Methods for treating multiple myeloma

Abstract

Embodiments of the invention relate to methods of treating multiple myeloma in a subject in need thereof, the method comprising administering to the subject a BCMAxCD3 bispecific antibody on a monthly dosing schedule.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 63 / 595,095, filed November 1, 2023, and U.S. Provisional Application Serial No. 63 / 644,276, filed May 8, 2024, 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, which is incorporated herein by reference in its entirety. The XML copy was created on October 4, 2024, named "258199062002(JBI6858WOPCT1)SequenceListing.xml", and has a size of 26,313 bytes. Technical Field

[0005] A method for treating multiple myeloma has been disclosed. Background Technology

[0006] Multiple myeloma (MM) is a cancer of plasma cells. Mechanistically, MM is characterized by the production of monoclonal proteins (M proteins) composed of pathological immunoglobulins or fragments of such pathological immunoglobulins that have lost their function. The proliferation of MM cells leads to subsequent migration from the normal bone marrow niche, while the overproduction of M proteins causes characteristic osteolytic lesions, increased susceptibility to infection, hypercalcemia, renal insufficiency or failure, and neurological complications.

[0007] Treatment options for multiple myeloma have improved over time and vary depending on the aggressiveness of the disease, potential prognostic factors, the patient's physical condition, and existing comorbidities. Treatment options include proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents, monoclonal antibodies (mAbs), antibody-drug conjugates, histone deacetylase inhibitors, nucleoprotein export inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and stem cell transplantation.

[0008] Despite these therapeutic gains, the disease relapses and is associated with additional risk factors (e.g., comorbidities or increasing age), thus ensuring the need for novel treatment approaches, such as new dosages and regimens. Multiple myeloma remains an incurable malignancy and an unmet medical need in newly diagnosed patients (such as elderly patients) where stem cell transplantation is not a viable option, and in patients with refractory disease who have already received standard of care, with significant morbidity and mortality. Treatment options that achieve rapid, deep, and durable clinical responses while providing a manageable safety profile remain in demand. Summary of the Invention

[0009] According to a specific embodiment of the invention, the BCMAxCD3 bispecific antibody (e.g., teritolamab) is administered monthly (Q4W) in the first 28-day BCMAxCD3 treatment cycle following a 28-day escalation period in which one or more escalating doses (and optionally one or more therapeutic doses) of the BCMAxCD3 bispecific antibody are administered.

[0010] One embodiment of the present invention provides a method for treating a subject with multiple myeloma in need, the method comprising treating the subject according to a treatment-effective regimen comprising consecutive 28-day BCMAxCD3 treatment cycles, wherein: during the escalation phase, one or more escalating doses of a BCMAxCD3 bispecific antibody (e.g., teratomab) are administered subcutaneously to the subject, and starting from the first BCMAxCD3 treatment cycle after the escalation phase, a therapeutic dose of the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject according to a monthly dosing schedule (Q4W).

[0011] In some embodiments, 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.

[0012] 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.

[0013] In some implementations, the BCMAxCD3 bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype.

[0014] In some implementations, the BCMAxCD3 bispecific antibody is an IgG4 isotype.

[0015] In some implementations, the BCMAxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0016] In some implementations, the BCMAxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A and L235A substitutions (according to EU designations) in its Fc region.

[0017] In some implementations, the BCMAxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, L235A, F405L and R409K substitutions (according to EU designations) in its Fc region.

[0018] In some implementations, the Fc region of the BCMA binding arm contains S228P, F234A and L235A replacements (according to EU designations) in its Fc region.

[0019] In some embodiments, the Fc region of the CD3 binding arm contains S228P, F234A, L235A, F405L and R409K replacements (according to EU designations) in its Fc region.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] In some implementations, the BCMAxCD3 bispecific antibody is teratomab.

[0025] In some implementations, each therapeutic dose of the BCMAxCD3 bispecific antibody is administered to the subject according to a monthly dosing schedule (Q4W) at a dose of 1.5 mg / kg or 3 mg / kg.

[0026] In some implementations, each therapeutic dose of the BCMAxCD3 bispecific antibody is administered to the subject at a dose of 1.5 mg / kg according to a monthly dosing schedule (Q4W).

[0027] In some implementations, each therapeutic dose of the BCMAxCD3 bispecific antibody is administered to the subject at a dose of 3 mg / kg according to a monthly dosing schedule (Q4W).

[0028] In some implementations, each treatment dose of the BCMAxCD3 bispecific antibody is administered to the subject on day 1 of each BCMAxCD3 treatment cycle, according to a monthly dosing schedule (Q4W).

[0029] In some implementations, the protocol does not include any BCMAxCD3 treatment cycle in which the subject is administered the BCMAxCD3 bispecific antibody on a two-week dosing schedule (Q2W).

[0030] In some implementations, the increment period is 28 days.

[0031] In some implementations, subjects are administered one to three incremental doses of the BCMAxCD3 bispecific antibody during the escalation period.

[0032] In some implementations, two incremental doses of the BCMAxCD3 bispecific antibody are administered to the subject during the escalation period.

[0033] In some implementations, the escalation period includes a first escalation dose of 0.06 mg / kg of the BCMAxCD3 bispecific antibody.

[0034] In some embodiments, the escalation period includes a first escalation dose of 0.06 mg / kg of BCMAxCD3 bispecific antibody and a second escalation dose of 0.3 mg / kg of BCMAxCD3 bispecific antibody.

[0035] In some implementations, in addition to 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.

[0036] In some implementations, in addition to one or more escalation doses, two therapeutic doses of the BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period.

[0037] In some implementations, in addition to one or more escalation doses, three therapeutic doses of the BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period.

[0038] In some implementations, the escalation period includes subcutaneous administration of two escalation doses and two therapeutic doses of the BCMAxCD3 bispecific antibody.

[0039] In some implementations, the escalation period includes subcutaneous administration of two escalation doses and three therapeutic doses of the BCMAxCD3 bispecific antibody.

[0040] In some embodiments, one or more therapeutic doses of the BCMAxCD3 bispecific antibody are administered during the escalation period at an amount of 0.72 mg / kg, 1.5 mg / kg, or 3.0 mg / kg.

[0041] In some implementations, the BCMAxCD3 bispecific antibody is administered at a dose of 1.5 mg / kg for each of one or more treatment doses administered during the escalation period.

[0042] In some implementations, two or three therapeutic doses of the BCMAxCD3 bispecific antibody are administered according to a weekly dosing schedule (QW) during the escalation period.

[0043] In some implementations, two therapeutic doses of the BCMAxCD3 bispecific antibody are administered according to a weekly dosing schedule (QW) during the escalation period.

[0044] In some implementations, three therapeutic doses of the BCMAxCD3 bispecific antibody are administered according to a weekly dosing schedule (QW) during the escalation period.

[0045] 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.

[0046] In some implementations, a second escalation dose is administered 2 to 4 days after the first escalation dose.

[0047] In some implementations, a second escalation dose is administered two days after the first escalation dose.

[0048] In some implementations, the first therapeutic dose is administered 4 to 7 days after the second escalation dose.

[0049] In some implementations, the first therapeutic dose is administered 5 days after the second escalation dose.

[0050] In some implementations, a second treatment dose is administered 5 to 9 days after the first treatment dose.

[0051] In some implementations, a second treatment dose is administered 7 days after the first treatment dose.

[0052] In some implementations, 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.

[0053] 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, a second treatment dose of 1.5 mg / kg, and a third treatment dose of 1.5 mg / kg to the subject.

[0054] In some implementations, a third treatment dose is administered 5 to 9 days after the second treatment dose.

[0055] In some implementations, a third treatment dose is administered 7 days after the second treatment dose.

[0056] In some implementations, 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.

[0057] In some implementations, 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; and each subsequent BCMAxCD3 treatment cycle includes subcutaneous administration of a treatment dose of 3 mg / kg of the BCMAxCD3 bispecific antibody on day 1 (i.e., according to the Q4W dosing schedule).

[0058] In some implementations, 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; and each subsequent BCMAxCD3 treatment cycle includes subcutaneous administration of a treatment dose of 3 mg / kg of the BCMAxCD3 bispecific antibody on day 1 (i.e., according to the Q4W dosing schedule).

[0059] In some implementations, a therapeutic dose of the BCMAxCD3 bispecific antibody is administered to the subject on a monthly dosing schedule (Q4W), regardless of whether or to what extent the subject demonstrates a clinical response to the regimen.

[0060] In some implementations, the escalation period is in the first cycle of the regimen, and the first BCMAxCD3 treatment cycle is in the second cycle of the regimen.

[0061] In some implementations, the regimen is a combination therapy that includes the administration of other anti-multiple myeloma agents in addition to the BCMAxCD3 bispecific antibody.

[0062] In some implementations, the regimen is a combination therapy, with the escalation phase occurring in the second cycle of the regimen, and the first BCMAxCD3 treatment cycle occurring in the third cycle of the regimen or later.

[0063] In some implementations, the regimen is a combination therapy, with the escalation phase occurring in the second cycle of the regimen, and the first BCMAxCD3 treatment cycle occurring in the third cycle of the regimen.

[0064] In some implementations, during the escalation period, subjects are subcutaneously administered a first dose of 0.06 mg / kg, a second dose of 0.3 mg / kg, a third dose of 1.5 mg / kg, and a fourth dose of 1.5 mg / kg of BCMAxCD3 bispecific antibody (e.g., teratumab), and starting from the first BCMAxCD3 treatment cycle after the escalation period, subjects are subcutaneously administered a therapeutic dose of 3 mg / kg of BCMAxCD3 bispecific antibody every 4 weeks (Q4W).

[0065] In some implementations, the escalation period is 28 days and occurs in the first cycle of the regimen; the first, second, third, and fourth doses are administered on days 1, 3, 8, and 15 of the first cycle, respectively, and a treatment dose of 3 mg / kg is administered on day 1 of the second cycle and on day 1 of each subsequent treatment cycle thereafter.

[0066] In some implementations, during the escalation period, subjects are subcutaneously administered a first dose of 0.06 mg / kg, a second dose of 0.3 mg / kg, a third dose of 1.5 mg / kg, a fourth dose of 1.5 mg / kg, and a fifth dose of 1.5 mg / kg of BCMAxCD3 bispecific antibody (e.g., teratumab). Starting from the first BCMAxCD3 treatment cycle after the escalation period, subjects are subcutaneously administered a therapeutic dose of 3 mg / kg of BCMAxCD3 bispecific antibody every 4 weeks (Q4W).

[0067] In some implementations, the escalation period is 28 days and occurs in the first cycle of the regimen; the first, second, third, fourth, and fifth doses are administered on days 1, 3, 8, 15, and 22 of the first cycle, respectively, and a treatment dose of 3 mg / kg is administered on day 1 of the second cycle and on day 1 of each subsequent treatment cycle thereafter.

[0068] In some implementations, the regimen is a combination therapy with an escalation period of 28 days occurring in the second cycle of the regimen; the first, second, third, and fourth doses of the BCMAxCD3 bispecific antibody are administered on days 1, 3, 8, and 15 of the second cycle, respectively, and a therapeutic dose of 3 mg / kg of the BCMAxCD3 bispecific antibody is administered on day 1 of the third cycle and on day 1 of each subsequent treatment cycle thereafter.

[0069] In some implementations, the regimen is a combination therapy with an escalation period of 28 days occurring in the second cycle of the regimen; the first, second, third, fourth, and fifth doses are administered on days 1, 3, 8, 15, and 22 of the first cycle, respectively, and a treatment dose of 3 mg / kg is administered on day 1 of the third cycle and on day 1 of each subsequent treatment cycle thereafter.

[0070] In some embodiments, the regimen comprises a combination therapy of administration of a BCMAxCD3 bispecific antibody (e.g., teratumab), daratumumab, and lenalidomide. In some embodiments, administration of daratumumab begins in cycle 1, administration of lenalidomide begins in cycle 1, and administration of the BCMAxCD3 bispecific antibody begins in cycle 2; wherein during the escalation phase of cycle 2, the subject is subcutaneously administered one or more escalation doses and at least one therapeutic dose of the BCMAxCD3 bispecific antibody, and wherein a therapeutic dose of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject monthly (Q4W) beginning in cycle 3.

[0071] However, all the methods described in this article, however expressed, can be described as having the corresponding uses, especially medical uses. Detailed Implementation

[0072] 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.

[0073] As used in this article, the singular forms “a,” “a,” and “the” include the plural forms.

[0074] 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.

[0075] 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.

[0076] "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 two completely different types, κ and λ.

[0077] 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.

[0078] “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.

[0079] SEQ ID NO: 1

[0080] MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR

[0081] "Bispecific" refers to antibodies that specifically bind to two different antigens or two different epitopes within the same antigen. Bispecific antibodies may have cross-reactivity with other related antigens, for example, cross-reactivity with the same antigen from other species (homologous) (such as humans or monkeys, such as cynomolgus macaques or pantroglodytes), or they may bind to epitopes shared between two or more different antigens.

[0082] "BCMAxCD3 bispecific antibody" refers to a bispecific antibody that specifically binds to BCMA and CD3.

[0083] "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.

[0084] "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.

[0085] SEQ ID NO: 2

[0086] MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGS KPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

[0087] SEQ ID NO: 3

[0088] DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD

[0089] 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.

[0090] "Combination" means administering two or more therapeutic agents to a subject. As used herein, "combination therapy" refers to an effective treatment regimen that includes administering two or more anti-multiple myeloma agents to a subject for the treatment of multiple myeloma; for example, in addition to teritumumab, combination therapy may also include the administration of daratumumab and / or lenalidomide.

[0091] 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.

[0092] 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.”

[0093] "Fcγ receptor" (FcγR) refers to the well-known FcγRI, FcγRIIa, FcγRIIb, or FcγRIII. Activation of FcγR includes FcγRI, FcγRIIa, and FcγRIII.

[0094] "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.

[0095] "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.

[0096] "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.

[0097] "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.

[0098] 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.

[0099] 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.

[0100] "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) was used to determine negative minimal residual disease status.

[0101] "Pharmaceutical composition" refers to a composition containing an active ingredient and a pharmaceutically acceptable carrier.

[0102] "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.

[0103] "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.

[0104] "Refractory" refers to cancers that are not suitable for surgical intervention and do not initially respond to treatment.

[0105] "Recurrent" refers to cancer that responds to treatment but subsequently relapses.

[0106] "Elevation dose" refers to the dose of the active agent administered to the subject prior to the therapeutic dose. The elevation 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 elevation doses followed by a higher therapeutic dose. As used herein with respect to BCMAxCD3 bispecific antibodies, "elevation period" refers to the initial phase of a therapeutically effective regimen in which at least one elevation dose of the BCMAxCD3 bispecific antibody is administered to the subject. The elevation period may also include one or more therapeutic doses, i.e., the elevation period may include one or more elevation doses followed by one or more therapeutic doses; for example, the elevation period may include two elevation doses followed by two therapeutic doses. In a preferred embodiment, the elevation period is 28 days, i.e., the elevation period is a 28-day cycle of a therapeutically effective regimen.

[0107] As used herein, “subject” refers to a human subject. Unless otherwise stated, the terms “patient” and “subject” are used interchangeably.

[0108] "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.

[0109] "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.

[0110] "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.

[0111] "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. In some embodiments, the dosing regimen may include different amounts of therapeutic dose, such as one or more therapeutic doses of 1.5 mg / kg, one or more therapeutic doses of 3 mg / kg, etc.

[0112] "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.

[0113] "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.

[0114] 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.

[0115] This article uses the standard single-letter and three-letter amino acid codes as shown in Table 1.

[0116] Table 1.

[0117]

[0118] BCMAxCD3 Bispecific Antibody and Its Uses

[0119] It is well known in the art that drug development is an unpredictable field. This lack of predictability is evidenced by the requirements of health authorities (such as the Food and Drug Administration) to establish safe and effective dosing regimens for each individual drug candidate in clinical trials. In the past decade (2011–2020), only 7.9% of all drug candidates in development received FDA approval from Phase I clinical trials. See Clinical Development Success Rates and Influencing Factors 2011–2020. Success rates are even lower in oncology, resulting in only 5.3% success rate for oncology drug candidates.

[0120] In oncology, even for drugs with established dosages for specific indications, the Food and Drug Administration (FDA) recommends further clinical studies to determine the optimal dosage for new indications; otherwise, patients may be exposed to unreasonable and significant risks, as well as other potential drawbacks. See, for example, Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases; Draft Guidance for Industry (January 2023).

[0121] Teritolimab (also known 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, indicated 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]). These 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 (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).

[0122] Patients with relapsed or refractory multiple myeloma (RRMM) are already at increased risk of infection, and bispecific antibodies targeting B-cell maturation antigen (BCMA) may contribute to this increased risk due to on-target / detumescent toxicity. In the MajesTEC-1 clinical study, patients (N=165) received teritumumab subcutaneously weekly according to an escalating dosing schedule (0.06 mg / kg and 0.3 mg / kg, spaced 2–4 days apart). During a median follow-up period of 21.6 months (range 0.26–32.69), infections were reported in 129 patients (78.2%). Overall, 86 patients (52.1%) experienced grade 3 / 4 infections, most commonly pneumonia (20.6%), COVID-19 (18.8%), sepsis (6.1%), and urinary tract infection (6.1%). Grade 3 / 4 neutropenia occurred in 65.5% of patients. Therefore, there is still a need for optimized dosing regimens for BCMAxCD3 bispecific antibodies with improved safety profiles.

[0123] Multiple myeloma remains an incurable malignancy and an unmet medical need in patients with newly diagnosed multiple myeloma, as well as those with relapsed or refractory disease who have received several therapies. Based in part on evolutionary data from the teratumab clinical development program (e.g., clinical data across multiple dosing cohorts and population pharmacokinetic models based on such clinical data), the inventors have developed a modified dosing schedule that provides an improved safety profile and enhanced efficacy. Such modified dosing schedules can vary depending on a specific indication or patient population (e.g., relapsed / refractory or newly diagnosed patients) and also on the therapy administered (e.g., BCMAxCD3 monotherapy) or combination of therapies. According to certain embodiments, the inventors have developed a modified dosing schedule for teratumab that includes monthly (Q4W) administration of teratumab starting in the second treatment cycle (e.g., immediately following the escalation phase in the first cycle). The implementation of the novel dosing regimen described in this article for the BCMAxCD3 bispecific antibody provides an improved safety profile compared to currently approved regimens, while maintaining deep and sustained efficacy.

[0124] The antibody of the present invention

[0125] According to this disclosure, any suitable BCMAxCD3 bispecific antibody known to those skilled in the art can be used in this invention. In a specific embodiment, the BCMAxCD3 bispecific antibody is teratomab.

[0126] 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.

[0127] 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.

[0128] In some implementations, the BCMAxCD3 bispecific antibody is chimeric, humanized, or human.

[0129] 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.

[0130] SEQ ID NO: 34:

[0131] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0132] 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 the selected IgG1, IgG2, and IgG4 allotypes.

[0133] Table 2.

[0134]

[0135] 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.

[0136] 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.

[0137] The Fc substitution that can be used to reduce CDC is the K322A substitution.

[0138] The well-known S228P substitution can also be performed in IgG4 antibodies to enhance IgG4 stability.

[0139] 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.

[0140] 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.

[0141] 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 residue numbers are based on the EU index.

[0142] In some implementations, the BCMAxCD3 bispecific antibody also contains proline at position 228, alanine at position 234, and alanine at position 235 of both HC1 and HC2.

[0143] Tables 3 and 4 provide sequences of exemplary embodiments of the BCMAxCD3 bispecific antibody according to the Kabat numbering system.

[0144] Table 3. Exemplary sequences of BCMA binding arms

[0145]

[0146] Table 4. Exemplary sequences of CD3 binding arms

[0147]

[0148] 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.

[0149] 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.

[0150] Further embodiments of the BCMAxCD3 bispecific antibody that can be used in the combination scheme of the present invention are described below.

[0151] In some embodiments, 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.

[0152] 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.

[0153] In some implementations, the BCMAxCD3 bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype.

[0154] In some implementations, the BCMAxCD3 bispecific antibody is an IgG4 isotype.

[0155] In some implementations, the BCMAxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0156] In some implementations, the BCMAxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A and L235A substitutions (according to EU designations) in its Fc region.

[0157] In some implementations, the BCMAxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, L235A, F405L and R409K substitutions (according to EU designations) in its Fc region.

[0158] In some implementations, the Fc region of the BCMA binding arm contains S228P, F234A and L235A replacements (according to EU designations) in its Fc region.

[0159] In some implementations, the Fc region of the CD3 CD3 binding arm contains S228P, F234A, L235A, F405L and R409K replacements (according to EU designations) in its Fc region.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] In some implementations, the BCMAxCD3 bispecific antibody is teratomab.

[0165] Multiple myeloma patient group

[0166] The BCMAxCD3 bispecific antibody disclosed herein is used to treat subjects with multiple myeloma. In some embodiments, the subject is newly diagnosed with multiple myeloma. In some embodiments, the subject is newly diagnosed with multiple myeloma and is ineligible for autologous stem cell transplantation (ASCT). In some embodiments, the subject has a newly diagnosed multiple myeloma and is ineligible for autologous stem cell transplantation (ASCT) as initial therapy or does not intend to undergo ASCT as initial therapy. In some embodiments, the subject is newly diagnosed with multiple myeloma and has previously received ASCT. In some embodiments, the subject is newly diagnosed with multiple myeloma and has completed induction therapy and subsequent ASCT (with or without consolidation). In some embodiments, the subject is newly diagnosed with multiple myeloma and has previously received 4 to 6 cycles of 3- or 4-drug induction therapy, including a proteasome inhibitor and / or IMiD, with or without an anti-CD38 monoclonal antibody, and single or tandem ASCT (in some embodiments, if the total number of induction plus consolidation cycles does not exceed 6, the subject receives a maximum of 2 cycles of ASCT followed by consolidation). In some implementations, the subject is newly diagnosed with multiple myeloma and qualifies for ASCT. In other implementations, the subject is newly diagnosed with multiple myeloma, qualifies for ASCT, and has not yet undergone ASCT. Unless otherwise specified, a diagnosis of multiple myeloma as described herein refers to a diagnosis of multiple myeloma based on the IMWG 2016 criteria.

[0167] In other implementations, the subject has relapsed or refractory disease to treatment with one or more prior anticancer therapies. Relapsed disease means the cancer has recurred. Refractory disease means the cancer has not improved with treatment or is no longer responsive to treatment.

[0168] In some implementations, the subject is relapsed or refractory to treatment with agents used to treat multiple myeloma or other hematologic malignancies.

[0169] In some implementations, the subjects had been treated with 2 to 14 lines of prior therapy.

[0170] In some implementation schemes, the subjects have received at least three lines of prior treatment.

[0171] In some implementation schemes, the subjects have received at least four lines of prior treatment.

[0172] In some implementation schemes, subjects have received at least five lines of prior treatment (five drug exposures).

[0173] In some implementation schemes, subjects have received at least three lines of prior therapy, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0174] In some implementation schemes, subjects have received at least four lines of prior therapy, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0175] In the specific implementation plan, the patient is relapsed or refractory or intolerant to last-line treatment (LOT); exposed to proteasome inhibitors, immunomodulatory drugs and anti-CD38 therapy; and has measurable disease.

[0176] In some implementations, the subject has received three prior anticancer therapies before receiving the BCMAxCD3 bispecific antibody. In one implementation, the three prior anticancer therapies are a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an antiCD38 antibody. In some such implementations, the proteasome inhibitor is bortezomib, carfilzomib, or esazolidinimide; the immunomodulatory drug (IMiD) is lenalidomide, pomalidomide, or thalidomide; and the antiCD38 antibody is daratumumab or esazolidinumab.

[0177] In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is lenalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is lenalidomide, and the anti-CD38 antibody is exatuximab. In another embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is pomalidomide, and the anti-CD38 antibody is exatuximab. In another embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is thalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is thalidomide, and the anti-CD38 antibody is exatuximab.

