeptides containing [specific components]. Antibodies also generally contain constant domains, some of which can be located in the constant region or in constant fragments or crystallizable fragments (Fc). H and V L These interact to form an Fv containing an antigen-binding region that specifically binds to one or more closely related antigens. Generally, the light chain from mammals is either a κ light chain or a λ light chain, and the heavy chain from mammals is α, δ, ε, γ, or μ. Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. The term “antibody” also encompasses humanized antibodies, primate-derived antibodies, human antibodies, and chimeric antibodies.

[0045] The terms "full-length antibody," "intact antibody," or "whole antibody" are used synonymously to refer to an antibody in a substantially intact form, as opposed to an antigen-binding fragment of an antibody. Specifically, whole antibodies include those having heavy and light chains containing an Fc region. The constant domain may be a wild-type sequence constant domain (e.g., a human wild-type sequence constant domain) or an amino acid sequence variant thereof.

[0046] An antibody "antigen-binding fragment" contains one or more variable regions of an intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2 and Fv fragments (scFv, di-scFv, tri-scFv), diabodies, linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0047] The term “complementarity-determining region” (synonyms, CDR, i.e., CDR1, CDR2, and CDR3) is used in the context of this disclosure to refer to amino acid residues in antibody variable regions whose presence is a major contributor to specific antigen binding. Each variable region typically has three CDR regions, identified as CDR1, CDR2, and CDR3. In one example, the amino acid positions assigned to CDRs and FRs are defined according to Kabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991 (also referred to herein as the “Kabat numbering system”).

[0048] As used herein, “variable region” refers to a portion of the light and / or heavy chain of an antibody, as defined herein, that specifically binds to an antigen and includes, for example, the amino acid sequences of CDRs, i.e., CDR1, CDR2, and CDR3, as well as framework regions (FRs). For example, a variable region may include three or four FRs (e.g., FR1, FR2, FR3, and optionally FR4) along with three CDRs. H This refers to the variable region of the heavy chain. L This refers to the variable region of the light chain.

[0049] For example, the amino acid positions assigned to CDR and FR are defined according to Kabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991 (also referred to herein as the “Kabat numbering system” or “Kabat”).

[0050] Other conventions, including corrective or alternative numbering systems for variable domains, include IMGT (Lefranc, et al. (2003), Dev Comp Immunol 27:55-77), Chothia (Chothia C, Lesk AM (1987), J Mal Biol 196:901-917; Chothia, et al. (1989), Nature 342:877-883), and AHo (Honegger A, Pluckthun A (2001), J Mol Biol 309:657-670). For convenience, examples of binding proteins in this disclosure may also be labeled according to IMGT.

[0051] The term "antibody heavy chain" is used herein to refer to the larger of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. Where used herein, "antibody light chain" refers to the smaller of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. κ-light chains and λ-light chains refer to the two main antibody light chain isotypes.

[0052] As used herein, the term “binding” with respect to the interaction between an antibody or its antigen-binding fragment and an antigen means that the interaction depends on the presence of a specific structure on the antigen (e.g., an antigenic determinant or epitope). For example, antibodies generally recognize and bind to specific protein structures, rather than proteins themselves. If an antibody binds to epitope “A”, the presence of a molecule containing epitope “A” (or free, unlabeled “A”) will reduce the amount of labeled “A” that binds to the antibody in a reaction involving labeled “A” and the antibody.

[0053] As used herein, the term “specifically binds” shall be interpreted to mean that the binding interaction between an antibody or its antigen-binding fragment and the kappa myeloma antigen depends on the presence of the antigenic determinant or epitope of the kappa myeloma antigen to which the antibody or its antigen-binding fragment binds. Thus, the antibody or its antigen-binding fragment preferentially binds to or recognizes the kappa myeloma antigenic determinant or epitope, even if it is present in a mixture of other molecules or organisms. For example, the antibody or its antigen-binding fragment reacts or associates with the kappa myeloma antigen or cells expressing the same more frequently and rapidly, for a longer duration and / or with higher affinity, compared to alternative antigens or cells. Furthermore, by reading this definition, it will be understood that, for example, an antibody or its antigen-binding fragment that specifically binds to the kappa myeloma antigen may or may not specifically bind to a second antigen. Thus, “specific binding” does not necessarily require exclusive or undetectable binding to another antigen. The term “specifically binds” may be used interchangeably with “selectively bind” herein. In general, references to bonding in this specification should be understood as meaning specific bonding, and each term should be understood as providing explicit support for the other terms.

[0054] Methods for determining specific binding will be apparent to those skilled in the art. In one example, the anti-KMA antibody according to this disclosure is brought into contact with kappa myeloma antigen or cells expressing it, or its variant or surrogate antigen. The binding of the antibody to the kappa myeloma antigen or variant or surrogate antigen is then determined, and it is considered that the antibody that binds to the kappa myeloma antigen, rather than the variant or surrogate antigen, as described above, specifically binds to the kappa myeloma antigen.

[0055] The term “antigen sink” is used in the context of this disclosure to describe monoclonal antibodies that bind to unintended targets (e.g., healthy cells), where these unintended targets “absorb” the antibody and act as a sink, thus preventing the antibody from reaching its intended tumor antigen target in vivo.

[0056] In the context of this disclosure, the term "combination drug regimen" is used to refer to a combination of therapeutic drugs administered to a subject in accordance with the drug regimens disclosed herein.

[0057] As used herein, the terms “subject” or “patient” may be used interchangeably and shall be interpreted as meaning any animal, including, for example, a human or a mammal. Examples of subjects include, but are not limited to, humans and non-human primates. For example, the subject is a human.

[0058] In the context of this disclosure, the term "therapeutic drug" is used to refer to a treatment, therapy, or drug.

[0059] Those skilled in the art will understand that the therapeutic agents disclosed herein are generally administered in stages. For example, “treatment stages” refer to periods used to rapidly control multiple myeloma and alleviate its symptoms. In certain cases, an induction stage precedes the treatment stage.

[0060] As used herein, the term “introduction phase” refers to the period prior to the commencement of the treatment phase.

[0061] In certain cases, a maintenance phase follows the treatment phase. As used herein, the term “maintenance phase” is used to refer to the period during which therapeutic drugs are continued to inhibit, or in certain cases, to prevent, relapse of multiple myeloma.

[0062] As used herein, the terms “once daily” or “daily” in the context of medication refer to the total dose of the drug (e.g., lenalidomide) administered to the subject per day. The dose may be divided into two or more doses per day, or it may be given as a single dose per day. For example, the total dose may be 25 mg administered daily as a single dose.

[0063] As used herein, the terms “once a week,” “weekly,” or “at least one week” in the context of medication refer to approximate numbers and may include every 7 ± 2 days, i.e., every 5 to 9 days. A “once a week” medication frequency may be every 5 days, every 6 days, every 7 days, every 8 days, or every 9 days.

[0064] As used herein, the terms “once a month,” “monthly,” or “at least every four weeks” in the context of medication refer to an approximate number and may include every 28 days ± 1 week, i.e., every 21 to 35 days. A “once a month” medication frequency may be every 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days.

[0065] The terms “carrier” and “excipient” refer to compositions of substances conventionally used in the art to preserve, administer, and / or enhance the biological activity of an active compound (see, for example, Remington's Pharmaceutical Sciences, 16th Ed., Mac Publishing Company (1980)). Carriers may also reduce any undesirable side effects of the active compound. A suitable carrier is, for example, stable and, for example, incapable of reacting with other components in the carrier. In one example, the carrier does not cause significant local or systemic adverse effects in the recipient at doses and concentrations used therapeutically.

[0066] Suitable carriers for this disclosure include those that have been conventionally used, such as water, physiological saline, dextrose aqueous solution, lactose, Ringer's solution, buffer solution, hyaluronan, and glycol, which are exemplary liquid carriers, particularly for solutions (in the case of isotonic solutions). Suitable pharmaceutical carriers and excipients include starch, cellulose, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, glycerol, propylene glycol, water, and ethanol.

