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WO2025096717A1 - Méthodes de traitement du myélome multiple - Google Patents

Méthodes de traitement du myélome multiple Download PDF

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Publication number
WO2025096717A1
WO2025096717A1 PCT/US2024/053808 US2024053808W WO2025096717A1 WO 2025096717 A1 WO2025096717 A1 WO 2025096717A1 US 2024053808 W US2024053808 W US 2024053808W WO 2025096717 A1 WO2025096717 A1 WO 2025096717A1
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WIPO (PCT)
Prior art keywords
subject
dose
bispecific antibody
treatment
cycle
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Inventor
Rachel KOBOS
Arnob BANERJEE
Jenna GOLDBERG
Katherine CHASTAIN
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Janssen Biotech Inc
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Janssen Biotech Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific

Definitions

  • MM multiple myeloma
  • M-proteins monoclonal proteins
  • Treatment options for multiple myeloma have improved over time and vary depending on the aggressiveness of the disease, underlying prognostic factors, physical condition of the patient, and existing comorbidities.
  • Therapeutic options include proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents, monoclonal antibodies (mAbs), antibody drug conjugate, histone deacetylase inhibitor, nuclear protein export inhibitor, chimeric antigen receptor (CAR) T cell therapy and stem cell transplantation.
  • monthly (Q4W) dosing of a BCMAxCD3 bispecific antibody begins in the first 28-day BCMAxCD3 treatment cycle following a 28-day step-up phase in which one or more step-up doses (and optionally one or more treatment doses) of the BCMAxCD3 bispecific antibody are administered.
  • An embodiment of the present invention provides a method of treating multiple myeloma in a subject in need thereof, comprising treating the subject according to a therapeutically effective regimen that comprises sequential 28-day BCMAxCD3 treatment cycles, wherein: one or more step-up doses of a BCMAxCD3 bispecific antibody (e.g., teclistamab) are subcutaneously administered to the subject during a step-up phase, and treatment doses of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase.
  • a BCMAxCD3 bispecific antibody e.g., teclistamab
  • the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising the HCDR1 of SEQ ID NO: 4, the HCDR2 of SEQ ID NO: 5, the HCDR3 of SEQ ID NO: 6, the LCDR1 of SEQ ID NO: 7, the LCDR2 of SEQ ID NO: 8 and the LCDR3 of SEQ ID NO: 9, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 14, the HCDR2 of SEQ ID NO: 15, the HCDR3 of SEQ ID NO: 16, the LCDR1 of SEQ ID NO: 17, the LCDR2 of SEQ ID NO: 18 and the LCDR3 of SEQ ID NO: 19.
  • 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
  • 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.
  • Docket No.258199.062002 JBI6858WOPCT1
  • the BCMAxCD3 bispecific antibody is an IgG1, an IgG2, an IgG3 or an IgG4 isotype.
  • the BCMAxCD3 bispecific antibody is an IgG4 isotype. [0013] In certain embodiments, the BCMAxCD3 bispecific antibody comprises one or more substitutions in its Fc region. [0014] In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering). [0015] In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A, L235A F405L and R409K substitutions in its Fc region (according to EU numbering).
  • the Fc region of the BCMA-binding arm comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).
  • the Fc region of the CD3-binding arm comprises S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region (according to EU numbering).
  • 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.
  • the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 23.
  • HC1 first heavy chain having at least 90% identity to the amino acid sequence of SEQ ID NO: 12
  • LC1 having at least 90% identity to the amino acid sequence of SEQ ID NO: 13
  • HC2 having at least 90% identity to the amino acid sequence of SEQ ID NO: 22
  • LC2 second light chain having at least 90% identity to the amino acid sequence of SEQ ID NO: 23.
  • the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 23.
  • the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 23.
  • the BCMAxCD3 bispecific antibody is teclistamab.
  • each treatment dose of the BCMAxCD3 bispecific antibody that is administered to the subject on the monthly dosing schedule (Q4W) is administered in an amount of 1.5 mg/kg or 3 mg/kg.
  • each treatment dose of the BCMAxCD3 bispecific antibody that is administered to the subject on the monthly dosing schedule (Q4W) is administered in an amount of 1.5 mg/kg.
  • each treatment dose of the BCMAxCD3 bispecific antibody that is administered to the subject on the monthly dosing schedule (Q4W) is administered in an amount of 3 mg/kg.
  • each treatment dose of the BCMAxCD3 bispecific antibody administered to the subject on the monthly dosing schedule (Q4W) is administered on Day 1 of each BCMAxCD3 treatment cycle.
  • the regimen does not include any BCMAxCD3 treatment cycles in which the BCMAxCD3 bispecific antibody is administered to the subject on a bi- weekly dosing schedule (Q2W).
  • the step-up phase is 28 days.
  • 1-3 step-up doses of the BCMAxCD3 bispecific antibody are administered to the subject during the step-up phase.
  • two step-up doses of the BCMAxCD3 bispecific antibody are administered to the subject during the step-up phase.
  • the step-up phase comprises a first step-up dose of 0.06 mg/kg of the BCMAxCD3 bispecific antibody.
  • the step-up phase comprises a first step-up dose of 0.06 mg/kg of the BCMAxCD3 bispecific antibody and a second step-up dose of 0.3 mg/kg of the BCMAxCD3 bispecific antibody.
  • one or more treatment doses of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during the step-up phase, in addition to the one or more step-up doses.
  • two treatment doses of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during the step-up phase, in addition to the one or more step-up doses.
  • three treatment doses of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during the step-up phase, in addition to the one or more step-up doses.
  • the step-up phase comprises subcutaneously administering two step-up doses and two treatment doses of the BCMAxCD3 bispecific antibody.
  • the step-up phase comprises subcutaneously administering two step-up doses and three treatment doses of the BCMAxCD3 bispecific antibody.
  • the one or more treatment doses of the BCMAxCD3 bispecific antibody administered during the step-up phase are administered in an amount of 0.72 mg/kg or 1.5 mg/kg or 3.0 mg/kg.
  • each of the one or more treatment doses of the BCMAxCD3 bispecific antibody administered during the step-up phase are administered in an amount of 1.5 mg/kg.
  • two or three treatment doses of the BCMAxCD3 bispecific antibody are administered during the step-up phase on a weekly dosing schedule (QW).
  • two treatment doses of the BCMAxCD3 bispecific antibody are administered during the step-up phase on a weekly dosing schedule (QW).
  • three treatment doses of the BCMAxCD3 bispecific antibody are administered during the step-up phase on a weekly dosing schedule (QW).
  • the step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg, a second step-up 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.
  • the second step-up dose is administered 2-4 days after first step-up dose.
  • the second step-up dose is administered 2 days after first step-up dose. Docket No.258199.062002 (JBI6858WOPCT1) [0046]
  • the first treatment dose is administered 4-7 days after the second step-up dose.
  • the first treatment dose is administered 5 days after the second step-up dose.
  • the second treatment dose is administered 5-9 days after the first treatment dose.
  • the second treatment dose is administered 7 days after the first treatment dose.
  • the step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg on Day 1, a second step-up 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.
  • the step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg, a second step-up 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.
  • the third treatment dose is administered 5-9 days after the second treatment dose.
  • the third treatment dose is administered 7 days after the second treatment dose.
  • the step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg on Day 1, a second step-up 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.
  • the step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg on Day 1, a second step-up 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 subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • the step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg on Day 1, a second step-up 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 Docket No.258199.062002 (JBI6858WOPCT1) BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • the treatment doses of the BCMAxCD3 bispecific antibody are administered to the subject on the monthly dosing schedule (Q4W) regardless of whether, or to what extent, the subject exhibits a clinical response to the regimen.
  • the step-up phase is in Cycle 1 of the regimen
  • the first BCMAxCD3 treatment cycle is in Cycle 2 of the regimen.
  • the regimen is a combination therapy comprising administration of other anti-multiple myeloma agents in addition to the BCMAxCD3 bispecific antibody.
  • the regimen is a combination therapy
  • the step-up phase is in Cycle 2 of the regimen
  • the first BCMAxCD3 treatment cycle is in Cycle 3 of the regimen, or later.
  • the regimen is a combination therapy
  • the step-up phase is in Cycle 2 of the regimen
  • the first BCMAxCD3 treatment cycle is in Cycle 3 of the regimen.
  • 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 are subcutaneously administered to the subject, and a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject every 4 weeks (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase.
  • the step-up phase is 28 days and occurs in Cycle 1 of the regimen; the first dose, the second dose, the third dose and the fourth dose are administered on Day 1, Day 3, Day 8 and Day 15 of Cycle 1, respectively, and the treatment dose of 3 mg/kg is administered on Day 1 of Cycle 2 and on Day 1 of each subsequent treatment cycle thereafter.
  • 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 are subcutaneously administered to the subject, and a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject every 4 weeks (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase.
  • the step-up phase is 28 days and occurs in Cycle 1 of the regimen; the first dose, the second dose, the third dose, the fourth dose and the fifth dose are administered on Day 1, Day 3, Day 8, Day 15 and Day 22 of Cycle 1, respectively, and the treatment dose of 3 mg/kg is administered on Day 1 of Cycle 2 and on Day 1 of each subsequent treatment cycle thereafter.
  • the regimen is a combination therapy
  • the step-up phase is 28 days and occurs in Cycle 2 of the regimen
  • the first dose, the second dose, the third dose and the fourth dose of the BCMAxCD3 bispecific antibody are administered on Day 1, Day 3, Day 8 and Day 15 of Cycle 2, respectively
  • the treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody is administered on Day 1 of Cycle 3 and on Day 1 of each subsequent treatment cycle thereafter.
  • the regimen is a combination therapy
  • the step-up phase is 28 days and occurs in Cycle 2 of the regimen
  • the first dose, the second dose, the third dose, the fourth dose and the fifth dose are administered on Day 1, Day 3, Day 8, Day 15 and Day 22 of Cycle 1, respectively
  • the treatment dose of 3 mg/kg is administered on Day 1 of Cycle 3 and on Day 1 of each subsequent treatment cycle thereafter.
  • the regimen is a combination therapy comprising administration of the BCMAxCD3 bispecific antibody (e.g., teclistamab), daratumumab and lenalidomide.
  • administration of the daratumumab starts in Cycle 1, administration of the lenalidomide starts in Cycle 1, and administration of the BCMAxCD3 bispecific antibody starts in Cycle 2; and wherein one or more step-up doses and at least one treatment dose of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase in Cycle 2, and wherein a treatment dose of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject monthly (Q4W) starting in Cycle 3.
  • All methods described herein, however expressed, may be described as corresponding uses, in particular medical uses.
  • DETAILED DESCRIPTION OF THE INVENTION [0070] The disclosed methods can be understood more readily by reference to the following detailed description.
  • Antibodies is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific etc., dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity.
  • “Full length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g. IgM).
  • Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CH1, hinge, CH2 and CH3).
  • Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL).
  • the VH and the VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • Immunoglobulins can be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence.
  • IgA and IgG are further sub-classified as the isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4.
  • Antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa ( ⁇ ) and lambda ( ⁇ ), based on the amino acid sequences of their constant domains.
  • Antigen binding fragment or “antigen binding domain” refers to a portion of an immunoglobulin molecule that binds an antigen.
  • Antigen binding fragments can be synthetic, enzymatically obtainable or genetically engineered polypeptides and include the VH, the VL, the VH and the VL, Fab, F(ab')2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, the HCDR1, the HCDR2 and/or the HCDR3 and the LCDR1, the LCDR2 and/or the LCDR3.
  • VH and VL domains can be linked together via a synthetic linker to form various types of single chain antibody designs where the VH/VL domains can pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Int. Patent Publ. Nos. WO1998/44001, WO1988/01649, WO1994/13804 and WO1992/01047.
  • scFv single chain Fv
  • BCMA refers to human B-cell maturation antigen, also known as CD269 or TNFRSF17 (UniProt Q02223).
  • BCMA The extracellular domain of BCMA encompasses residues 1- 54 of Q02223.
  • Human BCMA comprises the amino acid sequence of SEQ ID NO: 1.
  • SEQ ID NO: 1 MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGT NAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEK SRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTK TNDYCKSLPAALSATEIEKSISAR
  • Bispecific refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen.
  • the bispecific antibody can have cross- reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca cynomolgus (cynomolgus, cyno) or Pan troglodytes, or can bind an epitope that is shared between two or more distinct antigens.
  • homologs such as human or monkey
  • Macaca cynomolgus cynomolgus, cyno
  • Pan troglodytes or can bind an epitope that is shared between two or more distinct antigens.
  • BCMAxCD3 bispecific antibody refers to a bispecific antibody that specifically binds BCMA and CD3.
  • Cancer refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body.
  • CD3 refers to a human antigen which is expressed on T cells as part of the multimolecular T cell receptor (TCR) complex and which consists of a homodimer or heterodimer formed from the association of two or four receptor chains: CD3 epsilon, CD3 delta, CD3 zeta and CD3 gamma.
  • TCR multimolecular T cell receptor
  • Human CD3 epsilon comprises the amino acid sequence of SEQ ID NO: 2.
  • SEQ ID NO: 3 shows the extracellular domain of CD3 epsilon.
  • SEQ ID NO: 2 MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQY PGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKP EDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRK AKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI SEQ ID NO: 3 DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNI GSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD [0081] “CH3 region” or “CH3 domain” refers to the CH3 region of an immunoglobulin.
  • CH3 region of human IgG1 antibody corresponds to amino acid residues 341-446. However, the CH3 region can also be any of the other antibody isotypes as described herein.
  • “Combination” means that two or more therapeutics are administered to a subject.
  • a “combination therapy” refers to a therapeutically effective regimen that comprises administration of two or more anti-multiple myeloma agents to a subject to treat multiple myeloma; for example, a combination therapy may comprise administration of daratumumab and/or lenalidomide, in addition to teclistamab.
  • CDR complementarity determining regions
  • CDRs can be defined using various delineations such as 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).
  • Kabat Wang et al. J Exp Med 132: 211-50, 1970
  • Chothia Chothia et al. J Mol Biol 196: 901-17, 1987
  • IMGT Lefranc et al. Dev Comp Immunol 27: 55-77, 2003
  • AbM Martin and Thornton J Bmol Biol 263: 800-15, 1996.