[0178] In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is lenalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is lenalidomide, and the anti-CD38 antibody is esartanuximab. In another embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is pomalidomide, and the anti-CD38 antibody is esartanuximab. In another embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is thalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is thalidomide, and the anti-CD38 antibody is esartanuximab.

[0179] In one embodiment, the proteasome inhibitor is esazolidinyl, the immunomodulatory drug (IMiD) is lenalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is esazolidinyl, the immunomodulatory drug (IMiD) is lenalidomide, and the anti-CD38 antibody is esazolidinium. In another embodiment, the proteasome inhibitor is esazolidinyl, the immunomodulatory drug (IMiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is esazolidinyl, the immunomodulatory drug (IMiD) is pomalidomide, and the anti-CD38 antibody is esazolidinium. In another embodiment, the proteasome inhibitor is esazolidinyl, the immunomodulatory drug (IMiD) is thalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is esazolidinyl, the immunomodulatory drug (IMiD) is thalidomide, and the anti-CD38 antibody is esazolidinium.

[0180] In some implementations, the subject has relapsed or refractory history of treatment with one or more treatments or therapies, such as THALOMID. ® (Thalidomide), REVLIMID ® (Lenalidomide), POMALYST ® (Pomalidomide), Velcade ® (Bortezomib), NINLARO (Aisazomib), KYPROLIS ® (Carfizomi), FARADYK ® (panobinostat), AREDIA ® (Disodium aminohydroxybisphosphate), ZOMETA ® (Zoledronic acid), DARZALEX ® (Daralimumab), Elotozumab, Melphalan, Xpovio ® (Selinexor), Venclexta ® (Venetoclax), GSK 916, CAR-T therapy or other BCMA-targeted therapies.

[0181] Various qualitative and / or quantitative methods can be used to determine the relapsed or refractory nature of the disease. Possible associated symptoms include, for example, a decline or stabilization of the patient's health, or the recurrence or worsening of various symptoms associated with solid tumors, and / or the spread of cancer cells from one site to other organs, tissues, or cells.

[0182] In some implementations, multiple myeloma is relapsed or refractory to treatment with anti-CD38 antibody, celinizol, venetoclax, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotuzumab, esazozomib, melphalan, or thalidomide, or any combination thereof.

[0183] In one implementation, the anti-CD38 antibody is daratumumab.

[0184] In another implementation, the anti-CD38 antibody is exatuximab.

[0185] In some implementations, multiple myeloma is high-risk multiple myeloma. Subjects with high-risk multiple myeloma are known to have early relapse and poor prognosis and outcomes. Subjects may be classified as having high-risk multiple myeloma if they have one or more of the following cytogenetic abnormalities: t(4; 14)(p16; q32), t(14; 16)(q32; q23), del17p, 1qAmp, t(4; 14)(p16; q32) and t(14; 16)(q32; q23), t(4; 14)(p16; q32) and del17p, t(14; 16)(q32; q23) and del17p, or t(4; 14)(p16; q32), t(14; 16)(q32; q23) and del17p. In some implementations, the subject with high-risk multiple myeloma has one or more chromosomal abnormalities, including: t(4; 14)(p16; q32), t(14; 16)(q32; q23), del17p, 1qAmp, t(4; 14)(p16; q32) and t(14; 16)(q32; q23), t(4; 14)(p16; q32) and del17p, t(14; 16)(q32; q23) and del17p; or t(4; 14)(p16; q32), t(14; 16)(q32; q23) and del17p, or any combination thereof.

[0186] Cytogenetic abnormalities can be detected, for example, by fluorescence in situ hybridization (FISH). In two chromosomal translocations, oncogenes translocate to the IgH region on chromosome 14q32, leading to dysregulation of these genes. t(4; 14)(p16; q32) involves translocations of fibroblast growth factor receptor 3 (FGFR3) and a protein containing the multiple myeloma SET domain (MMSET) (also known as WHSC1 / NSD2), while t(14; 16)(q32; q23) involves a translocation of the MAF transcription factor C-MAF. 17p deletion (del17p) involves the loss of the p53 locus.

[0187] Chromosomal rearrangements can be identified using well-known methods, such as fluorescence in situ hybridization, chromosome karyotyping, pulsed-field gel electrophoresis, or sequencing.

[0188] BCMAxCD3 bispecific antibody administered monthly

[0189] According to certain embodiments, the inventors have developed novel dosing regimens for BCMAxCD3 bispecific antibodies that provide an improved safety profile compared to currently approved regimens, while maintaining deep and durable clinical responses over time. Based in part on evolutionary data from the teratomab clinical development program (e.g., evolutionary clinical data across multiple dosing cohorts and population PK models based on such clinical data), the inventors have developed modified dosing schedules. Such dosing schedules may vary, for example, according to a specific indication or patient population (e.g., relapsed / refractory patients or newly diagnosed patients), and also according to the therapy administered (e.g., BCMAxCD3 bispecific antibody monotherapy) or combination of therapies. According to certain embodiments, the inventors have developed a modified dosing schedule for BCMAxCD3 bispecific antibodies that includes monthly (Q4W) administration starting in the second BCMAxCD3 treatment cycle (e.g., immediately following the escalation phase in the first cycle). According to certain implementation schemes, such dosing schedules do not include any BCMAxCD3 treatment cycles in which the BCMAxCD3 bispecific antibody is administered every two weeks (Q2W).

[0190] As used herein, a “BCMAxCD3 treatment cycle” refers to each treatment cycle in a treatment-effective regimen in which at least one therapeutic dose of the BCMAxCD3 bispecific antibody is administered to the subject. In a preferred embodiment, an escalation period precedes the first BCMAxCD3 treatment cycle in a treatment-effective regimen. According to a specific embodiment, the BCMAxCD3 bispecific antibody is initiated monthly (Q4W) in the first BCMAxCD3 treatment cycle following an escalation period in which one or more escalation doses (and optionally one or more therapeutic doses) are administered. In some embodiments, the dosing regimen may include different amounts of therapeutic dose; for example, one or more therapeutic doses of 1.5 mg / kg may be administered during the escalation period, and then a therapeutic dose of 3 mg / kg may be administered in subsequent treatment cycles.

[0191] A "fixed dose," as used herein, also known as a "steady dose," refers to the dose administered to a subject without adjusting for their specific weight or body surface area. Therefore, a fixed dose (sometimes called a steady dose) is provided in absolute amounts (e.g., mg of drug), rather than in weight-based amounts (e.g., μg / kg or μg drug / kg body weight). For example, a steady dose in milligrams may be administered to a subject weighing 65 kg as to a subject weighing 85 kg. A steady dose may be administered according to a predefined weight category or class, but not modified based on the subject's specific weight. For example, a "steady dose A" may be administered if the patient is greater than a predefined threshold weight (e.g., >60 kg), while a different "steady dose B" may be administered if the patient is less than or equal to the predefined threshold weight (e.g., ≤60 kg).

[0192] 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.

[0193] Unless otherwise stated herein, BCMAxCD3 bispecific antibodies (such as teratumab) are administered according to a sequential 28-day treatment cycle dosing schedule. 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, with respect to 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.).

[0194] According to certain embodiments, administration of the BCMAxCD3 bispecific antibody is initiated in cycle 1 of an effective treatment regimen (e.g., cycle 1 is the escalation phase). According to other embodiments in which the BCMAxCD3 antibody is administered as part of a combination therapy with one or more additional anti-multiple myeloma agents, administration of the BCMAxCD3 bispecific antibody may begin in cycle 2 or later; that is, administration of one or more other anti-multiple myeloma agents (but not the BCMAxCD3 bispecific antibody) may begin in cycle 1, and administration of the BCMAxCD3 bispecific antibody may begin in cycle 2 or later. Therefore, according to such embodiments, the first treatment cycle (e.g., the escalation phase) including administration of the BCMAxCD3 bispecific antibody is cycle 2 or later.

[0195] As used herein, “Q4W” means once every four weeks (i.e., once every 28 days), “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 also referred to herein as “monthly”. The terms “Q4W” and “monthly” are used interchangeably to mean once every four weeks or once every 28 days (e.g., in a sequential 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). The treatment regimen administered every two weeks (Q2W) is also referred to herein as a bi-weekly dosing schedule. The treatment regimen administered every four weeks (Q4W) is also referred to herein as a monthly dosing schedule. Dosing regimens may be described herein in terms of dosage and frequency; for example, “C1: 1500 μg / kg QW” means administering 1500 μg / kg weekly during the first cycle of an effective treatment regimen, “C3-6: 3000 μg / kg Q2W” means administering 3000 μg / kg every two weeks from the third to the sixth cycle, “C3+: 3000 μg / kg Q4W” means administering 3000 μg / kg every four weeks starting from the third cycle, and so on.

[0196] 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.

[0197] As used in this article, the recommended phase 2 dose (RP2D) of teratumab refers to the FDA-approved weight-based regimen for teratumab monotherapy based on the MajesTEC-1 clinical study, which consists of a weekly subcutaneous (SC) administration of a therapeutic dose of teratumab at 1.5 mg / kg until disease progression or unacceptable toxicity, with the therapeutic dose previously being escalated at 0.06 mg / kg and 0.3 mg / kg.

[0198] As used herein, participants met the IMWG diagnostic criteria for multiple myeloma at the time of diagnosis. The IMWG diagnostic criteria are known in the art. Multiple myeloma is defined as ≥10% clonal BMPCs or biopsy-confirmed bone or extramedullary plasmacytoma. a and at least one of the following:

[0199] • Evidence of end-organ damage, specifically:

[0200] –C: Hypercalcemia: Serum calcium levels above ULN >0.25 mmol / L (>1 mg / dL) or >2.75 mmol / L (>11 mg / dL)

[0201] –R: Renal insufficiency: Creatinine clearance <40 mL / min b Or serum creatinine >177 μmol / L (>2 mg / dL)

[0202] –A: Anemia: Hemoglobin level below the lower limit of normal >20g / L or hemoglobin level <100g / L

[0203] –B: Bone lesions: bone X-ray, CT, or PET-CT c,d One or more osteolytic lesions

[0204] • Any one or more of the following malignant tumor biomarkers:

[0205] –Clone BMPC% a ≥60%

[0206] – Affected: Ratio of unaffected sFLC e ≥100

[0207] –> One MRI study of lesions f

[0208] a. Clonality should be established by showing κ / λ light chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. The percentage of plasma cells in bone marrow should preferably be estimated from core biopsy specimens; in cases of inconsistency between aspirate and core biopsy, the highest value should be used.

[0209] b. Measured or estimated by a verified equation.

[0210] c. If the bone marrow contains less than 10% clonal plasma cells, more than one bone lesion is required to differentiate it from solitary plasmacytoma with minimal bone marrow involvement.

[0211] d.PET-CT = 18F-fluorodeoxyglucose PET and CT.

[0212] e. These values ​​are based on serum Freelite assays (The Binding Site Group, Birmingham, UK). Affected FLC must be ≥100 mg / Lf. Each lesion must be 5 mm or larger.

[0213] According to embodiments of the present invention, the method for treating multiple myeloma effectively elicits a clinical response in subjects, as determined by the International Myeloma Working Group (IMWG) response criteria. Depending on the specific embodiment, the treatment is effective in eliciting a partial response (PR), a very good partial response (VGPR), a complete response (CR), or a strictly complete response (sCR) as determined by the IMWG 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 response (i.e., partial response, very good partial response, complete response, or strictly complete response). The IMWG criteria for response to treatment of multiple myeloma are provided in Table A below.

[0214] Table A

[0215]

[0216] CR = Complete Response; FLC = Free Light Chain; IMWG = International Myeloma Working Group; M protein = Monoclonal Paraprotein; MR = Minimal Response; PC = Plasma Cell; PD = Disease Progression; PR = Partial Response; sCR = Strict Complete Response; SD = Stable Disease; VGPR = Very Good Partial Response

[0217] a The presence / absence of clonal cells is based on the κ / λ ratio. Abnormal κ / λ ratios, determined by immunohistochemistry or immunofluorescence, require a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting the presence of abnormal clones is κ / λ > 4:1 or < 1:2.

[0218] 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.).

[0219] c Notes on the 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.

[0220] *Explanation of criteria used to encode CR and VGPR in participants where the only measurable disease is sFLC level: In addition to the CR criteria listed above, CR in such participants indicates a normal FLC ratio of 0.26 to 1.65. VGPR in such participants requires a reduction of ≥90% in the difference between affected and unaffected FLC levels.

[0221] 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.

[0222] Embodiments of the present invention provide a method for treating multiple myeloma in a subject in need, the method comprising treating the subject according to a treatment-effective regimen comprising consecutive BCMAxCD3 treatment cycles (e.g., 28-day treatment cycles), wherein: during the escalation phase, one or more escalating doses of a BCMAxCD3 bispecific antibody (e.g., teratomab) are administered subcutaneously to the subject, and starting from the first BCMAxCD3 treatment cycle after the escalation phase, a therapeutic dose of the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject according to a monthly dosing schedule (Q4W).

[0223] In some implementations, each therapeutic dose of the BCMAxCD3 bispecific antibody is administered to the subject according to a monthly dosing schedule (Q4W) at a dose of 1.5 mg / kg or 3 mg / kg.

[0224] In some implementations, each therapeutic dose of the BCMAxCD3 bispecific antibody is administered to the subject at a dose of 1.5 mg / kg according to a monthly dosing schedule (Q4W).

[0225] In some implementations, each therapeutic dose of the BCMAxCD3 bispecific antibody is administered to the subject at a dose of 3 mg / kg according to a monthly dosing schedule (Q4W).

[0226] In some implementations, each treatment dose of the BCMAxCD3 bispecific antibody is administered to the subject on day 1 of each BCMAxCD3 treatment cycle, according to a monthly dosing schedule (Q4W).

[0227] In some implementations, the protocol does not include any BCMAxCD3 treatment cycle in which the subject is administered the BCMAxCD3 bispecific antibody on a two-week dosing schedule (Q2W).

[0228] In some implementations, the increment period is 28 days.

[0229] In some implementations, subjects are administered one to three incremental doses of the BCMAxCD3 bispecific antibody during the escalation period.

[0230] In some implementations, two incremental doses of the BCMAxCD3 bispecific antibody are administered to the subject during the escalation period.

[0231] In some implementations, the escalation period includes a first escalation dose of 0.06 mg / kg of the BCMAxCD3 bispecific antibody.

[0232] In some embodiments, the escalation period includes a first escalation dose of 0.06 mg / kg of BCMAxCD3 bispecific antibody and a second escalation dose of 0.3 mg / kg of BCMAxCD3 bispecific antibody.

[0233] In some implementations, in addition to 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.

[0234] In some implementations, in addition to one or more escalation doses, two therapeutic doses of the BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period.

[0235] In some implementations, in addition to one or more escalation doses, three therapeutic doses of the BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period.

[0236] In some implementations, the escalation period includes subcutaneous administration of two escalation doses and two therapeutic doses of the BCMAxCD3 bispecific antibody.

[0237] In some implementations, the escalation period includes subcutaneous administration of two escalation doses and three therapeutic doses of the BCMAxCD3 bispecific antibody.

[0238] In some embodiments, one or more therapeutic doses of the BCMAxCD3 bispecific antibody are administered during the escalation period at an amount of 0.72 mg / kg, 1.5 mg / kg, or 3.0 mg / kg.

[0239] In some implementations, the BCMAxCD3 bispecific antibody is administered at a dose of 1.5 mg / kg for each of one or more treatment doses administered during the escalation period.

[0240] In some implementations, two or three therapeutic doses of the BCMAxCD3 bispecific antibody are administered according to a weekly dosing schedule (QW) during the escalation period.

[0241] In some implementations, two therapeutic doses of the BCMAxCD3 bispecific antibody are administered according to a weekly dosing schedule (QW) during the escalation period.

[0242] In some implementations, three therapeutic doses of the BCMAxCD3 bispecific antibody are administered according to a weekly dosing schedule (QW) during the escalation period.

[0243] 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.

[0244] In some implementations, a second escalation dose is administered 2 to 4 days after the first escalation dose.

[0245] In some implementations, a second escalation dose is administered two days after the first escalation dose.

[0246] In some implementations, the first therapeutic dose is administered 4 to 7 days after the second escalation dose.

[0247] In some implementations, the first therapeutic dose is administered 5 days after the second escalation dose.

[0248] In some implementations, a second treatment dose is administered 5 to 9 days after the first treatment dose.

[0249] In some implementations, a second treatment dose is administered 7 days after the first treatment dose.

[0250] In some implementations, 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.

[0251] 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, a second treatment dose of 1.5 mg / kg, and a third treatment dose of 1.5 mg / kg to the subject.

[0252] In some implementations, a third treatment dose is administered 5 to 9 days after the second treatment dose.

[0253] In some implementations, a third treatment dose is administered 7 days after the second treatment dose.

[0254] In some implementations, 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.

[0255] In some implementations, 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; and each subsequent BCMAxCD3 treatment cycle includes subcutaneous administration of a treatment dose of 3 mg / kg of the BCMAxCD3 bispecific antibody on day 1 (i.e., according to the Q4W dosing schedule).

[0256] In some implementations, 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; and each subsequent BCMAxCD3 treatment cycle includes subcutaneous administration of a treatment dose of 3 mg / kg of the BCMAxCD3 bispecific antibody on day 1 (i.e., according to the Q4W dosing schedule).

[0257] In some implementations, a therapeutic dose of the BCMAxCD3 bispecific antibody is administered to the subject on a monthly dosing schedule (Q4W), regardless of whether or to what extent the subject demonstrates a clinical response to the regimen.

[0258] In some implementations, the escalation period is in the first cycle of the regimen, and the first BCMAxCD3 treatment cycle is in the second cycle of the regimen.

[0259] In some implementations, the regimen is a combination therapy that includes the administration of other anti-multiple myeloma agents in addition to the BCMAxCD3 bispecific antibody.

[0260] In some implementations, the regimen is a combination therapy, with the escalation phase occurring in the second cycle of the regimen, and the first BCMAxCD3 treatment cycle occurring in the third cycle of the regimen or later.

[0261] In some implementations, the regimen is a combination therapy, with the escalation phase occurring in the second cycle of the regimen, and the first BCMAxCD3 treatment cycle occurring in the third cycle of the regimen.

[0262] In some implementations, during the escalation period, subjects are subcutaneously administered a first dose of 0.06 mg / kg, a second dose of 0.3 mg / kg, a third dose of 1.5 mg / kg, and a fourth dose of 1.5 mg / kg of BCMAxCD3 bispecific antibody (e.g., teratumab), and starting from the first BCMAxCD3 treatment cycle after the escalation period, subjects are subcutaneously administered a therapeutic dose of 3 mg / kg of BCMAxCD3 bispecific antibody every 4 weeks (Q4W).

[0263] In some implementations, the escalation period is 28 days and occurs in the first cycle of the regimen; the first, second, third, and fourth doses are administered on days 1, 3, 8, and 15 of the first cycle, respectively, and a treatment dose of 3 mg / kg is administered on day 1 of the second cycle and on day 1 of each subsequent treatment cycle thereafter.

[0264] In some implementations, during the escalation period, subjects are subcutaneously administered a first dose of 0.06 mg / kg, a second dose of 0.3 mg / kg, a third dose of 1.5 mg / kg, a fourth dose of 1.5 mg / kg, and a fifth dose of 1.5 mg / kg of BCMAxCD3 bispecific antibody (e.g., teratumab). Starting from the first BCMAxCD3 treatment cycle after the escalation period, subjects are subcutaneously administered a therapeutic dose of 3 mg / kg of BCMAxCD3 bispecific antibody every 4 weeks (Q4W).

[0265] In some implementations, the escalation period is 28 days and occurs in the first cycle of the regimen; the first, second, third, fourth, and fifth doses are administered on days 1, 3, 8, 15, and 22 of the first cycle, respectively, and a treatment dose of 3 mg / kg is administered on day 1 of the second cycle and on day 1 of each subsequent treatment cycle thereafter.

[0266] In some implementations, the regimen is a combination therapy with an escalation period of 28 days occurring in the second cycle of the regimen; the first, second, third, and fourth doses of the BCMAxCD3 bispecific antibody are administered on days 1, 3, 8, and 15 of the second cycle, respectively, and a therapeutic dose of 3 mg / kg of the BCMAxCD3 bispecific antibody is administered on day 1 of the third cycle and on day 1 of each subsequent treatment cycle thereafter.

[0267] In some implementations, the regimen is a combination therapy with an escalation period of 28 days occurring in the second cycle of the regimen; the first, second, third, fourth, and fifth doses are administered on days 1, 3, 8, 15, and 22 of the first cycle, respectively, and a treatment dose of 3 mg / kg is administered on day 1 of the third cycle and on day 1 of each subsequent treatment cycle thereafter.

[0268] In some embodiments, the regimen is a combination therapy comprising administration of a BCMAxCD3 bispecific antibody (e.g., teratolumab), daratumumab, and lenalidomide. In some embodiments, administration of daratumumab begins in cycle 1, administration of lenalidomide begins in cycle 1, and administration of the BCMAxCD3 bispecific antibody begins in cycle 2; wherein during the escalation phase of cycle 2, the subject is subcutaneously administered one or more escalation doses and at least one therapeutic dose of the BCMAxCD3 bispecific antibody, and wherein a therapeutic dose of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject monthly (Q4W) beginning in cycle 3.

[0269] Exemplary Implementation: Treatment Strategies for Newly Diagnosed Multiple Myeloma

[0270] According to certain embodiments of the invention, the inventors have developed a novel dosing regimen for treating multiple myeloma in subjects who are not eligible for autologous stem cell transplantation (ASCT) as an initial therapy or do not intend to undergo ASCT as an initial therapy.

[0271] Newly diagnosed multiple myeloma patients can be broadly categorized as "eligible for transplantation" or "ineligible for transplantation." Transplantation eligibility is typically based on age, health status, and comorbidities. For both eligible and ineligible patients, systemic therapy, usually administered with triple or quadruple therapy, is the primary supportive treatment. For eligible patients, this is combined with ASCT (autologous systemic therapy). DRd (daralimumab, lenalidomide, and dexamethasone) or VRd (bortezomib, lenalidomide, and dexamethasone) are two key treatment options, representing the standard of care, for newly diagnosed ineligible patients with multiple myeloma.

[0272] In clinical practice, treatment for newly diagnosed patients with multiple myeloma is evolving. High-dose ASCT therapy is not feasible for some patients, primarily due to advanced age, comorbidities, or frailty. In the United States, approximately 40% of all transplant-eligible patients do not receive high-dose therapy and ASCT as initial treatment. This development is driven by both the effectiveness of novel induction regimens without high-dose therapy and ASCT (e.g., DRd, VRd) and patient preference, and is expected to continue to increase. Recent and ongoing pivotal studies reflect this development and include (1) patients assessed as ineligible for clinical transplantation and (2) patients who are eligible for clinical transplantation but do not receive transplantation as their first-line treatment option (transplant delay). Results from several studies have shown similar overall survival outcomes for early ASCT compared to novel agent-based approaches without ASCT, suggesting that delaying ASCT is not associated with poor survival outcomes and may be a viable option for appropriate candidates. The IFM2009 study showed no OS benefit for participants randomized to VRd+early ASCT compared to those who received VRd+delayed ASCT until after the first relapse. Current NCCN guidelines support this approach and indicate that delayed ASCT following early stem cell collection and storage is an appropriate option (Class 1 recommendation: NCCN 2023).

[0273] Despite numerous treatment options, multiple myeloma remains incurable for the vast majority of patients. With each successive relapse, symptom recovery is accompanied by a decline in quality of life, and the duration of response typically decreases. Recent reports indicate that dropout rates between first-line and second-line therapy are as high as 50% in patients with multiple myeloma, and that first-line therapy achieves the longest possible progression-free survival (PFS) driving overall survival (OS). Therefore, a significant and critical unmet need remains for new treatment options that target alternative mechanisms of action, better control the disease, provide deeper and more durable responses, and produce better long-term outcomes, including maintaining health-related quality of life.