[0067] In the context of this disclosure, the term "analyte" is used to refer to molecules whose presence in a sample provides a quantitative or qualitative measure of gene expression. Exemplary analytes that indicate gene expression levels include RNA and proteins. Various methods for determining RNA and protein levels are known in the art. Exemplary methods include whole-genome sequencing, next-generation sequencing, NanoString technology, droplet digital PCR, quantitative RT-PCR, mass spectrometry, immunohistochemistry, and multiplex immunoassays. In one example, the analyte is a cytokine measured using a multiplex immunoassay (e.g., Bio-Plex Pro Human Cytokine Assay, Bio-Rad).

[0068] As used herein and in the appended claims, the singular and plural terms, for example, “a,” “an,” and “the,” optionally include multiple subjects unless otherwise explicitly indicated.

[0069] As used herein, the term “about” means ±10%, preferably ±5%, and more preferably ±1% of the specified value, unless otherwise stated.

[0070] The term "and / or," for example, "X and / or Y," is understood to mean "X and Y" or "X or Y," and is considered to provide explicit support for both meanings or either of them.

[0071] Throughout this specification, the word “comprise,” or variations such as “comprises” or “comprising,” will be understood to mean that they include the elements, integers, or steps, or groups of elements, integers, or steps, that are described, but not that they exclude any other elements, integers, or steps, or groups of elements, integers, or steps.

[0072] Combination medication regimens Treatment drugs In the context of this disclosure, the term "anti-KMA antibody" is used to refer to an antibody that binds to or specifically binds to kappa myeloma antigen (KMA). KMA is a membrane-bound light chain that is selective for kappa myeloma cells (Boux, HA. et al. (1983) J Exp Med. 158:1769). KMA is a unique cell surface antigen that is expressed on malignant plasma cells of kappa-limited multiple myeloma (κMM), ​​several lymphomas, and occasionally on amygdala B cells and in vitro activated B cells, but not on normal B cells of the bone marrow.

[0073] In one example, an anti-KMA antibody can bind to KMA-carrying cells. In another example, an anti-KMA antibody can kill KMA-carrying cells. For example, the anti-KMA antibody according to this disclosure can bind to and kill KMA-carrying malignant plasma cells. In one example, the anti-KMA antibody according to this disclosure does not bind to intact immunoglobulins. In other words, the exemplary anti-KMA antibody does not recognize the kappa light chain associated with the Ig heavy chain on intact Ig molecules, etc.

[0074] For example, the anti-KMA antibody of this disclosure does not bind to the kappa light chain associated with the heavy chain. For instance, the anti-KMA antibody does not bind to the kappa light chain of an antibody that also includes a heavy chain.

[0075] For example, an anti-KMA antibody may be the “K121 antibody” disclosed in Hutchinson et al. 2011, or a variant thereof, an antigen-binding fragment, or a humanized form. An exemplary humanized form is referred to and used synonymously in the context of this disclosure as “kappaMab” or “KM,” and is an antibody having a heavy chain variable region (VH) containing the amino acid sequence described in SEQ ID NO: 1 and a light chain variable region (VL) containing the amino acid sequence described in SEQ ID NO: 2. Therefore, in one example, an anti-KMA antibody is KM.

[0076] In another example, an anti-KMA antibody binds to or specifically binds to an epitope of KMA that is specifically bound by KM, or binds to or specifically binds to an epitope of KMA that competes with KM for binding to KMA, wherein KM has VH containing the amino acid sequence described in SEQ ID NO: 1 and VL containing the amino acid sequence described in SEQ ID NO: 2.

[0077] KM binds to an epitope of KMA located in the switch region of the kappa light chain (SEQ ID NO: 3). Amino acid substitutions in the epitope can increase the binding affinity of KM (Hutchinson et al. 2011). Therefore, in one example, an anti-KMA antibody according to this disclosure binds to or competes with antibodies that specifically bind to the region containing the amino acid sequence shown in SEQ ID NO: 3, which has at least one, at least two, or at least three amino acid substitutions.

[0078] In another example, the anti-KMA antibody according to this disclosure competes with antibodies that bind to or specifically bind to an epitope containing the amino acid sequence shown in SEQ ID NO: 4, which has at least one, at least two, or at least three amino acid substitutions. Exemplary substitutions include conserved amino acid substitutions, such as those listed below in Table 1. In one example, aspartic acid (Asp(D)) in SEQ ID NO: 4 is substituted with glutamic acid (Glu(E)) (SEQ ID NO: 5). Thus, in one example, the anti-KMA antibody according to this disclosure competes with antibodies that bind to or specifically bind to an epitope containing the amino acid sequence shown in SEQ ID NO: 5. [Table 1]

[0079] In another example, the anti-KMA antibody according to this disclosure competes with antibodies that bind to or specifically bind to an epitope containing the amino acid sequence shown in SEQ ID NO: 4.

[0080] Antibodies may be identified by their ability to compete for binding to KMA or its region or epitope using various methods known in the art. For example, antibody binding to KMA on kappa human myeloma cell lines (κHMCL) such as KMS-11, KMS-26, and JJN3 can be evaluated (Asvadi et al. 2015). In this procedure, anti-KMA antibodies such as KM are conjugated with biotin using an established procedure (Hofmann K, et al. (1982) Biochemistry 21:978-84). The antibodies are then evaluated by their ability to compete for binding of biotinylated KM antibodies to KMA on κHMCL cells. Binding of biotinylated KM to κHMCL cells may be evaluated by the addition of fluorescein-labeled streptavidin, which will bind to biotin on the labeled antibody. Next, the fluorescent staining of cells was quantified by flow cytometry, and the competitive effect of the expressed antibody was determined as the percentage of fluorescence levels obtained in the absence of competitors.

[0081] In another example, the anti-KMA antibody has a VH containing a CDR as shown in SEQ ID NOs. 6, 7, and 8, and a VL. In yet another example, the anti-KMA antibody has a VH containing a CDR as shown in SEQ ID NOs. 9, 10, and 11, and a VL. In yet another example, the anti-KMA antibody has a VH containing a CDR as shown in SEQ ID NOs. 6, 7, and 8, and a VL containing a CDR as shown in SEQ ID NOs. 9, 10, and 11.

[0082] In another example, the anti-KMA antibody has a VH containing a CDR as shown in SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 1. In yet another example, the anti-KMA antibody has a VL containing a CDR as shown in SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, and an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 2. In yet another example, the anti-KMA antibody has a VH containing a CDR as shown in SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 1, and a VL containing a CDR as shown in SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, and an amino acid sequence that is at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 2.

[0083] In another example, the anti-KMA antibody has VH containing the amino acid sequence shown in SEQ ID NO: 1 and VL containing the amino acid sequence shown in SEQ ID NO: 2.

[0084] In another example, the anti-KMA antibody has a CDR shown in SEQ ID NO: 1 and SEQ ID NO: 2, and the CDR is assigned using the Kabat numbering system. In yet another example, the anti-KMA antibody has a CDR shown in SEQ ID NO: 1 and SEQ ID NO: 2, and the CDR is assigned using the IMGT numbering system. In yet another example, the anti-KMA antibody has a CDR shown in SEQ ID NO: 1 and SEQ ID NO: 2, and the CDR is assigned using the Kabat EU numbering system.

[0085] In one example, the anti-KMA antibody is a naked antibody. In other examples, the anti-KMA antibody is a full-length antibody, an intact antibody, or a whole antibody. In one example, the anti-KMA antibody is monospecific.

[0086] In another example, an anti-KMA antibody is an antigen-binding fragment containing a CDR, as shown in SEQ ID NOs. 6, 7, 8, 9, 10, and 11.

[0087] In another example, the anti-KMA antibody comprises VH, which contains the amino acid sequence shown in SEQ ID NO: 12 or a humanized variant thereof, and VL, which contains the amino acid sequence shown in SEQ ID NO: 13 or a humanized variant thereof.

[0088] In another example, the anti-KMA antibody has a CDR or a humanized variant shown in SEQ ID NO: 12 and SEQ ID NO: 13, and the CDR is assigned using the Kabat numbering system. In yet another example, the anti-KMA antibody has a CDR or a humanized variant shown in SEQ ID NO: 12 and SEQ ID NO: 13, and the CDR is assigned using the IMGT numbering system. In yet another example, the anti-KMA antibody has a CDR or a humanized variant shown in SEQ ID NO: 12 and SEQ ID NO: 13, and the CDR is assigned using the Kabat EU numbering system.

