Methods for treating high-risk smoldering multiple myeloma

Abstract

Embodiments relate to methods of treating high-risk smoldering multiple myeloma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a BCMAxCD3 bispecific antibody.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 63 / 594,977, filed November 1, 2023, the entire contents of which are incorporated herein by reference.

[0003] Reference sequence list submitted electronically

[0004] This application contains a sequence list electronically filed in XML format, the entire contents of which are incorporated herein by reference. The XML copy was created on October 3, 2024, named "258199061802(JBI6854WOPCT1)SequenceListing.xml", and has a size of 26,334 bytes. Technical Field

[0005] A method for treating high-risk smoldering multiple myeloma has been disclosed. Background Technology

[0006] Smoking multiple myeloma (SMM) is a prodromal disease state that precedes the development of symptomatic multiple myeloma (a plasma cell cancer). Patients with SMM are often asymptomatic but are at risk of progressing to active multiple myeloma (MM). Treatment options for multiple myeloma have improved over time; however, despite recent therapeutic advancements, multiple myeloma remains an incurable malignancy with significant morbidity and mortality. There are currently no approved therapies for SMM, and safe and effective treatment options remain needed, particularly for patients with high-risk smoking multiple myeloma (HR-SMM) who are at high risk of developing active multiple myeloma. Summary of the Invention

[0007] A method for treating high-risk smoking multiple myeloma (HR-SMM) in a subject of need is provided, comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody (e.g., teritumumab) to the subject.

[0008] In some embodiments, the BCMAxCD3 bispecific antibody comprises: a BCMA binding domain containing HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3 binding domain containing HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19.

[0009] In some embodiments, the BCMA-binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3-binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.

[0010] In some implementations, the BCMAxCD3 bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype.

[0011] In some implementations, the BCMAxCD3 bispecific antibody is an IgG4 isotype.

[0012] In some implementations, the BCMAxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0013] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and contains proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235, respectively, in its Fc region (according to EU index number).

[0014] In some implementations, the BCMAxCD3 bispecific antibody is an IgG4 isotype and contains F405L and R409K substitutions (according to EU index number) in its Fc region.

[0015] In some embodiments, the Fc region of the BCMA binding arm contains proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235, respectively (according to EU index numbers).

[0016] In some embodiments, the Fc region of the CD3 binding arm contains, in addition to the F405L and R409K substitutions, proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235 (according to EU index numbers).

[0017] In some embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23.

[0018] In some embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 23.

[0019] In some embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 23.

[0020] In some embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 23.

[0021] In some implementations, the BCMAxCD3 bispecific antibody is teratomab.

[0022] In some implementations, the subjects have not received prior SMM-targeted therapy.

[0023] In some implementations, the BCMAxCD3 bispecific antibody is administered as a single therapy (i.e., without another concurrent SMM-targeted therapy).

[0024] In some implementations, the method includes subcutaneous administration of each dose of the BCMAxCD3 bispecific antibody.

[0025] In some implementations, the method includes treating the subject according to a treatment efficacy regimen comprising consecutive 28-day cycles of BCMAxCD3 treatment.

[0026] In some embodiments, the method includes administering a BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises: in cycle 1, subcutaneous administration of a first escalation dose of 0.06 mg / kg (e.g., on day 1), a second escalation dose of 0.3 mg / kg (e.g., on day 3), followed by a weekly (QW) treatment dose of 1.5 mg / kg (e.g., on days 8, 15, and 22); in cycle 2, subcutaneous administration of a weekly (QW) dose of 1.5 mg / kg (e.g., on days 1, 8, 15, and 22); in cycles 3–6, subcutaneous administration of a 2-week (Q2W) dose of 3 mg / kg (e.g., on days 1 and 15); and starting in cycle 7 (e.g., in cycles 7–12 or 7–24), subcutaneous administration of a monthly (Q4W) dose of 3 mg / kg (e.g., on day 1 of each cycle).

[0027] In some implementations, the clinical response achieved by this method in subjects is a partial response (PR), a very good partial response (VGPR), a complete response (CR), or a strict complete response (sCR), as defined by the IMWG (2016) response criteria.

[0028] In some embodiments, the method achieves an overall response rate (ORR) of 70% or higher in a subject population with HR-SMM. In some embodiments, the method achieves an overall response rate (ORR) of 75% or higher in a subject population with HR-SMM. In some embodiments, the method achieves an overall response rate (ORR) of 80% or higher in a subject population with HR-SMM. In some embodiments, the method achieves an overall response rate (ORR) of 85% or higher in a subject population with HR-SMM. In some embodiments, the method achieves an overall response rate (ORR) of 90% or higher in a subject population with HR-SMM. In some embodiments, the method achieves an overall response rate (ORR) of 95% or higher in a subject population with HR-SMM. In some embodiments, the method achieves an overall response rate (ORR) of 100% in a subject population with HR-SMM.

[0029] In some embodiments, the method achieved complete remission (CR) in at least 25% of a subject population with HR-SMM. In some embodiments, the method achieved CR in at least 30% of a subject population with HR-SMM. In some embodiments, the method achieved CR in at least 35% of a subject population with HR-SMM. In some embodiments, the method achieved CR in at least 40% of a subject population with HR-SMM.

[0030] In some implementations, the method achieves MRD-negative disease in subjects.

[0031] In some implementations, the subject's HR-SMM did not progress after the subject had received at least four 28-day cycles of treatment with the BCMAxCD3 bispecific antibody.

[0032] In some implementations, subjects are given BCMAxCD3 bispecific antibodies for up to twenty-four (24) 28-day treatment cycles to prevent the development of multiple myeloma.

[0033] In some implementations, subjects are given BCMAxCD3 bispecific antibodies for up to twelve (12) 28-day treatment cycles to prevent the development of multiple myeloma.

[0034] In some implementations, this method cures HR-SMM and prevents subjects from developing MM.

[0035] In some implementations, the method achieves a higher overall response rate (ORR) in a subject population with HR-SMM than in a reference subject population with HR-SMM who have been administered lenalidomide and dexamethasone but not the BCMAxCD3 bispecific antibody.

[0036] In some implementations, the method achieves a higher percentage of complete response (CR) in a population of subjects with HR-SMM than in a reference population of subjects with HR-SMM who have been administered lenalidomide and dexamethasone but not the BCMAxCD3 bispecific antibody.

[0037] However, all the methods described in this article, however expressed, can be described as having the corresponding uses, especially medical uses. Detailed Implementation

[0038] The disclosed methods can be more readily understood by referring to the following detailed description. It should be understood that the methods disclosed herein are not limited to the specific methods described and / or shown herein, and the terminology used herein is for illustrative purposes only and is not intended to limit the methods protected by the claims. All patents, published patent applications, and publications cited herein are incorporated herein by reference as if fully set forth herein.

[0039] As used herein, the singular forms “a,” “an,” and “the / that” include the plural forms.

[0040] Various terms relating to various aspects of the specification are used throughout the specification and claims. Unless otherwise specified, such terms are given their ordinary meaning in the art. Other specifically defined terms should be understood in accordance with the definitions provided herein.

[0041] When used in relation to numerical ranges, cutoff values, or specific values, “about” means within an acceptable range of error for a specific value as determined by one of ordinary skill in the art, which will depend in part on how the value was measured or determined, i.e., the limitations of the measurement system. In the context of a particular measurement, result, or embodiment, unless otherwise expressly stated in the embodiments or elsewhere in the specification, “about” means within one standard deviation or up to 5% (whichever is greater) according to convention in the art.

[0042] "Antibody" broadly refers to and includes immunoglobulin molecules, specifically including monoclonal antibodies (including murine monoclonal antibodies, human monoclonal antibodies, humanized monoclonal antibodies, and chimeric monoclonal antibodies), antigen-binding fragments, multispecific antibodies (such as bispecific antibodies, trispecific antibodies, tetraspecific antibodies, etc.), dimer, tetramer, or multimer antibodies, single-chain antibodies, domain antibodies, and any other modified conformation of immunoglobulin molecules containing an antigen-binding site with desired specificity. A "full-length antibody" comprises two heavy chains (HC) and two light chains (LC) linked by disulfide bonds, as well as their polymers (e.g., IgM). Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into hypervariable regions, called complementarity-determining regions (CDRs), and framework regions (FRs) interspersed therebetween. Each VH and VL consists of three CDR and four FR segments, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Immunoglobulins can be designated into five major classes based on the amino acid sequence of their heavy chain constant domain: IgA, IgD, IgE, IgG, and IgM. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Based on the amino acid sequence of their constant domain, antibody light chains of any vertebrate species can be designated into one of two completely different types: kappa (κ) and lambda (λ).

[0043] An "antigen-binding fragment" or "antigen-binding domain" refers to the portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments can be synthetic, enzymatically obtained, or genetically engineered polypeptides, and contain: VH, VL, VH and VL, Fab, F(ab')2, Fd, and Fv fragments; domain antibodies (dAbs) consisting of a VH domain or a VL domain; shark variable IgNAR domains; humped VH domains; or the smallest recognition unit consisting of amino acid residues of the CDRs of a mimic antibody (such as the FR3-CDR3-FR4 moiety, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3). The VH and VL domains can be linked together via synthetic linkers to form various types of single-chain antibody designs. Where the VH and VL domains are expressed by separate single-chain antibody constructs, the VH / VL domains can be paired intramolecularly or intermolecularly to form monovalent antigen binding sites, such as single-chain Fv (scFv) or bivalent antibodies; as described, for example, in International Patent Publications Nos. WO1998 / 44001, WO1988 / 01649, WO1994 / 13804 and WO1992 / 01047.

[0044] “BCMA” refers to the human B cell maturation antigen, also known as CD269 or TNFRSF17 (UniProt Q02223). The extracellular domain of BCMA covers residues 1-54 of Q02223. Human BCMA contains the amino acid sequence of SEQ ID NO: 1.

[0045] SEQ ID NO: 1

[0046] MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR

[0047] As used in this article, "bispecific antibody" refers to an antibody that specifically binds to two different antigens. Bispecific antibodies may be cross-reactive to other related antigens, for example, to the same antigens from other species (homologous) (such as humans or monkeys, such as cynomolgus macaques or pan troglodytes), or they may bind to epitopes shared between two or more different antigens.

[0048] "BCMAxCD3 bispecific antibody" refers to a bispecific antibody that specifically binds to BCMA and CD3.

[0049] "Cancer" refers to a wide variety of diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth lead to the formation of malignant tumors that invade adjacent tissues and can also metastasize to distant parts of the body via the lymphatic system or bloodstream. "Cancer" or "cancer tissue" can include tumors.

[0050] "CD3" refers to a human antigen expressed on T cells as part of a multimolecular T-cell receptor (TCR) complex and composed of homodimers or heterodimers formed by the association of two or four receptor chains: CD3ε, CD3δ, CD3ζ, and CD3γ. The human CD3ε chain contains the amino acid sequence of SEQ ID NO: 2. SEQ ID NO: 3 shows the extracellular domain of the CD3ε chain.

[0051] SEQ ID NO: 2

[0052] MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGS KPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

[0053] SEQ ID NO: 3

[0054] DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD

[0055] The "CH3 region" or "CH3 domain" refers to the CH3 region of an immunoglobulin. The CH3 region of the human IgG1 antibody corresponds to amino acid residues 341-446. However, the CH3 region can also be any of the other antibody isotypes described herein.

[0056] The complementarity-determining region (CDR) is the region of an antibody that binds to an antigen. CDRs can be defined using various descriptions, such as those by Kabat (Wu et al., J Exp Med 132: 211-50, 1970) (Kabat et al., "Sequences of Proteins of Immunological Interest", 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al., J Mol Biol 196: 901-17, 1987), IMGT (Lefranc et al., Dev Comp Immunol 27: 55-77, 2003), and AbM (Martin and Thornton, J Bmol Biol 263: 800-15, 1996). The correspondence between various depictions and variable region numbers is described (see, for example, Lefranc et al., Dev Comp Immunol 27: 55-77, 2003; Honegger and Pluckthun, J MolBiol 309:657-70, 2001; International Immunogenetics (IMGT) database; Web resource, http: / / www_imgt_org). Available programs (such as abYsis for UCL Business PLC) can be used to depict CDRs. Unless otherwise expressly stated in the specification, as used herein, the terms “CDR,” “HCDR1,” “HCDR2,” “HCDR3,” “LCDR1,” “LCDR2,” and “LCDR3” include CDRs defined by any of the methods described above (Kabat, Chothia, IMGT, or AbM). Preferably, as used herein, the terms “CDR,” “HCDR1,” “HCDR2,” “HCDR3,” “LCDR1,” “LCDR2,” and “LCDR3” include CDRs defined by the Kabat method.

[0057] The term “comprising” is intended to include examples covered by the terms “substantially consisting of” and “consisting of”; similarly, the term “substantially consisting of” is intended to include examples covered by the term “consisting of”. Unless the context expressly requires otherwise, throughout the specification and claims, the words “comprising,” “including,” etc., shall be understood in an inclusive sense, rather than an exclusive or exhaustive sense; that is, in the sense of “including but not limited to.”