[0274] In the field of oncology, even for drugs with established dosages for specific indications, the Food and Drug Administration (FDA) recommends further clinical studies to determine the optimal dosage for new indications; otherwise, patients may be exposed to unreasonable and significant risks, as well as other potential drawbacks. See, for example, Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases; Draft Guidance for Industry (January 2023). The inventors have developed novel dosing regimens for BCMAxCD3 bispecific antibodies that provide an improved safety profile compared to currently approved regimens, while achieving deep and durable efficacy. In particular, the inventors have developed novel dosing regimens for combination therapies, such as those comprising administration of teratolumab, daratumumab, and lenalidomide, which provide an improved safety profile compared to currently approved regimens, while achieving deep and durable efficacy.

[0275] Embodiments of the present invention provide a novel dosing regimen for treating multiple myeloma in subjects newly diagnosed with multiple myeloma who are ineligible for or do not intend to undergo autologous stem cell transplantation (ASCT) as initial therapy. As used herein, the newly diagnosed subject is diagnosed with multiple myeloma according to the IMWG diagnostic criteria and has not received any prior multiple myeloma or condensed myeloma therapy (but may have received short-term corticosteroids, not exceeding 40 mg dexamethasone or equivalent daily for up to 4 days, for a total of 160 mg dexamethasone or equivalent). Therefore, the newly diagnosed subject does not have relapsed / refractory multiple myeloma (RRMM), i.e., they have not experienced relapse and / or refractory to previous multiple myeloma therapy (but may have received short-term corticosteroids, not exceeding 40 mg dexamethasone or equivalent daily for up to 4 days, for a total of 160 mg dexamethasone or equivalent).

[0276] Subjects ineligible for ASCT as initial therapy may be ineligible for the following reasons: (i) advanced age, or (ii) the presence of comorbidities that may negatively impact tolerance to high-dose chemotherapy with ASCT. Subjects who “do not intend” to undergo ASCT as initial therapy are clinically adequately suited for ASCT, but this treatment option has been delayed.

[0277] According to one implementation scheme, teritumumab, daratumumab, and lenalidomide (“Tec-DR”) are administered as a combination therapy for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for or do not intend to undergo autologous stem cell transplantation as initial therapy.

[0278] According to certain implementation schemes, Tec-DR improved PFS (progression-free survival) and / or sustained MRD-negative CR (≥12 months) rates in newly diagnosed multiple myeloma patients who were not eligible for ASCT as initial therapy or did not intend to undergo ASCT as initial therapy, compared with DRd.

[0279] According to certain implementations, the combination of teratomab with subcutaneous daratumumab (SC) and lenalidomide provides an effective and safe approach with higher efficacy (e.g., mPFS, mOS, and MRD negative rates) compared to existing standards of care such as daratumumab, lenalidomide, and dexamethasone (DRd) and / or bortezomib, lenalidomide, and dexamethasone (VRd).

[0280] According to the alternative treatment approach, based on the effective treatment regimen shown in Table B below, teratumab, daratumumab, and lenalidomide (“Tec-DR”) are administered as a combination therapy for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplantation as initial therapy or do not intend to undergo autologous stem cell transplantation as initial therapy.

[0281] Table B. Alternative Treatment Methods

[0282]

[0283] IV = intravenous; PO = oral; Q2W = once every other week; SC = subcutaneous

[0284] According to the embodiments of the invention provided herein, teratolumab, daratumumab, and lenalidomide (“Tec-DR”) are administered as a combination therapy according to the treatment efficacy regimens shown in Table C below for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for or do not intend to undergo autologous stem cell transplantation as an initial therapy.

[0285] Table C. Exemplary Treatment Methods

[0286]

[0287] * Lenalidomide dosage may need to be adjusted for participants with renal insufficiency as determined by CrCl.

[0288] IV = Intravenous; Q2W = Every 2 weeks; Q4W = Every 4 weeks; SC = Subcutaneous

[0289] In the regimen shown in Table C, teratomab is administered after the DR induction cycle and then at a reduced frequency (Q4W) after the escalation phase is completed. It is believed that the earlier reduction in the DR induction cycle and teratomab frequency (Q4W administration at cycle 3) reduces infection rates while still achieving robust efficacy compared to the regimen shown in Table B.

[0290] According to one embodiment, a method for treating adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation as initial therapy or who do not intend to undergo autologous stem cell transplantation as initial therapy includes: administering a therapeutically effective combination therapy comprising a BCMAxCD3 bispecific antibody (e.g., teratolumab), daratumumab, and lenalidomide to the subject according to a 28-day treatment cycle dosing schedule, wherein administration of daratumumab begins in cycle 1, administration of lenalidomide begins in cycle 1, and administration of the BCMAxCD3 bispecific antibody begins in cycle 2; wherein during the escalation phase of cycle 2, the subject is subcutaneously administered one or more escalation doses and at least one therapeutic dose of the BCMAxCD3 bispecific antibody; and wherein a therapeutic dose of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject monthly (Q4W) starting in cycle 3. In some embodiments, the regimen also includes oral or intravenous administration of dexamethasone to the subject only in cycles 1 and 2.

[0291] According to another embodiment, a method for treating adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation as initial therapy or do not intend to undergo autologous stem cell transplantation as initial therapy includes administering to the subject a treatment-effective combination therapy comprising a BCMA x CD3 bispecific antibody (e.g., teritumumab), daratumumab, and lenalidomide according to a regimen comprising a 28-day cycle, wherein the regimen comprises:

[0292] For this BCMA x CD3 bispecific antibody (e.g., teratomab): In cycle 2, administer a first escalation dose of 60 μg / kg subcutaneously (e.g., on day 1 or day 2), a second escalation dose of 300 μg / kg subcutaneously (e.g., on day 3 or day 4), followed by a weekly (QW) dose of 1500 μg / kg (e.g., on day 8 and day 15), and in cycle 3 and all subsequent treatment cycles, administer a monthly (Q4W) dose of 3000 μg / kg subcutaneously (e.g., on day 1).

[0293] For daratumumab: 1800 mg subcutaneously every week (QW) during cycles 1-2 (e.g., on days 1, 8, 15, and 22); 1800 mg subcutaneously every two weeks (Q2W) during cycles 3-6 (e.g., on days 1 and 15); and 1800 mg subcutaneously every month (Q4W) during cycle 7 and all subsequent treatment cycles (e.g., on day 1); and for lenalidomide: 25 mg orally daily for the first 21 days of each 28-day cycle during cycle 1 and all subsequent treatment cycles.

[0294] In some implementations, the regimen also includes weekly (QW) oral or intravenous administration of 20 mg dexamethasone only during cycles 1-2 (e.g., on days 1, 8, 15, and 22).

[0295] As discussed in the Examples section below, clinical data from the safety introduction cohort of the Phase 3 teratomab study yielded unexpected findings. The safety introduction employed a DRd introduction dosing strategy (i.e., Drd administration in cycle 1 and Tec introduction in cycle 2, with escalation dosing concurrent with lenalidomide administration). This approach was used to explore whether DRd introduction would reduce the disease burden in newly diagnosed patients and further reduce the incidence and severity of CRS. However, the data indicated that the DRd introduction cycle did not result in a reduction in the severity of CRS events. Conversely, there was a potentially increased risk of higher-grade CRS when participants were exposed to lenalidomide concurrently with escalation dosing of Tec during cycle 1. Prior dexamethasone exposure prior to initiation of Tec may also have contributed to the infection outcome. While DRd introduction dosing resulted in higher-grade CRS, the early preliminary efficacy in these cohorts supports lower Tec exposure (early Q4W dosing). Therefore, the dosing schedule shown in Table D is believed to minimize Tec exposure and optimize tolerability and safety by completing escalation dosing in cycle 1 and transitioning to monthly dosing in cycle 2. According to some embodiments, teritumumab and daratumumab are started in cycle 1 and lenalidomide is added in cycle 2 after the escalation period, with a low frequency of dosing (i.e., Q4W) maintained to mitigate infection. According to some embodiments, the teritumumab SC dosing schedule includes two escalation doses (0.06 mg / kg and 0.3 mg / kg) on ​​days 2 and 4 of cycle 1, followed by 1.5 mg / kg on days 8 and 15 of cycle 1; and 3 mg / kg Q4W starting from day 1 of cycle 2.

[0296] According to certain implementation schemes, teratolumab, daratumumab, and lenalidomide (“Tec-DR”) are administered as a combination therapy, based on the treatment efficacy regimens shown in Table D below, for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for or do not intend to undergo autologous stem cell transplantation as an initial therapy.

[0297] Table D. Exemplary Treatment Methods

[0298]

[0299] * Lenalidomide dosage may need to be adjusted for participants with reduced CrCl.

[0300] **Dexamethasone (16 mg) will be administered as a pre-treatment medication on days 1, 2, 4 and 8 of cycle 1.

[0301] According to certain implementation schemes, compared to a scheme that includes starting lenalidomide administration in cycle 1 followed by BCMAxCD3 bispecific antibody administration in cycle 2, the risk of high-grade CRS in subjects is reduced when the scheme includes starting BCMAxCD3 bispecific antibody administration in cycle 1 followed by lenalidomide administration in cycle 2.

[0302] According to certain implementation schemes, compared to a scheme that includes starting lenalidomide and dexamethasone administration in cycle 1, followed by BCMAxCD3 bispecific antibody administration in cycle 2, the risk of high-grade CRS in subjects is reduced when the scheme includes starting BCMAxCD3 bispecific antibody administration in cycle 1, followed by lenalidomide and dexamethasone administration in cycle 2.

[0303] In some embodiments, the regimen comprises a combination therapy of administration of a BCMAxCD3 bispecific antibody (e.g., teratolumab), daratumumab, and lenalidomide. In some embodiments, administration of daratumumab begins in cycle 1, administration of the BCMAxCD3 bispecific antibody begins in cycle 1, and administration of lenalidomide begins in cycle 2; wherein one or more escalating doses and at least one therapeutic dose of the BCMAxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation phase of cycle 1, and wherein a therapeutic dose of the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject monthly (Q4W) beginning in cycle 2. In some embodiments, the regimen further comprises oral or intravenous administration of dexamethasone to the subject only in cycles 2 and 3.

[0304] In some implementations, the scheme includes:

[0305] For this BCMA x CD3 bispecific antibody (e.g., teratogen):

[0306] In cycle 1, a first escalation dose of 60 μg / kg was administered subcutaneously (e.g., on day 2), a second escalation dose of 300 μg / kg (e.g., on day 4), followed by weekly (QW) doses of 1500 μg / kg (e.g., on days 8 and 15), and

[0307] During cycle 2 and all subsequent treatment cycles, administer a monthly (Q4W) dose of 3000 μg / kg subcutaneously (e.g., on day 1).

[0308] Regarding this daralimumab:

[0309] During cycles 1-2, administer 1800 mg subcutaneously weekly (QW) (e.g., on days 1, 8, 15, and 22).

[0310] During cycles 3-6, administer 1800 mg subcutaneously every two weeks (Q2W) (e.g., on day 1 and day 15), and

[0311] During cycle 7 and all subsequent treatment cycles, administer 1800 mg subcutaneously monthly (Q4W) (e.g., on day 1); and

[0312] Regarding galenalidomide:

[0313] During cycle 2 and all subsequent treatment cycles, 25 mg is administered orally daily for the first 21 days of each 28-day cycle. In some embodiments, the regimen also includes: 20 mg of dexamethasone orally or intravenously weekly (QW) during cycles 2–3 (e.g., on days 1, 8, 15, and 22).

[0314] In some implementations, this method achieved a reduction in new infections over time in a population of subjects with newly diagnosed multiple myeloma compared to a population treated with combination therapy but receiving more frequent doses of BCMAxCD3 bispecific antibodies (e.g., QW and / or Q2W) in cycle 3 and all subsequent treatment cycles.

[0315] In some implementations, this method achieved a reduction in ≥ grade 3 new infections over time in a population of subjects with newly diagnosed multiple myeloma compared to a population treated with combination therapy but receiving more frequent doses of BCMAxCD3 bispecific antibodies (e.g., QW and / or Q2W) in cycle 3 and all subsequent treatment cycles.

[0316] In some implementations, the clinical response achieved by this method in subjects is a subject’s sCR, CR, VGPR, or PR, as defined by the IMWG (2016) response criteria.

[0317] In some implementations, the method achieves CR, VGPR, or PR in subjects, as defined by the IMWG (2016) response criteria.

[0318] In some implementations, the method achieves VGPR or PR in subjects, as defined by the IMWG (2016) response criteria.

[0319] In some implementations, the method achieved a median progression-free survival (mPFS) of at least 80 months, or at least 90 months, or at least 100 months, or at least 110 months in a population of subjects with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplantation (ASCT) as an initial therapy or who did not intend to undergo ASCT as an initial therapy.

[0320] In some implementations, the method achieves a CR or better response (i.e., sCR or CR) as defined by the IMWG (2016) response criteria in at least 60%, at least 65%, or at least 70% of subjects in a population with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy.

[0321] In some implementations, after approximately 50 months of treatment with combination therapy, the method achieved a sustained MRD-negative CR (≥12 months) rate of at least approximately 18%, or at least approximately 20%, or at least approximately 22%, or at least approximately 24%, or at least approximately 26% in a population of subjects with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who did not intend to undergo ASCT as initial therapy.

[0322] In some implementations, the method achieves median progression-free survival (mPFS) in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy. This mPFS is greater than the reference mPFS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy. This reference population has been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of combination therapy comprising a BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

[0323] In some implementations, the mPFS is at least about 10 months longer than the reference mPFS, or at least 20 months, or at least 30 months, or at least 40 months, or at least 50 months.

[0324] In some embodiments, the method achieves median overall survival (mOS) in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the mOS is greater than the reference mOS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, said reference population having been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of combination therapy comprising a BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

[0325] In some implementations, the mOS is at least 1 year longer than the reference mOS, or at least 2 years, or at least 3 years, or at least 4 years longer.

[0326] In some embodiments, the method achieves a sustained MRD-negative CR (≥12 months) rate in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the sustained MRD-negative CR (≥12 months) rate is greater than the reference sustained MRD-negative CR (≥12 months) rate achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the reference population has been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of combination therapy comprising a BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

[0327] In some implementations, after approximately 50 months of treatment, the rate of sustained MRD-negative CR (≥12 months) is at least 4%, or at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14% greater than the reference rate of sustained MRD-negative CR (≥12 months).

[0328] In some implementations, the reference population has been administered daratumumab, lenalidomide, and dexamethasone (DRd) according to the following schedule:

[0329] For this daratumumab: 1800 mg subcutaneously weekly (QW) during cycles 1-2 (e.g., on days 1, 8, 15, and 22); 1800 mg subcutaneously every two weeks (Q2W) during cycles 3-6 (e.g., on days 1 and 15); and 1800 mg subcutaneously monthly (Q4W) during cycle 7 and all subsequent treatment cycles (e.g., on day 1); and

[0330] Regarding galenalidomide:

[0331] During the first cycle and all subsequent treatment cycles, 25 mg was administered orally daily for the first 21 days of each 28-day cycle; and for this dexamethasone: 40 mg or 20 mg of dexamethasone was administered orally or intravenously weekly (QW) during the first cycle and all subsequent treatment cycles (e.g., on days 1, 8, 15, and 22).

[0332] Exemplary Implementation: Another Method for Treating Newly Diagnosed Multiple Myeloma

[0333] Under certain implementation schemes, subjects were newly diagnosed with multiple myeloma and had previously undergone ASCT.

[0334] Under certain implementation schemes, subjects were newly diagnosed with multiple myeloma and had completed induction therapy and subsequent ASCT (with or without consolidation).

[0335] Under certain implementation schemes, subjects were newly diagnosed with multiple myeloma and had previously received 4 to 6 cycles of induction therapy followed by ASCT.

[0336] According to certain implementation schemes, subjects were newly diagnosed with multiple myeloma and had previously received 4 to 6 cycles of 3- or 4-drug induction therapy, including proteasome inhibitors and / or IMiD, with or without anti-CD38 monoclonal antibodies, and single or tandem ASCT.

[0337] According to certain implementation schemes, if the total number of induction plus consolidation cycles does not exceed 6, the subject receives a maximum of 2 cycles of ASCT post-consolidation.

[0338] According to some implementation schemes, the scheme is a combination therapy that includes, in addition to the BCMAxCD3 bispecific antibody, administration of at least one other anti-multiple myeloma agent.

[0339] According to certain implementation schemes, the scheme is a combination therapy that includes the administration of lenalidomide and a BCMAxCD3 bispecific antibody, wherein the BCMAxCD3 bispecific antibody is teratomab.

[0340] According to certain implementation schemes, the escalation period is cycle 1 and includes subcutaneous administration of one or more escalating doses of BCMAxCD3 bispecific antibody to the subject, followed by one or more 1.5 mg / kg doses of BCMAxCD3 bispecific antibody; and each subsequent BCMAxCD3 treatment cycle includes subcutaneous administration of a therapeutic dose of 3 mg / kg of BCMAxCD3 bispecific antibody on day 1 (i.e., according to the Q4W dosing schedule).

[0341] According to certain implementation schemes, the escalation period is cycle 1 and includes subcutaneous administration of one or more escalating doses of BCMAxCD3 bispecific antibody to the subject, followed by one or more 1.5 mg / kg doses of BCMAxCD3 bispecific antibody according to the QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle includes subcutaneous administration of a therapeutic dose of 3 mg / kg of BCMAxCD3 bispecific antibody on day 1 (i.e., according to the Q4W dosing schedule).

[0342] According to certain implementation schemes, the escalation period is cycle 1 and includes subcutaneous administration of an escalating dose of BCMAxCD3 bispecific antibody to the subject, followed by two 1.5 mg / kg doses of BCMAxCD3 bispecific antibody according to the QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle includes subcutaneous administration of a therapeutic dose of 3 mg / kg of BCMAxCD3 bispecific antibody on day 1 (i.e., according to the Q4W dosing schedule).

[0343] According to certain implementation schemes, 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; and each subsequent BCMAxCD3 treatment cycle includes subcutaneous administration of a treatment dose of 3 mg / kg of BCMAxCD3 on day 1 (i.e., according to the Q4W dosing schedule).

[0344] According to some implementation schemes, the scheme is a combination therapy that includes the administration of lenalidomide and teratumab.

[0345] According to some implementation schemes, lenalidomide is administered once daily at a dose of 10 mg.

[0346] According to some implementation schemes, lenalidomide is not administered in the first cycle.

[0347] According to certain implementation schemes, lenalidomide is not administered in the first cycle, but in the second cycle and all subsequent cycles.

[0348] According to certain implementation schemes, lenalidomide is administered once daily at a dose of 10 mg, and if the subject tolerates 10 mg, the dose may be increased to 15 mg once daily on day 1 of cycle 5.

[0349] According to certain implementation schemes, the BCMAxCD3 bispecific antibody is administered for a limited duration of 26 cycles.

[0350] According to certain implementation schemes, the BCMAxCD3 bispecific antibody is administered for a limited duration of 13 cycles.

[0351] According to certain implementation schemes, the BCMAxCD3 bispecific antibody is administered in cycles 14–26 only if the subject achieves a complete or strictly complete response after 13 cycles (according to IMWG 2016 criteria).

[0352] Exemplary implementations of teratomab dosing regimens, including alone or in combination with lenalidomide, are provided in Table E below.

[0353] Table E: Exemplary Treatment Methods

[0354]

[0355] a. Subjects who achieved a complete or near-complete response after 13 treatment cycles discontinued teratumab but continued lenalidomide in the second year.

[0356] According to certain implementation schemes, the clinical response achieved by this method in subjects is sCR, CR, VGPR, or PR, as defined by the IMWG (2016) response criteria.

[0357] According to certain implementation schemes, this method achieves CR or sCR in subjects, as defined by the IMWG (2016) response criteria.

[0358] According to certain implementation schemes, this method achieves VGPR or PR in subjects, as defined by the IMWG (2016) response criteria.

[0359] According to certain implementations, the method achieves a CR or better response (i.e., sCR or CR) in at least 40%, or at least 45%, at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75% of subjects in a population with newly diagnosed multiple myeloma who have previously received autologous stem cell transplantation (ASCT), as defined by the IMWG (2016) response criteria.

[0360] According to certain implementations, this method achieved MRD negativity (10) in at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or at least 85% of subjects with newly diagnosed multiple myeloma who had previously received autologous stem cell transplantation (ASCT). -5 ).

[0361] According to certain embodiments, the method includes administering teratumab alone or a combination therapy comprising teratumab and lenalidomide, wherein the method achieves longer progression-free survival (PFS) and / or a greater 12-month MRD-negative complete response (CR) rate in a reference group of subjects with newly diagnosed multiple myeloma who have previously received autologous stem cell transplantation (ASCT), compared to a reference group that has received a regimen comprising lenalidomide without BCMAxCD3 bispecific antibody.

[0362] According to certain implementations, subjects with newly diagnosed multiple myeloma who are eligible for ASCT are treated with the treatment regimens described herein (e.g., including regimens that administer teratumab starting Q4W from cycle 2). According to certain implementations, the subjects have not previously received ASCT.

[0363] In some implementation schemes, a BCMAxCD3 bispecific antibody (e.g., teritumumab) is administered to the subject as part of induction therapy. As used herein, induction therapy refers to the first phase of treatment for multiple myeloma in the subject.

[0364] According to certain implementation schemes, a combination therapy comprising a BCMAxCD3 bispecific antibody (e.g., teratumab) and one or more other antimyeloma agents is administered to the subject as an induction therapy.

[0365] According to certain implementation schemes, subjects are administered multiple cycles of a BCMAxCD3 bispecific antibody (e.g., teratumab) and optionally one or more other antimyeloma agents as induction therapy.

[0366] According to certain implementation schemes, a combination therapy consisting of a BCMAxCD3 bispecific antibody (e.g., teratolumab) and one or more additional antimyeloma agents selected from the group consisting of daratumumab, lenalidomide, dexamethasone, and any combination thereof is administered to the subject as induction therapy.

[0367] According to certain implementation schemes, subjects are given a combination therapy including a BCMAxCD3 bispecific antibody (e.g., teratolumab), daratumumab, lenalidomide, and dexamethasone as an induction therapy.

[0368] According to certain implementation schemes, subjects are given a combination therapy comprising a BCMAxCD3 bispecific antibody (e.g., teratolumab), daratumumab, and lenalidomide as an induction therapy.

[0369] According to certain implementation schemes, subjects are administered 6 cycles of a BCMAxCD3 bispecific antibody (e.g., teritumumab) and optionally one or more other antimyeloma agents as induction therapy.

[0370] According to certain implementation schemes, subjects are given six cycles of combination therapy including a BCMAxCD3 bispecific antibody (e.g., teritumumab), daratumumab, lenalidomide, and dexamethasone as induction therapy.

[0371] According to certain implementation schemes, subjects are given six cycles of combination therapy including a BCMAxCD3 bispecific antibody (e.g., teritumumab), daratumumab, and lenalidomide as induction therapy.

[0372] In some implementation schemes, induction therapy is administered to the subject prior to autologous stem cell transplantation (ASCT). In some implementation schemes, induction therapy is administered to the subject, and then the subject undergoes autologous stem cell transplantation (ASCT).

[0373] According to certain implementation schemes, after ASCT, subjects are administered maintenance therapy comprising a BCMAxCD3 bispecific antibody (e.g., teratumab) and optionally one or more other antimyeloma agents. According to certain implementation schemes, after ASCT, subjects are administered maintenance therapy comprising a BCMAxCD3 bispecific antibody (e.g., teratumab) and daratumumab. According to certain implementation schemes, maintenance therapy comprises 6-20 treatment cycles, or 12-18 treatment cycles, or 12 treatment cycles.