[0089] In the context of this disclosure, the terms “immunomodulatory agent” or “IMiD” are used to refer to molecules that have multitropic effects, including direct induction of apoptosis in malignant tumor cells, interference with tumor-bone marrow stromal cell interactions, and increased antitumor immune responses.

[0090] In one example, IMiD is selected from the group consisting of lenalidomide, pomalidomide, and thalidomide.

[0091] For example, IMiD could be lenalidomide. In one example, IMiD could be pomalidomide. In another example, IMiD could be thalidomide.

[0092] The terms “CRBN E3 ligase modifier” or “CELMoD” are used in the context of this disclosure to refer to IMiD derivatives. For example, CELMoD is selected from the group consisting of CC-122, CC-220 (iverdimide), CC-90009, CC-92480, MDEG-541, and CC-886. This list is non-exclusive, and various other IMiDs and CELMoDs are known in the art (see, for example, the review by Holstein et al. 2018, incorporated herein by reference).

[0093] For example, CELMoD could be CC-122. In one example, CELMoD could be CC-220 (iverdmid). In another example, CELMoD could be CC-90009. In yet another example, CELMoD could be CC-92480. In yet another example, CELMoD could be MDEG-541. In yet another example, CELMoD could be CC-886.

[0094] The terms “steroid” or “corticosteroid” are used in the context of this disclosure to refer to a class of steroid hormones that are produced in the adrenal cortex or are produced synthetically, such as dexamethasone and prednisone (also referred to herein as prednisolone). For example, a steroid may be dexamethasone. In another example, a steroid may be prednisone.

[0095] Medication regimen The inventors have surprisingly shown that anti-KMA antibodies, such as KappaMab, are unexpectedly well-tolerated when administered in combination with lenalidomide and dexamethasone, with a favorable safety profile, suggesting that the dose of the anti-KMA antibody can be safely increased (e.g., to at least 30 mg / kg or more). Such combinations used in drug regimens may be particularly advantageous considering one or more of the following: increased therapeutic efficacy, improved outcomes, and a favorable safety profile.

[0096] For example, a favorable safety profile is determined based on the number or severity of reported adverse events, using the Common Terminology Criteria for Adverse Events v3.0 (CTCAE). For instance, an adverse event may be any undesirable and unintended event, symptom, or disease that is temporally related to the combination drug regimen.

[0097] In one example, adverse events may be hematological or non-hematological. In one example, hematological adverse events may be anemia, thrombocytopenia, lymphopenia, neutropenia, febrile neutropenia, or leukopenia. In one example, non-hematological adverse events may be rash, hyperglycemia, malaise, abdominal pain, constipation, diarrhea, nausea, hypophosphatemia, infusion-related reactions, peripheral neuropathy, insomnia, seizures, pain, URTI, pneumonia, and cellulitis. In one example, adverse events may be graded according to severity on a scale of 1 to 4.

[0098] In one example, a favorable safety profile is determined based on the evaluation of the subject's immune cells after treatment according to this disclosure. In one example, the subject's immune cells are evaluated using a blood analysis test such as whole blood count (CBC). CBC measures immune cell parameters such as red blood cells (e.g., hemoglobin and hematocrit), white blood cells (e.g., neutrophils), and platelets from a blood sample from the subject.

[0099] For example, subjects are evaluated after administration of 4 to 8 doses of the anti-KMA antibody of this disclosure. In one example, subjects are evaluated before the treatment phase (i.e., before administration of the anti-KMA antibody). In another example, subjects may be evaluated after 4 to 8 weeks of treatment. In yet another example, the subject's immune cells are compared to the subject's immune cells at baseline (i.e., before administration of the anti-KMA antibody). In one example, the subject's immune cells are monitored over time, and a favorable safety profile is characterized by no significant changes in the monitored cell(s). For example, the subject's immune cells can be monitored over time, and a favorable safety profile is characterized by no significant changes in the subject's immune cells. In one example, a favorable safety profile is characterized by no changes in the subject's immune cells after administration of 4 doses of an anti-KMA antibody such as KM. In another example, a favorable safety profile is characterized by no changes in the subject's immune cells after administration of 8 doses of an anti-KMA antibody such as KM. For example, immune cells include one or more or all of the following: red blood cells (e.g., hemoglobin and hematocrit), white blood cells (e.g., neutrophils), and platelets.

[0100] For example, hemoglobin can be used as a parameter to diagnose anemia. For instance, mild anemia can be diagnosed as a hemoglobin level ranging from 10 g / dL to the lower limit of normal, according to the National Cancer Institute (NCI) criteria. For example, moderate anemia can be diagnosed as a hemoglobin level of 10–8 g / dL, according to the NCI criteria. For example, severe anemia can be diagnosed as a hemoglobin level of 7.9–6.5 g / dL, according to the NCI criteria. For example, life-threatening anemia can be diagnosed as a hemoglobin level of less than 6.5 g / dL, according to the NCI criteria.

[0101] For example, grade 1 anemia can be diagnosed as a hemoglobin level of within the institutional lower limit of normal (LLN) to less than 10 g / dL, LLN to less than 6.2 mmol / L, LLN to less than approximately 100 g / L of 10 g / dL under the CTCAE grading. In one example, grade 2 anemia can be diagnosed as a hemoglobin level of less than 10.0 to 8.0 g / dL, less than 6.2 to 4.9 mmol / L, less than 100 to 80 g / L under the CTCAE grading. In one example, grade 3 anemia can be diagnosed as a hemoglobin level of less than 8.0 g / dL, less than 4.9 mmol / L, less than 80 g / L under the CTCAE grading.

[0102] In one example, thrombocytopenia can be diagnosed using the platelet count as a parameter. For example, grade 1 thrombocytopenia can be diagnosed as a platelet count of less than 75 to 100 × 10 9 / L. In one example, grade 2 thrombocytopenia can be diagnosed as a platelet count of less than 50 to 75 × 10 9 / L. In one example, grade 3 thrombocytopenia can be diagnosed as a platelet count of less than 25 to 50 × 10 9 / L. In one example, grade 4 thrombocytopenia can be diagnosed as a platelet count of less than 25 × 10 9 / L. It will be understood that the platelet thresholds are based on thresholds clinically relevant to chemotherapy and grades 2 - 4 of CTCAE V5.0.

[0103] In one example, neutropenia can be diagnosed using the absolute neutrophil count as a parameter. For example, grade 1 neutropenia can be diagnosed as an absolute neutrophil count (ANC) of approximately 1,500 ANC / μL. In one example, grade 2 neutropenia can be diagnosed as an absolute neutrophil count of 1,500 to 1,000 ANC / μL. In one example, grade 3 neutropenia can be diagnosed as an absolute neutrophil count of 1,000 to 500 ANC / μL. In one example, grade 4 neutropenia can be diagnosed as an absolute neutrophil count of less than 500 ANC / μL.

[0104] In one example, the dose of the anti-KMA antibody disclosed herein is at least 30 mg / kg. In another example, the dose of the anti-KMA antibody is in the range of about 30 mg / kg to about 90 mg / kg. In one example, the dose of the anti-KMA antibody is in the range of 30 mg / kg to 90 mg / kg. In another example, the dose of the anti-KMA antibody is in the range of about 30 mg / kg to about 60 mg / kg. In one example, the dose of the anti-KMA antibody is in the range of 30 mg / kg to 60 mg / kg. In another example, the dose of the anti-KMA antibody is in the range of about 30 mg / kg to about 45 mg / kg. In one example, the dose of the anti-KMA antibody is in the range of 30 mg / kg to 45 mg / kg. In another example, the dose of the anti-KMA antibody is 30 mg / kg. In another example, the dose of the anti-KMA antibody is 45 mg / kg. In another example, the dose of the anti-KMA antibody is 60 mg / kg. In another example, the dose of anti-KMA antibody is 90 mg / kg.