  • CDR CDR
  • HCDR1 CDR1
  • HCDR2 CDR3
  • LCDR1 CDR2
  • LCDR3 CDR3
  • CDR CDR
  • HCDR1 CDR1
  • HCDR2 CDR3
  • LCDR1 CDR2
  • LCDR3 CDRs defined by the method of Kabat.
  • “Comprising” is intended to include examples encompassed by the terms “consisting essentially of” and “consisting of”; similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.”
  • the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.
  • Fc gamma receptor refers to well-known FcJRI, FcJRIIa, FcJRIIb or FcJRIII. Activating FcJR includes FcJRI, FcJRIIa and FcJRIII.
  • Human antibody refers to an antibody that is optimized to have minimal immune response when administered to a human subject. Variable regions of human antibody are derived from human immunoglobulin sequences. If human antibody contains a constant region or a portion of the constant region, the constant region is also derived from human immunoglobulin sequences.
  • Human antibody comprises heavy and light chain variable regions that are “derived from” sequences of human origin if the variable regions of the human antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes.
  • Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci.
  • “Human antibody” typically contains amino acid differences when compared to the immunoglobulins expressed in humans due to differences between the systems used to obtain the human antibody and human immunoglobulin loci, introduction of somatic mutations or intentional introduction of substitutions into the frameworks or CDRs, or both.
  • human antibody is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in amino acid sequence to an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes.
  • human antibody can contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., (2000) J Mol Biol 296:57-86, or synthetic Docket No.258199.062002 (JBI6858WOPCT1) HCDR3 incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-96, and in Int. Patent Publ. No. WO2009/085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of “human antibody”.
  • Humanized antibody refers to an antibody in which at least one CDR is derived from non-human species and at least one framework is derived from human immunoglobulin sequences. Humanized antibody can include substitutions in the frameworks so that the frameworks can not be exact copies of expressed human immunoglobulin or human immunoglobulin germline gene sequences.
  • Identity refers to a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by aligning and comparing the sequences.
  • Percent (%) sequence identity with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN (DNAStar, Inc.) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • isolated refers to a homogenous population of molecules (such as synthetic polynucleotides or a protein such as an antibody) which have been substantially separated and/or purified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been subjected to at least one purification or isolation step.
  • molecules such as synthetic polynucleotides or a protein such as an antibody
  • isolated antibody refers to an antibody that is substantially free of other cellular material and/or chemicals and encompasses antibodies that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.
  • “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C- terminal lysine from the antibody heavy chain or post-translational modifications such as Docket No.258199.062002 (JBI6858WOPCT1) amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation.
  • Monoclonal antibodies typically bind one antigenic epitope.
  • a bispecific monoclonal antibody binds two distinct antigenic epitopes.
  • Monoclonal antibodies can have heterogeneous glycosylation within the antibody population.
  • Monoclonal antibody can be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent.
  • “Mutation” refers to an engineered or naturally occurring alteration in a polypeptide or polynucleotide sequence when compared to a reference sequence. The alteration can be a substitution, insertion or deletion of one or more amino acids or polynucleotides.
  • “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) in a patients on-study bone marrow sample relative to their reference bone marrow sample (i.e., Teclistamab treatment na ⁇ ve bone marrow sample). Based on this PerMillionCount, each sample is determined to be positive or negative. Samples are positive if the PerMillionCount is greater than or equal to the limit of sensitivity, otherwise they are negative.
  • Negative minimal residual disease status can be determined at a sensitivity of 0.01% (10 -4 ), 0.001% (10 -5 ) or 0.0001% (10 -6 ). Negative minimal residual disease status was determined using next generation sequencing (NGS).
  • “Pharmaceutical composition” refers to composition that comprises an active ingredient and a pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” or “excipient” refers to an ingredient in a pharmaceutical composition, other than the active ingredient, which is nontoxic to a subject.
  • Recombinant refers to DNA, antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means when segments from different sources are joined to produce recombinant DNA, antibodies or proteins.
  • Step-up dose refers to a dose of an active agent that is administered to a subject prior to a treatment dose. A step-up dose is lower than the treatment dose.
  • a “priming” dose strategy may include one or more lower step-up dose(s) followed by higher treatment doses.
  • a “step-up phase” refers to an initial phase of a therapeutically effective regimen in which at least one step-up dose of a Docket No.258199.062002 (JBI6858WOPCT1) BCMAxCD3 bispecific antibody is administered to the subject.
  • a step-up phase may also include one or more treatment doses, i.e., a step-up phase may include one or more step-up doses followed by one or more treatment doses; for example, a step-up phase may include two step-up doses followed by two treatment doses.
  • the step-up phase is 28 days, i.e., the step-up phase is a 28-day cycle of a therapeutically effective regimen.
  • Subject refers to a human subject. Except when noted, the terms “patient” and “subject” are used interchangeably.
  • T cell redirecting therapeutic refers to a molecule containing two or more binding regions, wherein one of the binding regions specifically binds a cell surface antigen on a target cell or tissue and wherein a second binding region of the molecule specifically binds a T cell antigen.
  • cell surface antigen include a tumor associated antigen, such as BCMA.
  • T cell antigen include, e.g., CD3.
  • “Therapeutically effective amount” refers to an amount effective, at doses and for periods of time necessary, to achieve a desired therapeutic result.
  • a therapeutically effective amount can vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics that include, for example, improved well-being of the patient.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder.
  • Beneficial or desired clinical results include alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if a subject was not receiving treatment.
  • Treatment dose refers to a dose of the active agent that is administered to a subject to treat a disease.
  • a treatment dose may be administered at a regular dosing interval on a repetitive basis (e.g. weekly, biweekly, monthly).
  • a treatment dose may be preceded by Docket No.258199.062002 (JBI6858WOPCT1) one or more step-up doses.
  • a dosing regimen may include treatment doses in different amounts, e.g., one or more treatment doses of 1.5 mg/kg, one or more treatment doses of 3 mg/kg, etc.
  • a patient that is “triple-class exposed” refers to a multiple myeloma patient that has previously been treated with (at a minimum) a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.
  • Tumor cell or a “cancer cell” refers to a cancerous, pre-cancerous or transformed cell, either in vivo, ex vivo, or in tissue culture, that has spontaneous or induced phenotypic changes.
  • Transformation/cancer is exemplified by morphological changes, immortalization of cells, aberrant growth control, foci formation, proliferation, malignancy, modulation of tumor specific marker levels, invasiveness, tumor growth in suitable animal hosts such as nude mice, and the like, in vitro, in vivo, and ex vivo.
  • Teclistamab also known as TECVAYLI® is the first BCMA-directed bispecific antibody approved for the treatment of patients with relapsed or refractory multiple myeloma.
  • Teclistamab is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least three or four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.
  • the efficacy Docket No.258199.062002 (JBI6858WOPCT1) of teclistamab is continuing to be evaluated in patients with relapsed or refractory multiple myeloma in a multi-center clinical study (MajesTEC-1, NCT03145181 [Phase 1] and NCT04557098 [Phase 2]).
  • teclistamab demonstrated rapid, deep and durable responses, with an overall response rate (ORR) of 63% and median progression-free survival (mPFS) of 11.3 months (see, e.g., 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 by reference herein).
  • grade 3/4 infections occurred in 86 patients (52.1%), 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.
  • modified dosing schedules may vary, depending on the specific indication or patient population (e.g., relapsed/refractory patients or newly diagnosed patients), and also depending on the therapy (e.g., BCMAxCD3 monotherapy) or combination of therapies administered.
  • the inventors developed modified dosing schedules of teclistamab that comprise monthly (Q4W) administration of teclistamab starting in its second treatment cycle (e.g., immediately following a step-up phase in Cycle 1).
  • Embodiments of novel dosing regimens described herein for BCMAxCD3 bispecific antibodies may provide improved Docket No.258199.062002 (JBI6858WOPCT1) safety profiles over currently approved regimens while maintaining deep and durable efficacy.
  • Antibodies of the present invention [0113] Any suitable BCMAxCD3 bispecific antibody known to those skilled in the art in view of the present disclosure can be used in the invention.
  • the BCMAxCD3 bispecific antibody is teclistamab.
  • Various bispecific antibody formats include formats described herein and recombinant IgG-like dual targeting molecules, wherein the two sides of the molecule each contain the Fab fragment or part of the Fab fragment of at least two different antibodies; IgG fusion molecules, wherein full length IgG antibodies are fused to an extra Fab fragment or parts of Fab fragment; Fc fusion molecules, wherein single chain Fv molecules or stabilized diabodies are fused to heavy-chain constant-domains, Fc-regions or parts thereof; Fab fusion molecules, wherein different Fab-fragments are fused together; ScFv- and diabody-based and heavy chain antibodies (e.g., domain antibodies, nanobodies) wherein different single chain Fv molecules or different diabodies or different heavy-chain antibodies (e.g.
  • bispecific formats include dual targeting molecules include Dual Targeting (DT)-Ig (GSK/Domantis), Two-in-one 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 Fusions (Academic Institution), SCORPION (Emergent BioSolutions/Trubion, Zymogenetics/BMS) and Dual Affinity Retargeting Technology (Fc- DART) (MacroGenics), F(ab)2 (Medarex/AMGEN), Dual-Action or Bis-Fab (Genentech), Dock-and-Lock (DNL) (I
  • the BCMAxCD3 bispecific antibody comprises any one of the BCMA binding domains described in WO2017/031104, the entire content of which is Docket No.258199.062002 (JBI6858WOPCT1) incorporated herein by reference.
  • the BCMAxCD3 bispecific antibody comprises any one of the CD3 binding domains described in WO2017/031104.
  • the BCMAxCD3 bispecific antibody comprises any one of the BCMAxCD3 bispecific antibodies described in WO2017/031104. [0116] In some embodiments, the BCMAxCD3 bispecific antibody is chimeric, humanized or human. [0117] In some embodiments, the bispecific antibody is an IgG1, an IgG2, an IgG3 or an IgG4 isotype. In preferred embodiments, the bispecific antibody is an IgG4 isotype. An exemplary wild-type IgG4 comprises an amino acid sequence of SEQ ID NO: 34.
  • SEQ ID NO: 34 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC PSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHN HYTQKSLSLSLGK [0118]
  • the bispecific antibody can be of any allotype.
  • the bispecific antibody comprises one or more Fc substitutions that reduces binding of the bispecific antibody to a FcJ receptor (FcJR) and/or reduces Fc effector functions such as C1q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) or phagocytosis (ADCP).
  • FcJR FcJ receptor
  • Fc positions that can be substituted to reduce binding of the Fc to the activating FcJR and subsequently to reduce effector function are substitutions 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, K214T/E233P/ L234V/L235A/G236-deleted/A327G/P331A/D365E/L358M on IgG1, H268Q/V309L/ A330S/P331S on IgG2, S267E/L328F on Ig
  • Fc substitutions that can be used to reduce CDC are a K322A substitution.
  • Well-known S228P substitution can further be made in IgG4 antibodies to enhance IgG4 stability.
  • the bispecific antibody comprises one or more asymmetric substitutions in a first CH3 domain or in a second CH3 domain, or in both the first CH3 domain and the second CH3 domain.
  • the one or more asymmetric substitutions is 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_Y407V/T394W, T366I_K392M_T394W/F405A_Y407V, T366L_K392M_T394W/F405A_Y407V, L351Y_Y407A/T366A_K409F, L351Y_Y407A/T366A_K409F, L351Y_Y407A/T366
  • the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in a first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in a second heavy chain (HC2), wherein residue numbering is according to the EU Index.
  • the BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2.
  • Tables 3 and 4 provide sequences of an exemplary embodiment of a BCMAxCD3 bispecific antibody, according to the Kabat numbering system.
  • Table 3 Exemplary sequences of a BCMA binding arm Region Sequence SEQ ID NO: HCDR1 SGSYFWG 4 HCDR2 SIYYSGITYYNPSLKS 5 HCDR3 HDGAVAGLFDY 6 LCDR1 GGNNIGSKSVH 7 LCDR2 DDSDRPS 8 LCDR3 QVWDSSSDHVV 9 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSGSYFWGWIRQ 10 PPGKGLEWIGSIYYSGITYYNPSLKSRVTISVDTSKNQFSLK LSSVTAADTAVYYCARHDGAVAGLFDYWGQGTLVTVSS VL SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQPPG 11 QAPVVVVYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGD EAV
  • the BCMAxCD3 bispecific antibody is teclistamab (also referred to herein as Tec), which has the sequences described in Tables 3 and 4. [0129] Teclistamab and its methods of use are described, for example, in WO 2017/031104, WO 2019/220369 and WO 2021/228783, which are incorporated by reference herein.
  • the BCMAxCD3 bispecific antibody has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the amino acid sequence of teclistamab.
  • the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising the HCDR1 of SEQ ID NO: 4, the HCDR2 of SEQ ID NO: 5, the HCDR3 of SEQ ID NO: 6, the LCDR1 of SEQ ID NO: 7, the LCDR2 of SEQ ID NO: 8 and the LCDR3 of SEQ ID NO: 9, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 14, the HCDR2 of SEQ ID NO: 15, the HCDR3 of SEQ ID NO: 16, the LCDR1 of SEQ ID NO: 17, the LCDR2 of SEQ ID NO: 18 and the LCDR3 of SEQ ID NO: 19.
  • 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 Docket No.258199.062002 (JBI6858WOPCT1) sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.
  • the BCMAxCD3 bispecific antibody is an IgG1, an IgG2, an IgG3 or an IgG4 isotype.
  • the BCMAxCD3 bispecific antibody is an IgG4 isotype. [0135] In certain embodiments, the BCMAxCD3 bispecific antibody comprises one or more substitutions in its Fc region. [0136] In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering). [0137] In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A, L235A F405L and R409K substitutions in its Fc region (according to EU numbering).
  • the Fc region of the BCMA-binding arm comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).
  • the Fc region of the CD3 CD3-binding arm comprises S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region (according to EU numbering).
  • 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.
  • the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 23.
  • HC1 first heavy chain having at least 90% identity to the amino acid sequence of SEQ ID NO: 12
  • LC1 having at least 90% identity to the amino acid sequence of SEQ ID NO: 13
  • HC2 having at least 90% identity to the amino acid sequence of SEQ ID NO: 22
  • LC2 second light chain having at least 90% identity to the amino acid sequence of SEQ ID NO: 23.
  • the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity to the amino acid Docket No.258199.062002 (JBI6858WOPCT1) sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 23.