[0374] Additional Implementation Plan

[0375] According to certain embodiments, teratumab is administered as part of a combination regimen containing talquetamab to subjects with RRMM who have previously received first- to fourth-line prior therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide. Such embodiments are described, for example, in WO2024 / 220682, which is incorporated herein by reference. According to certain embodiments, the subject is administered one or more escalating doses, followed by one or more 1.5 mg / kg doses of teratumab in cycle 1, followed by a 3 mg / kg Q4W treatment dose of teratumab starting from cycle 2. According to certain embodiments, the subject is administered teratumab in cycle 1 at escalating doses of 0.06 mg / kg and 0.3 mg / kg and two 1.5 mg / kg doses, and then at a 3 mg / kg Q4W treatment dose starting from cycle 2. According to certain implementation schemes, teratumab is administered to subjects in cycle 1 at escalating doses of 0.06 mg / kg and 0.3 mg / kg, followed by two 1.5 mg / kg doses, and then starting from cycle 2 at a treatment dose of 3 mg / kg Q4W; and teratumab is administered to subjects in cycle 1 at SC escalating doses of 0.01 mg / kg and 0.06 mg / kg, followed by a 0.4 mg / kg dose and a 0.8 mg / kg dose, followed by 0.8 mg / kg SC Q2W treatment doses in cycles 2–4, wherein starting from cycle 5, participants with a confirmed VGPR or better response may switch to teratumab Q4W; and starting from cycle 7, participants with a confirmed PR or better response must switch to teratumab 0.8 mg / kg Q4W.

[0376] According to one implementation, a method for treating a subject with multiple myeloma in need comprises treating the subject according to a treatment-effective regimen comprising consecutive 28-day cycles of BCMAxCD3 treatment, wherein, if criteria (1) through (4) are met, one or more escalating doses of teratumab are administered subcutaneously to the subject during the escalation phase (e.g., during the first cycle), and, starting from the first BCMAxCD3 treatment cycle after the escalation phase (e.g., starting from the second cycle), a therapeutic dose of teratumab is administered subcutaneously to the subject according to a monthly dosing schedule (Q4W), wherein if (1) the subject has a newly diagnosed multiple myeloma and is not eligible for ASCT as initial therapy or does not intend to undergo ASCT as initial therapy, and teratumab is used as an adjunct therapy... The following criteria are met: (1) a step includes administration of daratumumab and lenalidomide as part of a combination regimen; (2) the subject has a newly diagnosed multiple myeloma and teratolumab is administered as part of a combination regimen that further includes administration of lenalidomide after the subject receives induction therapy and subsequent ASCT; (3) the subject has a newly diagnosed multiple myeloma and teratolumab is administered as induction therapy as part of a combination regimen that further includes administration of daratumumab and lenalidomide (e.g., before the subject receives ASCT); or (4) the subject has received 1 to 4 lines of prior treatment including daratumumab and lenalidomide and teratolumab is administered as part of a combination regimen that further includes administration of taquiltumab.

[0377] According to one implementation scheme, a method for treating a subject with a newly diagnosed multiple myeloma comprises treating the subject according to a treatment-effective regimen comprising consecutive 28-day cycles of BCMAxCD3 treatment, wherein, if criteria (1) to (3) are met, one or more escalating doses of teritumumab are administered subcutaneously to the subject during the escalation phase (e.g., during the first cycle), and, starting from the first BCMAxCD3 treatment cycle after the escalation phase (e.g., starting from the second cycle), a therapeutic dose of teritumumab is administered subcutaneously to the subject according to a monthly dosing schedule (Q4W), wherein if: (1) the subject has a newly diagnosed multiple myeloma and does not meet the ASCT criteria. Criteria (1) through (3) are met if the subject is eligible for initial therapy or does not intend to undergo ASCT as initial therapy, and teratumab is administered as part of a combination regimen that further includes administration of daratumumab and lenalidomide; or (2) the subject has a newly diagnosed multiple myeloma, and teratumab is administered as part of a combination regimen that further includes administration of lenalidomide after the subject receives induction therapy and subsequent ASCT; or (3) the subject has a newly diagnosed multiple myeloma, and teratumab is administered as part of an induction therapy regimen that further includes administration of daratumumab and lenalidomide (e.g., before the subject receives ASCT).

[0378] According to one implementation, a method for treating a subject with a newly diagnosed multiple myeloma comprises treating the subject according to a treatment-effective regimen comprising consecutive 28-day cycles of BCMAxCD3 treatment, wherein if criterion (1) or (2) is met, one or more escalating doses of teratumab are administered subcutaneously to the subject during an escalation phase (e.g., during cycle 1), and a therapeutic dose of teratumab is administered subcutaneously to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle after the escalation phase (e.g., starting from cycle 2), wherein criterion (1) or (2) is met if: (1) the subject has a newly diagnosed multiple myeloma and is not eligible for ASCT as initial therapy or does not intend to undergo ASCT as initial therapy, and teratumab is administered as part of a combination regimen further comprising administration of daratumumab and lenalidomide, or (2) the subject has a newly diagnosed multiple myeloma, and teratumab is administered as part of a combination regimen further comprising administration of lenalidomide after the subject has received induction therapy and subsequent ASCT.

[0379] Alternative escalation dosing regimen

[0380] Embodiments of the present invention also provide alternative escalation dosing regimens for BCMAxCD3 bispecific antibodies, such as teratumab, which can limit CRS events to an earlier time point, thereby potentially shortening the CRS monitoring window. In the phase 1 / 2 single-arm MajesTEC-1 study, teratumab demonstrated manageable safety and rapid, deep, and durable responses. In MajesTEC-1, patients received escalation doses (SUDs) of 0.06 mg / kg and 0.3 mg / kg, followed by weekly doses of 1.5 mg / kg (recommended phase 2 dose). Cytokine release syndrome (CRS) occurred in 72% of patients (almost all grade 1 / 2); however, most events occurred during escalation; 24% of patients experienced CRS after the first treatment dose. Higher SUDs were evaluated in an exploratory Phase 1 cohort from MajesTEC-1: cohort 22 (SUDs of 0.1 mg / kg and 0.5 mg / kg, with a dose interval of 2 to 4 days) and cohort 23 (SUDs of 0.2 mg / kg and 0.7 mg / kg, with a dose interval of 2 to 4 days). Based on the results presented in this paper, higher SUDs are believed to limit CRS events to earlier time points, potentially shortening the CRS monitoring window and facilitating a timely transition of care to an outpatient setting.

[0381] According to one embodiment, a method of treating a subject with multiple myeloma in need includes administering to the subject a therapeutically effective amount of any BCMAxCD3 bispecific antibody (e.g., teratomab) described herein, wherein the method comprises subcutaneously administering only two escalating doses of the BCMAxCD3 bispecific antibody prior to a first therapeutic dose (e.g., a first therapeutic dose of 1.5 mg / kg), wherein the two escalating doses are administered (i) at a dose of 0.1 mg / kg followed by a dose of 0.5 mg / kg, or (ii) at a dose of 0.2 mg / kg followed by a dose of 0.7 mg / kg. According to some embodiments, the time between the two escalating doses is between approximately 2 days and approximately 4 days. Following the escalating doses, a therapeutic dose of the BCMAxCD3 bispecific antibody may be administered to the subject according to any therapeutic dosing regimen described herein.

[0382] In some implementation schemes, the subject has relapsed or refractory multiple myeloma. In some implementation schemes, the subject has previously received at least one, two, three, or four lines of prior therapy. In some implementation schemes, the subject has previously received at least three or four lines of prior therapy. In some implementation schemes, the subject has previously received, for example, one to three lines of prior therapy including at least two consecutive cycles of daratumumab and two consecutive cycles of lenalidomide. In some implementation schemes, the subject has previously received one to three lines of prior therapy including a proteasome inhibitor (PI) and lenalidomide. In some implementation schemes, the subject has previously received one to four lines of prior therapy including daratumumab and lenalidomide.

[0383] In some implementation schemes, the subject has a newly diagnosed multiple myeloma. In some implementation schemes, the subject has a newly diagnosed multiple myeloma and is not eligible for ASCT as initial therapy or does not intend to undergo ASCT as initial therapy. In some implementation schemes, the subject has a newly diagnosed multiple myeloma and has previously undergone ASCT. In some implementation schemes, the subject has a newly diagnosed multiple myeloma and has not yet undergone ASCT.

[0384] Toci preventive administration

[0385] Embodiments of the present invention provide a method for treating multiple myeloma in a subject in need by administering a therapeutically effective amount of tocilizumab to the subject prior to administration of a first dose of a BCMAxCD3 bispecific antibody (e.g., teritumab).

[0386] In some implementations, a single pre-treatment tocitabolumab dose (TOCI) reduces the incidence of CRS relative to the overall patient population, provided no new safety signals are identified and there is no evidence affecting response to teratumab. In some implementations, prophylactic TOCI reduces the risk of CRS in patients with a disease profile suitable for outpatient dosing, thereby reducing the hospitalization burden during teratumab escalation.

[0387] In some implementations, toci is administered as a single IV dose of 8 mg / kg prior to teratomab.

[0388] Exemplary Implementation

[0389] The following provides enumerated embodiments of the invention. These embodiments are merely exemplary and do not limit the scope of this disclosure or the appended claims.

[0390] 1. A method for treating a subject with multiple myeloma in need, the method comprising treating the subject according to a treatment-effective regimen comprising consecutive 28-day cycles of BCMAxCD3 treatment, wherein:

[0391] During the escalation phase, one or more escalating doses of the BCMAxCD3 bispecific antibody were administered subcutaneously to the subject, and

[0392] Starting from the first BCMAxCD3 treatment cycle after the escalation period, the subject is given a therapeutic dose of the BCMAxCD3 bispecific antibody subcutaneously according to a monthly dosing schedule (Q4W).

[0393] 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.

[0394] 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.

[0395] 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.

[0396] 5. The method according to any one of embodiments 1 to 4, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype.

[0397] 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.

[0398] 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 in its Fc region (according to EU index number).

[0399] 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.

[0400] 9. The method according to any one of embodiments 1 to 8, wherein the Fc region of the BCMA binding arm comprises proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235 (according to EU index number).

[0401] 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).

[0402] 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.

[0403] 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.

[0404] 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.

[0405] 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.

[0406] 15. 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 99% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 99% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 99% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 99% identity with the amino acid sequence of SEQ ID NO: 23.

[0407] 16. The method according to any one of embodiments 1 to 15, wherein the BCMAxCD3 bispecific antibody is teratogenab.

[0408] 17. The method according to any one of embodiments 1 to 16, wherein each therapeutic dose of the BCMAxCD3 bispecific antibody administered to the subject according to the monthly dosing schedule (Q4W) is administered at an amount of 1.5 mg / kg or 3 mg / kg.

[0409] 18. The method according to any one of embodiments 1 to 16, wherein each therapeutic dose of the BCMAxCD3 bispecific antibody administered to the subject according to the monthly dosing schedule (Q4W) is administered at an amount of 1.5 mg / kg.

[0410] 19. The method according to any one of embodiments 1 to 16, wherein each therapeutic dose of the BCMAxCD3 bispecific antibody administered to the subject according to the monthly dosing schedule (Q4W) is administered at an amount of 3 mg / kg.

[0411] 20. The method according to any one of embodiments 1 to 19, wherein each therapeutic dose of the BCMAxCD3 bispecific antibody administered to the subject according to the monthly dosing schedule (Q4W) is administered on day 1 of each BCMAxCD3 treatment cycle.

[0412] 21. The method according to any one of embodiments 1 to 20, wherein the embodiments do not include any BCMAxCD3 treatment cycle in which the subject is administered the BCMAxCD3 bispecific antibody according to a two-week dosing schedule (Q2W).

[0413] 22. The method according to any one of embodiments 1 to 21, wherein the increment period is 28 days.

[0414] 23. The method according to any one of embodiments 1 to 22, wherein the subject is administered one to three incremental doses of the BCMAxCD3 bispecific antibody during the incremental period.

[0415] 24. The method according to any one of embodiments 1 to 23, wherein two incremental doses of the BCMAxCD3 bispecific antibody are administered to the subject during the incremental period.

[0416] 25. The method according to any one of embodiments 1 to 24, wherein the escalation period comprises a first escalation dose of the BCMAxCD3 bispecific antibody of 0.06 mg / kg, or 0.1 mg / kg, or 0.2 mg / kg.

[0417] 26. The method according to any one of embodiments 1 to 25, wherein the escalation period comprises a first escalation dose of the BCMAxCD3 bispecific antibody of 0.06 mg / kg, or 0.1 mg / kg, or 0.2 mg / kg and a second escalation dose of the BCMAxCD3 bispecific antibody of 0.3 mg / kg, or 0.5 mg / kg, or 0.7 mg / kg.

[0418] 27. The method according to any one of embodiments 1 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.

[0419] 28. The method according to any one of embodiments 1 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.

[0420] 29. The method according to any one of embodiments 1 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.

[0421] 30. The method according to any one of embodiments 1 to 29, wherein the escalation period comprises subcutaneous administration of two escalation doses and two therapeutic doses of the BCMAxCD3 bispecific antibody.

[0422] 31. The method according to any one of embodiments 1 to 29, wherein the escalation period comprises subcutaneous administration of two escalation doses and three therapeutic doses of the BCMAxCD3 bispecific antibody.

[0423] 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.

[0424] 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.

[0425] 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.

[0426] 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.

[0427] 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.

[0428] 37. The method according to any one of embodiments 1 to 29, wherein the escalation period comprises subcutaneously administering to the subject (i) 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; or (ii) a first escalation dose of 0.1 mg / kg, a second escalation dose of 0.5 mg / kg, a first therapeutic dose of 1.5 mg / kg, and a second therapeutic dose of 1.5 mg / kg; or (iii) a first escalation dose of 0.2 mg / kg, a second escalation dose of 0.7 mg / kg, a first therapeutic dose of 1.5 mg / kg, and a second therapeutic dose of 1.5 mg / kg.

[0429] 38. The method according to embodiment 37, wherein the second incremental dose is administered 2 to 4 days after the first incremental dose.

[0430] 39. The method according to embodiment 37, wherein the second incremental dose is administered 2 days after the first incremental dose.

[0431] 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.

[0432] 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.

[0433] 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.

[0434] 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.

[0435] 44. The method according to any one of embodiments 1 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.

[0436] 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.

[0437] 46. ​​The method according to embodiment 45, wherein the third treatment dose is administered 5 to 9 days after the second treatment dose.

[0438] 47. The method according to embodiment 45, wherein the third treatment dose is administered 7 days after the second treatment dose.

[0439] 48. The method according to any one of embodiments 1 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.

[0440] 49. The method according to any one of embodiments 1 to 48, wherein:

[0441] The escalation period includes subcutaneous administration to the subject of (i) 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; or (ii) a first escalation dose of 0.1 mg / kg on day 1, a second escalation dose of 0.5 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; or (iii) a first escalation dose of 0.2 mg / kg on day 1, a second escalation dose of 0.7 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; and

[0442] Each subsequent BCMAxCD3 treatment cycle includes a subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0443] 50. The method according to any one of embodiments 1 to 48, wherein:

[0444] 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, or (ii) a first escalation dose of 0.1 mg / kg on day 1, a second escalation dose of 0.5 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, or (iii) a first escalation dose of 0.2 mg / kg on day 1, a second escalation dose of 0.7 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; and

[0445] Each subsequent BCMAxCD3 treatment cycle includes a subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0446] 51. The method according to any one of embodiments 1 to 50, wherein the subject is administered the therapeutic dose of the BCMAxCD3 bispecific antibody according to the monthly dosing schedule (Q4W), regardless of whether or to what extent the subject demonstrates a clinical response to the regimen.

[0447] 52. The method according to any one of embodiments 1 to 51, wherein the escalation period is in the first cycle of the embodiment, and the first BCMAxCD3 treatment cycle is in the second cycle of the embodiment.

[0448] 53. The method according to any one of embodiments 1 to 52, wherein the embodiment is a combination therapy comprising, in addition to the BCMAxCD3 bispecific antibody, administration of other anti-multiple myeloma agents.

[0449] 54. The method according to any one of embodiments 1 to 53, wherein the regimen is a combination therapy, the escalation phase is in the second cycle of the regimen, and the first BCMAxCD3 treatment cycle is in the third cycle of the regimen or later.

[0450] 55. The method according to any one of embodiments 1 to 53, wherein the regimen is a combination therapy, the escalation period is in the second cycle of the regimen, and the first BCMAxCD3 treatment cycle is in the third cycle of the regimen.

[0451] 56. The method according to any one of embodiments 1 to 16, wherein:

[0452] During the escalation phase, the subject was subcutaneously administered a first dose of 0.06 mg / kg, a second dose of 0.3 mg / kg, a third dose of 1.5 mg / kg, and a fourth dose of 1.5 mg / kg of the BCMAxCD3 bispecific antibody (e.g., teratumab).

[0453] Starting from the first BCMAxCD3 treatment cycle after the escalation period, the subject is subcutaneously administered a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg every 4 weeks (Q4W).

[0454] 57. The method according to implementation scheme 56, wherein:

[0455] The increment period is 28 days and occurs in the first cycle of the scheme;

[0456] The first dose, the second dose, the third dose, and the fourth dose were administered on days 1, 3, 8, and 15 of the first cycle, respectively.

[0457] The therapeutic dose of 3 mg / kg was administered on day 1 of the second cycle and on day 1 of each subsequent treatment cycle.

[0458] 58. The method according to any one of embodiments 1 to 16, wherein:

[0459] During the escalation phase, the subject was subcutaneously administered a first dose of 0.06 mg / kg, a second dose of 0.3 mg / kg, a third dose of 1.5 mg / kg, a fourth dose of 1.5 mg / kg, and a fifth dose of 1.5 mg / kg of the BCMAxCD3 bispecific antibody (e.g., teratumab).

[0460] Starting from the first BCMAxCD3 treatment cycle after the escalation period, the subject is subcutaneously administered a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg every 4 weeks (Q4W).

[0461] 59. The method according to implementation scheme 58, wherein:

[0462] The increment period is 28 days and occurs in the first cycle of the scheme;

[0463] The first dose, the second dose, the third dose, the fourth dose, and the fifth dose were administered on days 1, 3, 8, 15, and 22 of the first cycle, respectively, and the treatment dose of 3 mg / kg was administered on day 1 of the second cycle and on day 1 of each subsequent treatment cycle thereafter.

[0464] 60. The method according to implementation scheme 56, wherein:

[0465] The proposed treatment is a combination therapy.

[0466] The increment period is 28 days and occurs in the second cycle of the scheme;

[0467] The first, second, third, and fourth doses of the BCMAxCD3 bispecific antibody were administered on days 1, 3, 8, and 15 of cycle 2, respectively.

[0468] The therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg was administered on day 1 of cycle 3 and on day 1 of each subsequent treatment cycle thereafter.

[0469] 61. The method according to implementation scheme 58, wherein:

[0470] The proposed treatment is a combination therapy.

[0471] The increment period is 28 days and occurs in the second cycle of the scheme;

[0472] The first dose, the second dose, the third dose, the fourth dose, and the fifth dose were administered on days 1, 3, 8, 15, and 22 of the first cycle, respectively.

[0473] The therapeutic dose of 3 mg / kg was administered on day 1 of the third cycle and on day 1 of each subsequent treatment cycle.

[0474] 62. The method according to any one of embodiments 1 to 53, wherein the regimen is a combination therapy comprising administering the BCMAxCD3 bispecific antibody (e.g., teratumab), daratumumab, and lenalidomide.

[0475] 63. The method according to embodiment 62, wherein the administration of daratumumab begins in cycle 1, the administration of lenalidomide begins in cycle 1, and the administration of the BCMAxCD3 bispecific antibody begins in cycle 2; and wherein during the escalation phase of cycle 2, the subject is subcutaneously administered one or more escalation doses and at least one therapeutic dose of the BCMAxCD3 bispecific antibody, and wherein a therapeutic dose of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject monthly (Q4W) starting in cycle 3.

[0476] 64. The method according to embodiment 63, wherein the embodiment further comprises: administering dexamethasone orally or intravenously to the subject only during the first and second cycles.

[0477] 65. The method according to any one of embodiments 62 to 64, wherein the embodiments include:

[0478] For the BCMA x CD3 bispecific antibody (e.g., teratomab):

[0479] In cycle 2, a first escalation dose of 60 μg / kg was administered subcutaneously (e.g., on day 1 or 2), a second escalation dose of 300 μg / kg (e.g., on day 3 or 4), followed by weekly (QW) doses of 1500 μg / kg (e.g., on days 8 and 15), and

[0480] During cycle 3 and all subsequent treatment cycles, administer a monthly (Q4W) dose of 3000 μg / kg subcutaneously (e.g., on day 1).

[0481] Regarding the aforementioned daratumumab:

[0482] During cycles 1-2, administer 1800 mg subcutaneously weekly (QW) (e.g., on days 1, 8, 15, and 22).

[0483] During cycles 3-6, administer 1800 mg subcutaneously every two weeks (Q2W) (e.g., on day 1 and day 15), and

[0484] During cycle 7 and all subsequent treatment cycles, administer 1800 mg subcutaneously monthly (Q4W) (e.g., on day 1); and

[0485] Regarding the lenalidomide:

[0486] During the first cycle and all subsequent treatment cycles, 25 mg was administered orally daily for the first 21 days of each 28-day cycle.

[0487] 66. The method according to embodiment 65, wherein the embodiment further comprises: administering 20 mg of dexamethasone orally or intravenously weekly (QW) during cycles 1-2 (e.g., on days 1, 8, 15, and 22).

[0488] 67. The method according to any one of embodiments 62 to 66, wherein the method achieves a reduction in new infections over time in a population of subjects with newly diagnosed multiple myeloma compared to a population of subjects treated with the combination therapy but receiving more frequent doses of the BCMAxCD3 bispecific antibody (e.g., QW and / or Q2W) in cycle 3 and all subsequent treatment cycles.

[0489] 68. The method according to any one of embodiments 62 to 67, wherein the method achieves a reduction of ≥ grade 3 new infections over time in a subject population with newly diagnosed multiple myeloma compared to a subject population treated with the combination therapy but receiving more frequent doses of the BCMAxCD3 bispecific antibody (e.g., QW and / or Q2W) in cycle 3 and all subsequent treatment cycles.

[0490] 69. The method according to any one of embodiments 62 to 68, wherein the subject has a newly diagnosed multiple myeloma and is not eligible for autologous stem cell transplantation (ASCT) as an initial therapy or does not intend to undergo ASCT as an initial therapy.

[0491] 70. The method according to any one of embodiments 62 to 69, wherein the subject has a newly diagnosed multiple myeloma and is not eligible for autologous stem cell transplantation (ASCT) as an initial therapy.

[0492] 71. The method according to any one of embodiments 62 to 70, wherein the subject has a newly diagnosed multiple myeloma and does not intend to undergo autologous stem cell transplantation (ASCT) as initial therapy.

[0493] 72. The method according to any one of embodiments 62 to 71, wherein the clinical response achieved by the method in the subject is the subject's sCR, CR, VGPR or PR, as defined by the IMWG (2016) response criteria.

[0494] 73. The method according to any one of embodiments 62 to 72, wherein the method achieves CR, VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

[0495] 74. The method according to any one of embodiments 62 to 73, wherein the method achieves VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

[0496] 75. The method according to any one of embodiments 62 to 74, wherein the method achieves a median progression-free survival (mPFS) of at least 80 months, or at least 90 months, or at least 100 months, or at least 110 months in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy.

[0497] 76. The method according to any one of embodiments 62 to 75, wherein the method achieves a CR or better response (i.e., sCR or CR) as defined by the IMWG (2016) response criteria in at least 60%, at least 65%, or at least 70% of subjects in a population with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy.

[0498] 77. The method according to any one of embodiments 62 to 76, wherein after treatment with the combination therapy for about 50 months, the method achieved a sustained MRD-negative CR (≥12 months) rate of at least about 18%, or at least about 20%, or at least about 22%, or at least about 24%, or at least about 26% in a population of subjects with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who did not intend to undergo ASCT as initial therapy.

[0499] 78. The method according to any one of embodiments 62 to 77, wherein the method achieves median progression-free survival (mPFS) in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the mPFS is greater than the reference mPFS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, the reference population having been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of the combination therapy comprising the BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

[0500] 79. The method according to embodiment 78, wherein the mPFS is at least about 10 months, or at least 20 months, or at least 30 months, or at least 40 months, or at least 50 months longer than the reference mPFS.