[0105] As will be understood by those skilled in the art, the appropriate dose of IMiD or CELMoD will depend on the IMiD or CELMoD being administered. Exemplary general doses of IMiD or CELMoD range from approximately 5 mg to approximately 300 mg. For example, the dose of IMiD or CELMoD ranges from 5 mg to 300 mg. In one example, the dose of IMiD or CELMoD ranges from approximately 10 mg to approximately 200 mg. For example, the dose of IMiD or CELMoD ranges from 10 mg to 200 mg. In another example, the dose of IMiD or CELMoD is approximately 10 mg. In one example, the dose of IMiD or CELMoD is 10 mg. In another example, the dose of IMiD or CELMoD is approximately 15 mg. In yet another example, the dose of IMiD or CELMoD is approximately 25 mg. In yet another example, the dose of IMiD or CELMoD is 25 mg.

[0106] In one example, the dosage of lenalidomide ranges from approximately 5 mg to approximately 300 mg. For example, the dosage of lenalidomide ranges from approximately 10 mg to approximately 200 mg. For example, the dosage of lenalidomide ranges from approximately 10 mg to approximately 200 mg. In another example, the dosage of lenalidomide ranges from approximately 10 mg to approximately 25 mg. For example, the dosage of lenalidomide ranges from approximately 10 mg to approximately 25 mg. In yet another example, the dosage of lenalidomide is approximately 10 mg. In yet another example, the dosage of lenalidomide is approximately 15 mg. In yet another example, the dosage of lenalidomide is approximately 25 mg. In yet another example, the dosage of lenalidomide is 25 mg.

[0107] Suitable ImiD or CELMoD dosing can also be obtained from prescription information. For example, lenalidomide may be administered at 25 mg to newly diagnosed patients. In one case, lenalidomide may be initially administered at 10 mg and then increased to 15 mg or 25 mg if well tolerated.

[0108] The appropriate dose of a steroid will depend on the steroid being administered. A typical example of a steroid dose is in the range of approximately 5 mg to 300 mg. For example, the steroid dose is in the range of 5 mg to 300 mg. In one example, the steroid dose is in the range of approximately 10 mg to 100 mg. In another example, the steroid dose is in the range of 10 mg to 100 mg. In one example, the steroid dose is in the range of approximately 40 mg to 60 mg. In another example, the steroid dose is in the range of 40 mg to 60 mg. In yet another example, the steroid dose is approximately 40 mg. In one example, the steroid dose is 40 mg. In yet another example, the steroid dose is approximately 60 mg. In one example, the steroid dose is 60 mg. In yet another example, the steroid dose is approximately 25 mg. In one example, the steroid dose is 25 mg.

[0109] In one example, the dose of dexamethasone ranges from approximately 5 mg to approximately 300 mg. In another example, the dose of dexamethasone ranges from 5 mg to 300 mg. In another example, the dose of dexamethasone ranges from approximately 10 mg to approximately 100 mg. In another example, the dose of dexamethasone ranges from 10 mg to 100 mg. In one example, the dose of dexamethasone ranges from approximately 40 mg to approximately 60 mg. In yet another example, the dose of dexamethasone is approximately 40 mg. In yet another example, the dose of dexamethasone is approximately 60 mg. In yet another example, the dose of dexamethasone is approximately 25 mg. In yet another example, the dose of dexamethasone is 25 mg.

[0110] Appropriate steroid dosage can also be obtained from prescription information and modified as needed based on clinical response. For example, dexamethasone can be administered at 40 mg and reduced if specific side effects occur.

[0111] Treatment stage The treatment phases described herein include administering an anti-KMA antibody such as KM, ImiD or CELMoD, and a steroid. In one example, the treatment phase may include administering an anti-KMA antibody about once a week, ImiD or CELMoD about once a day, and a steroid about once a week. In another example, the treatment phase includes administering an anti-KMA antibody once a week (i.e., once a week). In yet another example, the treatment phase includes administering an anti-KMA antibody weekly for at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks. In yet another example, the treatment phase includes administering an anti-KMA antibody weekly for about 8 weeks. In these examples, the weekly administration can be referred to as a therapeutic dose (i.e., a treatment phase). The dose of the anti-KMA antibody may be increased or decreased throughout the treatment phase as needed. For example, the treatment phase may include administering KM once a week.

[0112] In one example, the administration of anti-KMA antibodies may be suspended for a certain period as needed (e.g., when attempting to resolve a serious adverse event or as a result of non-compliance by the subject). In another example, the administration of anti-KMA antibodies may be delayed for a certain period as needed. In yet another example, the administration of anti-KMA antibodies may be reduced for a certain period as needed.

[0113] In one example, the treatment phase may include administration of IMiD or CELMoD once daily (i.e., once every day). In another example, the treatment phase may include administration of IMiD or CELMoD once every two days. In yet another example, the treatment phase may include administration of IMiD or CELMoD once every three days. The dose of IMiD or CELMoD may be increased or decreased throughout the treatment phase as needed. For example, the treatment phase may include administration of lenalidomide once daily.

[0114] In one example, the treatment phase may include the administration of steroids once a week (i.e., every week). In another example, the treatment phase may include the administration of steroids once every two weeks (i.e., every other week). In yet another example, the treatment phase may include the administration of steroids once every three weeks. In yet another example, the treatment phase may include the administration of steroids once every four weeks. The dose of steroids may be increased or decreased throughout the treatment phase as needed. For example, the treatment phase may include the administration of dexamethasone once a week.

[0115] In one example, the duration of the treatment phase is at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks. In another example, the duration of the treatment phase is at least 6 weeks to at least 10 weeks. In yet another example, the duration of the treatment phase is at least 8 weeks.

[0116] Implementation phase In certain cases, the method of the present disclosure includes an induction phase. In one case, the induction phase precedes the treatment phase. In one case, the induction phase precedes the administration of an anti-KMA antibody to the subject. In one case, the induction phase includes the administration of IMiD or CELMoD intended to reduce the proliferation of multiple myeloma cells and improve the response to the anti-KMA antibody. In one case, the induction phase may include the administration of IMiD or CELMoD once daily (i.e., once every day). In another case, the induction phase may include the administration of IMiD or CELMoD once every two days. In yet another case, the induction phase may include the administration of IMiD or CELMoD once every three days. The dose of IMiD or CELMoD may be increased or decreased throughout the induction phase as needed.

[0117] For example, the induction phase may include the administration of IMiD or CELMoD at least one week, two weeks, three weeks, four weeks, or five weeks before the start of the treatment phase. For example, the induction phase may include the administration of IMiD or CELMoD at least one week before the start of the treatment phase.

[0118] In one example, the induction phase may include the administration of steroids to help reduce the proliferation of malignant cells, inhibit cytokine production necessary for the survival of malignant plasma cells, and reduce the activity of nuclear factor kappa B. In one example, the induction phase may include the administration of steroids twice a week. In another example, the induction phase may include the administration of steroids once a week (i.e., every week). In yet another example, the induction phase may include the administration of steroids every two weeks (i.e., every other week). The dose of steroids may be increased or decreased throughout the induction phase as needed.

[0119] In one example, the induction phase may include the administration of steroids at least one week, at least two weeks, at least three weeks, at least four weeks, or at least five weeks before the start of the treatment phase. In another example, the induction phase may include the administration of steroids at least one week before the start of the treatment phase. For example, the induction phase may include the administration of dexamethasone at least one week before the start of the treatment phase.

[0120] For example, the induction phase may include administering IMiD or CELMoD about once a day and steroids about once a week, at least one week before the start of the treatment phase.

[0121] For example, the implementation phase could last at least one week, at least two weeks, at least three weeks, or at least four weeks.

[0122] Maintenance stage In certain examples, the method of this disclosure includes a maintenance phase. In one example, the maintenance phase follows the treatment phase. In one example, the maintenance phase includes administration of an anti-KMA antibody every two weeks (i.e., every other week). In another example, the maintenance phase includes administration of an anti-KMA antibody once a month (i.e., monthly). For example, the maintenance phase includes administration of anti-KMA monthly for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, or at least eight weeks. In these examples, the monthly administration may be referred to as the maintenance dose (i.e., the maintenance phase, also known as the follow-up phase).