  • HC1 having at least 95% identity to the amino acid sequence of SEQ ID NO: 12
  • LC1 having at least 95% identity to the amino acid sequence of SEQ ID NO: 13
  • a second heavy chain (HC2) having at least 95% identity to the amino acid Docket No.258199.062002 JBI6858WOPCT1 sequence of SEQ ID NO: 22
  • LC2 second light chain having at least 95% identity to the amino acid sequence of SEQ ID NO:
  • the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 23.
  • the BCMAxCD3 bispecific antibody is teclistamab.
  • the BCMAxCD3 bispecific antibodies disclosed herein are for use in treating multiple myeloma in a subject.
  • the subject is newly diagnosed with multiple myeloma.
  • the subject is newly diagnosed with multiple myeloma and ineligible for ASCT.
  • the subject is newly diagnosed multiple myeloma and either ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy.
  • ASCT autologous stem cell transplant
  • the subject is newly diagnosed with multiple myeloma and previously received ASCT.
  • the subject is newly diagnosed with multiple myeloma and has completed induction therapy followed by ASCT (with or without consolidation).
  • the subject is newly diagnosed with multiple myeloma and previously received 4 to 6 cycles of 3- or 4-drug induction therapy that includes a proteasome inhibitor and/or an IMiD with or without anti- CD38 monoclonal antibody and a single or tandem ASCT (in certain embodiments, the subject has received post-ASCT consolidation for up to 2 cycles if the total number of induction plus consolidation cycles did not exceed 6).
  • the subject is newly diagnosed with multiple myeloma and is eligible for ASCT.
  • the subject is newly diagnosed with multiple myeloma, is eligible for ASCT, and has not yet received ASCT.
  • a diagnosis of multiple myeloma as described herein refers to a diagnosis of multiple myeloma according to IMWG 2016 criteria.
  • the subject is relapsed or refractory to treatment with one or more prior anti-cancer treatments.
  • Relapsed disease means a cancer has come back.
  • Refractory disease means a cancer has not improved with treatment or has stopped responding to treatment.
  • Docket No.258199.062002 JBI6858WOPCT1
  • the subject is relapsed or refractory to treatment with a therapeutic used to treat multiple myeloma or other hematological malignancies.
  • the subject has had been treated with from 2 to 14 prior lines of therapy. [0149] In certain embodiments, the subject has received at least three prior lines of therapy. [0150] In certain embodiments, the subject has received at least four prior lines of therapy. [0151] In certain embodiments, the subject has received at least five prior lines of therapy (penta-drug exposed). [0152] In certain embodiments, the subject has received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody. [0153] In certain embodiments, the subject has received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.
  • the patients are relapsed or refractory or intolerant to the last line of therapy (LOT); were exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy; and had measurable disease.
  • the subject has received three anti-cancer therapies prior to administration of the BCMAxCD3 bispecific antibody.
  • the three prior anti-cancer therapies are a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody.
  • the proteasome inhibitor is bortezomib, carfilzomib or ixazomib, the immunomodulatory drug (IMiD) is lenalidomide, pomalidomide or thalidomide and the anti-CD38 antibody is daratumumab or isatuximab.
  • the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is daratumumab.
  • the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is isatuximab.
  • the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti- CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is daratumumab.
  • the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is isatuximab. Docket No.258199.062002 (JBI6858WOPCT1) [0157]
  • the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is daratumumab.
  • the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is isatuximab.
  • the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is thalidomide and the anti- CD38 antibody is daratumumab.
  • the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is isatuximab.
  • the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is daratumumab.
  • the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is isatuximab.
  • the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti- CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is isatuximab.
  • the subject is refractory or relapsed to treatment with one or more treatments or therapies, such as THALOMID ® (thalidomide), REVLIMID ® (lenalidomide), POMALYST ® (pomalidomide), VELCADE ® (bortezomib), NINLARO (ixazomib), KYPROLIS ® (carfilzomib), FARADYK ® (panobinostat), AREDIA ® (pamidronate), ZOMETA ® (zoledronic acid), DARZALEX ® (daratumumab), elotozumab or melphalan, Xpovio ® (Selinexor), Venclexta ® (Venetoclax), GSK 916, CAR-T therapies, or other BCMA-directed therapies.
  • THALOMID ® thalidomide
  • REVLIMID ® lenalidomide
  • POMALYST ® pomalidomide
  • Symptoms that can be associated are for example a decline or plateau of the well-being of the patient or re-establishment or worsening of various symptoms Docket No.258199.062002 (JBI6858WOPCT1) associated with solid tumors, and/or the spread of cancerous cells in the body from one location to other organs, tissues or cells.
  • the multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody, selinexor, venetoclax, lenalinomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan or thalidomide, or any combination thereof.
  • the anti-CD38 antibody is daratumumab.
  • the anti-CD38 antibody is isatuximab
  • the multiple myeloma is a high-risk multiple myeloma.
  • Subjects with high-risk multiple myeloma are known to relapse early and have poor prognosis and outcome.
  • Subjects can be classified as having high-risk multiple myeloma is 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.
  • the subject having the high-risk multiple myeloma has one or more chromosomal abnormalities comprising: 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.
  • the cytogenetic abnormalities can be detected for example by fluorescent in situ hybridization (FISH).
  • FISH fluorescent in situ hybridization
  • an oncogene is translocated to the IgH region on chromosome 14q32, resulting in dysregulation of these genes.
  • t(4;14)(p16;q32) involves translocation of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain containing protein (MMSET) (also called WHSC1/NSD2)
  • t(14;16)(q32;q23) involves translocation of the MAF transcription factor C-MAF.
  • Deletion of 17p (del17p) involves loss of the p53 gene locus.
  • BCMAxCD3 bispecific antibody [0166] Chromosomal rearrangements can be identified using well known methods, for example fluorescent in situ hybridization, karyotyping, pulsed field gel electrophoresis, or sequencing.
  • Monthly administration of a BCMAxCD3 bispecific antibody [0167] In accordance with certain embodiments, the inventors have developed novel dosing regimens for BCMAxCD3 bispecific antibodies that may provide improved safety profiles over currently approved regimens while maintaining deep and durable clinical responses over time.
  • Such dosing schedules may vary, for example, depending on a particular indication or patient population (e.g., relapsed/refractory patients or newly diagnosed patients), and also depending on the therapy (e.g., BCMAxCD3 bispecific antibody monotherapy) or combination of therapies administered.
  • the inventors developed modified dosing schedules of BCMAxCD3 bispecific antibodies that comprise monthly (Q4W) administration starting in the second BCMAxCD3 treatment cycle (e.g., immediately following a step-up phase in Cycle 1). According to certain embodiments, such dosing schedules do not include any BCMAxCD3 treatment cycles in which the BCMAxCD3 bispecific antibody is administered bi-weekly (Q2W).
  • a “BCMAxCD3 treatment cycle” refers to each treatment cycle in a therapeutically effective regimen in which at least one treatment dose of a BCMAxCD3 bispecific antibody is administered to the subject.
  • the first BCMAxCD3 treatment cycle in a therapeutically effective regimen is preceded by a step-up phase.
  • monthly (Q4W) dosing of the BCMAxCD3 bispecific antibody begins in the first BCMAxCD3 treatment cycle following a step-up phase in which one or more step-up doses (and optionally one or more treatment doses) are administered.
  • a dosing regimen may include treatment doses in different amounts, e.g., one or more treatment doses of 1.5 mg/kg may be administered during a step-up phase and then treatment doses of 3 mg/kg may be administered in subsequent treatment cycles.
  • a fixed dose sometimes referred to as a flat dose, is therefore provided as an absolute amount of the agent (e.g., mg drug), and not as a weight-based amount (e.g. ⁇ g/kg or ⁇ g drug per kg body weight).
  • a subject weighing 65kg may be administered the same flat dose in milligrams as a subject weighing 85kg.
  • a flat dose may be administered according to a pre-defined class or category of body weight, but is not modified according to the subject’s specific weight.
  • a “Flat Dose A” may be administered if a patient is greater than a pre-defined threshold weight (e.g., > 60 kg), whereas a different “Flat Dose B” may be administered if the patent is less than or equal to the pre-defined threshold weight (e.g., ⁇ 60 kg).
  • Docket No.258199.062002 JBI6858WOPCT1
  • weight-based refers to administration of a dose amount that is based on the subject’s specific body weight; for example, 3 mg/kg refers to a dose of 3 milligrams of antibody per kilogram of the subject’s body weight.
  • a BCMAxCD3 bispecific antibody such as teclistamab
  • teclistamab is administered on a dosing schedule based on sequential 28-day treatment cycles, for example, Cycle 1 starts on Day 1 of Cycle 1 and ends on Day 28 of Cycle 1, and then Day 1 of Cycle 2 starts the day after Day 28 of Cycle 1 and ends on Day 28 of Cycle 2, and then Day 1 of Cycle 3 starts the day after Day 28 of Cycle 2 and ends on Day 28 of Cycle 3, and so on.
  • Cycle 1 refers to Cycle 1
  • C2 refers to Cycle 2
  • C3 refers to Cycle 3
  • Multiple cycles may also be described, e.g., “C3-6” refers to Cycles 3-6 (Cycles 3, 4, 5 and 6).
  • a cycle number with a “+” symbol refers to that cycle and all subsequent cycles, e.g., “C3+” refers to from and all subsequent cycles (i.e., C3, C4, C5, C6, C7, and so on).
  • administration of the BCMAxCD3 bispecific antibody begins in Cycle 1 of a therapeutically effective regimen (e.g., Cycle 1 is a step-up phase).
  • the BCMAxCD3 antibody 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 start in Cycle 2 or later, i.e., administration of one or more other anti-multiple myeloma agents (but not the BCMAxCD3 bispecific antibody) may start in Cycle 1 and administration of the BCMAxCD3 bispecific antibody starts in Cycle 2 or later.
  • the first treatment cycle that includes administration of the BCMAxCD3 bispecific antibody is Cycle 2 or later.
  • Q4W means once every four weeks (i.e., once every 28 days)
  • Q2W also referred to as “bi-weekly” or “biweekly”
  • QW also referred to as “weekly”
  • Q4W means once weekly.
  • Q4W is also referred to herein as “monthly.”
  • the terms “Q4W” and “monthly” are used interchangeably to refer to once every 4 weeks or once every 28 days (e.g., in sequential 28-day cycles, a first treatment dose occurs on Day 1 of Cycle 1, a second treatment dose occurs on Day 1 of Cycle 2, etc.).
  • Administration of a treatment dose once weekly is also referred to herein as a weekly dosing schedule; for example, a 28-day treatment cycle may have a weekly dosing schedule that comprises four doses one week apart from each other (e.g., on Days 1, 8, 15 and 22), or Docket No.258199.062002 (JBI6858WOPCT1) three doses one week apart from each other (e.g., on Days 8, 15 and 22), or two doses one week apart from each other (e.g., on Days 8 and 15).
  • Administration of a treatment dose once every two weeks (Q2W) is also referred to herein as a bi-weekly dosing schedule.
  • Dosing regimens may be described herein in terms of the dose amount and frequency; for example, “C1: 1500 ⁇ g/kg QW” refers to administration of 1500 ⁇ g/kg once per week in Cycle 1 of a therapeutically effective regimen, “C3-6: 3000 ⁇ g/kg Q2W” refers to administration of 3000 ⁇ g/kg once every two weeks from Cycle 3 through Cycle 6, “C3+: 3000 ⁇ g/kg Q4W” refers to administration of 3000 ⁇ g/kg once every four weeks starting in Cycle 3, etc.
  • teclistamab refers to the FDA-approved weight-based regimen for teclistamab monotherapy, based on the MajesTEC- 1 clinical study, which includes treatment doses of 1.5 mg/kg teclistamab subcutaneously (SC) administered weekly until disease progression or unacceptable toxicity, wherein the treatment doses are preceded by step-up doses of 0.06 and 0.3 mg/kg.
  • IMWG diagnostic criteria for multiple myeloma have been met when the participant was diagnosed.
  • IMWG diagnostic criteria are known in the art.
  • Multiple myeloma may be defined as clonal BMPCs ⁇ 10% or biopsy-proven bony or extramedullary plasmacytoma a and at least 1 of the following: x Evidence of end-organ damage, specifically: – C: Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the ULN or >2.75 mmol/L (>11 mg/dL) – R: Renal insufficiency: creatinine clearance ⁇ 40 mL per min b or serum creatinine >177 ⁇ mol/L (>2 mg/dL) –
  • Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used.
  • PET-CT 18F-fluorodeoxyglucose PET with CT. e. These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK).
  • methods of treating multiple myeloma are effective in eliciting a clinical response in a subject as determined by International Myeloma Working Group (IMWG) response criteria.
  • the methods of treatment are effective in eliciting a partial response (PR), a very good partial response (VGPR), a complete response (CR) or a stringent complete response (sCR), as determined by IMWG response criteria.
  • ORR overall response rate
  • PR partial response
  • IMWG criteria for response to Multiple Myeloma treatment are provided in Table A below.
  • An abnormal kappa/lambda ratio by immunohistochemistry or immunofluorescence requires a minimum of 100 plasma cells for analysis.
  • An abnormal ratio reflecting presence of an abnormal clone is kappa/lambda of >4:1 or ⁇ 1:2. b
  • it is possible that the original M-protein light chain isotype is still detected on immunofixation but the accompanying heavy-chain component has disappeared; this would not be considered as a CR even though the heavy-chain component is not detectable, because it is possible that the clone evolved to one that secreted only light chains.
  • CR in such participants indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above.
  • VGPR in such participants requires a ⁇ 90% decrease in the difference between involved and uninvolved FLC levels.
  • JBI6858WOPCT1 JBI6858WOPCT1 reference herein: Durie BG, Harousseau JL, Miguel JS, et al.
  • Embodiments of the present invention provide methods of treating multiple myeloma in a subject in need thereof, comprising treating the subject according to a therapeutically effective regimen that comprises sequential BCMAxCD3 treatment cycles (e.g., 28-day treatment cycles), wherein: one or more step-up doses of a BCMAxCD3 bispecific antibody (e.g., teclistamab) are subcutaneously administered to the subject during a step-up phase, and treatment doses of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase.
  • a BCMAxCD3 bispecific antibody e.g., teclistamab
  • each treatment dose of the BCMAxCD3 bispecific antibody that is administered to the subject on the monthly dosing schedule (Q4W) is administered in an amount of 1.5 mg/kg or 3 mg/kg.