[0501] 80. The method according to any one of embodiments 62 to 79, wherein the method achieves median overall survival (mOS) in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the mOS is greater than the reference mOS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, the reference population having been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of the combination therapy comprising the BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

[0502] 81. The method according to embodiment 80, wherein the mOS is at least 1 year, or at least 2 years, or at least 3 years, or at least 4 years longer than the reference mOS.

[0503] 82. The method according to any one of embodiments 62 to 81, wherein the method achieves a sustained MRD-negative CR (≥12 months) rate in a subject population with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the sustained MRD-negative CR (≥12 months) rate is greater than the reference sustained MRD-negative CR (≥12 months) rate achieved in a reference subject population with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the reference population has been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of the combination therapy comprising the BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

[0504] 83. The method according to embodiment 82, wherein after approximately 50 months of treatment, the sustained MRD-negative CR (≥12 months) rate is at least 4%, or at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14% greater than the reference sustained MRD-negative CR (≥12 months) rate.

[0505] 84. The method according to any one of embodiments 78 to 83, wherein the reference population has been administered the daralimumab, lenalidomide, and dexamethasone (DRd) according to the following schedule:

[0506] Regarding the aforementioned daratumumab:

[0507] During cycles 1-2, administer 1800 mg subcutaneously weekly (QW) (e.g., on days 1, 8, 15, and 22).

[0508] During cycles 3-6, administer 1800 mg subcutaneously every two weeks (Q2W) (e.g., on day 1 and day 15), and

[0509] During cycle 7 and all subsequent treatment cycles, administer 1800 mg subcutaneously monthly (Q4W) (e.g., on day 1); and

[0510] Regarding the lenalidomide:

[0511] In cycle 1 and all subsequent treatment cycles, 25 mg was administered orally daily for the first 21 days of each 28-day cycle; and

[0512] Regarding the aforementioned dexamethasone:

[0513] During the first cycle and all subsequent treatment cycles, administer 40 mg or 20 mg of dexamethasone orally or intravenously weekly (QW) (e.g., on days 1, 8, 15, and 22).

[0514] 85. The method according to any one of embodiments 1 to 53, wherein the embodiment is a combination therapy comprising administering the BCMAxCD3 bispecific antibody (e.g., teratumab), daratumumab, and lenalidomide.

[0515] 86. The method according to embodiment 85, wherein the administration of daratumumab begins in cycle 1, the administration of the BCMAxCD3 bispecific antibody begins in cycle 1, and the administration of lenalidomide begins in cycle 2; and wherein during the escalation phase of cycle 1, the subject is subcutaneously administered one or more escalation doses and at least one therapeutic dose of the BCMAxCD3 bispecific antibody, and wherein, starting in cycle 2, the subject is subcutaneously administered a therapeutic dose of the BCMAxCD3 bispecific antibody monthly (Q4W).

[0516] 87. The method according to embodiment 86, wherein the embodiment further comprises: administering dexamethasone orally or intravenously to the subject only during the second and third cycles.

[0517] 88. The method according to any one of embodiments 85 to 87, wherein the embodiments include:

[0518] For the BCMA x CD3 bispecific antibody (e.g., teratomab):

[0519] In cycle 1, a first escalation dose of 60 μg / kg was administered subcutaneously (e.g., on day 2), a second escalation dose of 300 μg / kg (e.g., on day 4), followed by weekly (QW) doses of 1500 μg / kg (e.g., on days 8 and 15), and

[0520] During cycle 2 and all subsequent treatment cycles, administer a monthly (Q4W) dose of 3000 μg / kg subcutaneously (e.g., on day 1).

[0521] Regarding the aforementioned daratumumab:

[0522] During cycles 1-2, administer 1800 mg subcutaneously weekly (QW) (e.g., on days 1, 8, 15, and 22).

[0523] During cycles 3-6, administer 1800 mg subcutaneously every two weeks (Q2W) (e.g., on day 1 and day 15), and

[0524] During cycle 7 and all subsequent treatment cycles, administer 1800 mg subcutaneously monthly (Q4W) (e.g., on day 1); and

[0525] Regarding the lenalidomide:

[0526] In the second cycle and all subsequent treatment cycles, 25 mg was administered orally daily for the first 21 days of each 28-day cycle.

[0527] 89. The method according to embodiment 88, wherein the embodiment further comprises: administering 20 mg of dexamethasone orally or intravenously weekly (QW) during cycles 2-3 (e.g., on days 1, 8, 15, and 22).

[0528] 90. The method according to any one of embodiments 85 to 89, wherein the subject has a newly diagnosed multiple myeloma and is not eligible for autologous stem cell transplantation (ASCT) as an initial therapy or does not intend to undergo ASCT as an initial therapy.

[0529] 91. The method according to any one of embodiments 85 to 89, wherein the subject has a newly diagnosed multiple myeloma and is not eligible for autologous stem cell transplantation (ASCT) as an initial therapy.

[0530] 92. The method according to any one of embodiments 85 to 89, wherein the subject has a newly diagnosed multiple myeloma and does not intend to undergo autologous stem cell transplantation (ASCT) as initial therapy.

[0531] 93. The method according to any one of embodiments 85 to 92, wherein the clinical response achieved by the method in the subject is the subject's sCR, CR, VGPR, or PR, as defined by the IMWG (2016) response criteria.

[0532] 94. The method according to any one of embodiments 85 to 92, wherein the method achieves CR, VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

[0533] 95. The method according to any one of embodiments 85 to 92, wherein the method achieves VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

[0534] 96. The method according to any one of embodiments 85 to 95, wherein the method achieves a median progression-free survival (mPFS) of at least 80 months, or at least 90 months, or at least 100 months, or at least 110 months in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy.

[0535] 97. The method according to any one of embodiments 85 to 96, wherein the method achieves a CR or better response (i.e., sCR or CR) as defined by the IMWG (2016) criteria in at least 60%, at least 65%, or at least 70% of subjects in a population with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy.

[0536] 98. The method according to any one of embodiments 85 to 97, wherein after treatment with the combination therapy for about 50 months, the method achieves a sustained MRD-negative CR (≥12 months) rate of at least about 18%, or at least about 20%, or at least about 22%, or at least about 24%, or at least about 26% in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy.

[0537] 99. The method according to any one of embodiments 85 to 98, wherein the method achieves median progression-free survival (mPFS) in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the mPFS is greater than the reference mPFS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, said reference population having been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of the combination therapy comprising the BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

[0538] 100. The method according to embodiment 99, wherein the mPFS is at least about 10 months, or at least 20 months, or at least 30 months, or at least 40 months, or at least 50 months longer than the reference mPFS.

[0539] 101. The method according to any one of embodiments 85 to 100, wherein the method achieves median overall survival (mOS) in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the mOS is greater than the reference mOS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, the reference population having been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of the combination therapy comprising the BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

[0540] 102. The method according to embodiment 101, wherein the mOS is at least 1 year, or at least 2 years, or at least 3 years, or at least 4 years longer than the reference mOS.

[0541] 103. The method according to any one of embodiments 85 to 102, wherein the method achieves a sustained MRD-negative CR (≥12 months) rate in a subject population with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the sustained MRD-negative CR (≥12 months) rate is greater than the reference sustained MRD-negative CR (≥12 months) rate achieved in a reference subject population with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, the reference population having been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of the combination therapy comprising the BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

[0542] 104. The method according to embodiment 103, wherein after approximately 50 months of treatment, the sustained MRD-negative CR (≥12 months) rate is at least 4%, or at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14% greater than the reference sustained MRD-negative CR (≥12 months) rate.

[0543] 105. The method according to any one of embodiments 85 to 104, wherein the reference population has been administered the daralimumab, lenalidomide, and dexamethasone (DRd) according to the following schedule:

[0544] Regarding the aforementioned daratumumab:

[0545] During cycles 1-2, administer 1800 mg subcutaneously weekly (QW) (e.g., on days 1, 8, 15, and 22).

[0546] During cycles 3-6, administer 1800 mg subcutaneously every two weeks (Q2W) (e.g., on day 1 and day 15), and

[0547] During cycle 7 and all subsequent treatment cycles, administer 1800 mg subcutaneously monthly (Q4W) (e.g., on day 1); and

[0548] Regarding the lenalidomide:

[0549] In cycle 1 and all subsequent treatment cycles, 25 mg was administered orally daily for the first 21 days of each 28-day cycle; and

[0550] Regarding the aforementioned dexamethasone:

[0551] During the first cycle and all subsequent treatment cycles, administer 40 mg or 20 mg of dexamethasone orally or intravenously weekly (QW) (e.g., on days 1, 8, 15, and 22).

[0552] 106. The method according to any one of embodiments 85 to 105, wherein, compared to a regimen that includes starting the administration of the lenalidomide in a first cycle and then starting the administration of the BCMAxCD3 bispecific antibody in a second cycle, the risk of high-grade CRS in the subject is reduced when the regimen includes starting the administration of the BCMAxCD3 bispecific antibody in a first cycle and then starting the administration of the lenalidomide in a second cycle.

[0553] 107. The method according to any one of embodiments 85 to 105, wherein, compared to a regimen that includes starting the administration of the lenalidomide and the dexamethasone in a first cycle, followed by starting the administration of the BCMAxCD3 bispecific antibody in a second cycle, the risk of high-grade CRS in the subject is reduced when the regimen includes starting the administration of the BCMAxCD3 bispecific antibody in a first cycle, followed by starting the administration of the lenalidomide and the dexamethasone in a second cycle.

[0554] 108. The method according to any one of embodiments 1 to 50, wherein the subject has a newly diagnosed multiple myeloma.

[0555] 109. The method according to any one of embodiments 1 to 50, wherein the subject is newly diagnosed with multiple myeloma and has previously undergone ASCT.

[0556] 110. The method according to any one of embodiments 1 to 50, wherein the subject is newly diagnosed with multiple myeloma and has completed induction therapy and subsequent ASCT (with or without consolidation).

[0557] 111. The method according to any one of embodiments 1 to 50, wherein the subject is newly diagnosed with multiple myeloma and has previously received 4 to 6 cycles of induction therapy and subsequent ASCT.

[0558] 112. The method according to any one of embodiments 1 to 50, wherein the subject is newly diagnosed with multiple myeloma and has previously received 4 to 6 cycles of 3- or 4-drug induction therapy, including a proteasome inhibitor and / or IMiD, with or without an anti-CD38 monoclonal antibody, and single or tandem ASCT.

[0559] 113. The method according to any one of embodiments 108 to 112, wherein if the total number of induction plus consolidation cycles does not exceed 6, the subject receives a maximum of 2 cycles of ASCT post-consolidation.

[0560] 114. The method according to any one of embodiments 108 to 113, wherein the embodiment is a combination therapy comprising, in addition to the BCMAxCD3 bispecific antibody, administration of at least one other anti-multiple myeloma agent.

[0561] 115. The method according to any one of embodiments 108 to 114, wherein the embodiment is a combination therapy comprising administration of lenalidomide and the BCMAxCD3 bispecific antibody.

[0562] 116. The method according to embodiment 115, wherein the BCMAxCD3 bispecific antibody is teratogenab.

[0563] 117. The method according to any one of embodiments 108 to 116, wherein the escalation period occurs in the first cycle and comprises subcutaneous administration of one or more escalating doses of the BCMAxCD3 bispecific antibody to the subject, followed by one or more doses of the BCMAxCD3 bispecific antibody at 1.5 mg / kg; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0564] 118. The method according to any one of embodiments 108 to 117, wherein the escalation period occurs in the first cycle and comprises subcutaneous administration of one or more escalating doses of the BCMAxCD3 bispecific antibody to the subject, followed by one or more 1.5 mg / kg doses of the BCMAxCD3 bispecific antibody according to the QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0565] 119. The method according to any one of embodiments 108 to 118, wherein the escalation period occurs in the first cycle and comprises subcutaneous administration of an escalating dose of the BCMAxCD3 bispecific antibody to the subject, followed by two 1.5 mg / kg doses of the BCMAxCD3 bispecific antibody according to the QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at a dose of 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0566] 120. The method according to any one of embodiments 108 to 119, wherein the escalation period comprises subcutaneous administration of the BCMAxCD3 bispecific antibody to the subject at 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; and

[0567] Each subsequent BCMAxCD3 treatment cycle includes a subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0568] 121. The method according to any one of embodiments 108 to 120, wherein the regimen is a combination therapy comprising administering lenalidomide and the BCMAxCD3 bispecific antibody, and wherein the BCMAxCD3 bispecific antibody is teratumab.

[0569] 122. The method according to embodiment 121, wherein the lenalidomide is administered once daily in an amount of 10 mg.

[0570] 123. The method according to embodiment 121 or 122, wherein the lenalidomide is not administered in the first cycle.

[0571] 124. The method according to any one of embodiments 121 to 123, wherein the lenalidomide is not administered in the first cycle, but in the second cycle and all subsequent cycles.

[0572] 125. The method according to any one of embodiments 121 to 124, wherein the lenalidomide is administered once daily in an amount of 10 mg, and if the subject tolerates 10 mg, the dose can be increased to 15 mg once daily on day 1 of cycle 5.

[0573] 126. The method according to any one of embodiments 121 to 125, wherein the BCMAxCD3 bispecific antibody is administered for a limited duration of 26 cycles.

[0574] 127. The method according to any one of embodiments 121 to 125, wherein the BCMAxCD3 bispecific antibody is administered for a limited duration of 13 cycles.

[0575] 128. The method according to any one of embodiments 121 to 125, wherein the BCMAxCD3 bispecific antibody is administered in cycles 14–26 only if the subject achieves a complete or strictly complete response (according to IMWG 2016 criteria) after 13 cycles.

[0576] 129. The method according to any one of embodiments 108 to 128, wherein the clinical response achieved by the method in the subject is the subject's sCR, CR, VGPR, or PR, as defined by the IMWG (2016) response criteria.

[0577] 130. The method according to any one of embodiments 108 to 128, wherein the method achieves CR or sCR in the subject as defined by the IMWG (2016) response criteria.

[0578] 131. The method according to any one of embodiments 108 to 128, wherein the method achieves VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

[0579] 132. The method according to any one of embodiments 108 to 128, wherein the method achieves a CR or better response (i.e., sCR or CR) as defined by the IMWG (2016) response criteria in at least 40%, or at least 45%, at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75% of subjects in a population with newly diagnosed multiple myeloma who have previously received autologous stem cell transplantation (ASCT).

[0580] 133. The method according to any one of embodiments 108 to 128, wherein the method achieves MRD negativity (10) in at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85% of subjects in a population with newly diagnosed multiple myeloma who have previously received autologous stem cell transplantation (ASCT). -5 ).

[0581] 134. The method according to any one of embodiments 108 to 128, wherein the method comprises administering teratumab alone or administering a combination therapy comprising teratumab and lenalidomide, and wherein the method achieves longer progression-free survival (PFS) and / or a greater 12-month MRD-negative complete response (CR) rate in a population of subjects with newly diagnosed multiple myeloma who have previously received autologous stem cell transplantation (ASCT) compared to a reference population of subjects who have previously received autologous stem cell transplantation (ASCT), the reference population having received a regimen comprising lenalidomide without BCMAxCD3 bispecific antibody.

[0582] 135. The method according to any one of embodiments 1 to 50, wherein the subject has a newly diagnosed multiple myeloma and is eligible for ASCT.

[0583] 136. The method according to embodiment 135, wherein the subject has not previously undergone ASCT.

[0584] 137. The method according to embodiment 135 or 136, wherein the subject is administered the BCMAxCD3 bispecific antibody (e.g., teritumumab) as part of induction therapy.

[0585] 138. The method according to any one of embodiments 135 to 137, wherein the subject is given a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teratumab) and one or more other antimyeloma agents as induction therapy.

[0586] 139. The method according to any one of embodiments 135 to 138, wherein the subject is administered multiple cycles of the BCMAxCD3 bispecific antibody (e.g., teritumumab) and optionally one or more other antimyeloma agents as induction therapy.

[0587] 140. The method according to any one of embodiments 135 to 139, wherein the subject is given a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teratolumab) and one or more additional antimyeloma agents selected from the group consisting of daratumumab, lenalidomide, dexamethasone, and any combination thereof as induction therapy.

[0588] 141. The method according to any one of embodiments 135 to 140, wherein the subject is administered a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teratumab), daratumumab, lenalidomide, and dexamethasone as an induction therapy.

[0589] 142. The method according to any one of embodiments 135 to 140, wherein the subject is administered a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teratumab), daratumumab, and lenalidomide as an induction therapy.

[0590] 143. The method according to any one of embodiments 135 to 142, wherein the subject is administered 4 to 8 cycles, preferably 6 cycles, of the BCMAxCD3 bispecific antibody (e.g., teritumumab) and optionally one or more other antimyeloma agents as induction therapy.

[0591] 144. The method according to any one of embodiments 135 to 143, wherein the subject is administered 6 cycles of a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teratumab), daratumumab, lenalidomide, and dexamethasone as an induction therapy.

[0592] 145. The method according to any one of embodiments 135 to 144, wherein the subject is given 4 to 8 cycles, preferably 6 cycles, of combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teritumumab), daratumumab and lenalidomide as induction therapy.

[0593] 146. The method according to any one of embodiments 137 to 145, wherein the induction therapy is administered to the subject prior to ASCT.

[0594] 147. The method according to any one of embodiments 135 to 146, wherein the first cycle comprises subcutaneously administering one or more escalating doses of the BCMAxCD3 bispecific antibody to the subject, followed by one or more doses of the BCMAxCD3 bispecific antibody at a dose of 1.5 mg / kg; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody at a dose of 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0595] 148. The method according to any one of embodiments 135 to 146, wherein the first cycle comprises subcutaneously administering one or more escalating doses of the BCMAxCD3 bispecific antibody to the subject, followed by one or more 1.5 mg / kg doses of the BCMAxCD3 bispecific antibody according to a QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0596] 149. The method according to any one of embodiments 135 to 146, wherein the first cycle comprises subcutaneous administration of an escalating dose of the BCMAxCD3 bispecific antibody to the subject, followed by two 1.5 mg / kg doses of the BCMAxCD3 bispecific antibody according to a QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at a dose of 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0597] 150. The method according to any one of embodiments 135 to 146, wherein the first cycle comprises subcutaneous administration of the BCMAxCD3 bispecific antibody to the subject at 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; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of the BCMAxCD3 bispecific antibody at a treatment dose of 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0598] 151. The method according to embodiment 135, wherein, after receiving ASCT, the subject is administered maintenance therapy comprising the BCMAxCD3 bispecific antibody (e.g., teratumab) and optionally one or more other antimyeloma agents.

[0599] 152. The method according to embodiment 135, wherein, after receiving ASCT, the subject is administered maintenance therapy comprising the BCMAxCD3 bispecific antibody (e.g., teratumab) and daratumumab.

[0600] 153. The method according to embodiment 151 or 152, wherein the maintenance therapy comprises 6-20 treatment cycles.

[0601] 154. The method according to implementation scheme 151 or 152, wherein the maintenance therapy comprises 12-18 treatment cycles.

[0602] 155. The method according to embodiment 151 or 152, wherein the maintenance therapy comprises 12 treatment cycles.

[0603] 156. The method according to any one of embodiments 151 to 155, wherein the first cycle comprises subcutaneously administering one or more escalating doses of the BCMAxCD3 bispecific antibody to the subject, followed by one or more doses of the BCMAxCD3 bispecific antibody at a dose of 1.5 mg / kg; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody at a dose of 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0604] 157. The method according to any one of embodiments 151 to 155, wherein the first cycle comprises subcutaneously administering one or more escalating doses of the BCMAxCD3 bispecific antibody to the subject, followed by one or more 1.5 mg / kg doses of the BCMAxCD3 bispecific antibody according to a QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0605] 158. The method according to any one of embodiments 151 to 155, wherein the first cycle comprises subcutaneous administration of an escalating dose of the BCMAxCD3 bispecific antibody to the subject, followed by two 1.5 mg / kg doses of the BCMAxCD3 bispecific antibody according to a QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at a dose of 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0606] 159. The method according to any one of embodiments 151 to 155, wherein the first cycle comprises subcutaneous administration of the BCMAxCD3 bispecific antibody to the subject at 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; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of the BCMAxCD3 bispecific antibody at a treatment dose of 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

[0607] 160. A method of treating a subject with multiple myeloma in need, the method comprising treating the subject according to a treatment-effective regimen comprising consecutive 28-day BCMAxCD3 treatment cycles, wherein if criteria (1) to (4) are met, one or more escalating doses of teratumab are administered subcutaneously to the subject during an escalation phase (e.g., during the first cycle) and a therapeutic dose of the teratumab is administered subcutaneously to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle following the escalation phase (e.g., starting from the second cycle), wherein if (1) the subject has a newly diagnosed multiple myeloma and is not eligible for ASCT as initial therapy or does not intend to undergo ASCT as initial therapy, and the teratumab is administered as further treatment... The following criteria are met: (1) teratolumab is administered as part of a combination regimen including daratumumab and lenalidomide; (2) the subject has a newly diagnosed multiple myeloma and teratolumab is administered as part of a combination regimen further including lenalidomide after the subject receives induction therapy and subsequent ASCT; (3) the subject has a newly diagnosed multiple myeloma and teratolumab is administered as induction therapy as part of a combination regimen further including daratumumab and lenalidomide (e.g., before the subject receives ASCT); or (4) the subject has received 1 to 4 lines of prior treatment including daratumumab and lenalidomide and teratolumab is administered as part of a combination regimen further including taquiltumab.

[0608] 161. A method for treating a newly diagnosed multiple myeloma in a subject in need, the method comprising treating the subject according to a treatment-effective regimen comprising consecutive 28-day BCMAxCD3 treatment cycles, wherein if criteria (1) to (3) are met, one or more escalating doses of teratumab are administered subcutaneously to the subject during an escalation phase (e.g., during the first cycle) and a therapeutic dose of the teratumab is administered subcutaneously to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle following the escalation phase (e.g., starting from the second cycle), wherein if: (1) the subject has a newly diagnosed multiple myeloma and does not meet the criteria for ASCT... The criteria (1) to (3) are met if the subject is eligible for initial therapy or does not intend to undergo ASCT as initial therapy, and the teratumab is administered as part of a combination regimen that further includes administration of daratumumab and lenalidomide; or (2) the subject has a newly diagnosed multiple myeloma, and the teratumab is administered as part of a combination regimen that further includes administration of lenalidomide after the subject receives induction therapy and subsequent ASCT; or (3) the subject has a newly diagnosed multiple myeloma, and the teratumab is administered as part of an induction therapy regimen that further includes administration of daratumumab and lenalidomide (e.g., before the subject receives ASCT).

[0609] 162. A method for treating a newly diagnosed multiple myeloma in a subject in need, the method comprising treating the subject according to a treatment-effective regimen comprising consecutive 28-day BCMAxCD3 treatment cycles, wherein, if criterion (1) or (2) is met, one or more escalating doses of teratumab are administered subcutaneously to the subject during an escalation phase (e.g., during the first cycle) and, starting from the first BCMAxCD3 treatment cycle following the escalation phase (e.g., starting from the second cycle), a treatment dose is administered subcutaneously to the subject according to a monthly dosing schedule (Q4W). The teratomab is provided if: (1) the subject has a newly diagnosed multiple myeloma and is not eligible for ASCT as initial therapy or does not intend to undergo ASCT as initial therapy, and the teratomab is administered as part of a combination regimen that further includes administration of daratumumab and lenalidomide, or (2) the subject has a newly diagnosed multiple myeloma, and the teratomab is administered as part of a combination regimen that further includes administration of lenalidomide after the subject has received induction therapy and subsequent ASCT, then criterion (1) or (2) is met.

[0610] 163. The method according to any one of embodiments 1 to 162, wherein the escalation period comprises administering only two escalation doses of the BCMAxCD3 bispecific antibody (e.g., teratomab) prior to administering the first therapeutic dose, wherein the two escalation doses are administered (i) at a dose of 0.1 mg / kg followed by a dose of 0.5 mg / kg, or (ii) at a dose of 0.2 mg / kg followed by a dose of 0.7 mg / kg.