[0058] "Fcγ receptor" (FcγR) refers to the well-known FcγRI, FcγRIIa, FcγRIIb, or FcγRIII. Activation of FcγR includes FcγRI, FcγRIIa, and FcγRIII.

[0059] "Human antibody" refers to an antibody optimized to produce a minimal immune response when administered to human subjects. The variable region of a human antibody is derived from a human immunoglobulin sequence. If a human antibody contains a constant region or a portion of a constant region, that constant region is also derived from a human immunoglobulin sequence. If the variable region of a human antibody is obtained using a system that uses human germline immunoglobulins or rearranged immunoglobulin genes, the human antibody contains both heavy-chain and light-chain variable regions "derived" from human-origin sequences. Exemplary systems of this kind include human immunoglobulin gene libraries displayed on bacteriophages and transgenic nonhuman animals, such as mice or rats carrying human immunoglobulin loci. Due to differences between the systems used to obtain human antibodies and human immunoglobulin loci, the introduction of somatic mutations, or the intentional substitution of elements introduced into the frame or CDR, or both, "human antibodies" typically contain amino acid differences compared to immunoglobulins expressed in humans. Typically, the amino acid sequence of a "human antibody" has at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence encoded by a human immunoglobulin gene or rearranged immunoglobulin gene. In some cases, a "human antibody" may comprise a common frame sequence derived from human frame sequence analysis (e.g., as described in Knappik et al., (2000) J Mol Biol 296:57-86) or a synthetic HCDR3 bound to a human immunoglobulin gene library displayed on a phage (e.g., as described in Shi et al., (2010) J Mol Biol 397:385-96 and International Patent Publication No. WO2009 / 085462). The definition of a "human antibody" does not include antibodies in which at least one CDR is derived from a non-human species.

[0060] "Humanized antibody" refers to an antibody in which at least one CDR is derived from a non-human species and at least one frame is derived from a human immunoglobulin sequence. Humanized antibodies may contain substitutions in the frame such that these frames may not be exact copies of the expressed human immunoglobulin or the germline gene sequence of human immunoglobulin.

[0061] "Identity" refers to the relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by sequence alignment and comparison. The "percentage of sequence identity (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to those in the reference polypeptide sequence, after sequence alignment and the introduction of gaps (if necessary) to achieve the maximum percentage of sequence identity, without considering any conserved substitutions as part of the sequence identity. Alignments performed for the purpose of determining the percentage of amino acid sequence identity can be performed in a variety of ways within the scope of the art, such as using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN (DNAStar, Inc.) software. Those skilled in the art can determine suitable parameters for sequence alignment, including any algorithms required to achieve maximum alignment across the full length of the compared sequences.

[0062] "Separated" refers to a homogeneous group of molecules (such as synthetic polynucleotides or proteins, such as antibodies) that have been substantially separated from and / or purified from other components in a system in which the molecules are produced (such as recombinant cells), as well as proteins that have undergone at least one purification or separation step. "Separated antibodies" refers to antibodies that are substantially free of other cellular material and / or chemicals, and covers antibodies separated to higher purities, such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity.

[0063] Monoclonal antibodies are antibodies derived from a substantially homogeneous population of antibody molecules, meaning that the individual antibodies within that population are identical, differing only in possible well-known modifications, such as removal of a C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation. Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies can exhibit heterogeneous glycosylation within an antibody population. Monoclonal antibodies can be monospecific or multispecific, such as bispecific, monovalent, divalent, or multivalent.

[0064] A "mutation" refers to an engineered or naturally occurring change in a polypeptide or polynucleotide sequence compared to a reference sequence. This change can be a substitution, insertion, or deletion of one or more amino acids or polynucleotides.

[0065] "Negative minimal residual disease status" or "negative MRD status" or "MRD negative" refers to the PerMillionCount (i.e., a point estimate of malignant myeloma cells per million nucleated cells) of a bone marrow sample in a patient study relative to its reference bone marrow sample (i.e., a bone marrow sample not treated with teratumab). Based on this PerMillionCount, each sample is determined to be positive or negative. If the PerMillionCount is greater than or equal to the sensitivity limit, the sample is positive; otherwise, they are negative. It can be 0.01% (10 -4 ), 0.001% (10 -5 ) or 0.0001% (10 -6 The sensitivity of next-generation sequencing (NGS) can be used to determine negative minimal residual disease status.

[0066] "Pharmaceutical composition" refers to a composition containing an active ingredient and a pharmaceutically acceptable carrier.

[0067] "Pharmaceutically acceptable carrier" or "excipient" refers to a component in a pharmaceutical composition other than the active ingredient that is non-toxic to the subject.

[0068] "Recombinant" refers to DNA, antibodies, and other proteins that are prepared, expressed, formed, or isolated through recombination when fragments from different sources are joined to produce recombinant DNA, antibodies, or proteins.

[0069] "Refractory" multiple myeloma refers to a disease that does not respond to therapy or does not respond to therapy after treatment has ceased.

[0070] "Relapsed" multiple myeloma refers to a disease that responds to previous treatments but subsequently progresses and requires new therapies.

[0071] "Elevation dose" refers to the dose of the active agent administered to the subject prior to the therapeutic dose. The escalation dose is lower than the therapeutic dose. To prevent or mitigate certain toxicities, such as cytokine release syndrome (CRS), an "initiating" dosing strategy may include one or more lower escalation doses followed by a higher therapeutic dose. An "escalation period" refers to the initial phase of a treatment regimen in which at least one escalation dose of the therapeutic agent is administered to the subject. An escalation period may also include one or more therapeutic doses, i.e., an escalation period may include one or more escalation doses followed by one or more therapeutic doses; for example, an escalation period may include two escalation doses followed by two therapeutic doses. In a specific implementation, the escalation period is 28 days, i.e., the escalation period is a 28-day cycle of a treatment regimen.

[0072] As used herein, “subject” refers to a human subject. Unless otherwise stated, the terms “patient” or “subject” are used interchangeably.

[0073] "T-cell redirection therapy" refers to a molecule containing two or more binding regions, wherein one of these binding regions specifically binds to a cell surface antigen on a target cell or tissue, and wherein a second binding region of the molecule specifically binds to a T-cell antigen. Examples of cell surface antigens include tumor-associated antigens such as BCMA. Examples of T-cell antigens include, for example, CD3. This dual-target / multi-target binding capability recruits T cells to the target cells or tissue, thereby eradicating the target cells or tissue.

[0074] "Therapeutic effective dose" refers to the amount that effectively achieves the desired therapeutic outcome at the required dose and time period. Therapeutic effective dose can vary depending on factors such as an individual's disease state, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improved patient health.

[0075] "Treatment" refers to both therapeutic treatment and preventative or defensive measures, the goal of which is to prevent or mitigate (reduce) undesirable physiological changes or disorders. Beneficial or desired clinical outcomes include symptom relief, reduction of disease severity, stable (i.e., no worsening) state of disease, delay or slowing of disease progression, improvement or mitigation of disease status, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean extended survival compared to the expected survival of a subject without treatment. Individuals requiring treatment include those already suffering from a condition or disorder, those susceptible to a condition or disorder, or those seeking to prevent a condition or disorder.

[0076] "Therapeutic dose" refers to the dose of an active agent administered to a subject for the treatment of a disease. Therapeutic doses may be administered on a repeated basis at regular dosing intervals (e.g., weekly, bi-weekly, monthly). One or more escalating doses may precede the therapeutic dose.

[0077] "Triple-class exposed" patients refer to multiple myeloma patients who have previously been treated with (at least) proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies.

[0078] "Tumor cells" or "cancer cells" refer to cancerous, precancerous, or transformed cells in vivo, in vitro, or in tissue cultures that exhibit spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. Although transformation can be triggered by infection with transforming viruses and the incorporation of new genomic nucleic acids, the uptake of exogenous nucleic acids or their exogenous forms can also be initiated spontaneously or after exposure to carcinogens, leading to mutations in endogenous genes. Examples of transformation / cancer include morphological changes in vitro, in vivo, and in vitro in suitable animal hosts (such as nude mice), cell immortalization, abnormal growth control, lesion formation, proliferation, malignancy, regulation of tumor-specific marker levels, invasion, and tumor growth.

[0079] Unless otherwise explicitly stated, throughout the specification, the amino acid residues in the antibody constant region are numbered according to the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD. (1991). Antibody constant chain numbers can be found, for example, on the ImMunoGeneTics website, IMGT Web Resources, and IMGT Scientific Charts.

[0080] This article uses the standard single-letter and three-letter amino acid codes as shown in Table 1.

[0081] Table 1.

[0082]

[0083] BCMAxCD3 bispecific antibody for the treatment of HR-SMM

[0084] Despite the development of effective targeted therapies for participants with multiple myeloma (MM) over the past decade, the clinical efficacy of targeted therapies is hampered by the emergence of drug resistance, clonal evolution, and disease progression, making the pursuit of a cure for MM even more unattainable. Even with the best combinations of currently available agents, a cure remains elusive for the majority of participants with MM. Therefore, treatment of the pre-smoking multiple myeloma (SMM) state, a precursor to MM, could lead to the ultimate prevention and cure of MM progression. Unbound by theory, early intervention in high-risk SMM is believed to offer the opportunity to prevent or delay disease progression or even cure it by aggressively targeting tumor cells before clonal heterogeneity occurs and before immune dysfunction and microenvironmental dysregulation develop.

[0085] The treatment goal for high-risk SMM should be to deliver the most effective therapy possible to ultimately achieve a cure or a significant prolongation of progression-free survival (PFS) without compromising safety. The inventors have developed a novel approach to treating high-risk SMM using a BCMAxCD3 bispecific antibody, which provides significant efficacy compared to patients with relapsed / refractory multiple myeloma receiving the same therapy.

[0086] Teritolimab (as TECVAYLI) ® Teritumab is the first BCMA-directed bispecific antibody approved for the treatment of patients with relapsed or refractory multiple myeloma. Teritumab is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell connector directed for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least three or four lines of prior therapy, including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies. The efficacy of teritumab was continuously evaluated in patients with relapsed or refractory multiple myeloma in multicenter clinical studies (MajesTEC-1, NCT03145181 [Phase 1] and NCT04557098 [Phase 2]). The studies included patients who had previously received at least three lines of prior therapy, including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies. In the MajesTEC-1 study, teratomab demonstrated rapid, deep, and durable responses at a median follow-up of 14.1 months, with an overall response rate (ORR) of 63% and a median progression-free survival (mPFS) of 11.3 months. The most common grade 3 / 4 hematologic adverse events (AEs) were neutropenia (64.2%), anemia (37%), lymphopenia (32.7%), and thrombocytopenia (21.2%). Infections occurred in 76.4% of patients (44.8% grade 3 / 4). The most common non-hematologic AE was cytokine release syndrome (CRS), all of which were grade 1 / 2 (72.1% of all grades) except for one transient grade 3 CRS. See, for example, Usmani SZ et al., Lancet 2021; 398:665-674; and Moreau P et al., New Engl J Med 2022; 387: 495-505, which are incorporated herein by reference.

[0087] Antibody

[0088] Any suitable BCMAxCD3 bispecific antibody known to those skilled in the art based on this disclosure may be used.

[0089] Various forms of bispecific antibodies include the forms described herein and recombinant IgG-like bitargeting molecules, wherein each flanking element contains Fab fragments or portions of Fab fragments of at least two different antibodies; IgG fusion molecules, wherein a full-length IgG antibody is fused with an additional Fab fragment or a portion of a Fab fragment; Fc fusion molecules, wherein a single-chain Fv molecule or a stable bivalent antibody is fused with a heavy chain constant domain, Fc region, or a portion thereof; Fab fusion molecules, wherein different Fab fragments are fused together; and heavy chain antibodies based on ScFv and bivalent antibodies (e.g., domain antibodies, nanobodies), wherein different single-chain Fv molecules or different bivalent antibodies or different heavy chain antibodies (e.g., domain antibodies, nanobodies) are fused with each other or with another protein or carrier molecule or a bispecific antibody generated via arm exchange. Exemplary bispecific forms include dual-targeting molecules, including dual-targeting (DT)-Ig (GSK / Domantis), a combination antibody (Genentech) and mAb2 (F-Star), dual variable domain (DVD)-Ig (Abbott), DuoBody (Genmab), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc fusion (AcademicInstitution), and SCORPION (Emergent). BioSolutions / Trubion, Zymogenetics / BMS) and dual-parental heavy-chain domain-only antibodies (Fc-DART) (MacroGenics), F(ab)2 (Medarex / AMGEN), bifunctional or Bis-Fab (Genentech), docking lock (DNL) (ImmunoMedics), bivalent bispecific antibodies (Biotecnol) and Fab-Fv (UCB-Celltech), bispecific T-cell connector (BITE) (Micromet), tandem bivalent antibody (Tandab) (Affimed), dual-parental heavy-chain domain-only antibodies (DART) (MacroGenics), single-chain bivalent antibodies (Academic), TCR-like antibodies (AIT, ReceptorLogics), human serum albumin ScFv fusion (Merrimack) and COMBODY (Epigen Biotech), dual-targeting nanobodies (Ablynx), and dual-targeting heavy-chain domain-only antibodies.Various forms of bispecific antibodies have been described, for example, in Chames and Baty (2009) Curr Opin Drug Disc Dev 12: 276 and Nunz-Prado et al. (2015) Drug Discovery Today 20(5):588-594.