  • each treatment dose of the BCMAxCD3 bispecific antibody that is administered to the subject on the monthly dosing schedule (Q4W) is administered in an amount of 1.5 mg/kg.
  • each treatment dose of the BCMAxCD3 bispecific antibody that is administered to the subject on the monthly dosing schedule (Q4W) is administered in an amount of 3 mg/kg.
  • each treatment dose of the BCMAxCD3 bispecific antibody administered to the subject on the monthly dosing schedule (Q4W) is administered on Day 1 of each BCMAxCD3 treatment cycle.
  • the regimen does not include any BCMAxCD3 treatment cycles in which the BCMAxCD3 bispecific antibody is administered to the subject on a bi- weekly dosing schedule (Q2W).
  • the step-up phase is 28 days.
  • 1-3 step-up doses of the BCMAxCD3 bispecific antibody are administered to the subject during the step-up phase.
  • two step-up doses of the BCMAxCD3 bispecific antibody are administered to the subject during the step-up phase.
  • the step-up phase comprises a first step-up dose of 0.06 mg/kg of the BCMAxCD3 bispecific antibody.
  • the step-up phase comprises a first step-up dose of 0.06 mg/kg of the BCMAxCD3 bispecific antibody and a second step-up dose of 0.3 mg/kg of the BCMAxCD3 bispecific antibody.
  • one or more treatment doses of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during the step-up phase, in addition to the one or more step-up doses.
  • two treatment doses of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during the step-up phase, in addition to the one or more step-up doses.
  • three treatment doses of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during the step-up phase, in addition to the one or more step-up doses.
  • the step-up phase comprises subcutaneously administering two step-up doses and two treatment doses of the BCMAxCD3 bispecific antibody.
  • the step-up phase comprises subcutaneously administering two step-up doses and three treatment doses of the BCMAxCD3 bispecific antibody.
  • the one or more treatment doses of the BCMAxCD3 bispecific antibody administered during the step-up phase are administered in an amount of 0.72 mg/kg or 1.5 mg/kg or 3.0 mg/kg.
  • each of the one or more treatment doses of the BCMAxCD3 bispecific antibody administered during the step-up phase are administered in an amount of 1.5 mg/kg.
  • two or three treatment doses of the BCMAxCD3 bispecific antibody are administered during the step-up phase on a weekly dosing schedule (QW).
  • two treatment doses of the BCMAxCD3 bispecific antibody are administered during the step-up phase on a weekly dosing schedule (QW).
  • three treatment doses of the BCMAxCD3 bispecific antibody are administered during the step-up phase on a weekly dosing schedule (QW).
  • the step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg, a second step-up 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.
  • the second step-up dose is administered 2-4 days after first step-up dose.
  • the second step-up dose is administered 2 days after first step-up dose.
  • the first treatment dose is administered 4-7 days after the second step-up dose.
  • the first treatment dose is administered 5 days after the second step-up dose.
  • the second treatment dose is administered 5-9 days after the first treatment dose.
  • the second treatment dose is administered 7 days after the first treatment dose.
  • the step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg on Day 1, a second step-up 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.
  • the step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg, a second step-up 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.
  • the third treatment dose is administered 5-9 days after the second treatment dose.
  • the third treatment dose is administered 7 days after the second treatment dose.
  • the step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg on Day 1, a second step-up 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 Docket No.258199.062002 (JBI6858WOPCT1) mg/kg on Day 15; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • the step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg on Day 1, a second step-up 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 comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • the treatment doses of the BCMAxCD3 bispecific antibody are administered to the subject on the monthly dosing schedule (Q4W) regardless of whether, or to what extent, the subject exhibits a clinical response to the regimen.
  • the step-up phase is in Cycle 1 of the regimen
  • the first BCMAxCD3 treatment cycle is in Cycle 2 of the regimen.
  • the regimen is a combination therapy comprising administration of other anti-multiple myeloma agents in addition to the BCMAxCD3 bispecific antibody.
  • the regimen is a combination therapy
  • the step-up phase is in Cycle 2 of the regimen
  • the first BCMAxCD3 treatment cycle is in Cycle 3 of the regimen, or later.
  • the regimen is a combination therapy
  • the step-up phase is in Cycle 2 of the regimen
  • the first BCMAxCD3 treatment cycle is in Cycle 3 of the regimen.
  • 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 are subcutaneously administered to the subject, and a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject every 4 weeks (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase.
  • the step-up phase is 28 days and occurs in Cycle 1 of the regimen; the first dose, the second dose, the third dose and the fourth dose are administered on Day 1, Day 3, Day 8 and Day 15 of Cycle 1, respectively, and the treatment dose of 3 mg/kg is administered on Day 1 of Cycle 2 and on Day 1 of each subsequent treatment cycle thereafter.
  • 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 are subcutaneously administered to the subject, and a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject every 4 weeks (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase.
  • the step-up phase is 28 days and occurs in Cycle 1 of the regimen; the first dose, the second dose, the third dose, the fourth dose and the fifth dose are administered on Day 1, Day 3, Day 8, Day 15 and Day 22 of Cycle 1, respectively, and the treatment dose of 3 mg/kg is administered on Day 1 of Cycle 2 and on Day 1 of each subsequent treatment cycle thereafter.
  • the regimen is a combination therapy
  • the step-up phase is 28 days and occurs in Cycle 2 of the regimen
  • the first dose, the second dose, the third dose and the fourth dose of the BCMAxCD3 bispecific antibody are administered on Day 1, Day 3, Day 8 and Day 15 of Cycle 2, respectively
  • the treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody is administered on Day 1 of Cycle 3 and on Day 1 of each subsequent treatment cycle thereafter.
  • the regimen is a combination therapy
  • the step-up phase is 28 days and occurs in Cycle 2 of the regimen
  • the first dose, the second dose, the third dose, the fourth dose and the fifth dose are administered on Day 1, Day 3, Day 8, Day 15 and Day 22 of Cycle 1, respectively
  • the treatment dose of 3 mg/kg is administered on Day 1 of Cycle 3 and on Day 1 of each subsequent treatment cycle thereafter.
  • the regimen is a combination therapy comprising administration of the BCMAxCD3 bispecific antibody (e.g., teclistamab), daratumumab and lenalidomide.
  • administration of the daratumumab starts in Cycle 1
  • administration of the lenalidomide starts in Cycle 1
  • administration of the BCMAxCD3 bispecific antibody starts in Cycle 2; and wherein one or more step-up doses and at least one treatment dose of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase in Cycle 2, and wherein a treatment dose of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject monthly (Q4W) starting in Cycle 3.
  • Systemic therapy typically administered as a triplet or quadruplet drug regimen, is the mainstay of treatment both for transplant-eligible and transplant-ineligible patients. It is used in combination with ASCT for those eligible.
  • DRd daratumumab, lenalidomide and dexamethasone
  • VRd bortezomib, lenalidomide and dexamethasone
  • the present inventors have developed novel dosing regimens for combination therapies, e.g., combination therapies comprising administration of teclistamab, daratumumab and lenalidomide, that may provide improved safety profiles over currently approved regimens while achieving deep and durable efficacy.
  • combination therapies comprising administration of teclistamab, daratumumab and lenalidomide
  • Embodiments of the present invention provide novel dosing regimens for the treatment of multiple myeloma in subjects with newly diagnosed multiple myeloma who are either ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy.
  • ASCT autologous stem cell transplant
  • subjects that are newly diagnosed have a diagnosis of multiple myeloma according to the IMWG diagnostic criteria and have not received any prior therapy for multiple myeloma or smoldering myeloma (but may have received a short course of corticosteroids, not exceeding 40 mg of dexamethasone, or equivalent per day for a maximum of 4 days, total of 160 mg dexamethasone or equivalent).
  • RRMM relapsed/refractory multiple myeloma
  • they are not relapsed and/or refractory to prior multiple myeloma therapy but may have received a short course of corticosteroids, not exceeding 40 mg of dexamethasone, or equivalent per day for a maximum of 4 days, total of 160 mg dexamethasone or equivalent.
  • Subjects that are ineligible for ASCT as initial therapy can be ineligible due to (i) advanced age, or (ii) presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with ASCT.
  • teclistamab, daratumumab and lenalidomide (“Tec- DR”) are administered as a combination therapy for the treatment of adult patients with newly diagnosed multiple myeloma who are either ineligible or not intended for autologous stem cell transplant as initial therapy.
  • teclistamab, daratumumab and lenalidomide are administered as a combination therapy for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant as initial therapy.
  • Tec-DR improves PFS (progression-free survival) and/or the rate of sustained MRD-negative CR ( ⁇ 12 months) compared with DRd in subjects with newly diagnosed multiple myeloma who are ineligible or not intended for ASCT as initial therapy.
  • teclistamab in combination with daratumumab subcutaneous (SC) and lenalidomide provide an efficacious and safe approach with higher efficacy rates (e.g., mPFS, mOS and MRD negativity rates) compared to the existing standard of care of daratumumab, lenalidomide and dexamethasone (DRd) and/or bortezomib, lenalidomide and dexamethasone (VRd).
  • efficacy rates e.g., mPFS, mOS and MRD negativity rates
  • teclistamab, daratumumab and lenalidomide (“Tec-DR”) are administered as a combination therapy for the treatment of adult patients with newly diagnosed multiple myeloma who are either ineligible or not intended for autologous stem cell transplant as initial therapy, according to the therapeutically effective regimen shown in Table B below. Table B.
  • a method for the treatment of adult patients with newly diagnosed multiple myeloma who are either ineligible or not intended for autologous stem cell transplant as initial therapy comprises: administering a therapeutically effective combination therapy to the subject comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), daratumumab, and lenalidomide, on a dosing schedule comprising sequential 28-day treatment cycles, wherein administration of the daratumumab starts in Cycle 1, administration of the lenalidomide starts in Cycle 1, and administration of the BCMAxCD3 bispecific antibody starts in Cycle 2; and wherein one or more step-up doses and at least one treatment dose of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase in Cycle 2, and wherein a treatment dose of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject monthly (Q4W) starting in Cycle 3.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • the regimen further comprises, in Cycles 1 and 2 only, orally or intravenously administering dexamethasone to the subject.
  • a method for the treatment of adult patients with newly diagnosed multiple myeloma who are either ineligible or not intended for autologous stem cell transplant as initial therapy comprises: administering a therapeutically effective combination therapy to the subject comprising the BCMA x CD3 bispecific antibody (e.g., teclistamab), daratumumab, and lenalidomide according to a regimen comprising 28-day cycles, wherein the regimen comprises: for the BCMA x CD3 bispecific antibody (e.g., teclistamab): in Cycle 2, subcutaneously administering a first step-up dose of 60 ⁇ g/kg (e.g., on Day 1 or Day 2), a second step-up dose of 300 ⁇ g/kg (e.g., on Day 3 or Day 4), and then weekly (QW) doses of 1500 ⁇ g
  • the regimen further comprises, in Cycles 1-2 only, orally or intravenously administering 20 mg of dexamethasone weekly (QW) (e.g., on Days 1, 8, 15 and 22).
  • QW dexamethasone weekly
  • clinical data from safety run-in cohorts in a Phase 3 Teclistmab study produced unexpected findings.
  • a Safety Run-In introduced a DRd lead-in dosing strategy (i.e., Drd dosing in Cycle 1 and introduction of Tec in Cycle 2 with step-up dosing occurring while lenalidomide is dosed). This approach was adopted to explore whether a DRd lead-in would reduce the burden of disease in newly diagnosed patients and further reduce the occurrence and severity of CRS.
  • the dosing schedule shown in Table D may minimize exposure to Tec and optimize tolerability and safety by completing step-up dosing in Cycle 1 and transitioning to monthly dosing in Cycle 2.
  • teclistamab and daratumumab are initiated in Cycle 1 and lenalidomide added in Cycle 2 after the step-up phase, and the less frequent (i.e., Q4W) dosing to mitigate infection is retained.
  • the teclistamab SC dose schedule comprises 2 step-up doses (0.06 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 starting from Cycle 2, 3 mg/kg Q4W on Day 1 of the cycle.
  • teclistamab, daratumumab and lenalidomide are administered as a combination therapy for the treatment of adult patients with newly diagnosed multiple myeloma who are either ineligible or not intended for autologous stem cell transplant as initial therapy, according to the therapeutically effective regimen shown in Table D below. Docket No.258199.062002 (JBI6858WOPCT1) Table D.
  • Exemplary Treatment Method Study Treatment Dose Schedule Teclistamab SC C1: 2 step-up doses (0.06 and 0.3 mg/kg) on Days 2 and 4 followed by treatment doses (1.5 mg/kg) on Days 8 and 15 C2+: Q4W treatment doses (3 mg/kg) on Day 1 Daratumumab SC 1800 mg C1-2: weekly on Days 1, 8, 15, and 22 C3-6: Q2W on Days 1 and 15 C7+: Q4W on Day 1 Lenalidomide oral 25 mg* C2+: D1-21 Dexamethasone oral/IV 20 mg** C2-3: weekly on Days 1, 8, 15, and 22 * Lenalidomide dose may need to be adjusted for participants with reduced CrCl.
  • a subject s risk of high-grade CRS is reduced when the regimen comprises the initiation of the BCMAxCD3 bispecific antibody administration in Cycle 1 followed by the initiation of the lenalidomide administration in Cycle 2, compared to a regimen that comprises initiation of the lenalidomide administration in Cycle 1 followed by initiation of the BCMAxCD3 bispecific antibody administration in Cycle 2.
  • a subject’s risk of high-grade CRS is reduced when the regimen comprises the initiation of the BCMAxCD3 bispecific antibody administration in Cycle 1 followed by the initiation of the lenalidomide administration and the dexamethasone administration in Cycle 2, compared to a regimen that comprises initiation of the lenalidomide administration and the dexamethasone administration in Cycle 1 followed by initiation of the BCMAxCD3 bispecific antibody administration in Cycle 2.
  • the regimen is a combination therapy comprising administration of the BCMAxCD3 bispecific antibody (e.g., teclistamab), daratumumab and lenalidomide.
  • administration of the daratumumab starts in Cycle 1, administration of the BCMAxCD3 bispecific antibody starts in Cycle 1, and administration of the lenalidomide starts in Cycle 2; and wherein one or more step-up doses and at least one treatment dose of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase in Cycle 1, and wherein a treatment dose of the Docket No.258199.062002 (JBI6858WOPCT1) BCMAxCD3 bispecific antibody is subcutaneously administered to the subject monthly (Q4W) starting in Cycle 2.