[0611] 164. A method of treating a subject with multiple myeloma in need, the method comprising administering to the subject a therapeutically effective amount of a BCMAxCD3 bispecific antibody (e.g., teratomab), wherein the method comprises subcutaneously administering only two escalating doses of the BCMAxCD3 bispecific antibody prior to subcutaneous administration of a first therapeutic dose, wherein the two escalating doses are administered (i) at a dose of 0.1 mg / kg followed by a dose of 0.5 mg / kg, or (ii) at a dose of 0.2 mg / kg followed by a dose of 0.7 mg / kg.

[0612] 165. The method according to embodiment 164, wherein the two incremental doses are administered at a rate of 0.1 mg / kg followed by a rate of 0.5 mg / kg.

[0613] 166. The method according to embodiment 164, wherein the two incremental doses are administered at a dose of 0.2 mg / kg followed by a dose of 0.7 mg / kg.

[0614] 167. The method according to any one of embodiments 163 to 166, wherein the time between the two incremental doses is between about 2 days and about 4 days.

[0615] 168. The method according to any one of embodiments 164 to 166, wherein the subject suffers from relapsed or refractory multiple myeloma.

[0616] 169. The method according to embodiment 168, wherein the subject has previously received at least one, at least two, at least three, or at least four lines of prior treatment.

[0617] 170. The method according to embodiment 168, wherein the subject has previously received, for example, first- to third-line prior treatment comprising at least two consecutive cycles of daratumumab and two consecutive cycles of lenalidomide.

[0618] 171. The method according to embodiment 168, wherein the subject has previously received 1-3 lines of prior treatment including a proteasome inhibitor (PI) and lenalidomide.

[0619] 172. The method according to embodiment 168, wherein the subject has previously received first- to fourth-line prior treatment including daratumumab and lenalidomide.

[0620] 173. The method according to embodiment 168, wherein the subject has a newly diagnosed multiple myeloma.

[0621] 174. The method according to embodiment 168, wherein the subject has a newly diagnosed multiple myeloma and is not eligible for ASCT as an initial therapy or does not intend to undergo ASCT as an initial therapy.

[0622] 175. The method according to embodiment 168, wherein the subject has a newly diagnosed multiple myeloma and has previously undergone ASCT.

[0623] 176. The method according to embodiment 168, wherein the subject has a newly diagnosed multiple myeloma and has not yet undergone ASCT.

[0624] Those skilled in the art will recognize that many changes and modifications can be made to the preferred embodiments of the invention, 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 that fall within the true spirit and scope of the invention.

[0625] Every patent, patent application, and publication cited or described in this document is incorporated herein by reference in its entirety.

[0626] Example

[0627] 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.

[0628] Example 1: Autologous stem cell transplantation as initial therapy in patients with newly diagnosed multiple myeloma who are ineligible for the procedure. Comparison of teratumab versus daratumumab in patients who are eligible or do not intend to undergo autologous stem cell transplantation as initial therapy The combination of SC and lenalidomide (Tec-DR) versus daratumumab SC, lenalidomide and dexamethasone (DRd), and taquilo A phase 3 randomized study of the combination of talemab with daratumumab SC and lenalidomide (Tal-DR) versus DRd. (MajesTEC-7)

[0629] This study will compare the combination of teratumab with daratumumab SC and lenalidomide (Tec-DR) versus daratumumab SC, lenalidomide, and dexamethasone (DRd), and the combination of taquitumab with daratumumab SC and lenalidomide (Tal-DR) versus DRd in a phase 3 randomized study (NCT05552222). The Tal-DR group will be added to the study after the start of the safety introductory phase. The overall objective is to compare the efficacy of Tec-DR and DRd, and Tal-DR and DRd, in terms of PFS (progression-free survival, which is the duration from the randomization date to disease progression or death (whichever comes first)) and minimal residual disease (MRD)-negative complete response (CR).

[0630] Antibody

[0631] 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.

[0632] Table 5. Sequence of the BCMA binding arm of teratumab

[0633]

[0634] Table 6. Sequence of the CD3 binding arm of teratumab

[0635]

[0636] Goals and End Points

[0637] Table 7.3 Objectives and endpoints of the study.

[0638]

[0639] Abbreviations: AE = Adverse Event; CR = Complete Response; IMWG = International Myeloma Working Group; mBCAM = Membrane BCMA; MRD = Minimal Residual Disease; rHuPH20 = Recombinant Human Hyaluronidase PH20; PR = Partial Response; sBCMA = Soluble BCMA; sCR = Strictly Complete Response; VGPR = Very Good Partial Response

[0640] Research Design

[0641] This is a randomized, open-label, multicenter, phase 3 study in adult participants with a newly diagnosed multiple myeloma according to the IMWG diagnostic criteria who are ineligible for or do not intend to undergo ASCT as initial therapy. Inclusion and exclusion criteria are provided below.

[0642] Inclusion criteria :

[0643] • Diagnosed with multiple myeloma according to the diagnostic criteria of the International Myeloma Working Group (IMWG).

[0644] • Newly diagnosed and not considered a candidate for high-dose chemotherapy with autologous stem cell transplantation (ASCT) for the following reasons: ineligible due to advanced age; ineligible due to the presence of onion-like conditions that may negatively affect tolerance to high-dose chemotherapy with ASCT; or ineligible due to delayed use of high-dose chemotherapy with ASCT as initial treatment.

[0645] • Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 2

[0646] • Female participants must agree not to become pregnant, breastfeed, or plan to become pregnant at the time of recruitment to this study or for 3 months after the final dose of the study treatment.

[0647] • Male participants must agree not to have children at the time of recruitment to this study or within 3 months after the final dose of the study treatment.

[0648] Exclusion criteria :

[0649] • The patient received a cumulative dose of systemic corticosteroids equivalent to or greater than (>=) 20 mg of dexamethasone within 14 days prior to randomization.

[0650] • Had plasma ablation within 28 days of randomization

[0651] • Those who have had a stroke, transient ischemic attack, or epilepsy within 6 months prior to randomization.

[0652] • Known hypersensitivity, hypersensitivity, or intolerance to teratomab excipients.

[0653] • Known contraindications to the use of daratumumab or lenalidomide according to local prescribing information.

[0654] Initial study intervention before modification based on clinical data

[0655] As described in the section titled “Updated Study Design Following Safety Introduction Cohort 1”, the study intervention described here was ultimately modified based on clinical data after the start of the study’s safety introduction phase:

[0656] Treatment was administered over a 28-day cycle. For the Tec-DR cohort: varying doses of teratumab (Tec) were administered concurrently with constant doses of daratumumab (dara), lenalidomide (len), and dexamethasone. For the DRd cohort: constant doses of daratumumab (dara), lenalidomide (len), and dexamethasone were administered.

[0657] - For fixed-dose teratomab, subjects were divided into two cohorts based on body weight. Subjects ≤60 kg received 3 mg and 15 mg teratomab SC escalations on days 2 and 4 of treatment cycle 1, followed by 100 mg SC on days 8, 15, and 22 of treatment cycle 1. 100 mg teratomab SC was administered weekly for the second treatment cycle, followed by 200 mg Q2W starting in treatment cycle 3, and 200 mg Q4W starting in treatment cycle 7. Subjects >60 kg received 4 mg and 25 mg teratomab SC escalations on days 2 and 4 of treatment cycle 1, followed by 150 mg SC on days 8, 15, and 22 of treatment cycle 1. 150 mg Tec SC was administered weekly for the second treatment cycle, followed by 300 mg Q2W starting in treatment cycle 3, and 300 mg Q4W starting in treatment cycle 7.

[0658] - Daramumab was administered to all subjects via SC injection at a dose of 1800 mg, containing 30,000 units of hyaluronidase to reduce the required injection volume. Daramumab SC was administered weekly during treatment cycles 1 and 2, every 2 weeks during treatment cycles 3–6, and every 4 weeks thereafter.

[0659] - Lenalidomide is administered orally at 25 mg daily for 21 days of a 28-day treatment cycle. Lenalidomide treatment begins in the second treatment cycle.

[0660] - For the Tec-DR cohort, dexamethasone was administered weekly at a dose of 20 mg orally or intravenously. For the Tec-DR cohort in the safety induction cohort 1, dexamethasone was administered during treatment cycles 2, 3, and 4. For the DRd cohort, dexamethasone was administered at a dose of 40 mg, or at a dose of 20 mg if the participant was older than 75 years or had a BMI less than 18.5. For the DRd cohort, weekly administration of dexamethasone continued throughout all cycles.

[0661] - When daratumumab and teritumumab are administered on the same day, daratumumab should be administered first. At least 20 hours after daratumumab SC, administer teritumumab at an escalating dose of 1. Administer the first therapeutic dose of teritumumab 3 hours after daratumumab. Administer subsequent therapeutic doses of teritumumab at least 15 minutes after daratumumab SC.

[0662] Treatment also includes required and optional pretreatment medications. Pretreatment medications include dexamethasone (glucocorticoid), IV or oral. Dexamethasone is administered at 16 mg on days 1, 2, 4, and 8 of the first treatment cycle. Dexamethasone is administered approximately 1 to 3 hours before daratumumab SC or teritumumab SC on days when daratumumab SC is not administered. Additional pretreatment medications include diphenhydramine (antihistamine) or an equivalent and acetaminophen (antipyretic). Diphenhydramine is administered at 25 mg to 50 mg on all days of daratumumab SC administration, on all escalation days, and on the first treatment day of teritumumab SC. Diphenhydramine is administered IV or oral 1 to 3 hours before daratumumab SC or teritumumab SC. Acetaminophen is administered at 650 mg to 1000 mg on all days of daratumumab SC administration, on all escalation days, and on the first treatment day of teritumumab SC. Acetaminophen should be administered IV or orally 1 to 3 hours prior to daratumumab SC or teritumumab SC. Optionally, montelukast (10 mg) may be administered by the examiner at their discretion before daratumumab administration. On days when daratumumab SC and teritumumab SC are administered together, a pre-treatment drug should be given before daratumumab SC. If there is a gap of more than 4 hours between administrations of the study drug, a repeat dose of dexamethasone 8 mg must be given before the bispecific antibody. Participants treated with Tec-DR who have experienced ≥ grade 2 CRS / sARR associated with teritumumab or daratumumab SC must receive dexamethasone 16 mg, diphenhydramine 25 mg to 50 mg or equivalent, and acetaminophen 650 mg to 1000 mg as pre-treatment drugs for at least subsequent doses of the study drug associated with the event. These event-driven pre-treatment drugs are not required if they have already been administered as part of the above-planned pre-treatment regimen. In participants treated with Tec-DR, the dexamethasone dose as part of the background treatment plan for cycles 2–4 can be used as an event-driven pretreatment.

[0663] Overview of the initial trial design prior to modifications based on clinical data

[0664] Eligible patients will be ≥18 years of age, have NDMM, and not eligible for ASCT as initial therapy or do not intend to undergo ASCT as initial therapy, have measurable disease, and have an ECOG performance status score of 0–2. The safety induction phase for Tec-DR will precede the randomization phase. Approximately 1000 patients will be randomized 1:1 to receive Tec-DR or DRd. Treatment will continue until disease progression, death, intolerable toxicity, loss of follow-up, withdrawal of consent, or study termination, whichever occurs first. The dual primary endpoints are PFS and minimal residual disease (MRD)-negative complete response (CR) lasting at least 12 months. Secondary endpoints include CR or better response, overall survival, MRD-negative CR rate, very good partial response or better response rate, PFS², patient-reported outcomes, and adverse events (AEs). Response will be assessed using the 2016 International Myeloma Working Group criteria. AEs will be classified according to the Common Terminology Standard for AEs v5.0, except for cytokine release syndrome and immune effector cell-related neurotoxicity syndrome, which will be classified according to the American Society for Transplantation and Cell Therapy guidelines. The results of this trial will provide insights into potential new treatment options (Tec-DR) for patients with NDMM that could offer improved outcomes.

[0665] Updated research design following the introduction of security into queue 1

[0666] Based on evolutionary data from the teratumab clinical development program, it was decided to investigate a modified dosing schedule after the start of Tec-DR safety introductory cohort 1. Therefore, a second Tec-DR safety introductory cohort 2 (n=30) will be conducted in the current study, with a modified teratumab schedule including the DRd introductory cycle, starting teratumab administration in cycle 2 and Q4W dosing in cycle 3. Additionally, the taquitumumab-DR (Tal-DR) regimen will be evaluated in safety introductory cohort 3 (n=30). Subsequently, approximately 1500 participants (500 per cohort) will be randomized 1:1:1 to Tec-DR and Tal-DR.

[0667] Table 8 provides the study treatments administered in the Tec-DR Safety Introduction Cohort 1 (Tec-DR SRI 1). Participants recruited in Safety Introduction Cohort 1 were initially treated with a fixed dose of teratumab in combination with DR. Following an implementation modification, all participants treated with a fixed dose of teratumab were switched to a weight-based teratumab regimen due to safety measures.

[0668] Table 8. Study Treatments Administered – Tec-DR – Safety Import Cohort 1

[0669]

[0670] IV = intravenous; PO = oral; Q2W = once every other week; SC = subcutaneous

[0671] For the randomization portion of this study, Table 9 provides the treatments to be administered to subjects in the DRd group.

[0672] Table 9. Study Treatments Administered – DRd – Randomization Part

[0673]

[0674] IV = intravenous; PO = oral; Q2W = once every other week; SC = subcutaneous

[0675] * Lenalidomide dosage may need to be adjusted for participants with reduced CrCl.

[0676] For participants aged >75 years or with a BMI <18.5 kg / m2, dexamethasone can be administered at a dose of 20 mg.

[0677] As of April 10, 2023, 26 participants with newly diagnosed multiple myeloma were recruited into the Tec-DR safety introductory cohort 1 of the current study and completed at least two cycles of treatment with Tec-DR. The median time from diagnosis to recruitment was 1 month (range: 0.16–4.76 months). The median age of participants at consent was 72.5 years (range: 66–84 years), and the majority (n=21, 81%) of participants were 70 years of age or older. The majority (n=22, 85%) of participants were ineligible for transplantation due to advanced age, and the remaining 15% of transplantation was delayed due to the need for novel therapies. Preliminary efficacy results of the TEC-DR combination are shown in Table 10 below, particularly the results of “VGPR or better” (VGPR, CR, or sCR) and “CR or better” (CR or sCR) response rates at a median follow-up period of 6.5 months (mFU).

[0678] Table 10.

[0679]

[0680] Regarding the safety profile observed in Tec-DR SRI 1, with a median follow-up of 6.7 months, the infection rate was 92.3% for any grade, 38.5% for grade 3+, and 34.6% for grade 3 or 4. Further optimization of the dosing regimen may reduce the infection rate, thereby improving the safety profile.

[0681] Updated safety / efficacy results for Tec-DR SRI 1 :

[0682] As of November 27, 2023, 26 patients received tec+DR (median, 11 cycles; range, 2–14), and 24 patients (92.3%) maintained treatment. The median follow-up period was 10.2 months (range, 2–12). At baseline, the median age was 72.5 years, 11.5% had an ECOG PS score of 2, and 15.4% had ≥1 soft tissue plasmacytoma. Transplantation was delayed in 4 patients (15.4%). Treatment-related adverse events (TEAEs) occurred in 100% of patients (grade 3 / 4 [gr], 22 patients [84.6%]). Infections occurred in 25 patients (96.2%; grade 3 / 4, 8 patients [30.8%]). CRS occurred in 16 patients (61.5%; all grade 1). ICANS occurred in 1 patient (grade 1). Grade 3 / 4 TEAEs occurring in ≥3 patients were neutropenia (13 [50%]), febrile neutropenia (5 [19.2%]), thrombocytopenia (4 [15.4%]), COVID-19 (3 ​​[11.5%]), maculopapular rash (3 [11.5%]), and hypertension (3 [11.5%]). One patient discontinued tec+DR due to withdrawal of consent. Two patients discontinued len due to TEAEs (grade 3 maculopapular rash and grade 4 neutropenia). One death due to a TEAE occurred during cycle 3 (pneumonia-influenza). The overall response rate was 92.3% (complete or better response, 73.1%; very good or better response, 92.3%). These results from the first SRI at MajesTEC-7 demonstrate a manageable safety profile and early efficacy of tec+DR in NDMM.

[0683] Tec-DR security import 2 and initial randomization of the Tec-DR group :

[0684] Table 11 provides the study treatments administered to the Tec-DR Safety Introduction Cohort 2 (Tec-DR SRI 2) and the initially randomized Tec-DR group. The dosing regimen used in Tec-DR SRI 2 was designed to achieve robust efficacy while improving the safety profile observed in Tec-DR SRI 1, including a reduction in infection rates.

[0685] Table 11. Tec-DR – Security Import Queue 2 and Initial Randomization Section

[0686]

[0687] * Lenalidomide dosage may need to be adjusted for participants with renal insufficiency as determined by CrCl.

[0688] As shown in Table 11, teratumab will be administered after the DR induction cycle and at a reduced frequency (Q4W) after the escalation period is completed. The early reduction in teratumab frequency (Q4W administration in cycle 3) is implemented to reduce the rate of severe infections. The teratumab SC dosing schedule for the safety induction cohort 2 of the study will include two escalation doses (0.06 mg / kg and 0.3 mg / kg) on ​​days 1 and 3 of cycle 2, followed by 1.5 mg / kg on days 8 and 15 of cycle 2, and 3 mg / kg Q4W from the start of cycle 3.

[0689] The modified dosing regimen of teratumab, to be evaluated in the safety introductory cohort 2, was supported by emerging data from participants with relapsed / refractory multiple myeloma treated with teratumab monotherapy (MajesTEC-1; Study 64407564MMY1001). In the updated results for MajesTEC-1 as of the clinical cutoff date of January 4, 2023, 63 responders receiving the RP2D dose (1.5 mg / kg QW) switched to Q2W therapy, with a median time to switch of 11.3 months (range: 1.0 to 24.7), and 9 of those participants switched from 1.5 mg / kg Q2W to 1.5 mg / kg Q4W. Of the 63 participants, 49 (77.8%) were disease-free, with a median follow-up of 12.6 months following the schedule change. For those participants who switched to 1.5 mg / kg Q2W dosing, the median DOR was not reached, and the 24-month event-free rate was 68.7% (95% CI: 53.6 to 79.7).

[0690] In addition, in the MajesTEC-1 study, among patients who maintained treatment for at least 12 months, those who switched to 1.5 mg / kg Q2W at 12 months had a lower incidence of infections during ≥ grade 3 treatment between 12 and 18 months of treatment than those who maintained 1.5 mg / kg QW for 12 months (15.6% vs. 33.3%).

[0691] Using a population pharmacokinetic (PK) model based on teratomab clinical data, it was estimated that the 3 mg / kg Q4W dosing regimen would have lower exposure (concentration-time profile) at steady state than the 1.5 mg / kg QW regimen, which is associated with a durable response. It was also estimated that the 3 mg / kg Q4W dosing regimen would achieve pharmacokinetic parameters C0 at steady state comparable to those achieved with a 1.5 mg / kg Q2W dosing regimen following a switch from 1.5 mg / kg QW. 谷 C 最大And AUC). In addition, it is estimated that the modified Q4W regimen will be similar to the exposure (concentration-time profile) of the 0.72 mg / kg QW dose, which has shown robust efficacy and good safety in combination with daratumumab and lenalidomide in MajesTEC-2 (Study 64007957MMY1004).

[0692] Updated research design following the import of security into queues 1 and 2. :

[0693] Safety Introduction 2 (SRI2) introduced a DRd introduction dosing strategy (i.e., Drd administration in cycle 1 and Tec introduction in cycle 2, with escalation dosing concurrent with lenalidomide administration). This approach was used to explore whether DRd introduction would reduce the disease burden in newly diagnosed patients and further reduce the incidence and severity of CRS. However, data indicated that the DRd introduction cycle did not result in a reduction in the severity of CRS events. Instead, there was a potentially increased risk of higher-grade CRS when participants were exposed to concurrent lenalidomide administration during the escalation of lenalidomide and Tec administration in cycle 1, supporting the reversal of the randomization portion to delayed lenalidomide initiation in cycle 2 (i.e., supporting a switch from the dosing schedule for the initial randomization portion shown in Table 11 to the updated dosing schedule for the randomization portion shown in Table 12 below). Furthermore, grade 5 infections were reported in 4 participants in SRI2, which could be explained at least in part by the high dose of steroids included in the DRd introduction.

[0694] Prior dexamethasone exposure prior to initiating Tec in SRI2 may also contribute to infection outcomes. While DRd introduction led to a higher grade of CRS (SRI1) and an increase in fatal infections (SRI2), early preliminary efficacy in these cohorts supports the lower exposure to Tec used in these groups. Therefore, the dosing schedule in the randomization portion minimizes Tec exposure and optimizes participant tolerability and safety by completing escalation dosing in cycle 1 and transitioning to monthly dosing in cycle 2. After the escalation period, teritumumab and daratumumab will be started in cycle 1, and lenalidomide will be added in cycle 2. The lower frequency (i.e., Q4W) dosing for infection mitigation implemented in SRI2 will be maintained. The updated teritumumab SC dosing schedule for the randomization portion of the study will include two escalation doses (0.06 mg / kg and 0.3 mg / kg) on ​​days 2 and 4 of cycle 1, followed by 1.5 mg / kg on days 8 and 15 of cycle 1. Starting from cycle 2, the dosing will be 3 mg / kg Q4W on day 1 of the cycle. Table 12 provides an overview of the study drug administration for participants in the updated randomization portion of the Tec-DR.

[0695] Table 12. Study treatments administered – updated Tec-DR randomization portion

[0696]

[0697] * Lenalidomide dosage may need to be adjusted for participants with reduced CrCl.

[0698] **Dexamethasone (16 mg) will be administered as a pre-treatment medication on days 1, 2, 4 and 8 of cycle 1.

[0699] Example 2: The combination of teratumab and lenalidomide and teratumab alone compared to lenalidomide alone A phase 3 study of limonene as maintenance therapy following autologous stem cell transplantation in participants with newly diagnosed multiple myeloma. Research (MajesTEC-4; NCT05243797)

[0700] Background and Acceptance Criteria

[0701] This is a multicenter, randomized, open-label phase 3 study in participants with newly diagnosed multiple myeloma evaluating the benefits of teritumumab in combination with lenalidomide and teritumumab alone versus lenalidomide alone as maintenance therapy after autologous stem cell transplantation.

[0702] Inclusion criteria include the following:

[0703] • Must be newly diagnosed with multiple myeloma according to IMWG criteria and have already received induction + / - consolidation therapy.

[0704] • Must have received only first-line therapy and achieved at least a partial response (≥PR) according to the IMWG 2016 response criteria (Kumar 2016), with no evidence of progression at the first treatment dose.

[0705] • The initial dose of lenalidomide must be intolerable.

[0706] • Must not have received any maintenance therapy.

[0707] • Having an ECOG performance status score of 0, 1, or 2 at screening and just before starting study treatment.

[0708] • Has clinical laboratory values ​​within the pre-specified range.

[0709] The exclusion criteria include the following:

[0710] • Has received any prior BCMA-directed therapy.

[0711] • Any prior therapy using immune cell redirecting agents or genetically modified adoptive cell therapy (e.g., chimeric antigen receptor-modified T cells, NK cells).

[0712] • Treatment may be interrupted due to any adverse events (AEs) associated with lenalidomide identified by the investigators.

[0713] • Progression can occur at any time during multiple myeloma therapy, prior to screening.

[0714] • Received a cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within 14 days prior to the first treatment dose.

[0715] • The patient received a live attenuated vaccine within 4 weeks prior to the first therapeutic dose. Inactive or non-replicating vaccines authorized for emergency use (e.g., COVID-19) are permitted.