[0123] In one example, the maintenance phase may include administration of IMiD or CELMoD once daily (i.e., once every day). In another example, the maintenance phase may include administration of IMiD or CELMoD once every two days. In yet another example, the maintenance phase may include administration of IMiD or CELMoD once every three days. The dose of IMiD or CELMoD may be increased or decreased throughout the maintenance phase as needed. For example, the maintenance phase may include administration of lenalidomide once daily.

[0124] In one example, the administration of IMiD may be suspended for a certain period as needed (for example, when trying to resolve serious adverse events such as cytopenia). In another example, the administration of IMiD may be delayed for a certain period as needed.

[0125] In one example, the maintenance phase may include steroid administration once a week (i.e., weekly). In another example, the maintenance phase may include steroid administration once every two weeks (i.e., every other week). In yet another example, the maintenance phase may include steroid administration once every three weeks. In yet another example, the maintenance phase may include steroid administration once every four weeks. The steroid dose may be increased or decreased throughout the maintenance phase as needed. For example, the maintenance phase may include dexamethasone administration once a week.

[0126] For example, the maintenance phase may include administration of an anti-KMA antibody approximately once a month, IMiD or CELMoD approximately once a day, and steroids approximately once a week.

[0127] In one example, the maintenance phase may last at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, or at least 14 weeks. For example, the maintenance phase may last at least 12 weeks. In another example, the maintenance phase may continue until disease progression (i.e., indefinitely).

[0128] Administration The drug regimens referenced above require administration via various routes. Exemplary routes of administration include intravenous administration as a bolus, continuous infusion over a period of time, or oral administration. Those skilled in the art will understand that the most appropriate route of administration will largely depend on the treatment being administered. For example, anti-KMA antibodies can be administered intravenously.

[0129] In one case, the anti-KMA antibody is administered intravenously via a bolus. In another case, the anti-KMA antibody is administered intravenously via a continuous infusion. In yet another case, the intravenous infusion of the anti-KMA antibody lasts for approximately 1-2 hours.

[0130] In one example, IMiD or CELMoD is administered orally. For example, these treatments may be administered orally via tablets. In another example, steroids are administered intravenously.

[0131] In one example, the anti-KMA antibody, IMiD or CELMoD, and steroid are administered as separate compositions. For example, the anti-KMA antibody, IMiD or CELMoD, and steroid can be administered sequentially. In this example, the administration of the anti-KMA antibody, IMiD or CELMoD, and steroid is carried out over a defined period (usually several hours or several days). In one example, the period between consecutive administrations is used for the administration of a second or third therapeutic agent. The duration of administration can range from several days to several weeks, provided that a sufficient level of the first therapeutic agent is still present at the time of administration to provide or supplement the therapeutic effect of the second or third therapeutic agent.

[0132] In one example, IMiD or CELMoD and steroids are administered via the same route. For example, both IMiD or CELMoD and steroids can be administered orally. In one example, IMiD or CELMoD can be given orally once daily at a dose of approximately 25 mg per day. For example, lenalidomide can be given orally once daily at a dose of approximately 25 mg. In one example, steroids can be given orally once weekly at a dose of approximately 40 mg per day. For example, dexamethasone can be given orally once daily at a dose of approximately 25 mg.

[0133] In one example, administration may be adjusted based on clinical evaluation or, if appropriate, on prescribing information. Exemplary clinical evaluations may include physical examination and assessment of hematological toxicity (e.g., determination of anemia, neutropenia, or thrombocytopenia).

[0134] Treatment methods For example, this disclosure relates to a method for treating multiple myeloma in a subject requiring treatment for multiple myeloma, the method comprising administering to the subject a treatment comprising an anti-KMA antibody, an immunomodulator (IMiD), or a cereblon E3 ligase modulator (CELMoD), and a steroid. For example, the method may include administering the above-described drug regimen.

[0135] As used herein, the terms “to treat,” “to cure,” or “to treat” include administering a therapeutically effective amount of anti-KMA antibody, IMiD, or CELMoD, and steroids to reduce or delay the onset or progression of multiple myeloma, or to reduce or eliminate at least one symptom of multiple myeloma.

[0136] The terms “multiple myeloma,” “myeloma,” or “MM” are used in the context of this disclosure to refer to cancer of plasma cells. In the context of this disclosure, these terms encompass secretory myeloma, non-secretory myeloma, light chain-only myeloma, smoldering myeloma, and related conditions. Exemplary related conditions include plasmacytoma, amyloidosis, and monoclonal gammopathy of undetermined importance.

[0137] In one example, multiple myeloma is a kappa-type myeloma. For example, multiple myeloma expresses KMA. In another example, multiple myeloma expresses kappa light chain. In yet another example, multiple myeloma expresses IgG kappa. In yet another example, multiple myeloma expresses IgA kappa.

[0138] Patients with multiple myeloma can be characterized into various populations. Exemplary populations are described in Rajkumar et al. 2011.

[0139] In one example, the multiple myeloma in the subject can be characterized as a progressive disease (Rajkumar et al. 2011). In other words, the method of this disclosure relates to the treatment of progressive multiple myeloma in the subject. Exemplary indicators of “progressive disease” include an increase of approximately 25% from the lowest response value in any one of the following: serum M component (e.g., an absolute increase of ≥0.5 g / dL) and / or urinary M component (e.g., an absolute increase of ≥200 mg / 24 hours). Other exemplary indicators include the clear development of new bone lesions or soft tissue plasmacytomas, or a clear increase in the size of existing bone lesions or soft tissue plasmacytomas, and the development of hypercalcemia (e.g., corrected serum calcium >11.5 mg / dL) that may be attributable solely to multiple myeloma. In one example, the multiple myeloma in the subject is relapsed and characterized as a progressive disease. In this example, the multiple myeloma in the subject may also be refractory to therapy.

[0140] In another example, the subject has primary refractory myeloma. "Primary refractory myeloma" is used to refer to a disease that does not respond to any therapy, in subjects who have never achieved anything more than a minimal response.

[0141] In another example, the subject has refractory myeloma. The term "refractory myeloma" is used to refer to a disease that does not respond to first-line or salvage therapy, or a disease that progresses within 60 days of the last treatment. In one example, the subject's multiple myeloma is refractory to anticancer therapy. In this context, the term "refractory" is used to refer to a series of anticancer therapies that are no longer therapeutically effective for the subject's multiple myeloma.

[0142] In one example, the multiple myeloma in question has relapsed. The term "relapsed myeloma" is used to refer to previously treated myeloma that has progressed and requires the initiation of salvage therapy, but does not meet the criteria for either "primary refractory myeloma" or "refractory myeloma."

[0143] In one example, a subject treated by the method of this disclosure may be refractory to at least one proteasome inhibitor. For example, the subject may be refractory to bortezomib. A “therapy line” is defined as one or more cycles of a planned treatment program. This may consist of one or more planned cycles of monotherapy or combination therapy, as well as a series of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous stem cell transplantation, followed by maintenance, is considered one therapy line.

[0144] In another example, the subject is refractory to at least two prior lines of therapy. In yet another example, the subject may be refractory to at least three, at least four, at least five, or at least six prior lines of therapy. In this example, at least one line of therapy may be lenalidomide.

[0145] In another example, the subjects have relapsed and refractory myeloma. "Relapsed and refractory myeloma" is used to refer to disease that does not respond to salvage therapy, or disease that progresses within 60 days of the last therapy in subjects who achieved a minimum response (MR) or better at some point before progression in the course of the disease.

[0146] In one example, multiple myeloma treated in accordance with this disclosure is characterized as a stable disease at the time of initial administration. In other words, the subject may be at a plateau stage at the time of initial administration. Exemplary criteria for a stable disease include stabilization of the M protein without further tumor regression despite continued treatment, little to no symptoms from myeloma, and / or no need for blood transfusions (Blade et al. 1998).

[0147] Subjects treated according to the methods of this disclosure have multiple myeloma or related conditions included in this disclosure.

[0148] In one example, a subject treated in accordance with this disclosure has received at least one prior line of therapy for the subject's multiple myeloma. For example, the subject's multiple myeloma may have relapsed. In another example, the subject has received at least two, at least three, at least four, at least five, or at least six prior lines of therapy. In these examples, the subject may have been able to achieve at least a minimal response to the subject's most recent line of therapy (e.g., a reduction of approximately 25% in M ​​protein).