  • the regimen further comprises: in Cycles 2 and 3 only, orally or intravenously administering dexamethasone to the subject.
  • the regimen comprises: for the BCMA x CD3 bispecific antibody (e.g., teclistamab): in Cycle 1, subcutaneously administering a first step-up dose of 60 ⁇ g/kg (e.g., on Day 2), a second step-up dose of 300 ⁇ g/kg (e.g., on Day 4), and then weekly (QW) doses of 1500 ⁇ g/kg (e.g., on Days 8 and 15), and in Cycle 2 and all subsequent treatment cycles, subcutaneously administering a monthly (Q4W) dose of 3000 ⁇ g/kg (e.g., on Day 1); for the daratumumab: in Cycles 1-2, subcutaneously administering 1800 mg weekly (QW) (e.g., on Days, 1, 8, 15 and 22), in Cycles 3-6, subcutaneously administering 1800 mg bi-weekly (Q2W) (e.g., on Days 1 and 15) and in Cycle 7 and all subsequent treatment cycles, subcutaneously administering
  • the regimen further comprises: in Cycles 2-3, orally or intravenously administering 20 mg of dexamethasone weekly (QW) (e.g., on Days 1, 8, 15 and 22).
  • QW dexamethasone weekly
  • the method achieves a decrease in new infections over time in a population of subjects with newly diagnosed multiple myeloma, compared to a population of subjects with newly diagnosed multiple myeloma that are treated with the combination therapy but receive more frequent doses of the BCMAxCD3 bispecific antibody (e.g., QW and/or Q2W) in Cycle 3 and all subsequent treatment cycles.
  • the BCMAxCD3 bispecific antibody e.g., QW and/or Q2W
  • the method achieves a decrease in new grade ⁇ 3 infections over time in a population of subjects with newly diagnosed multiple myeloma, compared to a population of subjects with newly diagnosed multiple myeloma that are treated with the combination therapy but receive more frequent doses of the BCMAxCD3 bispecific antibody (e.g., QW and/or Q2W) in Cycle 3 and all subsequent treatment cycles. Docket No.258199.062002 (JBI6858WOPCT1) [0250] In certain embodiments, the method achieves a clinical response in the subject that is a sCR, a CR, a VGPR, or a PR in the subject, as defined by IMWG (2016) response criteria.
  • the method achieves a CR, VGPR, or PR in the subject, as defined by IMWG (2016) response criteria.
  • the method achieves a VGPR or PR in the subject, as defined by IMWG (2016) response criteria.
  • 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 that are ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy.
  • mPFS median progression-free survival
  • the method achieves a CR or better (i.e., a sCR or a CR), as defined by IMWG (2016) response criteria, in at least 60%, or at least 65%, or at least 70% of subjects in a population with newly diagnosed multiple myeloma that are ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy.
  • a CR or better i.e., a sCR or a CR
  • ASCT autologous stem cell transplant
  • the method achieves a rate of sustained MRD-negative CR ( ⁇ 12 months) 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 that are ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy after about 50 months of treatment with the combination therapy.
  • a rate of sustained MRD-negative CR ⁇ 12 months
  • the method achieves a median progression-free survival (mPFS) in a population of subjects with newly diagnosed multiple myeloma that are ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy, wherein the mPFS is greater than a reference mPFS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are either ineligible or not intended for 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., teclistamab), daratumumab, and lenalidomide.
  • mPFS median progression-free survival
  • the mPFS is greater than the reference mPFS by 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.
  • the method achieves a median overall survival (mOS) in a population of subjects with newly diagnosed multiple myeloma that are ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy, wherein the mOS is Docket No.258199.062002 (JBI6858WOPCT1) greater than a reference mOS achieved in a reference population of subjects with newly diagnosed multiple myeloma who are either ineligible or not intended for 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., teclistamab), daratumumab, and le
  • the mOS is greater than the reference mOS by at least 1 year, or at least 2 years, or at least 3 years, or at least 4 years.
  • the method achieves a rate of sustained MRD-negative CR ( ⁇ 12 months) in a population of subjects with newly diagnosed multiple myeloma that are ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy, wherein said rate of sustained MRD-negative CR ( ⁇ 12 months) is greater than a reference rate of sustained MRD-negative CR ( ⁇ 12 months) achieved in a reference population of subjects with newly diagnosed multiple myeloma who are either ineligible or not intended for 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., teclistamab), daratumumab, and le
  • the rate of sustained MRD-negative CR ( ⁇ 12 months) is greater than the reference rate of sustained MRD- negative CR ( ⁇ 12 months) by at least 4%, or at least 6%, or at least 8%, or at least 10%, or at least 12%, or at least 14%.
  • said reference population has been administered the Daratumumab, Lenalidomide, and Dexamethasone (DRd) according to the following schedule: for the Daratumumab: in Cycles 1-2, subcutaneously administering 1800 mg weekly (QW) (e.g., on Days, 1, 8, 15 and 22), in Cycles 3-6, subcutaneously administering 1800 mg bi- weekly (Q2W) (e.g., on Days 1 and 15) and in Cycle 7 and all subsequent treatment cycles, subcutaneously administering 1800 mg monthly (Q4W) (e.g., on Day 1); and for the lenalidomide: in Cycle 1 and all subsequent treatment cycles, orally administering 25 mg daily for the first 21 days of each 28-day cycle; and for the dexamethasone: in Cycle 1 and all subsequent treatment cycles, orally or intravenously administering 40 mg or 20 mg of dexamethasone weekly (QW) (e.g., on Days 1, 8, 15 and 22).
  • the subject is newly diagnosed with multiple myeloma and previously received ASCT.
  • the subject is newly diagnosed with multiple myeloma and has completed induction therapy followed by ASCT (with or without consolidation).
  • ASCT with or without consolidation.
  • the subject is newly diagnosed with multiple myeloma and previously received 4 to 6 cycles of induction therapy followed by ASCT.
  • the subject is newly diagnosed with multiple myeloma and previously received 4 to 6 cycles of 3- or 4-drug induction therapy that includes a proteasome inhibitor and/or an IMiD with or without anti-CD38 monoclonal antibody and a single or tandem ASCT.
  • the subject has received post-ASCT consolidation for up to 2 cycles if the total number of induction plus consolidation cycles did not exceed 6.
  • the regimen is a combination therapy comprising administration of at least one other anti-multiple myeloma agent in addition to the BCMAxCD3 bispecific antibody.
  • the regimen is a combination therapy comprising administration of lenalidomide and the BCMAxCD3 bispecific antibody, wherein the BCMAxCD3 bispecific antibody is teclistamab.
  • the step-up phase is Cycle 1 and comprises subcutaneously administering to the subject one or more step-up doses of the BCMAxCD3 bispecific antibody followed by one or more 1.5 mg/kg doses of the BCMAxCD3 bispecific antibody; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • the step-up phase is Cycle 1 and comprises subcutaneously administering to the subject one or more step-up doses of the BCMAxCD3 bispecific antibody followed by one or more 1.5 mg/kg doses of the BCMAxCD3 bispecific antibody on a QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • the step-up phase is Cycle 1 and comprises subcutaneously administering to the subject step-up doses of the BCMAxCD3 bispecific antibody followed by two 1.5 mg/kg doses of the BCMAxCD3 bispecific antibody on a QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • the step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg on Day 1, a second step-up 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 of the BCMAxCD3 bispecific antibody; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • the regimen is a combination therapy comprising administration of lenalidomide and teclistamab.
  • the lenalidomide is administered in an amount of 10 mg once daily.
  • the lenalidomide is not administered in Cycle 1.
  • the lenalidomide is not administered in Cycle 1, and is administered in Cycle 2 and all subsequent cycles.
  • the lenalidomide is administered in an amount of 10 mg once daily and may be increased to 15 mg once daily on Cycle 5 Day 1 if 10 mg was tolerated by the subject.
  • the BCMAxCD3 bispecific antibody is administered for a finite duration of 26 cycles.
  • the BCMAxCD3 bispecific antibody is administered for a finite duration of 13 cycles.
  • the BCMAxCD3 bispecific antibody is administered in Cycles 14-26 only if the subject has achieved a complete response or stringent complete response (according to IMWG 2016 criteria) after 13 cycles.
  • An exemplary embodiment of a dosing regimen comprising teclistamab, alone or in combination with lenalidomide, is provided in Table E below.
  • the method achieves a clinical response in the subject that is a sCR, a CR, a VGPR, or a PR in the subject, as defined by IMWG (2016) response criteria.
  • the method achieves a CR or sCR in the subject, as defined by IMWG (2016) response criteria.
  • the method achieves a VGPR or PR in the subject, as defined by IMWG (2016) response criteria.
  • the method achieves a CR or better (i.e., a sCR or a CR), as defined by 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 that have previously received autologous stem cell transplant (ASCT).
  • ASCT autologous stem cell transplant
  • the method achieves MRD negativity (10 -5 ) 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 that have previously received autologous stem cell transplant (ASCT).
  • ASCT autologous stem cell transplant
  • the method comprises administration of teclistamab alone or administration of a combination therapy comprising teclistamab and lenalidomide, and wherein said method achieves greater progression-free survival (PFS) and/or greater 12-month MRD-negative complete response (CR) rate in a population of subjects with newly diagnosed multiple myeloma that have previously received autologous Docket No.258199.062002 (JBI6858WOPCT1) stem cell transplant (ASCT) compared to a reference population of subjects with newly diagnosed multiple myeloma that have previously received autologous stem cell transplant (ASCT), said reference population having been administered a regimen comprising lenalidomide without a BCMAxCD3 bispecific antibody.
  • PFS progression-free survival
  • CR 12-month MRD-negative complete response
  • treatment regimens as described herein are administered to a subject that has newly diagnosed multiple myeloma and is eligible for ASCT. According to certain embodiments, the subject has not previously received ASCT.
  • the subject is administered the BCMAxCD3 bispecific antibody (e.g., teclistamab) as part of an induction therapy.
  • an induction therapy refers to a subject’s first phase of treatment for multiple myeloma.
  • the subject is administered a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), and one or more additional antimyeloma agents, as an induction therapy.
  • the subject is administered multiple cycles of the BCMAxCD3 bispecific antibody (e.g., teclistamab), and optionally one or more additional antimyeloma agents, as an induction therapy.
  • the subject is administered a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), and one or more additional antimyeloma agents selected from the group consisting of daratumumab, lenalidomide, dexamethasone, and any combination thereof, as an induction therapy.
  • the subject is administered a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), daratumumab, lenalidomide, and dexamethasone, as an induction therapy.
  • the subject is administered a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), daratumumab, and lenalidomide, as an induction therapy.
  • the subject is administered 6 cycles of the BCMAxCD3 bispecific antibody (e.g., teclistamab), and optionally one or more additional antimyeloma agents, as an induction therapy.
  • the subject is administered 6 cycles of a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), daratumumab, lenalidomide, and dexamethasone, as an induction therapy. Docket No.258199.062002 (JBI6858WOPCT1) [0298] According to certain embodiments, the subject is administered 6 cycles of a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), daratumumab, and lenalidomide, as an induction therapy. [0299] According to certain embodiments, the subject is administered the induction therapy prior to having an autologous stem cell transplant (ASCT).
  • ASCT autologous stem cell transplant
  • the subject is administered the induction therapy and then the subject undergoes an autologous stem cell transplant (ASCT) [0300]
  • ASCT autologous stem cell transplant
  • the subject is administered a maintenance therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), and optionally one or more additional antimyeloma agents, after receiving ASCT.
  • the subject is administered a maintenance therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab) and daratumumab after receiving ASCT.
  • the maintenance therapy comprises 6-20 treatment cycles, or 12-18 treatment cycles, or 12 treatment cycles.
  • teclistamab is administered, as part of a combination regimen with talquetamab, to subjects iwith RRMM who have previously received 1 to 4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide.
  • an anti-CD38 antibody e.g., daratumumab
  • lenalidomide e.g., a subject is administered one or more step-up doses followed by one or more doses of 1.5 mg/kg of teclistamab in Cycle 1, and then 3 mg/kg Q4W treatment doses of teclistamab starting from Cycle 2.
  • a subject is administered teclistamab at step-up doses of 0.06 mg/kg and 0.3 mg/kg, and two doses of 1.5 mg/kg in Cycle 1, and then 3 mg/kg Q4W treatment dose starting from Cycle 2.
  • a subject is administered teclistamab at step-up doses of 0.06 mg/kg and 0.3 mg/kg, and two doses of 1.5 mg/kg in Cycle 1, and then 3 mg/kg Q4W treatment dose starting from Cycle 2; and talquetamab SC step-up doses of 0.01 mg/kg and 0.06 mg/kg, one dose of 0.4 mg/kg, and one dose of 0.8 mg/kg in Cycle 1, followed by 0.8 mg/kg SC Q2W treatment doses in Cycles 2-4, wherein, from Cycle 5, participants with response of confirmed VGPR or better can change to talquetamab Q4W; and from Cycle 7, participants with response of confirmed PR or better must be switched to talquetamab 0.8 mg/kg Q4W.
  • a method of treating multiple myeloma in a subject in need thereof comprises treating the subject according to a therapeutically effective regimen that comprises sequential 28-day BCMAxCD3 treatment cycles, wherein, if criteria (1)-(4) are met, then one or more step-up doses of teclistamab are subcutaneously administered to the subject during a step-up phase (e.g., during Cycle 1) and treatment doses of the teclistamab are subcutaneously administered to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase (e.g., starting from Cycle 2), wherein the criteria (1)-(4) are met if (1) the subject has newly diagnosed multiple myeloma and is ineligible or not intended for ASCT as initial therapy, and the teclistamab is administered as part of a combination regimen that further comprises administration of daratumumab
  • a method of treating newly diagnosed multiple myeloma in a subject in need thereof comprises treating the subject according to a therapeutically effective regimen that comprises sequential 28-day BCMAxCD3 treatment cycles, wherein, if criteria (1)-(3) are met, then one or more step-up doses of teclistamab are subcutaneously administered to the subject during a step-up phase (e.g., during Cycle 1) and treatment doses of the teclistamab are subcutaneously administered to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase (e.g., starting from Cycle 2), wherein the criteria (1)-(3) are met if: (1) the subject has newly diagnosed multiple myeloma and is ineligible or not intended for ASCT as initial therapy, and the teclistamab is administered as part of a combination regimen that further comprises administration of daratumumab and lenalidomide, or (2) the subject has newly diagnosed multiple mye
  • a method of treating newly diagnosed multiple myeloma in a subject in need thereof comprises treating the subject according to a therapeutically effective regimen that comprises sequential 28-day BCMAxCD3 treatment cycles, wherein, if criteria (1) or (2) are met, then one or more step-up doses of teclistamab are subcutaneously administered to the subject during a step-up phase (e.g., during Cycle 1) and treatment doses of the teclistamab are subcutaneously administered to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase (e.g., starting from Cycle 2), wherein the criteria (1) or (2) are met if: (1) the subject has newly diagnosed multiple myeloma and is ineligible or not intended for ASCT as initial therapy, and the teclistamab is administered as part of a combination regimen that further comprises administration of daratumumab and lenalidomide, or (2) the subject has newly diagnosed multiple mye
  • Embodiments of the present invention also provide alternative step-up dosing regimens for a BCMAxCD3 bispecific antibody such as teclistamab, which may confine CRS events to earlier time points, potentially shortening the CRS monitoring window.