[0716] Len maintenance after ASCT has significant progression-free survival and overall survival benefits and is considered the standard of care for transplant-eligible NDMM. However, patients (pt) eventually relapse, supporting the need for novel maintenance strategies to improve outcomes. Tec, a first-in-class B-cell maturation antigen × CD3 bispecific antibody, has demonstrated deep and durable responses in multiple myeloma (MM), leading to its approval for relapsed and refractory MM with three-category exposure. MajesTEC-4 / EMN30 is a multicenter, randomized, open-label phase 3 study evaluating Tec-Len, Tec, and Len maintenance therapy in NDMM following induction and ASCT ± consolidation.

[0717] Goals and End Points

[0718] The primary objective of this study was to compare the efficacy of teratomab combined with lenalidomide (Tec-Len) versus lenalidomide monotherapy (Len) in a maintenance setting, as well as the efficacy of teratomab monotherapy (Tec) versus lenalidomide monotherapy (Len), as assessed by progression-free survival (PFS) and 12-month MRD-negative complete remission (CR). Secondary objectives included further comparisons of efficacy, including overall survival (OS) (a key secondary endpoint), CR or better, MRD-negative CR, sustained MRD-negative CR and MRD seroconversion, PFS after next-line therapy (PFS2), time to next treatment (TTNT), and safety, pharmacokinetic (PK) and immunogenicity.

[0719] Security Import Queue

[0720] Prior to the randomization phase of the study, a first safety induction (SRI1) was performed. Participants in SRI1 received Tec-Len for 2 years or until confirmed progressive disease, death, intolerable toxicity, or withdrawal of consent, whichever occurred first. The SRI1 dosing schedule is provided in Table F below. Safety was evaluated after at least 20 participants had received at least 2 cycles of treatment. After reviewing the safety data, IDMC recommended continuing the study without modification. However, based on emerging data from MajesTEC-1 indicating a reduction in new episodes of serious infections and durable responses with lower frequency treatment administration, it was decided to further optimize the teratomab dosing regimen. Therefore, a second safety induction (SRI2) was performed starting in cycle 2 with Q4W teratomab administration. SRI2 consisted of two cohorts, one using Tec-Len (SRI2 Tec-Len) and one using Tec (SRI2 Tec). Safety was evaluated after at least 20 participants had received at least 2 cycles of treatment and were recommended to participate in the randomization phase of the study. During the randomization portion of the study, participants will be randomized 1:1:1 to receive Tec-Len (Group A), Len (Group B), or Tec (Group C). Participants will receive study treatment for two consecutive years or until confirmed progressive disease, death, intolerable toxicity, or withdrawal of consent, whichever occurs first. Participants receiving Tec-Len in SRI1, Tec-Len in SRI2, and those achieving confirmed CR or better after 13 treatment cycles in Group A will discontinue teratomab but continue lenalidomide in the second year.

[0721] Description of the treatment studied

[0722] For SRI1, SRI2, Tec-Len (Group A), Len (Group B), and Tec (Group C), study treatment was administered in 28-day cycles. Treatment continued for 2 years (i.e., 26 cycles). Participants in SRI1 were treated with a combination of teratumab and lenalidomide at weight-based doses and fixed doses, according to the protocol amendments approved during their recruitment and participation, and all were switched to the weight-based dosing schedule detailed below. Participants in SRI2 were treated with a weight-based SC teratumab and lenalidomide combination or teratumab alone. Similarly, teratumab in the randomized portion of the study was administered using the weight-based dosing schedule SC detailed in Table F below.

[0723] Table F: Dosing Schedule

[0724]

[0725] Participants who achieve confirmed CR or better after 13 treatment cycles in SRI1, SRI2 Tec-Len, or Group A will discontinue teratomab but continue lenalidomide in the second year.

[0726] The initial security import (SRI) results are provided below.

[0727] Methods for safety entry into the cohort: Eligible patients are ≥18 years old, have NDMM (according to the International Myeloma Working Group [IMWG] criteria), have received 4 to 6 cycles of 3- or 4-drug induction and single or tandem ASCT ± consolidation, including proteasome inhibitors and / or immunomodulatory drugs ± anti-CD38 antibodies, and have achieved a partial or better response according to the IMWG 2016 response criteria. Three cohorts were evaluated at different Tec dosing frequencies: Cohort 1 (Tec-Len) in which Tec was administered at 1.5 mg / kg QW for two cycles (C), followed by 3 mg / kg Q2W in C3-6 and 3 mg / kg Q4W in C7+; Cohort 2 (Tec-Len) in which Tec was administered at 1.5 mg / kg on days 8 and 15 in C1, followed by 3 mg / kg Q4W in C2+; and Cohort 3 (Tec) in which Tec was administered at 1.5 mg / kg on days 8 and 15 in C1, followed by 3 mg / kg Q4W in C2+. All patients received the same inpatient Tec escalation schedule (0.06 mg / kg; 0.3 mg / kg) in C1. In the Tec-Len cohort, 10 mg of Len was administered QD in C2-4 (15 mg thereafter if tolerated). Treatment duration was 2 years for all patients; in the Tec-Len cohort, Tec was discontinued after 13 treatment cycles if a complete response or better (≥CR) was achieved. Adverse events (AEs) were graded according to the Common Terminology Standard for Adverse Events v5.0. Cytokine release syndrome (CRS) and immune effector cell-related neurotoxicity syndrome (ICANS) were graded according to the American Association for Transplantation and Cell Therapy guidelines. Investigator-assessed responses were based on the IMWG 2016 criteria.

[0728] Results from the safety importation cohort: Among 3 cohorts, 94 patients were recruited (cohort 1, n = 32; cohort 2, n = 32; cohort 3, n = 30). At median follow-up of 14.4 months, 5.0 months, and 4.9 months, 97% of patients in each cohort (n = 31, 31, 29, respectively) remained on treatment. Baseline characteristics were generally balanced between cohorts with a median age of 58 to 59 years. Patients in cohorts 1, 2, and 3 received a median of 15, 6, and 6 maintenance cycles, respectively. Neutropenia and infections were the most common grade 3 / 4 treatment-emergent adverse events (TEAEs). Compared with cohort 1, the cumulative incidence of any-grade and grade 3 / 4 neutropenia at 4 months showed a decreasing trend in cohorts 2 and 3 with lower dosing frequencies of Tec (cohort 1: any-grade / grade 3 / 4 incidence, 69% / 66%; cohort 2: 44% / 41%; cohort 3: 37% / 28%). A similar trend was observed for all-grade infections with lower dosing frequencies of Tec (cohort 1: 78%; cohort 2: 63%; cohort 3: 61%). Among 68 / 94 (72.3%) patients with any-grade hypogammaglobulinemia, 63 / 68 (92.6%) received ≥1 dose of IVIg. The overall CRS rate was 43.6%, 6.4% was grade 2 and no high-grade events occurred. The CRS rate after the first treatment dose of Tec (1.5 mg / kg) was as low as 7.4%. ICANS was not reported. TEAEs led to treatment discontinuation in 2 patients (1 in each of cohorts 2 and 3) and 1 patient death (cohort 2; due to COVID-19 during C1, before Len initiation). In cohort 1, all 28 patients with MRD assessment at 12 months were in MRD-negative CR. Among patients who were MRD positive at study entry, 10 (100%) converted to MRD-negative CR during treatment. Among 16 patients with <CR at study entry, 100% achieved ≥CR during treatment. At the clinical cutoff, no patient had progression during treatment.

[0729] Conclusions from the safety importation cohort: Overall, Tec-Len and Tec can be safely administered as maintenance therapy after ASCT in NDMM. Compared with cohort 1, cohorts 2 and 3 showed a trend of improved early safety outcomes at lower dosing frequencies of Tec. At the initial cutoff, Tec-Len showed a deeper response and 100% MRD-negative CR rate at 12 months in evaluable patients in cohort 1. These data provide the basis for the randomized part of MajesTEC-4 / EMN30. The randomized part was conducted at a lower dosing frequency of Tec (3.0 mg / kg Q4W starting from cycle 2).

[0730] Example 3: Higher levels of teratumab in patients with relapsed or refractory multiple myeloma (RRMM) Incremental dose: Results from the MajesTEC-1 trial

[0731] In the Phase 1 / 2 single-arm MajesTEC-1 study, teratomab demonstrated manageable safety and rapid, deep, and durable responses. In MajesTEC-1, patients received escalating doses (SUDs) of 0.06 mg / kg and 0.3 mg / kg, followed by weekly doses of 1.5 mg / kg (the recommended Phase 2 dose). Cytokine release syndrome (CRS) occurred in 72% of patients (almost all Grade 1 / 2); however, most events occurred during escalation; 24% of patients experienced CRS after the first treatment dose. Higher SUDs were evaluated in exploratory Phase 1 cohorts from MajesTEC-1: Cohort 22 (SUDs of 0.1 mg / kg and 0.5 mg / kg, with 2 to 4 days between doses) and Cohort 23 (SUDs of 0.2 mg / kg and 0.7 mg / kg, with 2 to 4 days between doses). Following the SUD, patients received 1.5 mg / kg on days 1, 8, and 15 of Cycle 1, followed by 3 mg / kg every 4 weeks in subsequent cycles. Premedication requirements and permitted supportive care for the CRS were the same as for the RP2D cohort. Prophylactic tocilizumab was not permitted. The CRS was graded according to the Lee criteria and converted to the American Society for Transplantation and Cell Therapy (ASTCT) criteria to allow for comparison with RP2D. All adverse events (AEs) were graded according to the Common Terminology Standard for Adverse Events (CTCAE) version 4.03. Serum samples were collected to evaluate the pharmacokinetics (PK) of teratumab.

[0732] A total of 21 patients were recruited (cohort 22: n=10; cohort 23: n=11). Patient demographics and baseline disease characteristics were generally consistent with those in the RP2D cohort. The median follow-up for cohort 22 was 8.6 months (range, 3.4–10.6) and for cohort 23 was 3.2 months (range, 0.1–6.0). Overall, 22 CRS events were reported in 16 patients (8 in each cohort); all events were grade 1 / 2. Three patients (14.3%; 1 in cohort 22 and 2 in cohort 23) experienced recurrent CRS events. The overall incidence and severity of CRS events were comparable to those obtained using RP2D SUD (median follow-up: 14.1 months [range, 0.3–24.4]). CRS events primarily occurred during SUD. The median duration of CRS up to Day 1 of Cycle 1 was 2.0 days in Cohort 22 and 2.5 days in Cohort 23; the median duration of events was 2 days in both cohorts. All CRS events were resolved without any treatment interruption. Overall, all 8 patients (100%) in Cohort 22 and 7 of 8 patients (87.5%) in Cohort 23 experienced CRS and received supportive care; 5 of 8 patients (62.5%) in Cohort 22 and 4 of 8 patients (50.0%) in Cohort 23 experienced CRS and received tocilizumab. Of the 2 patients who experienced recurrent CRS during the escalation period, only 1 (Cohort 22; Grade 2) received tocilizumab; the other patient (Cohort 23; Grade 1) did not receive supportive care. One patient in Cohort 23 who experienced recurrent CRS after Day 1 of Cycle 1 did not receive tocilizumab but received corticosteroids. No new safety signals were observed in the higher SUD cohort, and its safety profile was comparable to that of RP2D. Based on limited preliminary data, the median maximum serum teratumab concentration following SUD administration was slightly higher in the higher SUD cohort compared to RP2D SUD. The trough concentrations in patients sensitized with the higher SUD were comparable to those observed with RP2D following a treatment dose of 1.5 mg / kg.

[0733] Key implications from these cohorts are that higher teratomab SUDs lead to earlier CRS events during treatment initiation, thus reducing the time required for CRS monitoring and potentially facilitating a shift to outpatient dosing. Higher SUDs result in slightly higher teratomab serum concentrations relative to RP2D during escalation, but have no effect on post-treatment teratomab exposure. CRS rates in the higher SUD cohorts were similar to those under RP2D; all events were grade 1 / 2, most occurred after the first SUD (including two grade 2 events in cohort 23), and none led to treatment discontinuation. No new safety signals were observed compared to RP2D SUDs.

Claims

1. A method for treating a subject with multiple myeloma in need, the method comprising treating the subject according to a treatment-effective regimen comprising consecutive 28-day cycles of BCMAxCD3 treatment, wherein: During the escalation phase, one or more escalating doses of the BCMAxCD3 bispecific antibody were administered subcutaneously to the subject, and Starting from the first BCMAxCD3 treatment cycle after the escalation period, the subject is given a therapeutic dose of the BCMAxCD3 bispecific antibody subcutaneously according to a monthly dosing schedule (Q4W).

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 in its Fc region (according to EU index number).

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 (according to EU index number) 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 (according to EU index number).

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

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 comprises a first heavy chain (HC1) having at least 99% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 99% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 99% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 99% identity with the amino acid sequence of SEQ ID NO:

23.

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

17. The method according to any one of claims 1 to 16, wherein each therapeutic dose of the BCMAxCD3 bispecific antibody administered to the subject according to the monthly dosing schedule (Q4W) is administered at an amount of 1.5 mg / kg or 3 mg / kg.

18. The method according to any one of claims 1 to 16, wherein each therapeutic dose of the BCMAxCD3 bispecific antibody administered to the subject according to the monthly dosing schedule (Q4W) is administered at an amount of 1.5 mg / kg.

19. The method according to any one of claims 1 to 16, wherein each therapeutic dose of the BCMAxCD3 bispecific antibody administered to the subject according to the monthly dosing schedule (Q4W) is administered at an amount of 3 mg / kg.

20. The method according to any one of claims 1 to 19, wherein each therapeutic dose of the BCMAxCD3 bispecific antibody administered to the subject according to the monthly dosing schedule (Q4W) is administered on day 1 of each BCMAxCD3 treatment cycle.

21. The method according to any one of claims 1 to 20, wherein the regimen does not include any BCMAxCD3 treatment cycle in which the subject is administered the BCMAxCD3 bispecific antibody according to a two-week dosing schedule (Q2W).

22. The method according to any one of claims 1 to 21, wherein the increment period is 28 days.

23. The method according to any one of claims 1 to 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 1 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 1 to 24, wherein the escalation period comprises a first escalation dose of the BCMAxCD3 bispecific antibody at 0.06 mg / kg.

26. The method according to any one of claims 1 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 1 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 1 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 1 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 1 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 1 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 1 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 1 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 1 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.

49. The method according to any one of claims 1 to 48, wherein: 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; and Each subsequent BCMAxCD3 treatment cycle includes a subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

50. The method according to any one of claims 1 to 48, wherein: 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; and Each subsequent BCMAxCD3 treatment cycle includes a subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

51. The method according to any one of claims 1 to 50, wherein the subject is administered the therapeutic dose of the BCMAxCD3 bispecific antibody according to the monthly dosing schedule (Q4W), regardless of whether or to what extent the subject demonstrates a clinical response to the regimen.

52. The method according to any one of claims 1 to 51, wherein the escalation period is in the first cycle of the regimen, and the first BCMAxCD3 treatment cycle is in the second cycle of the regimen.

53. The method according to any one of claims 1 to 52, wherein the regimen is a combination therapy comprising, in addition to the BCMAxCD3 bispecific antibody, administration of other anti-multiple myeloma agents.

54. The method according to any one of claims 1 to 53, wherein the regimen is a combination therapy, the escalation phase is in the second cycle of the regimen, and the first BCMAxCD3 treatment cycle is in the third cycle of the regimen or later.

55. The method according to any one of claims 1 to 53, wherein the regimen is a combination therapy, the escalation period is in the second cycle of the regimen, and the first BCMAxCD3 treatment cycle is in the third cycle of the regimen.

56. The method according to any one of claims 1 to 16, wherein: During the escalation phase, the subject was subcutaneously administered a first dose of 0.06 mg / kg, a second dose of 0.3 mg / kg, a third dose of 1.5 mg / kg, and a fourth dose of 1.5 mg / kg of the BCMAxCD3 bispecific antibody (e.g., teratumab). Starting from the first BCMAxCD3 treatment cycle after the escalation period, the subject is subcutaneously administered a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg every 4 weeks (Q4W).

57. The method according to claim 56, wherein: The increment period is 28 days and occurs in the first cycle of the scheme; The first dose, the second dose, the third dose, and the fourth dose were administered on days 1, 3, 8, and 15 of the first cycle, respectively. The therapeutic dose of 3 mg / kg was administered on day 1 of the second cycle and on day 1 of each subsequent treatment cycle.

58. The method according to any one of claims 1 to 16, wherein: During the escalation phase, the subject was subcutaneously administered a first dose of 0.06 mg / kg, a second dose of 0.3 mg / kg, a third dose of 1.5 mg / kg, a fourth dose of 1.5 mg / kg, and a fifth dose of 1.5 mg / kg of the BCMAxCD3 bispecific antibody (e.g., teratumab). Starting from the first BCMAxCD3 treatment cycle after the escalation period, the subject is subcutaneously administered a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg every 4 weeks (Q4W).

59. The method according to claim 58, wherein: The increment period is 28 days and occurs in the first cycle of the scheme; The first dose, the second dose, the third dose, the fourth dose, and the fifth dose were administered on days 1, 3, 8, 15, and 22 of the first cycle, respectively, and the treatment dose of 3 mg / kg was administered on day 1 of the second cycle and on day 1 of each subsequent treatment cycle thereafter.

60. The method of claim 56, wherein: The proposed treatment is a combination therapy. The increment period is 28 days and occurs in the second cycle of the scheme; The first, second, third, and fourth doses of the BCMAxCD3 bispecific antibody were administered on days 1, 3, 8, and 15 of cycle 2, respectively. The therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg was administered on day 1 of cycle 3 and on day 1 of each subsequent treatment cycle thereafter.

61. The method according to claim 58, wherein: The proposed treatment is a combination therapy. The increment period is 28 days and occurs in the second cycle of the scheme; The first dose, the second dose, the third dose, the fourth dose, and the fifth dose were administered on days 1, 3, 8, 15, and 22 of the first cycle, respectively. The therapeutic dose of 3 mg / kg was administered on day 1 of the third cycle and on day 1 of each subsequent treatment cycle.

62. The method according to any one of claims 1 to 53, wherein the regimen is a combination therapy comprising administering the BCMAxCD3 bispecific antibody (e.g., teratumab), daratumumab, and lenalidomide.

63. The method of claim 62, wherein the administration of daratumumab begins in cycle 1, the administration of lenalidomide begins in cycle 1, and the administration of the BCMAxCD3 bispecific antibody begins in cycle 2; and wherein during the escalation phase of cycle 2, the subject is subcutaneously administered one or more escalation doses and at least one therapeutic dose of the BCMAxCD3 bispecific antibody, and wherein a therapeutic dose of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject monthly (Q4W) starting in cycle 3.

64. The method of claim 63, wherein the scheme further comprises: Dexamethasone was administered orally or intravenously to the subjects only during cycle 1 and cycle 2.

65. The method according to any one of claims 62 to 64, wherein the scheme comprises: For the BCMA x CD3 bispecific antibody (e.g., teratomab): In cycle 2, a first escalation dose of 60 μg / kg was administered subcutaneously (e.g., on day 1 or 2), a second escalation dose of 300 μg / kg (e.g., on day 3 or 4), followed by weekly (QW) doses of 1500 μg / kg (e.g., on days 8 and 15), and During cycle 3 and all subsequent treatment cycles, administer a monthly (Q4W) dose of 3000 μg / kg subcutaneously (e.g., on day 1). Regarding the aforementioned daratumumab: During cycles 1-2, administer 1800 mg subcutaneously weekly (QW) (e.g., on days 1, 8, 15, and 22). During cycles 3-6, administer 1800 mg subcutaneously every two weeks (Q2W) (e.g., on day 1 and day 15), and During cycle 7 and all subsequent treatment cycles, administer 1800 mg subcutaneously monthly (Q4W) (e.g., on day 1); and Regarding the lenalidomide: During the first cycle and all subsequent treatment cycles, 25 mg was administered orally daily for the first 21 days of each 28-day cycle.

66. The method of claim 65, wherein the scheme further comprises: During cycles 1-2, administer 20 mg of dexamethasone orally or intravenously weekly (QW) (e.g., on days 1, 8, 15, and 22).

67. The method of any one of claims 62 to 66, wherein the method achieves a reduction in new infections over time in a population of subjects with newly diagnosed multiple myeloma compared to a population of subjects treated with the combination therapy but receiving more frequent doses of the BCMAxCD3 bispecific antibody (e.g., QW and / or Q2W) in cycle 3 and all subsequent treatment cycles.

68. The method of any one of claims 62 to 67, wherein the method achieves a reduction of ≥ grade 3 new infections over time in a population of subjects with newly diagnosed multiple myeloma compared to a population of subjects treated with the combination therapy but receiving more frequent doses of the BCMAxCD3 bispecific antibody (e.g., QW and / or Q2W) in cycle 3 and all subsequent treatment cycles.

69. The method according to any one of claims 62 to 68, wherein the subject has a newly diagnosed multiple myeloma and is not eligible for autologous stem cell transplantation (ASCT) as an initial therapy or does not intend to undergo ASCT as an initial therapy.

70. The method according to any one of claims 62 to 69, wherein the subject has a newly diagnosed multiple myeloma and is not eligible for autologous stem cell transplantation (ASCT) as an initial therapy.

71. The method according to any one of claims 62 to 70, wherein the subject has a newly diagnosed multiple myeloma and does not intend to undergo autologous stem cell transplantation (ASCT) as initial therapy.

72. The method according to any one of claims 62 to 71, wherein the clinical response achieved by the method in the subject is the subject's sCR, CR, VGPR, or PR, as defined by the IMWG (2016) response criteria.

73. The method according to any one of claims 62 to 72, wherein the method achieves CR, VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

74. The method according to any one of claims 62 to 73, wherein the method achieves VGPR or PR in the subject, as defined by the IMWG (2016) response criteria.

75. The method of any one of claims 62 to 74, wherein the method achieves a median progression-free survival (mPFS) of at least 80 months, or at least 90 months, or at least 100 months, or at least 110 months in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy.

76. The method of any one of claims 62 to 75, wherein the method achieves a CR or better response (i.e., sCR or CR) as defined by the IMWG (2016) response criteria in at least 60%, at least 65%, or at least 70% of subjects in a population with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy.

77. The method of any one of claims 62 to 76, wherein after treatment with the combination therapy for about 50 months, the method achieves a sustained MRD-negative CR (≥12 months) rate of at least about 18%, or at least about 20%, or at least about 22%, or at least about 24%, or at least about 26% in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as an initial therapy or who do not intend to undergo ASCT as an initial therapy.

78. The method of any one of claims 62 to 77, wherein the method achieves median progression-free survival (mPFS) in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the mPFS is greater than the reference mPFS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, the reference population having been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of the combination therapy comprising the BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

79. The method of claim 78, wherein the mPFS is at least about 10 months, or at least 20 months, or at least 30 months, or at least 40 months, or at least 50 months longer than the reference mPFS.

80. The method of any one of claims 62 to 79, wherein the method achieves median overall survival (mOS) in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the mOS is greater than a reference mOS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, the reference population having been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of the combination therapy comprising the BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

81. The method of claim 80, wherein the mOS is at least 1 year, or at least 2 years, or at least 3 years, or at least 4 years longer than the reference mOS.

82. The method of any one of claims 62 to 81, wherein the method achieves a sustained MRD-negative CR (≥12 months) rate in a subject population with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the sustained MRD-negative CR (≥12 months) rate is greater than the reference sustained MRD-negative CR (≥12 months) rate achieved in a reference subject population with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, the reference population having been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of the combination therapy comprising the BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

83. The method of claim 82, wherein after approximately 50 months of treatment, the sustained MRD-negative CR (≥12 months) rate is at least 4%, or at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14% greater than the reference sustained MRD-negative CR (≥12 months) rate.