[0090] In some embodiments, the BCMAxCD3 bispecific antibody comprises any one of the BCMA-binding domains described in WO2017 / 031104, the entire contents of which are incorporated herein by reference. In some embodiments, the BCMAxCD3 bispecific antibody comprises any one of the CD3-binding domains described in WO2017 / 031104. In some embodiments, the BCMAxCD3 bispecific antibody comprises any one of the bispecific antibodies described in WO2017 / 031104.

[0091] In some implementations, the BCMAxCD3 bispecific antibody is chimeric, humanized, or human.

[0092] In some embodiments, the bispecific antibody is an isotype of IgG1, IgG2, IgG3, or IgG4. In a preferred embodiment, the bispecific antibody is an isotype of IgG4. An exemplary wild-type IgG4 comprises the amino acid sequence of SEQ ID NO: 34.

[0093] SEQ ID NO: 34:

[0094] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0095] Bispecific antibodies can possess any allotype. It is expected that allotypes will not affect the properties of bispecific antibodies, such as binding or Fc-mediated effector function. The immunogenicity of therapeutic antibodies is associated with an increased risk of infusion reactions and a reduced duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which therapeutic antibodies induce an immune response in the host can be determined in part by antibody allotypes (Stickler et al., (2011) Genes and Immunity 12:213-21). Antibody allotypes are associated with amino acid sequence variations at specific positions in the constant region sequence of the antibody. Table 2 shows selected IgG1, IgG2, and IgG4 allotypes.

[0096] Table 2.

[0097]

[0098] In some embodiments, the bispecific antibody comprises one or more Fc substitutions that reduce the binding of the bispecific antibody to the Fcγ receptor (FcγR) and / or reduce Fc effector functions such as C1q binding, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), or phagocytosis (ADCP). Specific substitutions can be compared to wild-type IgG4 of SEQ ID NO: 34.

[0099] The following Fc sites can be substituted to reduce the binding of Fc to activated FcγR and subsequently reduce effector function: L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, and K214T / E233P / L234V / L235A / G236 deletion / A327G / P331 on IgG1. The residues are A / D365E / L358M, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236 deletion / G237A / P238S on IgG4, where the residue numbers are based on the EU index.

[0100] The Fc substitution that can be used to reduce CDC is the K322A substitution.

[0101] The well-known S228P substitution can also be performed in IgG4 antibodies to enhance IgG4 stability.

[0102] In some embodiments, the bispecific antibody contains one or more asymmetric substitutions in the first CH3 domain, the second CH3 domain, or both the first CH3 domain and the second CH3 domain.

[0103] In some embodiments, one or more asymmetric substitutions are selected from the group consisting of: F405L / K409R, wild-type / F405L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407 V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F , L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0104] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and contains phenylalanine at position 405 and arginine at position 409 in the first heavy chain (HC1), and leucine at position 405 and lysine at position 409 in the second heavy chain (HC2), wherein the residues are numbered according to the EU index.

[0105] In some implementations, the BCMAxCD3 bispecific antibody contains proline at position 228, alanine at position 234, and alanine at position 235 of both HC1 and HC2.

[0106] Tables 3 and 4 provide sequences of exemplary embodiments of the BCMAxCD3 bispecific antibody according to the Kabat numbering system.

[0107] Table 3. Exemplary sequences of BCMA binding arms

[0108]

[0109] Table 4. Exemplary sequences of CD3 binding arms

[0110]

[0111] In some embodiments, the BCMAxCD3 bispecific antibody is CC-93269, BI 836909, JNJ-64007957 (teratomab), or PF-06863135. In a preferred embodiment, the BCMAxCD3 bispecific antibody is teratomab (also referred to herein as Tec) having the sequences described in Tables 3 and 4.

[0112] Teritolumab and its methods of use are described, for example, in WO 2017 / 031104, WO 2019 / 220369 and WO2021 / 228783, which are incorporated herein by reference. According to a specific embodiment, the BCMAxCD3 bispecific monoclonal antibody has an amino acid sequence identity of at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% with teritolumab.

[0113] Another implementation scheme for the BCMAxCD3 bispecific antibody that can be used according to these methods is described below.

[0114] In some embodiments, the BCMAxCD3 bispecific antibody comprises: a BCMA binding domain containing HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3 binding domain containing HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19.

[0115] In some embodiments, the BCMA-binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3-binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.

[0116] In some implementations, the BCMAxCD3 bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype.

[0117] In some implementations, the BCMAxCD3 bispecific antibody is an IgG4 isotype.

[0118] In some implementations, the BCMAxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0119] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and contains proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235, respectively, in its Fc region (according to EU index number).

[0120] In some implementations, the BCMAxCD3 bispecific antibody is an IgG4 isotype and contains F405L and R409K substitutions (according to EU index number) in its Fc region.

[0121] In some embodiments, the Fc region of the BCMA binding arm contains proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235, respectively (according to EU index numbers).

[0122] In some embodiments, the Fc region of the CD3 binding arm contains, in addition to the F405L and R409K substitutions, proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235 (according to EU index numbers).

[0123] In some embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23.

[0124] In some embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 23.

[0125] In some embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 23.

[0126] In some embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 23.

[0127] In some implementations, the BCMAxCD3 bispecific antibody is teratomab.

[0128] Patients with high-risk smoldering multiple myeloma

[0129] The inventors have developed a novel method for treating subjects diagnosed with high-risk smoking multiple myeloma (HR-SMM). The BCMAxCD3 bispecific antibody disclosed herein is safe and effective in treating HR-SMM.

[0130] The diagnosis of smoking (asymptomatic) multiple myeloma (SMM) is based on the confirmed presence of M protein in serum (>3 gm / dL) or urine and / or the presence of 10–60% clonal bone marrow plasma cells (BMPC). SMM patients typically have a 10% annual risk of progression within the first 5 years. Therefore, SMM is considered to include a mixed population of high-risk patients who can benefit from early treatment intervention before irreversible organ damage and the onset of symptoms. These high-risk SMM patients are defined as having a 50% progression rate within 2 years. The basic logic is that early treatment interception of disease progression in these high-risk individuals will prevent / delay end-organ damage and all its complications. Furthermore, early intervention before clonal evolution accompanied by secondary mutational acquisition and immunosuppressive dysregulation of the microenvironment can lead to significant improvements in disease response, progression-free survival, and overall survival.

[0131] It is generally accepted in the art that patients with high-risk smoldering multiple myeloma typically meet the Mayo 2018 criteria of the SMM (“20-2-20” criteria) or the International Myeloma Working Group scoring system (see, for example, Lakshman A et al., Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J 2018; 8:59; and Mateos MV et al., International Myeloma Working Group risk stratification model for smoldering multiple myeloma. Blood Cancer J 2020; 10:102, these references are incorporated herein by reference). Therefore, patients with high-risk smoldering multiple myeloma typically meet one of the following two diagnostic criteria as shown in Table 7 (i.e., diagnostic criterion #1 or diagnostic criterion #2 below):

[0132] Table 7. HR-SMM Diagnostic Criteria

[0133]

[0134] The implementation plan provides a method for treating high-risk smoldering multiple myeloma (HR-SMM) in subjects of need, comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to the subject. In a preferred implementation plan, the subject has not received prior SMM-targeted therapy. In a preferred implementation plan, the BCMAxCD3 bispecific antibody is administered as a single therapy (i.e., no other concurrent SMM-targeted therapy is being administered).

[0135] In some embodiments, a method is provided for preventing or inhibiting the development of HR-SMM into symptomatic multiple myeloma (MM) in subjects of need, the method comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to the subject. In some embodiments, a method is provided for curing HR-SMM in subjects of need, the method comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to the subject. In some embodiments, a method is provided for achieving a complete response (CR) in subjects diagnosed with HR-SMM, the method comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to the subject. In some embodiments, a method is provided for achieving a 100% overall response rate (ORR) in a population of subjects diagnosed with HR-SMM, the method comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to each of the subjects.

[0136] Dosing regimen for the treatment of HR-SMM

[0137] The inventors have developed a novel dosing regimen for the treatment of HR-SMM that achieves deep and durable clinical responses.

[0138] As used herein, “weight-based” means dosage administered based on the subject’s specific body weight; for example, 3 mg / kg means a dose of 3 mg of antibody per kilogram of subject body weight. Unless otherwise stated herein, when the dose is described in “mg / kg” or “μg / kg”, weight-based administration is used.

[0139] Unless otherwise stated herein, BCMAxCD3 bispecific antibodies (such as teratumab) are administered according to a dosing schedule based on consecutive 28-day cycles. For example, cycle 1 begins on day 1 of cycle 1 and ends on day 28 of cycle 1, and then cycle 2 begins on day 1 of cycle 2 the day after day 28 of cycle 1 and ends on day 28 of cycle 2, and then cycle 3 begins on day 1 of cycle 2 the day after day 28 of cycle 2 and ends on day 28 of cycle 3, and so on. As used herein, regarding treatment cycles, “C1” refers to cycle 1, “C2” refers to cycle 2, “C3” refers to cycle 3, and so on. Multiple cycles may also be described, for example, “C3-6” refers to cycles 3-6 (cycles 3, 4, 5, and 6). Cycle numbers with a “+” sign refer to that cycle and all subsequent cycles; for example, “C3+” refers to cycle 3 and all subsequent cycles (i.e., C3, C4, C5, C6, C7, etc.).

[0140] As used herein, “Q4W” means once every four weeks, “Q2W” (also referred to as “bi-weekly” or “biweekly”) means once every two weeks, and “QW” (also referred to as “weekly”) means once a week. Q4W is sometimes referred to herein as “monthly”, but technically means once every four weeks or once every 28 days (e.g., in a 28-day cycle, the first treatment dose occurs on day 1 of cycle 1, the second treatment dose occurs on day 1 of cycle 2, and so on). Once-weekly (QW) administration of treatment doses is also referred to herein as a weekly dosing schedule; for example, a 28-day treatment cycle may have a weekly dosing schedule which includes four doses spaced one week apart (e.g., on days 1, 8, 15, and 22), or three doses spaced one week apart (e.g., on days 8, 15, and 22), or two doses spaced one week apart (e.g., on days 8 and 15). Once-bi-weekly (Q2W) administration of treatment doses is also referred to herein as a bi-weekly dosing schedule. The treatment dose is administered once every four weeks (Q4W), also referred to herein as a monthly dosing schedule. Dosing regimens may be described herein in terms of dosage and frequency; for example, “C1: 1.5 mg / kg QW” means administering 1.5 mg / kg once a week during the first cycle of an effective treatment regimen, “C3-6: 3 mg / kg Q2W” means administering 3 mg / kg once every two weeks from the third to the sixth cycle, “C7+: 3 mg / kg Q4W” means administering 3 mg / kg once every four weeks starting from the seventh cycle, and so on.

[0141] As used herein, a “BCMAxCD3 treatment cycle” refers to each treatment cycle in a treatment-effective regimen in which the subject is administered at least one therapeutic dose of the BCMAxCD3 bispecific antibody. In a preferred embodiment, an escalation phase precedes the first BCMAxCD3 treatment cycle in a treatment-effective regimen.

[0142] Additional abbreviations used in this article include the following: CR, complete response; PR, partial response; Q2W, once every 2 weeks; Q4W, once every 4 weeks; QW, once a week; RP2D, recommended phase 2 dose; SUD, escalation dose.

[0143] According to the implementation plan, the treatment method for HR-SMM effectively elicits a clinical response in the subjects, as determined by the International Myeloma Working Group (IMWG) 2016 response criteria. According to the specific implementation plan, the treatment method effectively elicits a partial response (PR), a very good partial response (VGPR), a complete response (CR), or a strict complete response (sCR), as determined by the IMWG 2016 response criteria. As used herein, the overall response rate (ORR) refers to the percentage of patients in the population who achieve a partial response (PR) or a better outcome (i.e., partial response, very good partial response, complete response, or strict complete response). Unless otherwise specified herein, PR, VGPR, CR, and sCR are as defined by the IMWG (2016) criteria. The IMWG (2016) response criteria are known in the art and are provided in Table A below.

[0144] Table 8.

[0145]

[0146]

[0147] CR = Complete Response; FLC = Free Light Chain; Ig = Immunoglobulin; M protein = Monoclonal protein; PC = Plasma cell; PR = Partial Response; sCR = Strict Complete Response; SPD = Sum of the products of the largest vertical diameters of the measured lesions; VGPR = Very Good Partial Response.

[0148] a. Criteria for CR and VGPR in participants whose only measurable disease was determined by serum FLC levels: In addition to the CR criteria listed above, CR in these participants indicates a normal FLC ratio of 0.26 to 1.65 (or the reference range of the study's sponsoring central laboratory: 0.22 to 1.52). VGPR in these participants requires a reduction of ≥90% in the difference between affected and unaffected FLC levels.

[0149] b. In some cases, the original M protein light chain isoform may still be detectable at immunofixation, but the accompanying heavy chain component has disappeared; this will not be considered CR, even if the heavy chain component is undetectable, because the clone may evolve into a clone that only secretes the light chain. Therefore, if a participant has IgAλ myeloma, in order to be considered a CR, there should be no detectable IgA at serum or urine immunofixation; if free λ is detected without IgA, it must be accompanied by a different heavy chain isoform (IgG, IgM, etc.).