  • teclistamab demonstrated manageable safety with rapid, deep, and durable responses.
  • steps-up doses SUVs
  • 1.5 mg/kg weekly recommended phase 2 dose
  • Cytokine release syndrome occurred in 72% of patients (nearly all grade 1/2); although most events occurred during step up; 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 and 0.5 mg/kg with 2-4 days between doses) and Cohort 23 (SUDs of 0.2 and 0.7 mg/kg with 2-4 days between doses). Based on results described herein, it is believed that higher SUDs may confine CRS events to earlier time points, potentially shortening the CRS monitoring window, and facilitating prompt transition of care to the outpatient setting.
  • a method of treating multiple myeloma in a subject in need thereof comprises administering to the subject a therapeutically effective amount of any of the BCMAxCD3 bispecific antibodies described herein (e.g., teclistamab), wherein the Docket No.258199.062002 (JBI6858WOPCT1) method comprises subcutaneously administering only two step-up doses of the BCMAxCD3 bispecific antibody before subcutaneously administering a first treatment dose (e.g., a first treatment dose of 1.5 mg/kg), wherein the two step-up doses are administered either (i) in an amount of 0.1 mg/kg followed by an amount of 0.5 mg/kg, or (ii) in an amount of 0.2 mg/kg followed by an amount of 0.7 mg/kg.
  • a first treatment dose e.g., a first treatment dose of 1.5 mg/kg
  • the time between the two step-up doses is between about 2 days and about 4 days.
  • the subject may be administered treatment doses of the the BCMAxCD3 bispecific antibody according to any of the treatment dosing regimens described herein.
  • the subject has relapsed or refractory multiple myeloma.
  • the subject has previously received at least one, at least two, at least three or at least four prior lines of therapy.
  • the subject has previously received at least three or at least four prior lines of therapy.
  • the subject has previously received 1-3 prior lines of therapy, e.g., including a minimum of two consecutive cycles of daratumumab and two consecutive cycles of lenalidomide.
  • the subject has previously received 1-3 prior lines of therapy, including a proteasome inhibitor (PI) and lenalidomide.
  • the subject has previously received 1 to 4 prior lines of therapy including daratumumab and lenalidomide.
  • the subject has newly diagnosed multiple myeloma.
  • the subject has newly diagnosed multiple myeloma and is ineligible or not intended for ASCT as initial therapy.
  • a single dose of toci before teclistamab treatment reduces the incidence of CRS relative to the overall patient population with no new safety signals and no evidence of impact on response to teclistamab.
  • prophylactic toci Docket No.258199.062002 JBI6858WOPCT1 reduces CRS risk in patients with disease profiles suitable for outpatient dosing, reducing the burden of hospitalization during teclistamab step-up dosing.
  • toci is administered prior to teclistamab as a single 8 mg/kg IV dose.
  • a method of treating multiple myeloma in a subject in need thereof comprising treating the subject according to a therapeutically effective regimen that comprises sequential 28-day BCMAxCD3 treatment cycles, wherein: one or more step-up doses of a BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase, and treatment doses of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase.
  • Q4W monthly dosing schedule
  • the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising the HCDR1 of SEQ ID NO: 4, the HCDR2 of SEQ ID NO: 5, the HCDR3 of SEQ ID NO: 6, the LCDR1 of SEQ ID NO: 7, the LCDR2 of SEQ ID NO: 8 and the LCDR3 of SEQ ID NO: 9, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 14, the HCDR2 of SEQ ID NO: 15, the HCDR3 of SEQ ID NO: 16, the LCDR1 of SEQ ID NO: 17, the LCDR2 of SEQ ID NO: 18 and the LCDR3 of SEQ ID NO: 19. 3.
  • 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
  • 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.
  • the BCMAxCD3 bispecific antibody is an IgG1, an IgG2, an IgG3 or an IgG4 isotype. 5.
  • the BCMAxCD3 bispecific antibody is an IgG4 isotype. Docket No.258199.062002 (JBI6858WOPCT1) 6. The method of any of embodiments 1-5, wherein the BCMAxCD3 bispecific antibody comprises one or more substitutions in its Fc region. 7. The method of any of embodiments 1-6, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises Proline/Alanine/Alanine substitutions at amino acid positions 228/234/235, respectively, in its Fc region (according to EU index numbering). 8.
  • the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises F405L and R409K substitutions in its Fc region (according to EU index numbering).
  • 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 numbering).
  • the Fc region of the CD3 binding arm comprises Proline/Alanine/Alanine substitutions at amino acid positions 228/234/235, respectively, in addition to F405L and R409K substitutions (according to EU index numbering).
  • 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 BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 23.
  • HC1 first heavy chain having at least 90% identity to the amino acid sequence of SEQ ID NO: 12
  • LC1 having at least 90% identity to the amino acid sequence of SEQ ID NO: 13
  • a second heavy chain HC2 having at least 90% identity to the amino acid sequence of SEQ ID NO: 22
  • LC2 having at least 90% identity to the amino acid sequence of SEQ ID NO: 23.
  • the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 23. 14.
  • the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity to the amino acid Docket No.258199.062002 (JBI6858WOPCT1) sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 23. 15.
  • the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 99% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 99% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 99% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 99% identity to the amino acid sequence of SEQ ID NO: 23.
  • HC1 first heavy chain
  • LC1 first light chain
  • HC2 having at least 99% identity to the amino acid sequence of SEQ ID NO: 22
  • LC2 second light chain having at least 99% identity to the amino acid sequence of SEQ ID NO: 23.
  • each treatment dose of the BCMAxCD3 bispecific antibody that is administered to the subject on the monthly dosing schedule (Q4W) is administered in an amount of 1.5 mg/kg or 3 mg/kg. 18.
  • each treatment dose of the BCMAxCD3 bispecific antibody that is administered to the subject on the monthly dosing schedule (Q4W) is administered in an amount of 1.5 mg/kg.
  • each treatment dose of the BCMAxCD3 bispecific antibody that is administered to the subject on the monthly dosing schedule (Q4W) is administered in an amount of 3 mg/kg. 20.
  • each treatment dose of the BCMAxCD3 bispecific antibody administered to the subject on the monthly dosing schedule (Q4W) is administered on Day 1 of each BCMAxCD3 treatment cycle.
  • the regimen does not include any BCMAxCD3 treatment cycles in which the BCMAxCD3 bispecific antibody is administered to the subject on a bi-weekly dosing schedule (Q2W).
  • the step-up phase is 28 days.
  • 1-3 step-up doses of the BCMAxCD3 bispecific antibody are administered to the subject during the step-up phase. 24.
  • step-up phase comprises a first step-up dose of 0.06 mg/kg, or 0.1 mg/kg, or 0.2 mg/kg of the BCMAxCD3 bispecific antibody and a second step-up dose of 0.3 mg/kg, or 0.5 mg/kg, or 0.7 mg/kg of the BCMAxCD3 bispecific antibody.
  • step-up phase comprises a first step-up dose of 0.06 mg/kg, or 0.1 mg/kg, or 0.2 mg/kg of the BCMAxCD3 bispecific antibody and a second step-up dose of 0.3 mg/kg, or 0.5 mg/kg, or 0.7 mg/kg of the BCMAxCD3 bispecific antibody.
  • step-up phase comprises subcutaneously administering two step-up doses and three treatment doses of the BCMAxCD3 bispecific antibody.
  • step-up phase comprises subcutaneously administering two step-up doses and three treatment doses of the BCMAxCD3 bispecific antibody.
  • the one or more treatment doses of the BCMAxCD3 bispecific antibody administered during the step-up phase are administered in an amount of 0.72 mg/kg or 1.5 mg/kg or 3.0 mg/kg.
  • 33 The method of any of embodiments 27-31, wherein each of the one or more treatment doses of the BCMAxCD3 bispecific antibody administered during the step-up phase are administered in an amount of 1.5 mg/kg. 34.
  • step-up phase comprises subcutaneously administering to the subject (i) a first step-up dose of 0.06 mg/kg, a second step-up 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; or (ii) a first step-up dose of 0.1 mg/kg, a second step-up dose of 0.5 mg/kg, a first treatment dose of 1.5 mg/kg and a second treatment dose of 1.5 mg/kg; or (iii) a first step-up dose of 0.2 mg/kg, a second step-up dose of 0.7 mg/kg, a first treatment dose of 1.5 mg/kg and a second treatment dose of 1.5 mg/kg;.
  • step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg on Day 1, a second step-up 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.
  • step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg, a second step-up 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. 46.
  • the step-up phase comprises subcutaneously administering to the subject (i) a first step-up dose of 0.06 mg/kg on Day 1, a second step-up 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 step-up dose of 0.1 mg/kg on Day 1, a second step-up 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 step-up dose of 0.2 mg/kg on Day 1, a second step-up 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 each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on
  • the step-up phase comprises subcutaneously administering to the subject a first step- up dose of 0.06 mg/kg on Day 1, a second step-up 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 step-up dose of 0.1 mg/kg on Day 1, a second step-up 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 step-up dose of 0.2 mg/kg on Day 1, a second step-up 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, or (iii) a first step-up dose
  • 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 are subcutaneously administered to the subject, and a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject every 4 weeks (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase.
  • the step-up phase is 28 days and occurs in Cycle 1 of the regimen; the first dose, the second dose, the third dose and the fourth dose are administered on Day 1, Day 3, Day 8 and Day 15 of Cycle 1, respectively, and the treatment dose of 3 mg/kg is administered on Day 1 of Cycle 2 and on Day 1 of each subsequent treatment cycle thereafter. 58.
  • 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 are subcutaneously administered to the subject, and a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject every 4 weeks (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase.
  • the regimen is a combination therapy
  • the step-up phase is 28 days and occurs in Cycle 2 of the regimen
  • the first dose, the second dose, the third dose and the fourth dose of the BCMAxCD3 bispecific antibody are administered on Day 1, Day 3, Day 8 and Day 15 of Cycle 2, respectively, and the treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody is administered on Day 1 of Cycle 3 and on Day 1 of each subsequent treatment cycle thereafter.
  • the regimen is a combination therapy
  • the step-up phase is 28 days and occurs in Cycle 2 of the regimen
  • the first dose, the second dose, the third dose, the fourth dose and the fifth dose are administered on Day 1, Day 3, Day 8, Day 15 and Day 22 of Cycle 1, respectively, and the treatment dose of 3 mg/kg is administered on Day 1 of Cycle 3 and on Day 1 of each subsequent treatment cycle thereafter.
  • the regimen is a combination therapy comprising administration of the BCMAxCD3 bispecific antibody (e.g., teclistamab), daratumumab and lenalidomide.
  • the regimen comprises: for the BCMA x CD3 bispecific antibody (e.g., teclistamab): Docket No.258199.062002 (JBI6858WOPCT1) in Cycle 2, subcutaneously administering a first step-up dose of 60 ⁇ g/kg (e.g., on Day 1 or Day 2), a second step-up dose of 300 ⁇ g/kg (e.g., on Day 3 or Day 4), and then weekly (QW) doses of 1500 ⁇ g/kg (e.g., on Days 8 and 15), and in Cycle 3 and all subsequent treatment cycles, subcutaneously administering a monthly (Q4W) dose of 3000 ⁇ g/kg (e.g., on Day 1); for the daratumumab: in Cycles 1-2, subcutaneously administering 1800 mg weekly (QW) (e.g., on Days, 1, 8, 15 and 22), in Cycles 3-6, subcutaneously administering 1800 mg bi-weekly (
  • 66 The method of embodiment 65, wherein the regimen further comprises: in Cycles 1-2, orally or intravenously administering 20 mg of dexamethasone weekly (QW) (e.g., on Days 1, 8, 15 and 22).
  • QW dexamethasone weekly
  • 67 The method of any of embodiments 62-66, wherein the method achieves a decrease in new infections over time in a population of subjects with newly diagnosed multiple myeloma, compared to a population of subjects with newly diagnosed multiple myeloma that are treated with the combination therapy but receive more frequent doses of the BCMAxCD3 bispecific antibody (e.g., QW and/or Q2W) in Cycle 3 and all subsequent treatment cycles.
  • the BCMAxCD3 bispecific antibody e.g., QW and/or Q2W
  • any of embodiments 62-69 wherein the subject has newly diagnosed multiple myeloma and is ineligible for autologous stem cell transplant (ASCT) as initial therapy.
  • ASCT autologous stem cell transplant
  • 71 The method of any of embodiments 62-70, wherein the subject has newly diagnosed multiple myeloma and is not intended for autologous stem cell transplant (ASCT) as initial therapy.
  • 72 The method of any of embodiments 62-71, wherein the method achieves a clinical response in the subject that is a sCR, a CR, a VGPR, or a PR in the subject, as defined by IMWG (2016) response criteria.
  • 73 The method of any of embodiments 62-69, wherein the subject has newly diagnosed multiple myeloma and is ineligible for autologous stem cell transplant (ASCT) as initial therapy.
  • 72 The method of any of embodiments 62-71, wherein the method achieves a clinical response in the subject that is a sCR,
  • any of embodiments 62-75 wherein the method achieves a CR or better (i.e., a sCR or a CR), as defined by IMWG (2016) response criteria, in at least 60%, or at least 65%, or at least 70% of subjects in a population with newly diagnosed multiple myeloma that are ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy.