84. The method according to any one of claims 78 to 83, wherein the reference population has been administered the daralimumab, lenalidomide, and dexamethasone (DRd) according to the following schedule: Regarding the aforementioned daratumumab: During cycles 1-2, administer 1800 mg subcutaneously weekly (QW) (e.g., on days 1, 8, 15, and 22). During cycles 3-6, administer 1800 mg subcutaneously every two weeks (Q2W) (e.g., on day 1 and day 15), and During cycle 7 and all subsequent treatment cycles, administer 1800 mg subcutaneously monthly (Q4W) (e.g., on day 1); and Regarding the lenalidomide: In cycle 1 and all subsequent treatment cycles, 25 mg was administered orally daily for the first 21 days of each 28-day cycle; and Regarding the aforementioned dexamethasone: During the first cycle and all subsequent treatment cycles, administer 40 mg or 20 mg of dexamethasone orally or intravenously weekly (QW) (e.g., on days 1, 8, 15, and 22).

85. The method according to any one of claims 1 to 53, wherein the regimen is a combination therapy comprising administering the BCMAxCD3 bispecific antibody (e.g., teratumab), daratumumab, and lenalidomide.

86. The method of claim 85, wherein the administration of daratumumab begins in cycle 1, the administration of the BCMAxCD3 bispecific antibody begins in cycle 1, and the administration of lenalidomide begins in cycle 2; and wherein during the escalation phase of cycle 1, the subject is subcutaneously administered one or more escalation doses and at least one therapeutic dose of the BCMAxCD3 bispecific antibody, and wherein in cycle 2, the subject is subcutaneously administered a therapeutic dose of the BCMAxCD3 bispecific antibody monthly (Q4W).

87. The method of claim 86, wherein the scheme further comprises: Dexamethasone was administered orally or intravenously to the subjects only during cycles 2 and 3.

88. The method according to any one of claims 85 to 87, wherein the scheme comprises: For the BCMA x CD3 bispecific antibody (e.g., teratomab): In cycle 1, a first escalation dose of 60 μg / kg was administered subcutaneously (e.g., on day 2), a second escalation dose of 300 μg / kg (e.g., on day 4), followed by weekly (QW) doses of 1500 μg / kg (e.g., on days 8 and 15), and During cycle 2 and all subsequent treatment cycles, administer a monthly (Q4W) dose of 3000 μg / kg subcutaneously (e.g., on day 1). Regarding the aforementioned daratumumab: During cycles 1-2, administer 1800 mg subcutaneously weekly (QW) (e.g., on days 1, 8, 15, and 22). During cycles 3-6, administer 1800 mg subcutaneously every two weeks (Q2W) (e.g., on day 1 and day 15), and During cycle 7 and all subsequent treatment cycles, administer 1800 mg subcutaneously monthly (Q4W) (e.g., on day 1); and Regarding the lenalidomide: In the second cycle and all subsequent treatment cycles, 25 mg was administered orally daily for the first 21 days of each 28-day cycle.

89. The method of claim 88, wherein the scheme further comprises: During cycles 2-3, administer 20 mg of dexamethasone orally or intravenously weekly (QW) (e.g., on days 1, 8, 15, and 22).

90. The method of any one of claims 85 to 89, wherein the subject has a newly diagnosed multiple myeloma and is not eligible for autologous stem cell transplantation (ASCT) as an initial therapy or does not intend to undergo ASCT as an initial therapy.

91. The method according to any one of claims 85 to 89, wherein the subject has a newly diagnosed multiple myeloma and is not eligible for autologous stem cell transplantation (ASCT) as an initial therapy.

92. The method according to any one of claims 85 to 89, wherein the subject has a newly diagnosed multiple myeloma and does not intend to undergo autologous stem cell transplantation (ASCT) as initial therapy.

93. The method according to any one of claims 85 to 92, wherein the clinical response achieved by the method in the subject is the subject's sCR, CR, VGPR, or PR, as defined by the IMWG (2016) response criteria.

94. The method according to any one of claims 85 to 92, wherein the method achieves CR, VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

95. The method according to any one of claims 85 to 92, wherein the method achieves VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

96. The method of any one of claims 85 to 95, wherein the method achieves a median progression-free survival (mPFS) of at least 80 months, or at least 90 months, or at least 100 months, or at least 110 months in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy.

97. The method of any one of claims 85 to 96, wherein the method achieves a CR or better response (i.e., sCR or CR) as defined by the IMWG (2016) criteria in at least 60%, at least 65%, or at least 70% of subjects in a population with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy.

98. The method of any one of claims 85 to 97, wherein after treatment with the combination therapy for about 50 months, the method achieves a sustained MRD-negative CR (≥12 months) rate of at least about 18%, or at least about 20%, or at least about 22%, or at least about 24%, or at least about 26% in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as an initial therapy or who do not intend to undergo ASCT as an initial therapy.

99. The method of any one of claims 85 to 98, wherein the method achieves median progression-free survival (mPFS) in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the mPFS is greater than the reference mPFS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, the reference population having been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of the combination therapy comprising the BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

100. The method of claim 99, wherein the mPFS is at least about 10 months, or at least 20 months, or at least 30 months, or at least 40 months, or at least 50 months longer than the reference mPFS.

101. The method of any one of claims 85 to 100, wherein the method achieves median overall survival (mOS) in a population of subjects with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the mOS is greater than a reference mOS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, the reference population having been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of the combination therapy comprising the BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

102. The method of claim 101, wherein the mOS is at least 1 year, or at least 2 years, or at least 3 years, or at least 4 years longer than the reference mOS.

103. The method of any one of claims 85 to 102, wherein the method achieves a sustained MRD-negative CR (≥12 months) rate in a subject population with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) as initial therapy or who do not intend to undergo ASCT as initial therapy, wherein the sustained MRD-negative CR (≥12 months) rate is greater than the reference sustained MRD-negative CR (≥12 months) rate achieved in a reference subject population with newly diagnosed multiple myeloma who are ineligible for ASCT as initial therapy or who do not intend to undergo ASCT as initial therapy, the reference population having been administered daratumumab, lenalidomide, and dexamethasone (DRd) instead of the combination therapy comprising the BCMA x CD3 bispecific antibody (e.g., teritolumab), daratumumab, and lenalidomide.

104. The method of claim 103, wherein after approximately 50 months of treatment, the sustained MRD-negative CR (≥12 months) rate is at least 4%, or at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14% greater than the reference sustained MRD-negative CR (≥12 months) rate.

105. The method according to any one of claims 85 to 104, wherein the reference population has been administered the daralimumab, lenalidomide, and dexamethasone (DRd) according to the following schedule: Regarding the aforementioned daratumumab: During cycles 1-2, administer 1800 mg subcutaneously weekly (QW) (e.g., on days 1, 8, 15, and 22). During cycles 3-6, administer 1800 mg subcutaneously every two weeks (Q2W) (e.g., on day 1 and day 15), and During cycle 7 and all subsequent treatment cycles, administer 1800 mg subcutaneously monthly (Q4W) (e.g., on day 1); and Regarding the lenalidomide: In cycle 1 and all subsequent treatment cycles, 25 mg was administered orally daily for the first 21 days of each 28-day cycle; and Regarding the aforementioned dexamethasone: During the first cycle and all subsequent treatment cycles, administer 40 mg or 20 mg of dexamethasone orally or intravenously weekly (QW) (e.g., on days 1, 8, 15, and 22).

106. The method according to any one of claims 85 to 105, wherein, compared to a regimen that includes starting the administration of the lenalidomide in a first cycle and then starting the administration of the BCMAxCD3 bispecific antibody in a second cycle, the risk of high-grade CRS in the subject is reduced when the regimen includes starting the administration of the BCMAxCD3 bispecific antibody in a first cycle and then starting the administration of the lenalidomide in a second cycle.

107. The method according to any one of claims 85 to 105, wherein, compared to a regimen comprising initiating the administration of the lenalidomide and the dexamethasone in a first cycle, followed by initiating the administration of the BCMAxCD3 bispecific antibody in a second cycle, the risk of high-grade CRS in the subject is reduced when the regimen comprises initiating the administration of the BCMAxCD3 bispecific antibody in a first cycle, followed by initiating the administration of the lenalidomide and the dexamethasone in a second cycle.

108. The method according to any one of claims 1 to 50, wherein the subject has a newly diagnosed multiple myeloma.

109. The method according to any one of claims 1 to 50, wherein the subject is newly diagnosed with multiple myeloma and has previously undergone ASCT.

110. The method according to any one of claims 1 to 50, wherein the subject has been newly diagnosed with multiple myeloma and has completed induction therapy and subsequent ASCT (with or without consolidation).

111. The method of any one of claims 1 to 50, wherein the subject is newly diagnosed with multiple myeloma and has previously received 4 to 6 cycles of induction therapy and subsequent ASCT.

112. The method according to any one of claims 1 to 50, wherein the subject is newly diagnosed with multiple myeloma and has previously received 4 to 6 cycles of 3- or 4-drug induction therapy, including a proteasome inhibitor and / or IMiD, with or without an anti-CD38 monoclonal antibody, and single or tandem ASCT.

113. The method according to any one of claims 108 to 112, wherein if the total number of induction plus consolidation cycles does not exceed 6, the subject receives a maximum of 2 cycles of ASCT post-consolidation.

114. The method according to any one of claims 108 to 113, wherein the regimen comprises, in addition to the BCMAxCD3 bispecific antibody, a combination therapy of administering at least one other anti-multiple myeloma agent.

115. The method according to any one of claims 108 to 114, wherein the regimen is a combination therapy comprising administration of lenalidomide and the BCMAxCD3 bispecific antibody.

116. The method of claim 115, wherein the BCMAxCD3 bispecific antibody is teratumab.

117. The method of any one of claims 108 to 116, wherein the escalation period occurs in the first cycle and comprises subcutaneous administration of one or more escalating doses of the BCMAxCD3 bispecific antibody to the subject, followed by one or more doses of the BCMAxCD3 bispecific antibody at 1.5 mg / kg; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

118. The method of any one of claims 108 to 117, wherein the escalation period occurs in the first cycle and comprises subcutaneous administration of one or more escalating doses of the BCMAxCD3 bispecific antibody to the subject, followed by one or more 1.5 mg / kg doses of the BCMAxCD3 bispecific antibody according to the QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

119. The method according to any one of claims 108 to 118, wherein the escalation period occurs in the first cycle and comprises subcutaneous administration of an escalating dose of the BCMAxCD3 bispecific antibody to the subject, followed by two 1.5 mg / kg doses of the BCMAxCD3 bispecific antibody according to the QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

120. The method according to any one of claims 108 to 119, wherein the escalation period comprises subcutaneous administration of the BCMAxCD3 bispecific antibody to the subject at 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, and a second therapeutic dose of 1.5 mg / kg on day 15; and Each subsequent BCMAxCD3 treatment cycle includes a subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

121. The method according to any one of claims 108 to 120, wherein the regimen is a combination therapy comprising administering lenalidomide and the BCMAxCD3 bispecific antibody, and wherein the BCMAxCD3 bispecific antibody is teratumab.

122. The method of claim 121, wherein the lenalidomide is administered once daily in an amount of 10 mg.

123. The method according to claim 121 or 122, wherein the lenalidomide is not administered in the first cycle.

124. The method according to any one of claims 121 to 123, wherein the lenalidomide is not administered in the first cycle, but in the second cycle and all subsequent cycles.

125. The method according to any one of claims 121 to 124, wherein the lenalidomide is administered once daily in an amount of 10 mg, and if the subject tolerates 10 mg, the dose may be increased to 15 mg once daily on day 1 of cycle 5.

126. The method according to any one of claims 121 to 125, wherein the BCMAxCD3 bispecific antibody is administered for a limited duration of 26 cycles.

127. The method according to any one of claims 121 to 125, wherein the BCMAxCD3 bispecific antibody is administered for a limited duration of 13 cycles.

128. The method according to any one of claims 121 to 125, wherein the BCMAxCD3 bispecific antibody is administered in cycles 14-26 only if the subject achieves a complete or strictly complete response (according to IMWG 2016 criteria) after 13 cycles.

129. The method according to any one of claims 108 to 128, wherein the clinical response achieved by the method in the subject is the subject's sCR, CR, VGPR, or PR, as defined by the IMWG (2016) response criteria.

130. The method of any one of claims 108 to 128, wherein the method achieves CR or sCR in the subject as defined by the IMWG (2016) response criteria.

131. The method according to any one of claims 108 to 128, wherein the method achieves VGPR or PR in the subject as defined by the IMWG (2016) response criteria.

132. The method of any one of claims 108 to 128, wherein the method achieves a CR or better response (i.e., sCR or CR) as defined by the IMWG (2016) response criteria in at least 40%, or at least 45%, at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75% of subjects in a population with newly diagnosed multiple myeloma who have previously received autologous stem cell transplantation (ASCT).

133. The method of any one of claims 108 to 128, wherein the method achieves MRD negativity (10) in at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85% of subjects in a population with newly diagnosed multiple myeloma who have previously received autologous stem cell transplantation (ASCT). -5 ).

134. The method of any one of claims 108 to 128, wherein the method comprises administering teratumab alone or a combination therapy comprising teratumab and lenalidomide, and wherein the method achieves longer progression-free survival (PFS) and / or a greater 12-month MRD-negative complete response (CR) rate in a population of subjects with newly diagnosed multiple myeloma who have previously received autologous stem cell transplantation (ASCT) compared to a reference population of subjects who have previously received autologous stem cell transplantation (ASCT), the reference population having received a regimen comprising lenalidomide without BCMAxCD3 bispecific antibody.

135. The method according to any one of claims 1 to 50, wherein the subject has a newly diagnosed multiple myeloma and is eligible for ASCT.

136. The method of claim 135, wherein the subject has not previously undergone ASCT.

137. The method of claim 135 or 136, wherein the subject is administered the BCMAxCD3 bispecific antibody (e.g., teritumumab) as part of induction therapy.

138. The method according to any one of claims 135 to 137, wherein the subject is given a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teritumumab) and one or more other antimyeloma agents as an induction therapy.

139. The method according to any one of claims 135 to 138, wherein the subject is administered multiple cycles of the BCMAxCD3 bispecific antibody (e.g., teritumumab) and optionally one or more other antimyeloma agents as induction therapy.

140. The method of any one of claims 135 to 139, wherein the subject is given a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teratolumab) and one or more additional antimyeloma agents selected from the group consisting of daratumumab, lenalidomide, dexamethasone, and any combination thereof as induction therapy.

141. The method according to any one of claims 135 to 140, wherein the subject is given a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teratumab), daratumumab, lenalidomide, and dexamethasone as an induction therapy.

142. The method according to any one of claims 135 to 140, wherein the subject is given a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teratumab), daratumumab, and lenalidomide as an induction therapy.

143. The method according to any one of claims 135 to 142, wherein the subject is administered 4 to 8 cycles, preferably 6 cycles, of the BCMAxCD3 bispecific antibody (e.g., teritumumab) and optionally one or more other antimyeloma agents as induction therapy.

144. The method according to any one of claims 135 to 143, wherein the subject is given six cycles of combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teratumab), daratumumab, lenalidomide, and dexamethasone as induction therapy.

145. The method according to any one of claims 135 to 144, wherein the subject is given 4 to 8 cycles, preferably 6 cycles, of combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teritumumab), daratumumab, and lenalidomide as induction therapy.

146. The method according to any one of claims 137 to 145, wherein the induction therapy is administered to the subject prior to performing ASCT.

147. The method of any one of claims 135 to 146, wherein the first cycle comprises subcutaneously administering one or more escalating doses of the BCMAxCD3 bispecific antibody to the subject, followed by one or more doses of the BCMAxCD3 bispecific antibody at a dose of 1.5 mg / kg; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody at a dose of 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

148. The method of any one of claims 135 to 146, wherein the first cycle comprises subcutaneously administering one or more escalating doses of the BCMAxCD3 bispecific antibody to the subject, followed by one or more 1.5 mg / kg doses of the BCMAxCD3 bispecific antibody according to a QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

149. The method of any one of claims 135 to 146, wherein the first cycle comprises subcutaneous administration of an escalating dose of the BCMAxCD3 bispecific antibody to the subject, followed by two 1.5 mg / kg doses of the BCMAxCD3 bispecific antibody according to a QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at a dose of 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

150. The method according to any one of claims 135 to 146, wherein the first cycle comprises subcutaneous administration of the BCMAxCD3 bispecific antibody to the subject at 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; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of the BCMAxCD3 bispecific antibody at a treatment dose of 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

151. The method of claim 135, wherein, after receiving ASCT, the subject is administered maintenance therapy comprising the BCMAxCD3 bispecific antibody (e.g., teritumumab) and optionally one or more other antimyeloma agents.

152. The method of claim 135, wherein, after receiving ASCT, the subject is administered maintenance therapy comprising the BCMAxCD3 bispecific antibody (e.g., teritumumab) and daratumumab.

153. The method of claim 151 or 152, wherein the maintenance therapy comprises 6-20 treatment cycles.

154. The method of claim 151 or 152, wherein the maintenance therapy comprises 12-18 treatment cycles.

155. The method of claim 151 or 152, wherein the maintenance therapy comprises 12 treatment cycles.

156. The method according to any one of claims 151 to 155, wherein the first cycle comprises subcutaneously administering one or more escalating doses of the BCMAxCD3 bispecific antibody to the subject, followed by one or more doses of the BCMAxCD3 bispecific antibody at a dose of 1.5 mg / kg; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody at a dose of 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

157. The method of any one of claims 151 to 155, wherein the first cycle comprises subcutaneously administering one or more escalating doses of the BCMAxCD3 bispecific antibody to the subject, followed by one or more 1.5 mg / kg doses of the BCMAxCD3 bispecific antibody according to a QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a therapeutic dose of the BCMAxCD3 bispecific antibody at 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

158. The method according to any one of claims 151 to 155, wherein the first cycle comprises subcutaneous administration of an escalating dose of the BCMAxCD3 bispecific antibody to the subject, followed by two 1.5 mg / kg doses of the BCMAxCD3 bispecific antibody according to a QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of a therapeutic dose of the BCMAxCD3 bispecific antibody at a dose of 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

159. The method according to any one of claims 151 to 155, wherein the first cycle comprises subcutaneous administration of the BCMAxCD3 bispecific antibody to the subject at 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, and a second therapeutic dose of 1.5 mg / kg on day 15; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneous administration of the BCMAxCD3 bispecific antibody at a therapeutic dose of 3 mg / kg on day 1 (i.e., according to the Q4W dosing schedule).

160. A method of treating a subject with multiple myeloma in need, the method comprising treating the subject according to a treatment-effective regimen comprising consecutive 28-day BCMAxCD3 treatment cycles, wherein if criteria (1) to (4) are met, one or more escalating doses of teratumab are administered subcutaneously to the subject during an escalation phase (e.g., during the first cycle) and a therapeutic dose of the teratumab is administered subcutaneously to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle following the escalation phase (e.g., starting from the second cycle), wherein if (1) the subject has a newly diagnosed multiple myeloma and is not eligible for ASCT as initial therapy or does not intend to undergo ASCT as initial therapy, and the teratumab is administered as further treatment... The following criteria are met: (1) teratolumab is administered as part of a combination regimen including daratumumab and lenalidomide; (2) the subject has a newly diagnosed multiple myeloma and teratolumab is administered as part of a combination regimen further including lenalidomide after the subject receives induction therapy and subsequent ASCT; (3) the subject has a newly diagnosed multiple myeloma and teratolumab is administered as induction therapy as part of a combination regimen further including daratumumab and lenalidomide (e.g., before the subject receives ASCT); or (4) the subject has received 1 to 4 lines of prior treatment including daratumumab and lenalidomide and teratolumab is administered as part of a combination regimen further including taquiltumab.

161. A method for treating a newly diagnosed multiple myeloma in a subject in need, the method comprising treating the subject according to a treatment-effective regimen comprising consecutive 28-day BCMAxCD3 treatment cycles, wherein if criteria (1) to (3) are met, one or more escalating doses of teratumab are administered subcutaneously to the subject during an escalation phase (e.g., during the first cycle) and a therapeutic dose of the teratumab is administered subcutaneously to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle following the escalation phase (e.g., starting from the second cycle), wherein if: (1) the subject has a newly diagnosed multiple myeloma and does not meet the criteria for ASCT... The criteria (1) to (3) are met if the subject is eligible for initial therapy or does not intend to undergo ASCT as initial therapy, and the teratumab is administered as part of a combination regimen that further includes administration of daratumumab and lenalidomide; or (2) the subject has a newly diagnosed multiple myeloma, and the teratumab is administered as part of a combination regimen that further includes administration of lenalidomide after the subject receives induction therapy and subsequent ASCT; or (3) the subject has a newly diagnosed multiple myeloma, and the teratumab is administered as part of an induction therapy regimen that further includes administration of daratumumab and lenalidomide (e.g., before the subject receives ASCT).

162. A method for treating a newly diagnosed multiple myeloma in a subject in need, the method comprising treating the subject according to a treatment-effective regimen comprising consecutive 28-day BCMAxCD3 treatment cycles, wherein, if criterion (1) or (2) is met, one or more escalating doses of teratumab are administered subcutaneously to the subject during an escalation phase (e.g., during the first cycle) and, starting from the first BCMAxCD3 treatment cycle following the escalation phase (e.g., starting from the second cycle), a treatment dose is administered subcutaneously to the subject according to a monthly dosing schedule (Q4W). The teratomab is provided if: (1) the subject has a newly diagnosed multiple myeloma and is not eligible for ASCT as initial therapy or does not intend to undergo ASCT as initial therapy, and the teratomab is administered as part of a combination regimen that further includes administration of daratumumab and lenalidomide, or (2) the subject has a newly diagnosed multiple myeloma, and the teratomab is administered as part of a combination regimen that further includes administration of lenalidomide after the subject has received induction therapy and subsequent ASCT, then criterion (1) or (2) is met.

163. The method according to any one of claims 1 to 162, wherein the escalation period comprises administering only two escalation doses of the BCMAxCD3 bispecific antibody (e.g., teratomab) prior to administering the first therapeutic dose, wherein the two escalation doses are administered (i) at a dose of 0.1 mg / kg followed by a dose of 0.5 mg / kg, or (ii) at a dose of 0.2 mg / kg followed by a dose of 0.7 mg / kg.

164. A method of treating a subject with multiple myeloma in need, the method comprising administering to the subject a therapeutically effective amount of a BCMAxCD3 bispecific antibody (e.g., teratomab), wherein the method comprises subcutaneously administering only two escalating doses of the BCMAxCD3 bispecific antibody prior to subcutaneous administration of a first therapeutic dose, wherein the two escalating doses are administered (i) at a dose of 0.1 mg / kg followed by a dose of 0.5 mg / kg, or (ii) at a dose of 0.2 mg / kg followed by a dose of 0.7 mg / kg.

165. The method of claim 164, wherein the two escalating doses are administered at a rate of 0.1 mg / kg followed by 0.5 mg / kg.

166. The method of claim 164, wherein the two escalating doses are administered at a rate of 0.2 mg / kg followed by 0.7 mg / kg.

167. The method according to any one of claims 163 to 166, wherein the time between the two incremental doses is between about 2 days and about 4 days.

168. The method according to any one of claims 164 to 166, wherein the subject suffers from relapsed or refractory multiple myeloma.

169. The method of claim 168, wherein the subject has previously received at least one, two, three, or four lines of prior treatment.

170. The method of claim 168, wherein the subject has previously received, for example, first- to third-line prior treatment comprising at least two consecutive cycles of daratumumab and two consecutive cycles of lenalidomide.

171. The method of claim 168, wherein the subject has previously received 1-3 lines of prior treatment including a proteasome inhibitor (PI) and lenalidomide.

172. The method of claim 168, wherein the subject has previously received first- to fourth-line prior treatment including daratumumab and lenalidomide.

173. The method of claim 168, wherein the subject has a newly diagnosed multiple myeloma.

174. The method of claim 168, wherein the subject has a newly diagnosed multiple myeloma and is not eligible for ASCT as an initial therapy or does not intend to undergo ASCT as an initial therapy.

175. The method of claim 168, wherein the subject has a newly diagnosed multiple myeloma and has previously undergone ASCT.

176. The method of claim 168, wherein the subject has a newly diagnosed multiple myeloma and has not yet undergone ASCT.

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