[0149] In another example, the subject has a serum kappa free light chain level of less than approximately 350 mg / ml. In yet another example, the subject has a serum kappa free light chain level of less than approximately 300 mg / ml. In yet another example, the subject has a serum kappa free light chain level of less than approximately 275 mg / ml. In yet another example, the subject has a serum kappa free light chain level of less than approximately 250 mg / ml.

[0150] In another example, the method of the present disclosure also relates to the treatment of multiple myeloma in subjects having high serum cytokine levels. For example, the method of the present disclosure relates to the treatment of multiple myeloma in a subject and comprises selecting a subject having high serum levels of one or more of the following factors compared to control serum levels: hepatocyte growth factor (HGF), macrophage inhibitor (MIF), CCL27, G-CSF, CXCL9, and CXCL10, and administering an anti-KMA antibody to the subject. In one embodiment of the examples of the present, the serum analyte levels described herein are determined by immunoassay.

[0151] In one example, the high serum level of HGF is above approximately 0.5 ng / ml. In another example, the high serum level of HGF is above approximately 0.6 ng / ml, 0.7 ng / ml, 0.8 ng / ml, 0.9 ng / ml, 1.0 ng / ml, 1.1 ng / ml, 1.2 ng / ml, 1.3 ng / ml, 1.4 ng / ml, or 1.5 ng / ml. In yet another example, the high serum level of HGF is at least approximately 1.6 ng / ml. In yet another example, the high serum level of HGF is at least 1.6 ng / ml.

[0152] In another example, elevated serum levels of MIF exceed approximately 5000 pg / ml. In yet another example, elevated serum levels of MIF exceed approximately 5200 pg / ml, 5400 pg / ml, 5600 pg / ml, 5800 pg / ml, 6000 pg / ml, 6200 pg / ml, 6400 pg / ml, 6600 pg / ml, 6800 pg / ml, or 7200 pg / ml. In one example, elevated serum levels of MIF exceed 5000 pg / ml.

[0153] In another example, elevated serum levels of CCL27 exceed approximately 500 pg / ml. In yet another example, elevated serum levels of CCL27 exceed approximately 600 pg / ml, 700 pg / ml, 800 pg / ml, 900 pg / ml, 1000 pg / ml, 1100 pg / ml, 1200 pg / ml, 1300 pg / ml, 1400 pg / ml, or 1500 pg / ml. In one example, elevated serum levels of CCL27 exceed 500 pg / ml.

[0154] In another example, elevated serum levels of G-CSF exceed approximately 55 pg / ml. In yet another example, elevated serum levels of G-CSF exceed approximately 65 pg / ml, 75 pg / ml, 85 pg / ml, 95 pg / ml, 105 pg / ml, 115 pg / ml, 125 pg / ml, 135 pg / ml, 145 pg / ml, or 155 pg / ml. In one example, elevated serum levels of G-CSF exceed 55 pg / ml.

[0155] In another example, elevated serum levels of CXCL9 exceed approximately 550 pg / ml. In yet another example, elevated serum levels of CXCL9 exceed approximately 600 pg / ml, 650 pg / ml, 700 pg / ml, 750 pg / ml, 800 pg / ml, 850 pg / ml, 900 pg / ml, 950 pg / ml, 1000 pg / ml, or 1050 pg / ml. In one example, elevated serum levels of CXCL9 exceed 550 pg / ml.

[0156] In another example, elevated serum levels of CXCL10 exceed approximately 850 pg / ml. In yet another example, elevated serum levels of CXCL10 exceed approximately 900 pg / ml, 950 pg / ml, 1000 pg / ml, 1050 pg / ml, 1100 pg / ml, 1150 pg / ml, 1200 pg / ml, 1250 pg / ml, 1300 pg / ml, or 1350 pg / ml. In yet another example, elevated serum levels of CXCL10 exceed 850 pg / ml.

[0157] High serum cytokine levels are determined in samples obtained from the subjects.

[0158] Additional steps In another example, the methods of the present disclosure further include administering or treating one or more additional agents, such as anticancer agents, proteasome inhibitors, or autologous stem cell transplantation. Exemplary anticancer agents include histone deacetylase inhibitors such as panobinostat or vorinostat, antibodies such as elotuzumab, daratumumab, and isatuximab, or anti-PD1 antibodies such as pembrolizumab, nivolumab, and atezolizumab. Exemplary proteasome inhibitors include marizomib, oprozomib, epixomicin, salinosporamide A, carfilzomib, ixazomib, and bortezomib. Autologous stem cell transplantation involves using healthy hematopoietic stem cells from the subject's body to replace diseased or damaged bone marrow.

[0159] In one example, at least one additional drug may be administered. For example, bortezomib may be administered. In other examples, at least two, at least three, at least four, at least five, or at least six additional drugs may be administered.

[0160] kit The combination drug regimens disclosed herein may be provided in kits or packs. For example, the combinations of treatments disclosed herein may be packaged in a suitable container with written instructions for treating the above-mentioned conditions (e.g., multiple myeloma).

[0161] For example, the anti-KMA antibody may be provided in single or multi-dose quantities. For instance, the anti-KMA antibody may be provided in a single-dose container such as a vial. For example, the anti-KMA antibody may be provided in multiple single-dose containers sufficient for at least eight weeks of treatment. For instance, a kit or pack may contain at least eight vials of pre-prepared KM.

[0162] For example, IMiD or CELMoD may be provided in single or multi-dose quantities. For instance, IMiD or CELMoD may be provided in single-dose containers, such as pre-packaged tablets. For example, IMiD or CELMoD may be provided in multiple single-dose containers sufficient for at least eight weeks of treatment. For instance, a kit or pack may contain at least 60 pre-packaged tablets of lenalidomide.

[0163] In one example, the steroid may be provided in single-dose or multi-dose quantities. For example, the steroid may be provided in a single-dose container, such as a pre-packaged tablet. In one example, the steroid may be provided in multiple single-dose containers sufficient for at least eight weeks of treatment. For example, a kit or pack may contain at least eight pre-packaged tablets of dexamethasone.

[0164] This disclosure includes the following non-limiting embodiments. [Examples]

[0165] Example 1 - Materials and Method Initial clinical trial plan Initial clinical trials were conducted to investigate four dose levels of KMA (0.3 mg / kg, 1.0 mg / kg, 3.0 mg / kg, and 10 mg / kg). Assay data were collected up to day 45 for patients in these dose groups, demonstrating that KMA could be detected at least up to day 15, even at low doses. These initial data suggest that anti-KMA antibodies are not subject to the phenomenon known as antigen sinking, and consequently, anti-KMA antibodies are likely to expose KMA cells without requiring higher dose levels. Therefore, combined with the known potential for monoclonal antibody-induced immunotoxicity at higher doses, anti-KMA antibodies were considered candidates for lower dosing. Accordingly, the Phase IIb trial described below was designed based on these low doses.

[0166] research design A phase IIb multicenter, open-label, sequential cohort study evaluating kappamab (KM) monotherapy (KM, stage 1) followed by kappamab in combination with lenalidomide (LEN) and dexamethasone (DEX) (KM-Rd, stage 2) in relapsed / refractory multiple myeloma (κRRMM). The primary selection criteria for both stages were advanced kappa-restricted multiple myeloma (κMM) (International Myeloma Working Group (IMWG) criteria, according to Kumar et al. 2016), 1–3 prior therapy lines, and no prior exposure to LEN.

[0167] Study stage, medication and discontinuation criteria Recruitment was planned for a total of 60 patients, with the initial intention of treating 30 patients per stage. In Stage 1, patients received KM (10 mg / kg intravenous (IV) infusion) weekly for 8 weeks, followed by maintenance every 4 weeks. In Stage 2, KM dosing followed Stage 1, but separately from Cycle 1 (28-day cycles from Cycle 2 onwards), with the addition of 25 mg of LEN on days 1-21 of each 28-day cycle and 40 mg of DEX weekly, as patients started LEN for 21 days and DEX one week before starting KM (Figure 1). All patients received antiviral medication, thromboembolic prophylaxis, and osteolytic prophylaxis in accordance with institutional practice. Treatment continued until unacceptable toxicity, progression, death, or withdrawal of consent. Response rates and any adverse events (AEs) were regularly assessed.