  • a CR or better i.e., a sCR or a CR
  • ASCT autologous stem cell transplant
  • any of embodiments 62-76 wherein the method achieves a rate of sustained MRD-negative CR ( ⁇ 12 months) 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 that are ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy after about 50 months of treatment with the combination therapy.
  • a rate of sustained MRD-negative CR ⁇ 12 months
  • mPFS median progression-free survival
  • ASCT autologous stem cell transplant
  • mPFS median overall survival
  • ASCT autologous stem cell transplant
  • mOS is greater than the reference mOS by at least 1 year, or at least 2 years, or at least 3 years, or at least 4 years.
  • 82. The method of any of embodiments 62-81, wherein the method achieves a rate of sustained MRD-negative CR ( ⁇ 12 months) in a population of subjects with newly diagnosed multiple myeloma that are ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy, wherein said rate of sustained MRD-negative CR ( ⁇ 12 months) is greater than a reference rate of sustained MRD-negative CR ( ⁇ 12 months) achieved in a reference population of subjects with newly diagnosed multiple myeloma who are either ineligible or not intended for 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., teclistamab
  • the regimen is a combination therapy comprising administration of the BCMAxCD3 bispecific antibody (e.g., teclistamab), daratumumab and lenalidomide.
  • administration of the daratumumab starts in Cycle 1
  • administration of the BCMAxCD3 bispecific antibody starts in Cycle 1
  • administration of the lenalidomide starts in Cycle 2
  • one or more step-up doses and at least one treatment dose of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase in Cycle 1
  • a treatment dose of the BCMAxCD3 bispecific antibody is subcutaneously administered to the subject monthly (Q4W) starting in Cycle 2.
  • the regimen further comprises: in Cycles 2 and 3 only, orally or intravenously administering dexamethasone to the subject.
  • the regimen comprises: for the BCMA x CD3 bispecific antibody (e.g., teclistamab): in Cycle 1, subcutaneously administering a first step-up dose of 60 ⁇ g/kg (e.g., on Day 2), a second step-up dose of 300 ⁇ g/kg (e.g., on Day 4), and then weekly (QW) doses of 1500 ⁇ g/kg (e.g., on Days 8 and 15), and Docket No.258199.062002 (JBI6858WOPCT1) in Cycle 2 and all subsequent treatment cycles, subcutaneously administering a monthly (Q4W) dose of 3000 ⁇ g/kg (e.g., on Day 1); for the daratumumab: in Cycles 1-2, subcutaneously administering 1800
  • 89 The method of embodiment 88, wherein the regimen further comprises: in Cycles 2-3, orally or intravenously administering 20 mg of dexamethasone weekly (QW) (e.g., on Days 1, 8, 15 and 22).
  • QW dexamethasone weekly
  • 90 The method of any of embodiments 85-89, wherein the subject has newly diagnosed multiple myeloma and is either ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy.
  • ASCT autologous stem cell transplant
  • 91 The method of any of embodiments 85-89, wherein the subject has newly diagnosed multiple myeloma and is ineligible for autologous stem cell transplant (ASCT) as initial therapy.
  • ASCT autologous stem cell transplant
  • any of embodiments 85-89 wherein the subject has newly diagnosed multiple myeloma and is not intended for autologous stem cell transplant (ASCT) as initial therapy.
  • ASCT autologous stem cell transplant
  • 93 The method of any of embodiments 85-92, wherein the method achieves a clinical response in the subject that is a sCR, a CR, a VGPR, or a PR in the subject, as defined by IMWG (2016) response criteria.
  • 94 The method of any of embodiments 85-92, wherein the method achieves a CR, VGPR, or PR in the subject, as defined by IMWG (2016) response criteria. 95.
  • any of embodiments 85-96 wherein the method achieves a CR or better (i.e., a sCR or a CR), as defined by IMWG (2016) response criteria, in at least 60%, or at least 65%, or at least 70% of subjects in a population with newly diagnosed multiple myeloma that are ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy.
  • a CR or better i.e., a sCR or a CR
  • ASCT autologous stem cell transplant
  • any of embodiments 85-97 wherein the method achieves a rate of sustained MRD-negative CR ( ⁇ 12 months) 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 that are ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy after about 50 months of treatment with the combination therapy.
  • a rate of sustained MRD-negative CR ⁇ 12 months
  • mPFS median progression-free survival
  • ASCT autologous stem cell transplant
  • mPFS median overall survival
  • ASCT autologous stem cell transplant
  • any of embodiments 85-102 wherein the method achieves a rate of sustained MRD-negative CR ( ⁇ 12 months) in a population of subjects with newly diagnosed multiple myeloma that are ineligible or not intended for autologous stem cell transplant (ASCT) as initial therapy, wherein said rate of sustained MRD-negative CR ( ⁇ 12 months) is greater than a reference rate of sustained MRD-negative CR ( ⁇ 12 months) achieved in a reference population of subjects with newly diagnosed multiple myeloma who are either ineligible or not intended for 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., teclistamab), daratumumab, and lenalidomide.
  • the BCMA x CD3 bispecific antibody e.g., teclistamab
  • daratumumab e.g.,
  • step-up phase occurs in Cycle 1 and comprises subcutaneously administering to the subject one or more step-up doses of the BCMAxCD3 bispecific antibody followed by one or more 1.5 mg/kg doses of the BCMAxCD3 bispecific antibody on a QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • step-up phase comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg on Day 1, a second step-up 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 of the BCMAxCD3 bispecific antibody; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule). 121.
  • any of embodiments 121-124 wherein the lenalidomide is administered in an amount of 10 mg once daily and may be increased to 15 mg once daily on Cycle 5 Day 1 if 10 mg was tolerated by the subject.
  • the BCMAxCD3 bispecific antibody is administered for a finite duration of 26 cycles.
  • the BCMAxCD3 bispecific antibody is administered for a finite duration of 13 cycles. 128.
  • a CR or better i.e., a sCR or a CR
  • 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 that have previously received autologous stem cell transplant (ASCT).
  • ASCT autologous stem cell transplant
  • PFS progression-free survival
  • CR 12-month MRD-negative complete response
  • the subject is administered a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), and one or more additional antimyeloma agents, as an induction therapy.
  • a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), and one or more additional antimyeloma agents, as an induction therapy.
  • any of embodiments 135-138 wherein the subject is administered multiple cycles of the BCMAxCD3 bispecific antibody (e.g., teclistamab), and optionally one or more additional antimyeloma agents, as an induction therapy.
  • the subject is administered a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), and one or more additional antimyeloma agents selected from the group consisting of daratumumab, lenalidomide, dexamethasone, and any combination thereof, as an induction therapy.
  • a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), and one or more additional antimyeloma agents selected from the group consisting of daratumumab, lenalidomide, dexamethasone, and any combination thereof, as an induction therapy.
  • any of embodiments 135-140 wherein the subject is administered a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), daratumumab, lenalidomide, and dexamethasone, as an induction therapy.
  • a combination therapy comprising the BCMAxCD3 bispecific antibody (e.g., teclistamab), daratumumab, and lenalidomide, as an induction therapy.
  • the first cycle comprises subcutaneously administering to the subject one or more step-up doses of the BCMAxCD3 bispecific antibody followed by one or more 1.5 mg/kg doses of the BCMAxCD3 bispecific antibody; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • the first cycle comprises subcutaneously administering to the subject one or more step-up doses of the BCMAxCD3 bispecific antibody followed by one or more 1.5 mg/kg doses of the BCMAxCD3 bispecific antibody
  • each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • the first cycle comprises subcutaneously administering to the subject one or more step-up doses of the BCMAxCD3 bispecific antibody followed by one or more 1.5 mg/kg doses of the BCMAxCD3 bispecific antibody on a QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • the first cycle comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg on Day 1, a second step-up 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 of the BCMAxCD3 bispecific antibody; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a Docket No.258199.062002 (JBI6858WOPCT1) treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule). 151.
  • the method of embodiment 151 or 152, wherein the maintenance therapy comprises 6-20 treatment cycles.
  • the maintenance therapy comprises 12-18 treatment cycles.
  • the maintenance therapy comprises 12 treatment cycles.
  • the first cycle comprises subcutaneously administering to the subject one or more step-up doses of the BCMAxCD3 bispecific antibody followed by one or more 1.5 mg/kg doses of the BCMAxCD3 bispecific antibody; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule). 157.
  • the first cycle comprises subcutaneously administering to the subject one or more step-up doses of the BCMAxCD3 bispecific antibody followed by one or more 1.5 mg/kg doses of the BCMAxCD3 bispecific antibody on a QW dosing schedule; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • the first cycle comprises subcutaneously administering to the subject a first step-up dose of 0.06 mg/kg on Day 1, a Docket No.258199.062002 (JBI6858WOPCT1) second step-up 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 of the BCMAxCD3 bispecific antibody; and each subsequent BCMAxCD3 treatment cycle comprises subcutaneously administering a treatment dose of 3 mg/kg of the BCMAxCD3 bispecific antibody on Day 1 (i.e., on the Q4W dosing schedule).
  • a method of treating multiple myeloma in a subject in need thereof comprising treating the subject according to a therapeutically effective regimen that comprises sequential 28-day BCMAxCD3 treatment cycles, wherein, if criteria (1)-(4) are met, then one or more step-up doses of teclistamab are subcutaneously administered to the subject during a step-up phase (e.g., during Cycle 1) and treatment doses of the teclistamab are subcutaneously administered to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase (e.g., starting from Cycle 2), wherein the criteria (1)-(4) are met if (1) the subject has newly diagnosed multiple myeloma and is ineligible or not intended for ASCT as initial therapy, and the teclistamab is administered as part of a combination regimen that further comprises administration of daratumumab and lenalidomide, or (2) the subject has newly diagnosed multiple myeloma, and the teclistam
  • a method of treating newly diagnosed multiple myeloma in a subject in need thereof comprising treating the subject according to a therapeutically effective regimen that comprises sequential 28-day BCMAxCD3 treatment cycles, wherein, if criteria (1)-(3) are met, then one or more step-up doses of teclistamab are subcutaneously administered to the subject during a step-up phase (e.g., during Cycle 1) and treatment doses of the teclistamab are subcutaneously administered to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase (e.g., starting from Cycle 2), wherein the criteria (1)-(3) are met if: (1) the subject has newly diagnosed multiple myeloma and is ineligible or not intended for ASCT as initial therapy, and the teclistamab is administered as part of a combination regimen that further comprises administration of Docket No.258199.062002 (JBI6858WOPCT1) daratumumab and len
  • a method of treating newly diagnosed multiple myeloma in a subject in need thereof comprising treating the subject according to a therapeutically effective regimen that comprises sequential 28-day BCMAxCD3 treatment cycles, wherein, if criteria (1) or (2) are met, then one or more step-up doses of teclistamab are subcutaneously administered to the subject during a step-up phase (e.g., during Cycle 1) and treatment doses of the teclistamab are subcutaneously administered to the subject on a monthly dosing schedule (Q4W) starting from the first BCMAxCD3 treatment cycle after the step-up phase (e.g., starting from Cycle 2), wherein the criteria (1) or (2) are met if: (1) the subject has newly diagnosed multiple myeloma and is ineligible or not intended for ASCT as initial therapy, and the teclistamab is administered as part of a combination regimen that further comprises administration of daratumumab and lenalidomide, or (2) the subject has newly diagnosed multiple myeloma, and
  • step-up phase comprises administering only two step-up doses of the BCMAxCD3 bispecific antibody (e.g., teclistamab) before administering a first treatment dose, wherein the two step-up doses are administered either (i) in an amount of 0.1 mg/kg followed by an amount of 0.5 mg/kg, or (ii) in an amount of 0.2 mg/kg followed by an amount of 0.7 mg/kg. 164.
  • BCMAxCD3 bispecific antibody e.g., teclistamab
  • a method of treating multiple myeloma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a BCMAxCD3 bispecific antibody (e.g., teclistamab), wherein the method comprises subcutaneously administering only two step-up doses of the BCMAxCD3 bispecific antibody before subcutaneously administering a first treatment dose, wherein the two step-up doses are administered either (i) in an amount of 0.1 mg/kg followed by an amount of 0.5 mg/kg, or (ii) in an amount of 0.2 mg/kg followed by an amount of 0.7 mg/kg. 165.
  • a BCMAxCD3 bispecific antibody e.g., teclistamab
  • the method of embodiment 164 wherein the two step-up doses are administered in an amount of 0.1 mg/kg followed by an amount of 0.5 mg/kg. Docket No.258199.062002 (JBI6858WOPCT1) 166.
  • the method of embodiment 164, wherein the two step-up doses are administered in an amount of 0.2 mg/kg followed by an amount of 0.7 mg/kg. 167.
  • the method of any of embodiments 163-166, wherein the time between the two step-up doses is between about 2 days and about 4 days. 168.
  • PI proteasome inhibitor
  • Example 1 A Phase 3 Randomized Study Comparing Teclistamab in Combination with Daratumumab SC and Lenalidomide (Tec-DR) versus Daratumumab SC, Lenalidomide, and Dexamethasone (DRd), and Talquetamab in Combination with Daratumumab SC and Lenalidomide (Tal-DR) versus DRd, in Patients with Newly Diagnoses Multiple Myeloma Who are Either Ineligible or not Intended for Autologous Stem Cell Transplant as Initial Therapy (MajesTEC-7) [0317] A Phase 3 randomized study comparing teclistamab in combination with daratumumab SC and lenalidomide (Tec-DR) versus daratumumab SC, lenalidomide, and dexamethasone (DRd), and Talquetamab in Combination with Daratumumab SC and Lenalidomide (Tal-DR) versus DRd, will be carried out (NCT0555
  • the Tal-DR arm of the study was added after initiation of the safety run-in phase of the study.
  • the overall aim is to compare the efficacy between Tec-DR and DRd, and Tal-DR and DRd, in terms of PFS (progression-free survival, which refers to duration from the date of randomization to either progressive disease or death, whichever comes first) and minimal residual disease (MRD)- negative complete response (CR).
  • PFS progression-free survival, which refers to duration from the date of randomization to either progressive disease or death, whichever comes first
  • MRD minimal residual disease
  • CR minimal residual disease
  • Antibodies [0319] Anti-BCMA/anti-CD3 antibody teclistamab (also called Tec) (e.g., described in WO2017031104A1, the content of which is incorporated herein by reference in its entirety) was made by Janssen Pharmaceuticals.
  • Teclistamab comprises a BCMA binding arm BCMB69 and a CD3 binding arm CD3B219, the amino acid sequences of which are shown in Table 5 and Table 6, respectively.