[0150] c. Clarification of criteria used to encode disease progression: Bone marrow criteria for disease progression are only used for participants with no disease that can be measured by M protein and FLC levels; “25% increase” refers to M protein and FLC, not bone lesions or soft tissue plasmacytoma, and “minimum response value” does not need to be a confirmed value.

[0151] The IMWG criteria for response to treatment of multiple myeloma are also described in, for example, Durie et al., Kumar et al., and Rajkumar et al., which are incorporated herein by reference: Durie BG, Harousseau JL, Miguel JS et al., International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-1473; Kumar S, Paiva B, Anderson KC et al., International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016; 17(8):e328-346; Rajkumar SV, Harousseau JL, Durie B et al., Consensus recommendations for the uniform reporting of clinical Trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 117(18):4691-4695.

[0152] The implementation scheme provides a method for treating high-risk smoldering multiple myeloma (HR-SMM) in subjects of need, comprising treating subjects according to a treatment-effective regimen comprising consecutive cycles of BCMAxCD3 treatment. In a preferred embodiment, each consecutive cycle of BCMAxCD3 treatment is 28 days.

[0153] In some implementations, the method includes subcutaneous administration of each dose of the BCMAxCD3 bispecific antibody.

[0154] In some embodiments, one or more escalating doses of the BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period (e.g., where the escalation period is the first cycle of a treatment-effective regimen comprising consecutive 28-day cycles of BCMAxCD3 treatment). In a preferred embodiment, the escalation period is 28 days.

[0155] In some implementations, the subject is administered one to three incremental doses of the BCMAxCD3 bispecific antibody during the escalation period. For example, in some implementations, the subject is administered two incremental doses of the BCMAxCD3 bispecific antibody during the escalation period.

[0156] In some embodiments, the escalation period includes a first escalation dose of 0.06 mg / kg of the BCMAxCD3 bispecific antibody. For example, in some embodiments, the escalation period includes a first escalation dose of 0.06 mg / kg of the BCMAxCD3 bispecific antibody and a second escalation dose of 0.3 mg / kg of the BCMAxCD3 bispecific antibody.

[0157] In some embodiments, in addition to one or more escalation doses, one or more therapeutic doses of BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period. For example, in some embodiments, after one or more escalation doses have been administered, two or three therapeutic doses of BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period. In some embodiments, each therapeutic dose of BCMAxCD3 bispecific antibody administered during the escalation period is 0.72 mg / kg, 1.5 mg / kg, or 3.0 mg / kg. In a preferred embodiment, each of the one or more therapeutic doses of BCMAxCD3 bispecific antibody administered during the escalation period is administered at an amount of 1.5 mg / kg.

[0158] In some embodiments, the escalation period includes subcutaneous administration of two escalation doses and three therapeutic doses of the BCMAxCD3 bispecific antibody. In other embodiments, the escalation period includes subcutaneous administration of two escalation doses and two therapeutic doses of the BCMAxCD3 bispecific antibody. In a preferred embodiment, two or three therapeutic doses of the BCMAxCD3 bispecific antibody are administered according to a weekly dosing schedule (QW) during the escalation period.

[0159] In some implementations, the escalation period includes subcutaneous administration of a first escalation dose of 0.06 mg / kg, a second escalation dose of 0.3 mg / kg, a first treatment dose of 1.5 mg / kg, and a second treatment dose of 1.5 mg / kg to the subject.

[0160] In some embodiments, the second escalation dose is administered 2 to 4 days after the first escalation dose. In some embodiments, the second escalation dose is administered 2 days after the first escalation dose. In some embodiments, the first treatment dose is administered 4 to 7 days after the second escalation dose. In some embodiments, the first treatment dose is administered 5 days after the second escalation dose. In some embodiments, the second treatment dose is administered 5 to 9 days after the first treatment dose. In some embodiments, the second treatment dose is administered 7 days after the first treatment dose.

[0161] In some embodiments, the escalation period includes subcutaneous administration of a first escalation dose of 0.06 mg / kg, a second escalation dose of 0.3 mg / kg, a first treatment dose of 1.5 mg / kg, a second treatment dose of 1.5 mg / kg, and a third treatment dose of 1.5 mg / kg. In some embodiments, the third treatment dose is administered 5 to 9 days after the second treatment dose. In some embodiments, the third treatment dose is administered 7 days after the second treatment dose.

[0162] In some embodiments, the escalation period includes subcutaneous administration of a first escalation dose of 0.06 mg / kg on day 1, a second escalation dose of 0.3 mg / kg on day 3, a first treatment dose of 1.5 mg / kg on day 8, and a second treatment dose of 1.5 mg / kg on day 15. In some embodiments, the escalation period includes subcutaneous administration of a first escalation dose of 0.06 mg / kg on day 1, a second escalation dose of 0.3 mg / kg on day 3, a first treatment dose of 1.5 mg / kg on day 8, a second treatment dose of 1.5 mg / kg on day 15, and a third treatment dose of 1.5 mg / kg on day 22.

[0163] In some embodiments, the method includes administering a BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises: in cycle 1, subcutaneous administration of one or more escalating doses followed by two or more weekly (QW) treatment doses, and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneous administration of weekly (QW) treatment doses.

[0164] In some embodiments, the method includes administering a BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises: in cycle 1, subcutaneous administration of one or more escalating doses followed by two or more weekly (QW) treatment doses, and in one or more subsequent BCMAxCD3 treatment cycles (e.g., one BCMAxCD3 treatment cycle), subcutaneous administration of a weekly (QW) treatment dose, and then in one or more subsequent BCMAxCD3 treatment cycles (e.g., four BCMAxCD3 treatment cycles), subcutaneous administration of a bi-weekly (Q2W) treatment dose.

[0165] In some embodiments, the method includes administering a BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises: in cycle 1, subcutaneous administration of one or more escalating doses followed by two or more weekly (QW) treatment doses; and in one or more subsequent BCMAxCD3 treatment cycles (e.g., one BCMAxCD3 treatment cycle), subcutaneous administration of a weekly (QW) treatment dose; and then in one or more subsequent BCMAxCD3 treatment cycles (e.g., four BCMAxCD3 treatment cycles), subcutaneous administration of a bi-weekly (Q2W) treatment dose; and then in one or more subsequent BCMAxCD3 treatment cycles (e.g., six, twelve, or eighteen BCMAxCD3 treatment cycles), subcutaneous administration of a monthly (Q4W) treatment dose.

[0166] In some embodiments, the method includes administering a BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises: in cycle 1, subcutaneous administration of one or more escalating doses followed by two or more weekly (QW) treatment doses; in cycle 2, subcutaneous administration of a weekly (QW) treatment dose; in cycles 3-6, subcutaneous administration of a bi-weekly (Q2W) treatment dose; and, starting in cycle 7 (e.g., in cycles 7-12 or 7-24), subcutaneous administration of a monthly (Q4W) treatment dose.

[0167] In some embodiments, the BCMAxCD3 bispecific antibody is administered to the subject at a dose of 1.5 mg / kg or 3 mg / kg per treatment dose. In a preferred embodiment, the treatment dose is 1.5 mg / kg per week (QW), 3.0 mg / kg per two weeks (Q2W), and 3.0 mg / kg per month (Q4W).

[0168] In some embodiments, the method includes administering a BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises: in cycle 1, subcutaneous administration of one or more escalating doses followed by two or more weekly (QW) treatment doses of 1.5 mg / kg, and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneous administration of a weekly (QW) dose of 1.5 mg / kg.

[0169] In some embodiments, the method includes administering a BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises: in cycle 1, subcutaneous administration of one or more escalating doses followed by two or more weekly (QW) treatment doses of 1.5 mg / kg; in one or more subsequent BCMAxCD3 treatment cycles, subcutaneous administration of a weekly (QW) dose of 1.5 mg / kg; and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneous administration of a bi-weekly (Q2W) dose of 3.0 mg / kg.

[0170] In some embodiments, the method includes administering a BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises: in cycle 1, subcutaneous administration of one or more escalating doses followed by two or more weekly (QW) treatment doses of 1.5 mg / kg; in one or more subsequent BCMAxCD3 treatment cycles, subcutaneous administration of a weekly (QW) dose of 1.5 mg / kg; in one or more subsequent BCMAxCD3 treatment cycles, subcutaneous administration of a bi-weekly (Q2W) dose of 3.0 mg / kg; and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneous administration of a monthly (Q4W) dose of 3.0 mg / kg.

[0171] In some embodiments, the method includes administering a BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen includes: in cycle 1, subcutaneous administration of one or more escalating doses followed by two or more weekly (QW) doses of 1.5 mg / kg; in cycle 2, subcutaneous administration of a weekly (QW) dose of 1.5 mg / kg; and in cycles 3–6, subcutaneous administration of a bi-weekly (Q2W) dose of 3.0 mg / kg; and

[0172] Begin in cycle 7 (e.g., in cycles 7-12 or 7-24), administer a subcutaneous treatment dose of 3.0 mg / kg per month (Q4W).

[0173] In some embodiments, the method includes administering a BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises: in cycle 1, subcutaneous administration of one or more escalating doses followed by two or more weekly (QW) treatment doses of 1.5 mg / kg (e.g., on days 8, 15, and 22); in cycle 2, subcutaneous administration of a weekly (QW) dose of 1.5 mg / kg (e.g., on days 1, 8, 15, and 22); in cycles 3–6, subcutaneous administration of a 2-week (Q2W) dose of 3 mg / kg (e.g., on days 1 and 15); and starting in cycle 7 (e.g., in cycles 7–12 or 7–24), subcutaneous administration of a monthly (Q4W) dose of 3 mg / kg (e.g., on day 1 of each cycle).

[0174] In some embodiments, the method includes administering a BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises: in cycle 1, subcutaneous administration of a first escalation dose of 0.06 mg / kg (e.g., on day 1), a second escalation dose of 0.3 mg / kg (e.g., on day 3), followed by a weekly (QW) treatment dose of 1.5 mg / kg (e.g., on days 8, 15, and 22); in cycle 2, subcutaneous administration of a weekly (QW) dose of 1.5 mg / kg (e.g., on days 1, 8, 15, and 22); in cycles 3–6, subcutaneous administration of a 2-week (Q2W) dose of 3 mg / kg (e.g., on days 1 and 15); and starting in cycle 7 (e.g., in cycles 7–12 or 7–24), subcutaneous administration of a monthly (Q4W) dose of 3 mg / kg (e.g., on day 1 of each cycle).

[0175] The following provides an exemplary implementation of the dosing regimen:

[0176] 1. Cycle 1: Dosage is administered on days 1, 3, 8, 15, and 22 of a 28-day treatment cycle. Incremental doses are given on days 1 and 3 of Cycle 1; therapeutic doses are given on days 8, 15, and 22 of Cycle 1.

[0177] 2. Second cycle (28-day cycle): Dosage is administered on days 1, 8, 15, and 22.

[0178] 3. Cycles 3-6 (28-day cycle): Treatment is administered on day 1 and day 15.

[0179] 4. Cycles 7-24 (28-day cycle): Treatment is administered on day 1.

[0180] Exemplary implementations of the dosing regimen are also provided in Table 9 (cycle 1) and Table 10 (cycles 2-24).

[0181] Table 9. Treatment Cycle 1 (Incremental Phase) of an Exemplary Dosing Regimen

[0182]

[0183] *Weight-based dosing calculations based on institutional standards

[0184] Table 10. Cycles 2-24 of the exemplary dosing regimen

[0185]

[0186] *Weight-based dosing calculations based on institutional standards

[0187] Another exemplary implementation of the dosing regimen is provided in Table 11 (cycle 1) and Table 12 (cycles 2-12).

[0188] Table 11. Treatment Cycle 1 (Incremental Phase) of an Exemplary Dosing Regimen

[0189]

[0190] *Weight-based dosing calculations based on institutional standards

[0191] Table 12. Cycles 2-12 of the exemplary dosing regimen

[0192]

[0193] *Weight-based dosing calculations based on institutional standards

[0194] According to certain embodiments, one or more pretreatment drugs are administered to the subject prior to the administration of a dose of the BCMAxCD3 bispecific antibody. According to certain embodiments, one or more pretreatment drugs are administered to the subject during cycle 1 (escalation phase). According to certain embodiments, one or more pretreatment drugs are administered to the subject during both cycle 1 (escalation phase) and cycle 2. According to certain embodiments, one or more pretreatment drugs are selected from the group consisting of dexamethasone, diphenhydramine, acetaminophen, and any combination thereof. According to exemplary embodiments, pretreatment drugs are administered to the subject as shown in Table 13, where “x” indicates the date on which the pretreatment drug is administered.

[0195] Table 13. Pre-treatment medications

[0196]

[0197] In some implementations, the clinical response achieved by this method in subjects is a partial response (PR), a very good partial response (VGPR), a complete response (CR), or a strict complete response (sCR), as defined by the IMWG (2016) response criteria.

[0198] In some implementations, the method achieves CR, VGPR, or PR in subjects, as defined by the IMWG (2016) response criteria.