[0168] Combined KM-Rd cohort compared to matched controls (Rd-MRDR) The overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) of the KM-Rd cohort were compared to a concurrent control group of κMM patients who had received Rd for RRMM (Rd-MRDR group) and were matched for age, sex, and prior therapy lines, identified through the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) (www.mrdr.net.au / ) (Table 3). Patients also had similar combinations of prior therapy type, number of prior lines, and cytogenetic risk. The KM-Rd group had a higher proportion of patients with a baseline ISS stage 2 diagnosis (55%) compared to the MRDR cohort (45%) and the KM cohort (22%). Both the KM-Rd and MRDR cohorts had 26% of patients with baseline ISS stage 3, while the KM cohort had 33% of patients with baseline ISS stage 3. A limitation of this Rd-MRDR dataset was that patient disease status was recorded only every four months; however, an advantage of this dataset was that OS was regularly cross-referenced with the Australian Institutes of Health and Welfare National Death Index (www.aihw.gov.au / about-our-data / our-data-collections / national-death-index). Importantly, both the KM-Rd cohort and Rd MRDR controls were treated within the same period with similar supportive care and access to both reimbursed pomalidomide and carfilzomib, but not with either CD38-targeted immunotherapy or BCMA-targeted immunotherapy.

[0169] Research endpoints The primary endpoint for both Stage 1 and Stage 2 was the clinical benefit rate (CBR). The primary and secondary endpoints are summarized in Table 2. Patients were assessed every 28 days for both OS and PFS during the trial. Comparisons of CBR, ORR, OS, and PFS between the KM-Rd and Rd-MRDR groups were made after data cutoff. Assessment of duration of response (DoR) and time to next treatment (TTNT) was performed only in the KM-Rd group; DoR and TTNT data were not available in the Rd-MRDR group. [Table 2]

[0170] Statistical approach The chi-squared test was used to compare demographic and baseline characteristics between the KM-Rd cohort and Rd-MRDR controls. CBR and ORR were estimated as simple percentages, and 95% confidence intervals (CIs) were calculated as specified in the protocol using the pbeta and qbeta functions in R version 4. Each descriptive analysis of the time-to-event endpoints (DoR, TTNT, OS, and PFS) at each stage used the Kaplan-Meier (positive limit) method to estimate the survival function, and conventional 95% confidence intervals (CIs) for median survival, DoR, TTNT, OS, and PFS were calculated using the Brookmeyer and Crowley method. The median of potential follow-up was estimated by inverting the censoring index in the Kaplan-Meier analysis. TTNT and competing mortality risks before switching to another therapy were investigated by calculating the cumulative occurrence function using the cmprsk library (versions 2.2-11) in R version 4. Comparisons of the time-to-event endpoint between the KM cohort and the KM-Rd cohort, and between the KM-Rd cohort and the Rd-MRDR control, were performed using log-rank tests and summarized as hazard ratios with 95% confidence intervals calculated using Cox proportional hazards regression models. These analyses were performed using SPSS v27 and Stata 16.1. Two-sided p-values ​​< 0.05 were taken to demonstrate statistical significance.

[0171] Example 2 - Clinical Evaluation Kappamab dose cohort Of the planned 60 patients, 59 were enrolled between November 2016 and July 2019. Demographic and baseline characteristics of Stage 1, Stage 2, and Rd-MRDR patients are described in Table 3. Recruitment for Stage 1 (KM cohort) was terminated early because the first PoC criterion was not met and the posterior predicted probability calculation of CBR indicated a low probability of PoC being declared (n=19). Recruitment for Stage 2 (KM-Rd cohort) was expanded to 30 to 40 patients. [Table 3]

[0172] At the study termination date, two patients (5%) in Stage 2 remained in the study. In the other patients, the reasons for discontinuation were disease progression (Stage 1 = 16 / 19 [84%], Stage 2 = 31 / 40 [70%]), withdrawal of consent unrelated to KM toxicity (Stage 1 = 3 / 19 [16%], Stage 2 = 4 / 40 [10%]), and toxicity due to LEN administration (Stage 2 = 3 / 40 [7.5%]). In Stage 2, two patients (5%) died during the study from causes deemed unrelated to the investigational drug by the principal investigator (pneumonia, n=1; unknown cause, n=1).

[0173] Primary and secondary endpoints for Stage 1 and Stage 2 The CBRs for Stage 1 and Stage 2 were 5% (95% CI: 0.5-21.1%) [1 / 19, PR=1] and 93% (95% CI: 79.9-97.3%) [37 / 40, CR=3 / 37 (8.1%), VGPR=11 / 37 (29.7%), PR=19 / 37 (51.4%), MR=4 / 37 (10.8%), respectively, and the ORRs were 5% [1 / 19] and 83% (95% CI: 67.7-91.1%) [33 / 40], respectively. The median PFS for Stage 1 and Stage 2 was 2.0 months (95% CI: 0.0–4.7 months) and 12.7 months (95% CI: 6.6–18.8 months), respectively (HR 0.25, 95% CI 0.13–0.47, p<0.001), and the median OS was not reached in either stage. The median DoR and TTNT for Stage 2 were 12.9 months (95% CI: 6.2–19.6 months) (Figure 2) and 21.9 months (95% CI: 12.6–28.3 months), respectively. Furthermore, at 12 and 24 months in Stage 2, the cumulative incidence of switching to another treatment was 27.5% (95% CI 13.5–43.5%) and 55.1% (95% CI 35.3–71.1%), respectively, while the cumulative incidence of death before switching to another treatment remained at 8.8% (95% CI 2.2–21.6%) between 7.4 and 30.7 months (Figure 3).

[0174] Comparison of Stage 2 KM-Rd cohort and Rd-MRDR cohort Of the 77 patients in the Rd-MRDR cohort, 51 (66%) had available response data for both CBR and ORR (Table 4). KM-Rd was superior to Rd-MRDR, with CBR at 93% vs. 63% and ORR at 83% vs. 45%, both with p<0.001 (Figure 4). Of the 77 patients in the Rd-MRDR control group, 75 had survival data, and there was no difference in PFS between KM-Rd and Rd-MRDR, with a median PFS of 12.7 months vs. 10.3 months, 95% CI 6.23 vs. 23.57, p=0.55. However, the OS benefit was significant, with a median OS of 27.8 months (not achieved vs. 27.8 months), p=0.02, HR 0.46 (95% CI 0.25 vs. 0.87) (Figure 5). [Table 4]

[0175] Observation of M protein and serum free light chain (sFLC) data in stage 1 and 2 patients Figure 6 shows serum M protein and kappa free light chain (κFLC) data for each stage. Notably, in Stage 1, one patient showed a response to the disease based on a decrease in M ​​protein levels, but sFLC increased. In addition, one MM patient with only FLC maintained reduced sFLC levels throughout 31 cycles of treatment. In Stage 2, the majority of patients responded to KM-Rd (Panel C). The median percentage change from baseline in sFLC increased in cycle 3 (i.e., after 9 doses), then decreased, and remained below baseline.

[0176] safety Surprisingly, KM demonstrated a very favorable toxicity profile even when administered as a combination therapy (KM-Rd). In Stage 1, 3 out of 19 patients (15.8%) experienced infusion-related reactions (IRRs), with one Grade 1 and two Grade 2 reactions. In Stage 2, eight IRRs were observed (six of which occurred during the first infusion). There was one Grade 3 IRR and seven Grade 12 IRRs, and no patients discontinued treatment due to IRRs. Notably, the patient with a Grade 3 IRR recovered after receiving hydrocortisone, salbutamol, and loratadine in the clinic before being admitted for observation. No hematological toxicity was reported with KM alone, but the rates of anemia (12.5%), neutropenia (32.5%), and thrombocytopenia (18%) seen in Stage 2 with KM-Rd were as expected with Rd administration (Table 5). The most frequently reported non-hematological adverse events were fatigue, insomnia, musculoskeletal pain, peripheral neuropathy, and diarrhea (Table 6). [Table 5] [Table 6]

[0177] The low incidence of KM treatment-related adverse events observed in previous clinical trials supports doses of KM exceeding 10 mg / kg in combination with immunomodulatory agents (IMiD) / cereblon E3 ligase modulators (CELMoD) and steroid therapy. Essentially, the safety profile of KM-Rd replicates that seen with Rd (Dimopoulos et al. 2007, Weber et al. 2007), which involved only rare (14%) and low-grade KM-related IRRs. The absence of increased neutropenia and infection rates in the KM-Rd cohort compared to Rd administration in the literature likely reflects a very limited pattern of KMA expression, where KMA is found only in malignant plasma cells and a limited number of amygdala B cells (Walker et al. 1985, Hutchinson et al. 2014).