  • Table 5 Sequences of BCMA binding arm of Teclistamab Region Sequence SEQ ID NO: BCMB69 HCDR1 SGSYFWG 4 HCDR2 SIYYSGITYYNPSLKS 5 HCDR3 HDGAVAGLFDY 6 LCDR1 GGNNIGSKSVH 7 Docket No.258199.062002 (JBI6858WOPCT1) LCDR2 DDSDRPS 8 LCDR3 QVWDSSSDHVV 9 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSGSY 10 FWGWIRQPPGKGLEWIGSIYYSGITYYNPSLKS RVTISVDTSKNQFSLKLSSVTAADTAVYYCAR HDGAVAGLFDYWGQGTLVTVSS VL SYVLTQPPSVSVAPGQTARITCGGN
  • x To explore the relationship between MRD negativity with duration and depth of clinical response in participants treated with Tec-DR and DRd. x To explore predictive biomarkers of response and resistance, including prognostic and disease markers at baseline, during treatment, and in relation to efficacy parameters x To identify patient subgroups that could respond differently to Tec-DR and DRd.
  • Tec-DR cohorts varying doses of Teclistamab (Tec) are administered with a constant dose of daratumumab (dara), lenalidomide (len), and dexamethasone.
  • Tec-DR cohorts constant doses of daratumumab (dara), lenalidomide (len), and dexamethasone are administered.
  • JBI6858WOPCT1 JBI6858WOPCT1
  • teclistamab fixed dosing subjects are stratified into two cohorts based on weight.
  • Teclistamab SC 100 mg is administered weekly for the second treatment cycle, followed by 200 mg Q2W starting at treatment cycle 3, and 200 mg Q4W starting at treatment cycle 7.
  • Tec SC 150 mg is administered weekly for the second treatment cycle, followed by 300 mg Q2W starting at treatment cycle 3, and 300 mg Q4W starting at treatment cycle 7.
  • - Daratumumab is administered to all subjects by SC injection at a dose of 1800 mg with 30000 units hyaluronidase to decrease injection volume required.
  • Daratumumab SC is administered weekly in treatment cycles 1 and 2, Q2W in treatment cycles 3-6, and Q4W thereafter.
  • - Lenalidomide is administered orally at 25 mg every day for 21 days of a 28- day treatment cycle. Lenalidomide treatment started at treatment cycle 2.
  • dexamethasone is administered orally or intravenously at 20 mg weekly.
  • dexamethasone is administered during treatment cycles 2, 3, and 4.
  • dexamethasone is administered at 40 mg, or if the participant is greater than 75 years of age or has a BMI less than 18.5 dexamethasone is administered at a dose of 20 mg.
  • dexamethasone is administered weekly for all cycles. - When daratumumab and teclistamab are administered on the same day, daratumumab is administered first. Step-up dose 1 of teclistamab is administered at least 20 hours after daratumumab SC. The first treatment dose of teclistamab is administered 3 hours after daratumumab. Subsequent treatment doses of teclistamab are administered at least 15 minutes after daratumumab SC.
  • the treatment also includes required and optional pretreatment medications.
  • the pretreatment medications include dexamethasone (glucocorticoid), IV or Docket No.258199.062002 (JBI6858WOPCT1) oral.
  • Dexamethasone is administered at 16 mg on days 1, 2, 4 and 8 of treatment cycle 1.
  • Dexamthasone is administered approximately 1 to 3 hours prior to daratumumab SC or teclistamab SC on days on which daratumumab SC is not administered.
  • Additional pretreatment medications include diphenhydramine (anti-histamine) or an equivalent and acetaminophen (antipyretic).
  • Diphenhydramine is administered at 25 mg to 50 mg on all days daratumumab SC is administered, on days of all step-up doses and first treatment dose of teclistamab SC.
  • Diphenhydramine is administered IV or oral 1 to 3 hours prior to daratumumab SC or teclistamab SC.
  • Acetaminophen is administered at 650 mg to 1000 mg on all days daratumumab SC is administered, on days of all step-up doses and first treatment dose of teclistamab SC.
  • Acetaminophen is administered IV or oral 1 to 3 hours prior to daratumumab SC or teclistamab SC.
  • montelukast (10 mg) may be administered at the discretion of the examiner prior to administration of daratumumab.
  • pretreatment medications should be given prior to daratumumab SC. If there are greater than 4 hours between administration of study drugs, a repeat dose of dexamethasone 8 mg must be given prior to the bispecific antibody.
  • a participant treated with Tec-DR who experiences Grade ⁇ 2 CRS/sARR related to teclistamab or daratumumab SC must receive dexamethasone 16 mg, diphenhydramine 25 to 50 mg or equivalent, and acetaminophen 650 to 1000 mg as pretreatment medication for at least the subsequent dose of the study drug to which the event was related.
  • dexamethasone doses scheduled as background treatment for Cycles 2-4 in participants treated with Tec-DR can be used as event-driven pretreatment medication.
  • the dual primary endpoints are PFS and minimal residual disease (MRD)-negative complete response (CR) sustained for at least 12 months. Secondary endpoints include rate of CR or better, overall survival, rate of MRD-negative CR, rate of very good partial response or better, PFS2, patient-reported outcomes, and adverse events (AEs). Response will be assessed using 2016 International Myeloma Working Group criteria. AEs will be graded by Common Terminology Criteria for AEs v5.0, except for cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, which will be graded by American Society for Transplantation and Cellular Therapy guidelines. Results from this trial will provide insights into a possible new treatment regimen (Tec-DR) for patients with NDMM, which may provide improved outcomes.
  • MRD minimal residual disease
  • CR complete response
  • Secondary endpoints include rate of CR or better, overall survival, rate of MRD-negative CR, rate of very good partial response or better, PFS2, patient-reported outcomes, and adverse events (AEs). Response will be
  • Tec-DR SRI 1 The study treatment that was administered for the Tec-DR Safety Run-In Cohort 1 (Tec-DR SRI 1) is provided in Table 8. Participants enrolled in Safety Run-in Cohort 1 were initially treated with fixed dose teclistamab in combination with DR. Following implementation of a protocol amendment, due to a safety measure, all participants treated with fixed dose teclistamab were transitioned to weight-based teclistamab. Table 8.
  • Dose Schedule Teclistamab SC C2 2 step-up doses (0.06 and 0.3 mg/kg) on Days 1 and 3 followed by treatment doses (1.5 mg/kg) on Days 8 and 15 C3+: Q4W treatment doses (3 mg/kg) on Day 1
  • Dexamethasone oral/IV 20 mg C1-2: weekly on Days 1, 8, 15, and 22 * Lenalidomide dose may need to be adjusted for participants with renal insufficiency as determined by CrCl.
  • teclistamab will be given after a DR lead-in cycle, and at a reduced frequency (Q4W) after the step-up phase is complete.
  • the early reduction in frequency of teclistamab (Q4W dosing at Cycle 3) was implemented with the aim of reducing the rate of severe infections.
  • the teclistamab SC dose schedule for Safety Run-in Cohort 2 of the study will include 2 step-up doses (0.06 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 starting from Cycle 3.
  • the dosing schedule in the Randomized Part minimizes exposure to Tec and optimizes tolerability and safety for participants by completing step-up dosing in Cycle 1 and transitioning to monthly dosing in Cycle 2.
  • Teclistamab and daratumumab will be initiated in Cycle 1 and lenalidomide added in Cycle 2 after the step-up phase.
  • the less frequent (i.e., Q4W) dosing implemented in SRI2 to mitigate infection is retained.
  • the teclistamab SC dose schedule for the Updated Randomized Part of the study will include 2 step-up doses (0.06 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.
  • Inclusion Criteria include the following: x Must have a new diagnosis of multiple myeloma according to IMWG criteria and have received induction +/- consolidation. x Must have received only one line of therapy and achieved at least a partial response ( ⁇ PR) as per IMWG 2016 response criteria (Kumar 2016) without evidence of progression at the time of first treatment dose. x Must not be intolerant to the starting dose of lenalidomide. x Must not have received any maintenance therapy. x Have an ECOG performance status score of 0, 1, or 2 at screening and immediately prior to the start of administration of study treatment x Have clinical laboratory values within prespecified range. [0349] Exclusion Criteria include the following: x Received any prior BCMA-directed therapy.
  • x Any previous therapy with an immune cell redirecting agent or gene modified adoptive cell therapy (eg, chimeric antigen receptor modified T cells, NK cells). x Discontinued treatment due to any AE related to lenalidomide as determined by the investigator. x Progressed on multiple myeloma therapy at any time prior to screening. x Received a cumulative dose of corticosteroids equivalent to ⁇ 140 mg of prednisone within the 14 days prior to first treatment dose. x Received a live, attenuated vaccine within 4 weeks before first treatment dose. Non- live vaccines or non-replicating authorized for emergency use (eg. COVID-19) are allowed.
  • an immune cell redirecting agent or gene modified adoptive cell therapy eg, chimeric antigen receptor modified T cells, NK cells.
  • MajesTEC-4/EMN30 is a multicenter, randomized, open-label, Phase 3 study evaluating Tec-Len, Tec, and Len maintenance therapy in NDMM after induction and ASCT, ⁇ consolidation.
  • Objectives and Endpoints [0352] The primary objective of this study is to compare the efficacy of teclistamab in combination with lenalidomide (Tec-Len) with that of lenalidomide monotherapy (Len), and the efficacy of teclistamab monotherapy (Tec) with that of lenalidomide monotherapy (Len) in the maintenance setting, as assessed by PFS and 12-month MRD-negative CR.
  • SRI1 Safety Run-In Cohorts
  • SRI2 includes 2 cohorts, one with Tec-Len (SRI2 Tec-Len) and one with Tec (SRI2 Tec).
  • a safety evaluation was performed after at least 20 participants received at least 2 cycles of treatment and recommended to proceed to the randomized portion of the study.
  • Tec-Len Arm A
  • Len Arm B
  • Tec Arm C
  • Participants will receive study treatment continuously for 2 years Docket No.258199.062002 (JBI6858WOPCT1) or until confirmed progressive disease, death, intolerable toxicity, or consent withdrawal, whichever occurs first.
  • Participants receiving Tec-Len in SRI1, Tec-Len in SRI2, and in Arm A who achieve a confirmed CR or better after 13 cycles of treatment will discontinue teclistamab but continue lenalidomide for the second year.
  • Study treatment is administered on 28-day cycles for SRI1, SRI2, Tec-Len (Arm A), Len (Arm B), and Tec (Arm C). Treatment continues for 2 years (ie, 26 cycles). Participants in SRI1 were treated with both weight-based and fixed dose teclistamab in combination with lenalidomide per the protocol amendment(s) approved during their enrollment and participation and have all switched to the weight-based dosing schedule as detailed below. Participants in SRI2 are treated with weight-based SC teclistamab in combination with lenalidomide or teclistamab alone. Similarly, teclistamab in the randomized portion of the study will be administered SC using a weight-based dose schedule as detailed in Table F below.
  • Table F Dose Schedules Treatment Cycle Dose Schedule (28-day cycle) Teclistamab SC (SRI1) Cycle 1 Step-up Dose 1: 0.06 mg/kg on Day 1 Step-up Dose 2: 0.3 mg/kg on Day 3 Treatment Dose: 1.5 mg/kg on Days 8, 15, and 22 Cycle 2 Treatment Dose: 1.5 mg/kg weekly on Days 1, 8, 15, and 22 Cycle 3-6 Treatment Dose: 3 mg/kg Q2W on Days 1 and 15 Cycle 7-26 a Treatment Dose: 3 mg/kg Q4W on Day 1 Teclistamab SC Cycle 1 Step-up Dose 1: 0.06 mg/kg on Day 1 (SRI2, Arm A, and Step-up Dose 2: 0.3 mg/kg on Day 3 Arm C) Treatment Dose: 1.5 mg/kg on Days 8 and 15 Cycle 2-26 a Treatment Dose: 3 mg/kg Q4W on Day 1 Lenalidomide PO Cycle 2-4 10 mg daily for 28 days (SRI1, SRI2 Tec-Len Cycle 5-
  • AEs Adverse events
  • CRS Cytokine release syndrome
  • ICANS immune effector cell-associated neurotoxicity syndrome
  • the overall CRS rate was 43.6%, with 6.4% Grade 2 and no high-grade events.
  • the CRS rate following the first treatment dose of Tec (1.5 mg/kg) was low at 7.4%.
  • No ICANS were reported.
  • TEAEs led to treatment discontinuations in 2 pts (1 each in Cohorts 2 and 3) and death in 1 pt (Cohort 2; due to COVID-19 during C1, prior to the start of Len).
  • all 28 pts with MRD assessments at 12 mo were in MRD negative CR.
  • MRD positive pts at study entry 10 (100%) converted to MRD negative CR during treatment.
  • Example 3 Higher Teclistamab Step-up Dosing in Patients With Relapsed or Refractory Multiple Myeloma (RRMM): Results From the MajesTEC-1 Trial [0361] In the phase 1/2, single-arm MajesTEC-1 study, teclistamab demonstrated manageable safety with rapid, deep, and durable responses. In MajesTEC-1, patients received step-up doses (SUDs) of 0.06 and 0.3 mg/kg followed by 1.5 mg/kg weekly (recommended phase 2 dose). Cytokine release syndrome (CRS) occurred in 72% of patients (nearly all grade 1/2); although most events occurred during step up; 24% of patients experienced CRS after the first treatment dose.
  • SSDs step-up doses
  • CRS Cytokine release syndrome
  • CRS events occurred primarily during SUDs. Median onset of CRS through Cycle 1 Day 1 was 2.0 days in Cohort 22 and 2.5 days in Cohort 23; median event duration was 2 days in both cohorts. All CRS events resolved, and none led to treatment discontinuation.
  • Rates of CRS in the higher SUD cohorts were similar to those with the RP2D; all events were grade 1/2, most occurred after the first SUD (including both grade 2 events in Cohort 23), and none led to treatment discontinuation. No new safety signals were observed compared with the RP2D SUDs.

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Abstract

Des modes de réalisation de la présente invention concernent des méthodes de traitement du myélome multiple chez un sujet en ayant besoin, comprenant l'administration au sujet d'un anticorps bispécifique BCMAxCD3 selon un schéma posologique mensuel.
PCT/US2024/053808 2023-11-01 2024-10-31 Méthodes de traitement du myélome multiple Pending WO2025096717A1 (fr)

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