[0199] In some implementations, the method achieves VGPR or PR in subjects, as defined by the IMWG (2016) response criteria.

[0200] In some implementations, the method achieved an overall response rate (ORR) of 70% or higher in a population of subjects with HR-SMM.

[0201] In some implementations, the method achieved an overall response rate (ORR) of 75% or higher in a population of subjects with HR-SMM.

[0202] In some implementations, the method achieved an overall response rate (ORR) of 80% or higher in a population of subjects with HR-SMM.

[0203] In some implementations, the method achieved an overall response rate (ORR) of 85% or higher in a population of subjects with HR-SMM.

[0204] In some implementations, the method achieved an overall response rate (ORR) of 90% or higher in a population of subjects with HR-SMM.

[0205] In some implementations, the method achieved an overall response rate (ORR) of 95% or higher in a population of subjects with HR-SMM.

[0206] In some implementations, this method achieved a 100% overall response rate (ORR) in a population of subjects with HR-SMM.

[0207] In some implementations, the method achieved complete remission (CR) in at least 25% of the subject population with HR-SMM.

[0208] In some implementations, the method achieved complete remission (CR) in at least 30% of the subject population with HR-SMM.

[0209] In some implementations, the method achieved complete remission (CR) in at least 35% of the subject population with HR-SMM.

[0210] In some implementations, the method achieved complete remission (CR) in at least 40% of the subject population with HR-SMM.

[0211] In some implementations, the method achieves MRD-negative disease in subjects.

[0212] In some implementations, the HR-SMM of a subject does not progress after the subject has received at least four 28-day cycles of treatment with the BCMAxCD3 bispecific antibody. In some implementations, the subject is administered the BCMAxCD3 bispecific antibody for up to twenty-four (24) 28-day treatment cycles to prevent the subject from developing multiple myeloma.

[0213] In some implementations, administering the BCMAxCD3 bispecific antibody to subjects for up to twelve (12) 28-day treatment cycles prevents subjects from developing multiple myeloma. In some implementations, this method cures HR-SMM and prevents subjects from developing MM.

[0214] In some implementations, the method achieves a higher overall response rate (ORR) in a subject population with HR-SMM than in a reference subject population with HR-SMM who have been administered lenalidomide and dexamethasone but not the BCMAxCD3 bispecific antibody.

[0215] In some implementations, the method achieves a higher percentage of complete response (CR) in a population of subjects with HR-SMM than in a reference population of subjects with HR-SMM who have been administered lenalidomide and dexamethasone but not the BCMAxCD3 bispecific antibody.

[0216] Exemplary Implementation

[0217] The following are some examples of embodiments. These embodiments are merely exemplary and do not limit the scope of this disclosure or the appended claims.

[0218] 1. A method for treating a subject with high-risk smoking multiple myeloma (HR-SMM) in need, the method comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to the subject.

[0219] 2. The method according to embodiment 1, wherein the BCMAxCD3 bispecific antibody comprises: a BCMA binding domain comprising HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3 binding domain comprising HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19.

[0220] 3. The method according to embodiment 1 or 2, wherein the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.

[0221] 4. The method according to any one of embodiments 1 to 3, wherein the BCMAxCD3 bispecific antibody is an IgG1, IgG2, IgG3 or IgG4 isotype.

[0222] 5. The method according to any one of embodiments 1 to 4, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype.

[0223] 6. The method according to any one of embodiments 1 to 5, wherein the BCMAxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0224] 7. The method according to any one of embodiments 1 to 6, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype and contains proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235 respectively (according to EU index number) in its Fc region.

[0225] 8. The method according to any one of embodiments 1 to 7, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype and contains F405L and R409K substitutions (according to EU index number) in its Fc region.

[0226] 9. The method according to any one of embodiments 1 to 8, wherein the Fc region of the BCMA binding arm contains proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235 (according to EU index number).

[0227] 10. The method according to any one of embodiments 1 to 9, wherein the Fc region of the CD3 binding arm contains, in addition to the F405L and R409K substitutions, proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235 (according to EU index numbers).

[0228] 11. The method according to any one of embodiments 1 to 10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23.

[0229] 12. The method according to any one of embodiments 1 to 10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 23.

[0230] 13. The method according to any one of embodiments 1 to 10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 23.

[0231] 14. The method according to any one of embodiments 1 to 10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 23.

[0232] 15. The method according to any one of embodiments 1 to 10, wherein the BCMAxCD3 bispecific antibody is teratogenab.

[0233] 16. The method according to any one of embodiments 1 to 15, wherein the subject has not received prior SMM-targeted therapy.

[0234] 17. The method according to any one of embodiments 1 to 16, wherein the subject does not have symptomatic multiple myeloma.

[0235] 18. The method according to any one of embodiments 1 to 17, wherein the BCMAxCD3 bispecific antibody is administered as a single therapy (i.e., without another concurrent SMM-targeted therapy).

[0236] 19. The method according to any one of embodiments 1 to 18, wherein the method comprises subcutaneous administration of each dose of the BCMAxCD3 bispecific antibody.

[0237] 20. The method according to any one of embodiments 1 to 19, wherein the method comprises treating the subject according to a treatment efficacy regimen comprising consecutive 28-day BCMAxCD3 treatment cycles.

[0238] 21. The method according to any one of embodiments 1 to 20, wherein one or more escalating doses of the BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period (e.g., wherein the escalation period is the first cycle of a treatment efficacy regimen comprising consecutive 28-day BCMAxCD3 treatment cycles).

[0239] 22. The method according to implementation scheme 21, wherein the increment period is 28 days.

[0240] 23. The method according to any embodiment 21 or 22, wherein the subject is administered one to three incremental doses of the BCMAxCD3 bispecific antibody during the incremental period.

[0241] 24. The method according to any one of embodiments 21 to 23, wherein two incremental doses of the BCMAxCD3 bispecific antibody are administered to the subject during the incremental period.

[0242] 25. The method according to any one of embodiments 21 to 24, wherein the escalation period comprises a first escalation dose of the BCMAxCD3 bispecific antibody of 0.06 mg / kg.

[0243] 26. The method according to any one of embodiments 21 to 25, wherein the escalation period comprises a first escalation dose of the BCMAxCD3 bispecific antibody of 0.06 mg / kg and a second escalation dose of the BCMAxCD3 bispecific antibody of 0.3 mg / kg.

[0244] 27. The method according to any one of embodiments 21 to 26, wherein, in addition to the one or more escalating doses, one or more therapeutic doses of the BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period.

[0245] 28. The method according to any one of embodiments 21 to 27, wherein, in addition to the one or more escalating doses, two therapeutic doses of the BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period.

[0246] 29. The method according to any one of embodiments 21 to 28, wherein, in addition to the one or more escalating doses, three therapeutic doses of the BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period.

[0247] 30. The method according to any one of embodiments 21 to 29, wherein the escalation period comprises subcutaneous administration of two escalation doses and two therapeutic doses of the BCMAxCD3 bispecific antibody.

[0248] 31. The method according to any one of embodiments 21 to 29, wherein the escalation period comprises subcutaneous administration of two escalation doses and three therapeutic doses of the BCMAxCD3 bispecific antibody.

[0249] 32. The method according to any one of embodiments 27 to 31, wherein the one or more therapeutic doses of the BCMAxCD3 bispecific antibody administered during the escalation period are administered at an amount of 0.72 mg / kg, 1.5 mg / kg, or 3.0 mg / kg.

[0250] 33. The method according to any one of embodiments 27 to 31, wherein the BCMAxCD3 bispecific antibody in each of the one or more treatment doses administered during the escalation period is administered at an amount of 1.5 mg / kg.

[0251] 34. The method according to any one of embodiments 27 to 33, wherein two or three therapeutic doses of the BCMAxCD3 bispecific antibody are administered according to a weekly dosing schedule (QW) during the escalation period.

[0252] 35. The method according to any one of embodiments 27 to 33, wherein two therapeutic doses of the BCMAxCD3 bispecific antibody are administered according to a weekly dosing schedule (QW) during the escalation period.

[0253] 36. The method according to any one of embodiments 27 to 33, wherein three therapeutic doses of the BCMAxCD3 bispecific antibody are administered according to a weekly dosing schedule (QW) during the escalation period.

[0254] 37. The method according to any one of embodiments 21 to 29, wherein the escalation period comprises subcutaneously administering to the subject a first escalation dose of 0.06 mg / kg, a second escalation dose of 0.3 mg / kg, a first therapeutic dose of 1.5 mg / kg, and a second therapeutic dose of 1.5 mg / kg.

[0255] 38. The method according to embodiment 37, wherein the second incremental dose is administered 2 to 4 days after the first incremental dose.

[0256] 39. The method according to embodiment 37, wherein the second incremental dose is administered 2 days after the first incremental dose.

[0257] 40. The method according to any one of embodiments 37 to 39, wherein the first therapeutic dose is administered 4 to 7 days after the second incremental dose.

[0258] 41. The method according to any one of embodiments 37 to 39, wherein the first therapeutic dose is administered 5 days after the second incremental dose.

[0259] 42. The method according to any one of embodiments 37 to 41, wherein the second therapeutic dose is administered 5 to 9 days after the first therapeutic dose.

[0260] 43. The method according to any one of embodiments 37 to 41, wherein the second treatment dose is administered 7 days after the first treatment dose.

[0261] 44. The method according to any one of embodiments 21 to 43, wherein the escalation period comprises subcutaneous administration of a first escalation dose of 0.06 mg / kg on day 1, a second escalation dose of 0.3 mg / kg on day 3, a first treatment dose of 1.5 mg / kg on day 8, and a second treatment dose of 1.5 mg / kg on day 15 to the subject.

[0262] 45. The method according to any one of embodiments 37 to 44, wherein the escalation period comprises subcutaneously administering to the subject a first escalation dose of 0.06 mg / kg, a second escalation dose of 0.3 mg / kg, a first therapeutic dose of 1.5 mg / kg, a second therapeutic dose of 1.5 mg / kg, and a third therapeutic dose of 1.5 mg / kg.

[0263] 46. ​​The method according to embodiment 45, wherein the third treatment dose is administered 5 to 9 days after the second treatment dose.

[0264] 47. The method according to embodiment 45, wherein the third treatment dose is administered 7 days after the second treatment dose.

[0265] 48. The method according to any one of embodiments 21 to 47, wherein the escalation period comprises subcutaneous administration of a first escalation dose of 0.06 mg / kg on day 1, a second escalation dose of 0.3 mg / kg on day 3, a first treatment dose of 1.5 mg / kg on day 8, a second treatment dose of 1.5 mg / kg on day 15, and a third treatment dose of 1.5 mg / kg on day 22.

[0266] 49. The method according to any one of embodiments 1 to 48, the method comprising administering the BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises:

[0267] During the first cycle, one or more escalating doses are administered subcutaneously, followed by two or more weekly (QW) treatment doses.

[0268] In one or more subsequent BCMAxCD3 treatment cycles, a weekly (QW) treatment dose is administered subcutaneously.

[0269] 50. The method according to any one of embodiments 1 to 48, the method comprising administering the BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises:

[0270] During the first cycle, one or more escalating doses are administered subcutaneously, followed by two or more weekly (QW) treatment doses.

[0271] In one or more subsequent BCMAxCD3 treatment cycles (e.g., one BCMAxCD3 treatment cycle), a weekly (QW) treatment dose is administered subcutaneously, and then...

[0272] In one or more subsequent BCMAxCD3 treatment cycles (e.g., four BCMAxCD3 treatment cycles), a treatment dose is administered subcutaneously every two weeks (Q2W).

[0273] 51. The method according to any one of embodiments 1 to 48, the method comprising administering the BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises:

[0274] During the first cycle, one or more escalating doses are administered subcutaneously, followed by two or more weekly (QW) treatment doses.

[0275] In one or more subsequent BCMAxCD3 treatment cycles (e.g., one BCMAxCD3 treatment cycle), a weekly (QW) treatment dose is administered subcutaneously, and then...

[0276] In one or more subsequent BCMAxCD3 treatment cycles (e.g., four BCMAxCD3 treatment cycles), a subcutaneous treatment dose is administered every two weeks (Q2W), and then...

[0277] In one or more subsequent BCMAxCD3 treatment cycles (e.g., six, twelve, or eighteen BCMAxCD3 treatment cycles), a monthly (Q4W) treatment dose is administered subcutaneously.

[0278] 52. The method according to any one of embodiments 1 to 48, the method comprising administering the BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises:

[0279] During the first cycle, one or more escalating doses are administered subcutaneously, followed by two or more weekly (QW) treatment doses.

[0280] During cycle 2, a weekly (QW) treatment dose was administered subcutaneously.

[0281] During cycles 3-6, the treatment dose was administered subcutaneously every two weeks (Q2W); and

[0282] Begin in cycle 7 (e.g., in cycles 7-12 or 7-24), administer a monthly (Q4W) treatment dose subcutaneously.

[0283] 53. The method according to any one of embodiments 1 to 52, wherein the BCMAxCD3 bispecific antibody is administered to the subject at a dose of 1.5 mg / kg or 3 mg / kg (e.g., wherein each weekly treatment dose is 1.5 mg / kg, each bi-weekly treatment dose is 3.0 mg / kg, and each monthly treatment dose is 3.0 mg / kg).