[0178] Those skilled in the art will understand that numerous variations and / or modifications may be made to the present invention, as shown in certain embodiments, without departing from the spirit or scope of the invention as broadly described. Therefore, these embodiments should be considered in all respects as illustrative and not limiting.

[0179] All publications discussed above are incorporated in their entirety into this specification.

[0180] Any considerations relating to documents, actions, materials, devices, articles, etc., included herein are for the sole purpose of providing context to the present invention. None of these matters, either in whole or in part, should be deemed to have existed prior to the priority date of each claim of this application, to form part of the prior art, or to have been common general knowledge in the art relating to the present invention.

[0181] References [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

Claims

1. A method for treating multiple myeloma in a subject requiring treatment for multiple myeloma, wherein the method is applied to the subject, (i) at least 30 mg / kg of anti-KMA antibody, (ii) Immunomodulatory agents (IMiD) or Cereblon E3 ligase modulators (CELMoD), (iii) A method comprising administering a treatment including a steroid.

2. The aforementioned anti-KMA antibody, V Ｈ And, V Ｌ and, including, the V Ｈ However, it includes a complementarity-determining region (CDR) 1 containing the amino acid sequence shown in SEQ ID NO: 6, a CDR 2 containing the amino acid sequence shown in SEQ ID NO: 7, and a CDR 3 containing the sequence shown in SEQ ID NO: 8, and the V Ｌ The method according to claim 1, wherein the CDR1 comprises the amino acid sequence shown in SEQ ID NO: 9, the CDR2 comprises the amino acid sequence shown in SEQ ID NO: 10, and the CDR3 comprises the sequence shown in SEQ ID NO:

11.

3. The method according to claim 1 or 2, wherein the anti-KMA antibody has a heavy chain variable region (VH) containing the sequence described in SEQ ID NO: 1 and a light chain variable region (VL) containing the sequence described in SEQ ID NO:

2.

4. The method according to any one of claims 1 to 3, wherein the IMiD is lenalidomide, pomalidomide, or thalidomide.

5. The method according to any one of claims 1 to 4, wherein the IMiD is lenalidomide.

6. The method according to any one of claims 1 to 3, wherein the CELMoD is iverdmid or CC-92480.

7. The method according to any one of claims 1 to 6, wherein approximately 25 mg of the IMiD or CELMoD is administered to the subject.

8. The method according to any one of claims 1 to 7, wherein the steroid is dexamethasone or prednisone.

9. The method according to any one of claims 1 to 8, wherein the steroid is dexamethasone.

10. The method according to any one of claims 1 to 9, wherein approximately 40 mg of the steroid is administered to the subject.

11. The treatment, at the treatment stage, applies to the subject, (i) once a week, at least 30 mg / kg of the anti-KMA antibody, (ii) Once a day, with the IMiD or the CELMoD, (iii) The method according to any one of claims 1 to 10, comprising administering the steroid once a week.

12. The method according to claim 11, wherein the duration of the treatment stage is at least 6 weeks to at least 10 weeks.

13. The method according to claim 11 or 12, further comprising administering the IMiD or CELMoD to the subject once daily for at least three weeks prior to the commencement of the aforementioned treatment stage.

14. The method according to any one of claims 11 to 13, further comprising administering a steroid to the subject at least one week before the commencement of the treatment stage.

15. The method according to any one of claims 1 to 14, wherein the target immune cells are maintained at a level equivalent to that of the target immune cells before administration of the anti-KMA antibody.

16. The method according to any one of claims 11 to 14, wherein the target immune cells are maintained at a level equivalent to the target immune cells after the treatment stage.

17. The method according to claim 15, wherein the target immune cells are one or more or all of the following: red blood cells, white blood cells, and platelets.

18. The aforementioned target, (i) Once a month, at least 30 mg / kg of the anti-KMA antibody, (ii) Once a day, with the IMiD or the CELMoD, (iii) A maintenance phase comprising administering the steroid once a week, The method according to any one of claims 11 to 17, further comprising a maintenance step which follows the treatment step.

19. The method according to claim 18, wherein the duration of the maintenance stage is at least 12 weeks.

20. The method according to claim 18 or 19, wherein the maintenance stage is continued until the progression of the disease.

21. The method according to any one of claims 1 to 20, wherein approximately 30 mg / kg of the anti-KMA antibody is administered to the subject.

22. The method according to any one of claims 1 to 21, wherein the anti-KMA antibody is formulated for intravenous injection.

23. The method according to any one of claims 1 to 22, wherein the subject has received at least one, at least two, at least three, at least four, at least five, or at least six prior therapy lines.

24. The method according to any one of claims 1 to 23, wherein the subject achieves at least a minimal response (a 25% reduction in M ​​protein) to the subject's most recent line of therapy.

25. The method according to any one of claims 1 to 24, wherein the subject is refractory to at least one, at least two, at least three, or at least four prior treatment lines.

26. The method according to any one of claims 1 to 25, wherein the subject is refractory to at least one proteasome inhibitor, IMiD or CELMoD, or autologous stem cell transplantation.

27. The method according to any one of claims 1 to 26, wherein the subject has recurrent myeloma.

28. The method according to any one of claims 1 to 27, wherein the subject multiple myeloma is recurrent and refractory to at least one proteasome inhibitor, IMiD or CELMoD, or autologous stem cell transplantation.

29. The method according to any one of claims 1 to 12 and 14 to 27, wherein the subject does not have prior exposure to the IMiD or the CELMoD.

30. (i) at least 30 mg / kg of anti-KMA antibody, (ii) Immunomodulatory agents (IMiD) or Cereblon E3 ligase modulators (CELMoD), (iii) A combination drug regimen for use in the treatment of multiple myeloma in a subject, comprising a steroid.

31. The combination drug regimen according to claim 30, wherein approximately 25 mg of the IMiD or CELMoD is administered to the subject.

32. The combination drug regimen according to claim 30 or 31, wherein approximately 40 mg of the steroid is administered to the subject.

33. The combination drug regimen according to any one of claims 30 to 32, wherein the combination is administered once a week during the treatment phase.

34. The aforementioned treatment stage is, (i) once a week, at least 30 mg / kg of the anti-KMA antibody, (ii) Once a day, with the IMiD or the CELMoD, (iii) A combination drug regimen according to any one of claims 30 to 33, comprising the administration of the steroid once a week.

35. The combination drug regimen according to any one of claims 30 to 34, wherein the duration of the treatment stage is at least 6 weeks to at least 10 weeks.

36. A combination drug regimen according to any one of claims 30 to 35, further comprising administering the IMiD or CELMoD to the subject once daily for at least three weeks prior to the commencement of the aforementioned treatment stage.

37. A combination drug regimen according to any one of claims 30 to 36, further comprising administering a steroid to the subject at least one week before the commencement of the treatment stage.

38. The aforementioned target, (i) Once a month, at least 30 mg / kg of the anti-KMA antibody, (ii) Once a day, with the IMiD or the CELMoD, (iii) A maintenance phase comprising administering the steroid once a week, A combination drug regimen according to any one of claims 30 to 37, further comprising a maintenance stage which follows the treatment stage.

39. A kit for the treatment of multiple myeloma in the subject, (i) At least 30 mg / kg of anti-KMA antibody in single or multi-dose doses, (ii) Single-dose or multi-dose immunomodulatory drugs (IMiD) or cereblon E3 ligase modulators (CELMoD), (iii) Single-dose or multi-dose steroids, (iv) A kit comprising the anti-KMA antibody, the IMiD or the CELMoD, and instructions for using the steroid.

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