[0284] 54. The method according to any one of embodiments 1 to 53, the method comprising administering the BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises:

[0285] During the first cycle, one or more escalating doses were administered subcutaneously, followed by two or more weekly (QW) treatment doses of 1.5 mg / kg.

[0286] During one or more subsequent BCMAxCD3 treatment cycles, a weekly (QW) treatment dose of 1.5 mg / kg is administered subcutaneously.

[0287] 55. The method according to any one of embodiments 1 to 54, the method comprising administering the BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises:

[0288] During the first cycle, one or more escalating doses were administered subcutaneously, followed by two or more weekly (QW) treatment doses of 1.5 mg / kg.

[0289] During one or more subsequent BCMAxCD3 treatment cycles, a subcutaneous treatment dose of 1.5 mg / kg was administered weekly (QW), and then...

[0290] During one or more subsequent BCMAxCD3 treatment cycles, a subcutaneous dose of 3.0 mg / kg is administered every two weeks (Q2W).

[0291] 56. The method according to any one of embodiments 1 to 55, the method comprising administering the BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises:

[0292] During the first cycle, one or more escalating doses were administered subcutaneously, followed by two or more weekly (QW) treatment doses of 1.5 mg / kg.

[0293] During one or more subsequent BCMAxCD3 treatment cycles, a subcutaneous treatment dose of 1.5 mg / kg was administered weekly (QW), and then...

[0294] In one or more subsequent BCMAxCD3 treatment cycles, a subcutaneous dose of 3.0 mg / kg was administered every two weeks (Q2W), and then...

[0295] During one or more subsequent BCMAxCD3 treatment cycles, a monthly (Q4W) treatment dose of 3.0 mg / kg is administered subcutaneously.

[0296] 57. The method according to any one of embodiments 1 to 56, the method comprising administering the BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises:

[0297] During the first cycle, one or more escalating doses are administered subcutaneously, followed by two or more weekly (QW) treatment doses of 1.5 mg / kg.

[0298] During cycle 2, a weekly (QW) treatment dose of 1.5 mg / kg was administered subcutaneously.

[0299] During cycles 3-6, a subcutaneous treatment dose of 3.0 mg / kg was administered every two weeks (Q2W); and

[0300] Begin in cycle 7 (e.g., in cycles 7-12 or 7-24), administer a subcutaneous treatment dose of 3.0 mg / kg per month (Q4W).

[0301] 58. The method according to any one of embodiments 1 to 57, the method comprising administering the BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises:

[0302] During the first cycle, one or more escalating doses are administered subcutaneously, followed by two or more weekly (QW) treatment doses of 1.5 mg / kg (e.g., on days 8, 15, and 22).

[0303] During cycle 2, a weekly (QW) dose of 1.5 mg / kg was administered subcutaneously (e.g., on days 1, 8, 15, and 22).

[0304] During cycles 3–6, administer subcutaneous doses of 3 mg / kg every two weeks (Q2W) (e.g., on day 1 and day 15); and

[0305] Start in cycle 7 (e.g., in cycles 7-12 or 7-24), administer a subcutaneous dose of 3 mg / kg per month (Q4W) (e.g., on day 1 of each cycle).

[0306] 59. The method according to any one of embodiments 1 to 58, the method comprising administering the BCMAxCD3 bispecific antibody (e.g., teratomab) according to a regimen comprising a 28-day cycle, wherein the regimen comprises:

[0307] In the first cycle, a first escalation dose of 0.06 mg / kg is administered subcutaneously (e.g., on day 1), a second escalation dose of 0.3 mg / kg is administered (e.g., on day 3), and then a weekly (QW) treatment dose of 1.5 mg / kg is administered (e.g., on days 8, 15, and 22).

[0308] During cycle 2, a weekly (QW) dose of 1.5 mg / kg was administered subcutaneously (e.g., on days 1, 8, 15, and 22).

[0309] During cycles 3–6, administer subcutaneous doses of 3 mg / kg every two weeks (Q2W) (e.g., on day 1 and day 15); and

[0310] Start in cycle 7 (e.g., in cycles 7-12 or 7-24), administer a subcutaneous dose of 3 mg / kg per month (Q4W) (e.g., on day 1 of each cycle).

[0311] 60. The method according to any one of embodiments 1 to 59, wherein the clinical response achieved by the method in the subject is a partial response (PR), a very good partial response (VGPR), a complete response (CR), or a strictly complete response (sCR), as defined by the IMWG (2016) response criteria.

[0312] 61. The method according to any one of embodiments 1 to 59, wherein the method achieves CR, VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

[0313] 62. The method according to any one of embodiments 1 to 59, wherein the method achieves VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

[0314] 63. The method according to any one of embodiments 1 to 62, wherein the method achieves an overall response rate (ORR) of 70% or higher in a subject population with HR-SMM.

[0315] 64. The method according to any one of embodiments 1 to 62, wherein the method achieves an overall response rate (ORR) of 75% or higher in a subject population with HR-SMM.

[0316] 65. The method according to any one of embodiments 1 to 62, wherein the method achieves an overall response rate (ORR) of 80% or higher in a subject population with HR-SMM.

[0317] 66. The method according to any one of embodiments 1 to 62, wherein the method achieves an overall response rate (ORR) of 85% or higher in a subject population with HR-SMM.

[0318] 67. The method according to any one of embodiments 1 to 62, wherein the method achieves an overall response rate (ORR) of 90% or higher in a subject population with HR-SMM.

[0319] 68. The method according to any one of embodiments 1 to 62, wherein the method achieves an overall response rate (ORR) of 95% or higher in a subject population with HR-SMM.

[0320] 69. The method according to any one of embodiments 1 to 62, wherein the method achieved a 100% overall response rate (ORR) in a subject population with HR-SMM.

[0321] 70. The method according to any one of embodiments 1 to 69, wherein the method achieves CR in at least 25% of the subject population with HR-SMM.

[0322] 71. The method according to any one of embodiments 1 to 69, wherein the method achieves CR in at least 30% of the subject population with HR-SMM.

[0323] 72. The method according to any one of embodiments 1 to 69, wherein the method achieves CR in at least 35% of the subject population with HR-SMM.

[0324] 73. The method according to any one of embodiments 1 to 69, wherein the method achieves CR in at least 40% of the subject population with HR-SMM.

[0325] 74. The method according to any one of embodiments 1 to 73, wherein the method achieves MRD-negative disease in the subject.

[0326] 75. The method according to any one of embodiments 1 to 74, wherein the subject's HR-SMM does not progress after the subject has received at least four 28-day cycles of treatment with the BCMAxCD3 bispecific antibody.

[0327] 76. The method according to any one of embodiments 1 to 75, wherein the subject is administered the BCMAxCD3 bispecific antibody for a maximum of twenty-four (24) 28-day treatment cycles to prevent the subject from developing multiple myeloma.

[0328] 77. The method according to any one of embodiments 1 to 75, wherein the subject is administered the BCMAxCD3 bispecific antibody for up to twelve (12) 28-day treatment cycles to prevent the subject from developing multiple myeloma.

[0329] 78. The method according to any one of embodiments 1 to 77, wherein the method cures the HR-SMM and prevents the subject from developing MM.

[0330] 79. The method according to any one of embodiments 1 to 78, wherein the overall response rate (ORR) achieved by the method in a subject population with HR-SMM is greater than the ORR achieved in a reference subject population with HR-SMM, the reference population having been administered lenalidomide and dexamethasone but not the BCMAxCD3 bispecific antibody.

[0331] 80. The method according to any one of embodiments 1 to 79, wherein the percentage of complete response (CR) achieved by the method in a subject population with HR-SMM is greater than the percentage of CR achieved in a reference subject population with HR-SMM, the reference population having been administered lenalidomide and dexamethasone but not the BCMAxCD3 bispecific antibody.

[0332] Those skilled in the art will recognize that many changes and modifications can be made to the preferred embodiments, and that such changes and modifications can be made without departing from the spirit of the invention. Therefore, the appended claims are intended to cover all such equivalent variations.

[0333] Every patent, patent application, and publication cited or described in this document is incorporated herein by reference in its entirety.

[0334] Example

[0335] The following examples are provided to further describe some embodiments of the implementations disclosed herein. These examples are intended to illustrate, and not limit, the disclosed implementations.

[0336] Example 1: A randomized phase II platform study of a bispecific antibody in high-risk smoldering myeloma (Immuno-PRISM)

[0337] Antibody

[0338] The anti-BCMA / anti-CD3 antibody teratumab (also known as Tec) (e.g., described in WO2017031104A1, the contents of which are incorporated herein by reference in their entirety) was manufactured by Janssen Pharmaceuticals. Teratumab comprises the BCMA-binding arm BCMB69 and the CD3-binding arm CD3B219, the amino acid sequences of which are shown in Tables 5 and 6, respectively.

[0339] Table 5. Sequence of the BCMA binding arm of teratumab

[0340]

[0341] Table 6. Sequence of the CD3 binding arm of teratumab

[0342]

[0343] Purpose :

[0344] The study evaluated the anticancer activity of a bispecific antibody, including teratumab (also known as “TEC” or “Tec”), relative to a control group of lenalidomide and dexamethasone for the treatment of high-risk smoking multiple myeloma (HR-SMM).

[0345] method :

[0346] This is a multi-arm, randomized, phase II platform study evaluating TEC relative to lenalidomide and dexamethasone in the HR-SMM. Eligibility criteria include HR-SMM according to the Mayo 2018 “20-2-20” model, a total IMWG risk score of 9 or higher, and other previously identified high-risk criteria, including the PETHEMA criteria, evolutionary SMM, and high-risk FISH abnormalities.

[0347] This study had an initial safety induction cohort of 6 patients treated with TEC. All patients received two escalating doses of subcutaneous TEC. During the safety induction, patients received TEC at a dose lower than the recommended phase 2 dose (RP2D). If no dose-limiting toxicities (DLTs) were observed, the next cohort received TEC at the RP2D. Once the safety induction was complete, a randomization trial was initiated with a 2:1 randomization of TEC (30 patients) versus a control group (15 patients) of lenalidomide and dexamethasone. The duration of treatment was 24 cycles. TEC was administered weekly at a dose of 1.5 mg / kg for cycles 1 and 2, followed by 3 mg / kg on days 1 and 15 of cycles 3 through 6, and monthly from cycle 7 onwards for a total of 24 cycles (2 years). For the control group, lenalidomide was administered orally at a dose of 25 mg on days 1–21, and dexamethasone 40 mg was administered weekly for 24 cycles during the 28-day cycle period. All eligible patients underwent stem cell collection after four cycles of therapy.

[0348] The primary objective is complete response rate. Secondary objectives include progression-free survival (PFS), objective response rate (ORR), MRD negativity rate, pharmacokinetics and safety of TEC. Exploratory objectives include mass spectrometry quantification of the M protein, molecular evolution of tumor cells, and immunobiomarkers of response.

[0349] Qualification Standards :

[0350] Selection criteria

[0351] - Age > 18 years old.

[0352] - High-risk SMM is defined as having one of the following two criteria:

[0353] 1) High risk according to the "20-2-20" standard is defined as the presence of any two of the following:

[0354] • Serum M- peak ≥ 2 gm / dL

[0355] • The ratio of affected to unaffected free light chains (FLCs) is ≥ 20

[0356] • Bone marrow plasma cells (BMPC) % ≥ 20%

[0357] Alternatively, use the following scoring system, with a total score of 9 points:

[0358] • Free Light Chain (FLC) Ratio

[0359] o>10-25 = 2

[0360] o>25-40 = 3

[0361] o> 40 = 5

[0362] • Serum M protein (g / dL)

[0363] o>1.5-3 = 3

[0364] o>3 = 4

[0365] • Bone marrow plasma cells (BMPC) %

[0366] o>15-20 = 2

[0367] o>20-30 = 3

[0368] o>30-40 = 5

[0369] o>40 = 6

[0370] • Abnormal fluorescence in situ hybridization (FISH) (t(4,14), t(14,16), 1q gain or del13q = 2)

[0371] 2) ≥10% of BMPC exists and at least one of the following:

[0372] • Evolutionary pattern:

[0373] o Evolution of M protein over a 6-month period (eMP: serum M protein increase ≥10%); or

[0374] o A decrease of ≥ 0.5 g / dl in eHb over a 12-month period; or

[0375] The progressive increase in affected light chains > 10% and the light chain ratio > 8% over a 6-month period.

[0376] • Abnormal PC immunophenotype (≥ 95% of BMPCs are clonal) and a reduction in ≥ 1 unaffected immunoglobulin isotype. (IgG only; IgA and IgM will be considered)

[0377] • High-risk cytogenetics are defined as the presence of t(4;14), t(14;16), t(14;20), 17p deletions, TP53 mutations, and 1q gains.

[0378] • For those with monoclonal light chain smoldering multiple myeloma, monoclonal light chain excretion > 200 mg / 24 hours.

[0379] - There is no evidence of the CRAB standard* or the new active MM standard (SLIM-CRAB), which includes the following:

[0380] 1) Increased calcium levels: Corrected serum calcium is above the upper limit of normal >0.25 mmol / L (>1 mg / dL) or >2.75 mmol / L (>11 mg / dL).

[0381] 2) Renal insufficiency (attributable to multiple myeloma);

[0382] 3) Anemia (Hgb is below the lower limit of normal by 2 g / dL or <10 g / dL);

[0383] 4) Bone lesions (osteolytic lesions or diffuse osteoporosis with compression fractures)

[0384] 5) There is no evidence of the following new criteria for active MM, which include the following:

[0385] 6) Bone marrow plasma cells >60%

[0386] 7) Serum affected / unaffected FLC ratio ≥100

[0387] 8) If urinary monoclonal protein <200mg / 24h, a serum affected / unaffected FLC ratio >100 is not considered MDE. 82

[0388] 9) MRI showing more than one focal lesion

[0389] *Participants with CRAB criteria attributable to conditions other than the studied disease may be eligible after discussion with the sponsoring investigator.

[0390] -ECOG Performance Status (PS) 0, 1, or 2

[0391] - Obtain the following lab values ​​within 28 days prior to registration:

[0392] •ANC >1000 / mL

[0393] • PLT >75,000 / mL

[0394] • Total bilirubin ≤ 2.0 mg / dL (If the total bilirubin is elevated, check direct bilirubin; if it is normal, the patient meets the criteria.)

[0395] •AST < 2.5 x Upper Limit of Institutional Normal (ULN)

[0396] •ALT < 2.5 x Upper limit of institutional normal value (ULN)

[0397] • Estimated creatinine clearance CLcr ≥ 60 mL / min (Cockcroft-Gault formula).

[0398] - All female participants of childbearing age must have a negative pregnancy test result before enrollment.

[0399] Exclusion criteria

[0400] - Prior SMM-targeted therapy was administered within 6 months of starting treatment in the study. To avoid including primary refractory cases in the lenalidomide group, participants receiving prior lenalidomide-based therapy should have at least MR to be considered for enrollment in the trial.

[0401] - Any evidence of symptomatic multiple myeloma or CRAB criteria, including the presence of a myeloma-defining event (MDE). Any prior therapy for active myeloma should also be excluded. Prior therapy for smoldering myeloma is not an exclusion criterion. Bisphosphonates are not excluded.

[0402] - Other concurrent chemotherapy, immunotherapy, radiotherapy, or any adjuvant therapy considered investigational. Prior therapies using bisphosphonates are permitted. Prior radiotherapy for solitary plasmacytoma is permitted, but must have been administered at least 6 months prior to enrollment in the trial. Prior clinical trials or therapies for smoking MM or MGUS are permitted according to the above exclusion criteria.

[0403] - May interfere with serious medical or mental illnesses that may affect participation in this clinical study.

[0404] - Diagnosed with another malignant tumor or received treatment for another malignant tumor within 2 years of enrollment.

[0405] - Uncontrolled intermittent illnesses, including but not limited to persistent or active infections, symptomatic congestive heart failure, unstable angina, arrhythmias, or mental illnesses / social conditions that would limit compliance with study requirements.

[0406] -I plan to become a father when I enroll in the study or within 90 days after receiving the last dose of the study drug.

[0407] -Pregnant or breastfeeding or planning to become pregnant at the time of enrollment in the study or within 90 days after receiving the last dose of the study drug.

[0408] - Known seropositivity or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).

[0409] Participants who tested positive for hepatitis B virus due to the hepatitis B vaccine were eligible.

[0410] Participants who are positive for HIV1 and 2 antibodies, hepatitis B core antibody, or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.

[0411] - Contraindications, life-threatening allergies, hypersensitivity, or intolerance to any investigational drug or its excipients (refer to the Teritolumab Investigator's Manual and appropriate package insert).

[0412] -Previously or simultaneously exposed to any of the following:

[0413] • Investigational vaccine within 4 weeks

[0414] • Live attenuated vaccine within 4 weeks prior to randomization

[0415] • Monoclonal antibody therapy within 21 days

[0416] • Cytotoxic therapy within 14 days

[0417] • PI therapy within 14 days

[0418] • IMiD therapy within 14 days

[0419] • Radiation therapy within 14 days or local radiation within 7 days

[0420] - During the 14-day period prior to the first dose of the study drug, the maximum cumulative dose of corticosteroids was ≥140 mg prednisone or an equivalent dose (excluding pretreatment medications) (Appendix 10).

[0421] - Known active CNS involvement or clinical signs of meningeal involvement in multiple myeloma. If either of these is suspected, a negative whole-brain MRI and lumbar cytology examination are required.

[0422] - Myelodysplastic syndrome or active malignancy (i.e., progression within the last 24 months or requiring a change in treatment). Only the following exceptions are allowed:

[0423] • Non-muscle-invasive bladder cancer that is considered completely curable and has been treated within the last 24 months.

[0424] • Skin cancer (non-melanoma or melanoma) that has been treated and is considered completely cured within the last 24 months.

[0425] • Non-invasive cervical cancer that is considered completely cured and treated within the last 24 months.

[0426] • Localized prostate cancer (N0M0):

[0427] oGleason score ≤6, with or without treatment and under surveillance within the last 24 months.

[0428] An oGleason score of 3+4, having been treated for >6 months prior to full study screening and considered to have a very low risk of relapse, or

[0429] • A history of localized prostate cancer and receiving androgen deprivation therapy, and is considered to have a very low risk of recurrence.

[0430] • Breast cancer: Well-treated lobular carcinoma or ductal carcinoma in situ, or a history of localized breast cancer and receiving anti-hormonal agents and considered to have a very low risk of recurrence.

[0431] • Other malignant tumors that are considered curable and have a very low risk of recurrence.

[0432] - Stroke or epileptic seizure within 6 months prior to signing the ICF agreement

[0433] -The following heart conditions are present:

[0434] • New York Heart Association class III or IV congestive heart failure

[0435] • Myocardial infarction or coronary artery bypass grafting ≤6 months prior to randomization

[0436] • A clinically significant history of ventricular arrhythmias or unexplained syncope, believed not to be essentially vasovagal or dehydration-related.

[0437] • History of severe non-ischemic cardiomyopathy

[0438] - Those who have undergone major surgery within 2 weeks prior to the start of the study treatment, or who have not yet fully recovered from surgery, or who plan to undergo major surgery during the period during which the participant is expected to receive treatment in the study, or within 2 weeks after the administration of the last dose of the study treatment.

[0439] Note: Participants scheduled for procedures under local anesthesia may participate. Vertebroplasty or vertebroplasty is not considered a major surgery. If there is any doubt as to whether a procedure is considered a major surgery, the researcher must consult with the appropriate sponsor representative and resolve any issues before recruiting participants for the study.

[0440] - Comorbid medical or psychiatric conditions or illnesses that may interfere with the research process or results, or that the researcher believes may pose a risk to participation in the study, such as:

[0441] • Uncontrolled diabetes defined by hemoglobin A1C > 8.5

[0442] • Acute diffuse infiltrative lung disease

[0443] • Evidence of active systemic viral, fungal, or bacterial infection requiring systemic antimicrobial therapy.

[0444] • Based on clinical symptoms and laboratory tests, a history of autoimmune diseases other than vitiligo, type 1 diabetes, and a previous autoimmune thyroiditis with current normal thyroid function.

[0445] • Disabling mental illness (e.g., alcohol or drug abuse), severe dementia, or altered mental status.

[0446] • Any other issues that would impair a participant's ability to receive or tolerate planned treatment at the study site, to understand informed consent, or any situation that the investigator believes would not be in the best interest of the participant (e.g., impair well-being) or that might prevent, limit, or confuse the program-specified assessment.

[0447] • Medical history of not adhering to recommended medical treatment

[0448] Results: At the data cutoff, 19 patients were enrolled in the study, with a median follow-up period of 6 months. The median age was 59 years (range 35–73), including 9 women (47%) and 10 men (53%). 64% of patients with evaluable FISH results had high-risk abnormalities, including: 1q gain (7 patients), t(4;14) gain (1 patient).

[0449] No DLT was observed in the safety introductory cohort and patients are now being recruited into the randomized portion of the trial. In the TEC cohort (12 patients), grade 3 or higher hematologic toxicities were neutropenia (4 patients, regressed) and thrombocytopenia (1 patient, regressed). Grade 3 or higher non-hematologic toxicities were increased ALT in 3 patients (grade 3, regressed) and pancreatitis in 1 patient (grade 3, regressed). Nine patients developed infections, but only one had a grade 3 infection (sinusitis). The remaining infections were low-grade and mostly upper respiratory tract infections (6 patients). One patient had grade 2 uveitis. 75% of patients developed CRS (all were grade 1 and regressed, except for two patients with grade 2 CRS who required tocilizumab). No patients experienced ICANN, and no delayed neurotoxicity was observed. All patients treated with TEC received IVIG, with an average IgG level of 418 mg / dL at the start of IVIG treatment. 64% of patients achieved IgG normalization within two IVIG doses.

[0450] In the TEC treatment cohort (12 patients), the ORR was 100%, with 42% achieving CR, 25% achieving VGPR, and 33% achieving PR. Four high-risk FISH patients receiving TEC achieved CR within 5 cycles. In the lenalidomide and dexamethasone control group (3 patients), the ORR was 66%, and no complete responses have been reported to date. Of the 8 evaluable patients treated with TEC, 10... -6 The MRD negativity rate was 100%, including 2 patients with VGPR-MRD-negative disease. The mean time to achieve MRD negativity observed in evaluable patients was 4.25 cycles. No patients progressed during treatment. Stem cell harvesting was successfully achieved in all eligible patients, with a mean stem cell yield of 9.06 × 10⁶. 6 CD34+ cells / kg.

[0451] Conclusion: Teritumumab demonstrated significant activity in HR-SMM compared to RRMM: 100% ORR, MRD-negative disease in 100% of evaluable patients to date, and a significantly improved overall safety profile.

Claims

1. A method for treating a subject with high-risk smoking multiple myeloma (HR-SMM) in need, the method comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to the subject.

2. The method according to claim 1, wherein the BCMAxCD3 bispecific antibody comprises: a BCMA binding domain comprising HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3 binding domain comprising HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO:

19.

3. The method according to claim 1 or 2, wherein the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:

21.

4. The method according to any one of claims 1 to 3, wherein the BCMAxCD3 bispecific antibody is an IgG1, IgG2, IgG3 or IgG4 isotype.

5. The method according to any one of claims 1 to 4, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype.

6. The method according to any one of claims 1 to 5, wherein the BCMAxCD3 bispecific antibody contains one or more substitutions in its Fc region.

7. The method according to any one of claims 1 to 6, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype and contains proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235, respectively, in its Fc region.

8. The method according to any one of claims 1 to 7, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype and contains F405L and R409K substitutions in its Fc region.

9. The method according to any one of claims 1 to 8, wherein the Fc region of the BCMA binding arm comprises proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235, respectively.

10. The method according to any one of claims 1 to 9, wherein the Fc region of the CD3 binding arm contains, in addition to the F405L and R409K substitutions, proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235, respectively.

11. The method according to any one of claims 1 to 10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO:

23.

12. The method according to any one of claims 1 to 10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 90% identity with the amino acid sequence of SEQ ID NO:

23.

13. The method according to any one of claims 1 to 10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO:

23.

14. The method according to any one of claims 1 to 10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 98% identity with the amino acid sequence of SEQ ID NO:

23.

15. The method according to any one of claims 1 to 10, wherein the BCMAxCD3 bispecific antibody is teratogenab.

16. The method according to any one of claims 1 to 15, wherein the subject has not received prior SMM-targeted therapy.

17. The method according to any one of claims 1 to 16, wherein the subject does not have symptomatic multiple myeloma.

18. The method according to any one of claims 1 to 17, wherein the BCMAxCD3 bispecific antibody is administered as a monotherapy (i.e., without another concurrent SMM-targeted therapy).

19. The method according to any one of claims 1 to 18, the method comprising subcutaneous administration of each dose of the BCMAxCD3 bispecific antibody.

20. The method according to any one of claims 1 to 19, the method comprising treating the subject according to a treatment efficacy regimen comprising consecutive 28-day BCMAxCD3 treatment cycles.

21. The method according to any one of claims 1 to 20, wherein one or more escalating doses of the BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period.

22. The method of claim 21, wherein the increment period is 28 days.

23. The method according to any one of claims 21 or 22, wherein the subject is administered one to three incremental doses of the BCMAxCD3 bispecific antibody during the incremental period.

24. The method according to any one of claims 21 to 23, wherein two incremental doses of the BCMAxCD3 bispecific antibody are administered to the subject during the incremental period.

25. The method according to any one of claims 21 to 24, wherein the escalation period comprises a first escalation dose of the BCMAxCD3 bispecific antibody of 0.06 mg / kg.

26. The method according to any one of claims 21 to 25, wherein the escalation period comprises a first escalation dose of the BCMAxCD3 bispecific antibody of 0.06 mg / kg and a second escalation dose of the BCMAxCD3 bispecific antibody of 0.3 mg / kg.

27. The method according to any one of claims 21 to 26, wherein, in addition to the one or more escalating doses, one or more therapeutic doses of the BCMAxCD3 bispecific antibody are also administered subcutaneously to the subject during the escalation period.

28. The method according to any one of claims 21 to 27, wherein, in addition to the one or more escalating doses, two therapeutic doses of the BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period.

29. The method according to any one of claims 21 to 28, wherein, in addition to the one or more escalating doses, three therapeutic doses of the BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period.

30. The method according to any one of claims 21 to 29, wherein the escalation phase comprises subcutaneous administration of two escalation doses and two therapeutic doses of the BCMAxCD3 bispecific antibody.

31. The method according to any one of claims 21 to 29, wherein the escalation phase comprises subcutaneous administration of two escalation doses and three therapeutic doses of the BCMAxCD3 bispecific antibody.

32. The method according to any one of claims 27 to 31, wherein the one or more therapeutic doses of the BCMAxCD3 bispecific antibody administered during the escalation period are administered at an amount of 0.72 mg / kg, 1.5 mg / kg, or 3.0 mg / kg.

33. The method according to any one of claims 27 to 31, wherein the BCMAxCD3 bispecific antibody in each of the one or more treatment doses administered during the escalation period is administered at an amount of 1.5 mg / kg.

34. The method according to any one of claims 27 to 33, wherein two or three therapeutic doses of the BCMAxCD3 bispecific antibody are administered according to a weekly dosing schedule (QW) during the escalation period.

35. The method according to any one of claims 27 to 33, wherein two therapeutic doses of the BCMAxCD3 bispecific antibody are administered according to a weekly dosing schedule (QW) during the escalation period.

36. The method according to any one of claims 27 to 33, wherein three therapeutic doses of the BCMAxCD3 bispecific antibody are administered according to a weekly dosing schedule (QW) during the escalation period.

37. The method according to any one of claims 21 to 29, wherein the escalation period comprises subcutaneously administering to the subject a first escalation dose of 0.06 mg / kg, a second escalation dose of 0.3 mg / kg, a first therapeutic dose of 1.5 mg / kg, and a second therapeutic dose of 1.5 mg / kg.

38. The method of claim 37, wherein the second incremental dose is administered 2 to 4 days after the first incremental dose.

39. The method of claim 37, wherein the second incremental dose is administered 2 days after the first incremental dose.

40. The method according to any one of claims 37 to 39, wherein the first therapeutic dose is administered 4 to 7 days after the second incremental dose.

41. The method according to any one of claims 37 to 39, wherein the first therapeutic dose is administered 5 days after the second incremental dose.

42. The method according to any one of claims 37 to 41, wherein the second therapeutic dose is administered 5 to 9 days after the first therapeutic dose.

43. The method according to any one of claims 37 to 41, wherein the second treatment dose is administered 7 days after the first treatment dose.

44. The method according to any one of claims 21 to 43, wherein the escalation period comprises subcutaneous administration of a first escalation dose of 0.06 mg / kg on day 1, a second escalation dose of 0.3 mg / kg on day 3, a first treatment dose of 1.5 mg / kg on day 8, and a second treatment dose of 1.5 mg / kg on day 15 to the subject.

45. The method according to any one of claims 37 to 44, wherein the escalation period comprises subcutaneously administering to the subject a first escalation dose of 0.06 mg / kg, a second escalation dose of 0.3 mg / kg, a first therapeutic dose of 1.5 mg / kg, a second therapeutic dose of 1.5 mg / kg, and a third therapeutic dose of 1.5 mg / kg.

46. ​​The method of claim 45, wherein the third therapeutic dose is administered 5 to 9 days after the second therapeutic dose.

47. The method of claim 45, wherein the third treatment dose is administered 7 days after the second treatment dose.

48. The method according to any one of claims 21 to 47, wherein the escalation period comprises subcutaneous administration of a first escalation dose of 0.06 mg / kg on day 1, a second escalation dose of 0.3 mg / kg on day 3, a first therapeutic dose of 1.5 mg / kg on day 8, a second therapeutic dose of 1.5 mg / kg on day 15, and a third therapeutic dose of 1.5 mg / kg on day 22 to the subject.

49. The method according to any one of claims 1 to 48, the method comprising administering the BCMAxCD3 bispecific antibody according to a protocol comprising a 28-day cycle, wherein the protocol comprises: During the first cycle, one or more escalating doses are administered subcutaneously, followed by two or more weekly (QW) treatment doses. In one or more subsequent BCMAxCD3 treatment cycles, a weekly (QW) treatment dose is administered subcutaneously.

50. The method according to any one of claims 1 to 48, the method comprising administering the BCMAxCD3 bispecific antibody according to a regimen comprising a 28-day cycle, wherein the regimen comprises: During the first cycle, one or more escalating doses are administered subcutaneously, followed by two or more weekly (QW) treatment doses. In one or more subsequent BCMAxCD3 treatments, a weekly (QW) treatment dose is administered subcutaneously, and then... In one or more subsequent BCMAxCD3 treatment cycles, the treatment dose is administered subcutaneously every two weeks (Q2W).

51. The method according to any one of claims 1 to 48, the method comprising administering the BCMAxCD3 bispecific antibody according to a protocol comprising a 28-day cycle, wherein the protocol comprises: During the first cycle, one or more escalating doses are administered subcutaneously, followed by two or more weekly (QW) treatment doses. In one or more subsequent BCMAxCD3 treatment cycles, a weekly (QW) treatment dose is administered subcutaneously, and then... In one or more subsequent BCMAxCD3 treatment cycles, a subcutaneous dose is administered every two weeks (Q2W), and then... In one or more subsequent BCMAxCD3 treatment cycles, a monthly (Q4W) treatment dose is administered subcutaneously.

52. The method according to any one of claims 1 to 48, the method comprising administering the BCMAxCD3 bispecific antibody according to a regimen comprising a 28-day cycle, wherein the regimen comprises: During the first cycle, one or more escalating doses are administered subcutaneously, followed by two or more weekly (QW) treatment doses. During cycle 2, a weekly (QW) treatment dose was administered subcutaneously. During cycles 3-6, the treatment dose was administered subcutaneously every two weeks (Q2W); and Begin in cycle 7 with subcutaneous administration of monthly (Q4W) treatment doses.

53. The method according to any one of claims 1 to 52, wherein each therapeutic dose of the BCMAxCD3 bispecific antibody is administered to the subject at an amount of 1.5 mg / kg or 3 mg / kg.

54. The method according to any one of claims 1 to 53, the method comprising administering the BCMAxCD3 bispecific antibody according to a regimen comprising a 28-day cycle, wherein the regimen comprises: During the first cycle, one or more escalating doses were administered subcutaneously, followed by two or more weekly (QW) treatment doses of 1.5 mg / kg. During one or more subsequent BCMAxCD3 treatment cycles, a weekly (QW) treatment dose of 1.5 mg / kg is administered subcutaneously.

55. The method according to any one of claims 1 to 54, the method comprising administering the BCMAxCD3 bispecific antibody according to a regimen comprising a 28-day cycle, wherein the regimen comprises: During the first cycle, one or more escalating doses were administered subcutaneously, followed by two or more weekly (QW) treatment doses of 1.5 mg / kg. During one or more subsequent BCMAxCD3 treatment cycles, a subcutaneous treatment dose of 1.5 mg / kg was administered weekly (QW), and then... During one or more subsequent BCMAxCD3 treatment cycles, a subcutaneous dose of 3.0 mg / kg is administered every two weeks (Q2W).

56. The method according to any one of claims 1 to 55, the method comprising administering the BCMAxCD3 bispecific antibody according to a regimen comprising a 28-day cycle, wherein the regimen comprises: During the first cycle, one or more escalating doses were administered subcutaneously, followed by two or more weekly (QW) treatment doses of 1.5 mg / kg. During one or more subsequent BCMAxCD3 treatment cycles, a subcutaneous treatment dose of 1.5 mg / kg was administered weekly (QW), and then... In one or more subsequent BCMAxCD3 treatment cycles, a subcutaneous dose of 3.0 mg / kg was administered every two weeks (Q2W), and then... During one or more subsequent BCMAxCD3 treatment cycles, a monthly (Q4W) treatment dose of 3.0 mg / kg is administered subcutaneously.

57. The method according to any one of claims 1 to 56, the method comprising administering the BCMAxCD3 bispecific antibody according to a regimen comprising a 28-day cycle, wherein the regimen comprises: During the first cycle, one or more escalating doses are administered subcutaneously, followed by two or more weekly (QW) treatment doses of 1.5 mg / kg. During cycle 2, a weekly (QW) treatment dose of 1.5 mg / kg was administered subcutaneously. During cycles 3-6, a subcutaneous treatment dose of 3.0 mg / kg was administered every two weeks (Q2W); and Begin in cycle 7 with a monthly (Q4W) treatment dose of 3.0 mg / kg administered subcutaneously.

58. The method according to any one of claims 1 to 57, the method comprising administering the BCMAxCD3 bispecific antibody according to a regimen comprising a 28-day cycle, wherein the regimen comprises: During the first cycle, one or more escalating doses are administered subcutaneously, followed by two or more weekly (QW) treatment doses of 1.5 mg / kg. During cycle 2, a subcutaneous dose of 1.5 mg / kg was administered weekly (QW). During cycles 3-6, administer subcutaneously at a dose of 3 mg / kg every two weeks (Q2W); and Begin in cycle 7 with a subcutaneous dose of 3 mg / kg per month (Q4W).

59. The method according to any one of claims 1 to 58, the method comprising administering the BCMAxCD3 bispecific antibody according to a protocol comprising a 28-day cycle, wherein the protocol comprises: In the first cycle, a first escalation dose of 0.06 mg / kg was administered subcutaneously, followed by a second escalation dose of 0.3 mg / kg, and then a weekly (QW) treatment dose of 1.5 mg / kg. During cycle 2, a subcutaneous dose of 1.5 mg / kg was administered weekly (QW). During cycles 3-6, administer subcutaneously at a dose of 3 mg / kg every two weeks (Q2W); and Begin in cycle 7 with a subcutaneous dose of 3 mg / kg per month (Q4W).

60. The method according to any one of claims 1 to 59, wherein the clinical response achieved by the method in the subject is a partial response (PR), a very good partial response (VGPR), a complete response (CR), or a strictly complete response (sCR), as defined by the IMWG (2016) response criteria.

61. The method according to any one of claims 1 to 59, wherein the method achieves CR, VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

62. The method according to any one of claims 1 to 59, wherein the method achieves VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

63. The method according to any one of claims 1 to 62, wherein the method achieves an overall response rate (ORR) of 70% or higher in a subject population with HR-SMM.

64. The method according to any one of claims 1 to 62, wherein the method achieves an overall response rate (ORR) of 75% or higher in a subject population with HR-SMM.

65. The method according to any one of claims 1 to 62, wherein the method achieves an overall response rate (ORR) of 80% or higher in a subject population with HR-SMM.

66. The method according to any one of claims 1 to 62, wherein the method achieves an overall response rate (ORR) of 85% or higher in a subject population with HR-SMM.

67. The method according to any one of claims 1 to 62, wherein the method achieves an overall response rate (ORR) of 90% or higher in a subject population with HR-SMM.

68. The method according to any one of claims 1 to 62, wherein the method achieves an overall response rate (ORR) of 95% or higher in a subject population with HR-SMM.

69. The method according to any one of claims 1 to 62, wherein the method achieves a 100% overall response rate (ORR) in a subject population with HR-SMM.

70. The method according to any one of claims 1 to 69, wherein the method achieves CR in at least 25% of a subject population with HR-SMM.

71. The method according to any one of claims 1 to 69, wherein the method achieves CR in at least 30% of the subject population with HR-SMM.

72. The method according to any one of claims 1 to 69, wherein the method achieves CR in at least 35% of the subject population with HR-SMM.

73. The method according to any one of claims 1 to 69, wherein the method achieves CR in at least 40% of the subject population with HR-SMM.

74. The method according to any one of claims 1 to 73, wherein the method achieves MRD-negative disease in the subject.

75. The method according to any one of claims 1 to 74, wherein the subject's HR-SMM does not progress after the subject has received at least four 28-day cycles of treatment with the BCMAxCD3 bispecific antibody.

76. The method according to any one of claims 1 to 75, wherein the subject is administered the BCMAxCD3 bispecific antibody for up to twenty-four (24) 28-day treatment cycles to prevent the subject from developing multiple myeloma.

77. The method according to any one of claims 1 to 75, wherein the subject is administered the BCMAxCD3 bispecific antibody for up to twelve (12) 28-day treatment cycles to prevent the subject from developing multiple myeloma.

78. The method according to any one of claims 1 to 77, wherein the method cures the HR-SMM and prevents the subject from developing MM.

79. The method according to any one of claims 1 to 78, wherein the overall response rate (ORR) achieved by the method in a subject population with HR-SMM is greater than the ORR achieved in a reference subject population with HR-SMM, the reference population having been administered lenalidomide and dexamethasone but not the BCMAxCD3 bispecific antibody.

80. The method of any one of claims 1 to 79, wherein the percentage of complete response (CR) achieved by the method in a subject population with HR-SMM is greater than the percentage of CR achieved in a reference subject population with HR-SMM, the reference population having been administered lenalidomide and dexamethasone but not the BCMAxCD3 bispecific antibody.

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