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WO2025094107A1 - Méthodes de traitement du myélome multiple indolent à haut risque - Google Patents

Méthodes de traitement du myélome multiple indolent à haut risque Download PDF

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Publication number
WO2025094107A1
WO2025094107A1 PCT/IB2024/060769 IB2024060769W WO2025094107A1 WO 2025094107 A1 WO2025094107 A1 WO 2025094107A1 IB 2024060769 W IB2024060769 W IB 2024060769W WO 2025094107 A1 WO2025094107 A1 WO 2025094107A1
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Prior art keywords
treatment
doses
bispecific antibody
dose
bcmaxcd3
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Rachel KOBOS
Irene GHOBRIAL
Omar Nadeem
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype

Definitions

  • Smoldering multiple myeloma is a precursor disease state that precedes the development of symptomatic multiple myeloma, which is a cancer of the plasma cells.
  • Patients with SMM usually do not have symptoms but are at risk for progressing to active multiple myeloma (MM).
  • Treatment options for multiple myeloma have improved overtime; however, despite recent therapeutic achievements, multiple myeloma remains an incurable malignancy with significant morbidity and mortality.
  • There are currently no approved therapies for SMM and there remains a need for safe and effective treatment options, in particular for patients with high-risk smoldering multiple myeloma (HR-SMM), who are at high risk of developing active multiple myeloma.
  • HR-SMM high-risk smoldering multiple myeloma
  • a method of treating high-risk smoldering multiple myeloma comprising administering to the subject a therapeutically effective amount of a BCMAxCD3 bispecific antibody (e.g., teclistamab).
  • 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, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.
  • the BCMAxCD3 bispecific antibody is an IgGl, an IgG2, an IgG3 or an IgG4 isotype.
  • the BCMAxCD3 bispecific antibody is an IgG4 isotype.
  • the BCMAxCD3 bispecific antibody comprises one or more substitutions in its Fc region.
  • 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).
  • 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.
  • 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.
  • the subject has not received prior SMM directed therapy.
  • the BCMAxCD3 bispecific antibody is administered as a monotherapy (i.e., without another concurrent SMM directed therapy).
  • the method comprises subcutaneously administering each dose of the BCMAxCD3 bispecific antibody.
  • the method comprises treating the subject according to a therapeutically effective regimen that comprises sequential 28-day BCMAxCD3 treatment cycles.
  • the method comprises administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering a first step-up dose of 0.06 mg/kg (e.g., on Day 1), a second step-up dose of 0.3 mg/kg (e.g., on Day 3), and then weekly (QW) treatment doses of 1.5 mg/kg (e.g., on Days 8, 15 and 22), in Cycle 2, subcutaneously administering weekly (QW) doses of 1.5 mg/kg (e.g., on Days 1, 8, 15 and 22), in Cycles 3-6, subcutaneously administering bi-weekly (Q2W) doses of 3 mg/kg (e.g., on Days 1 and 15); and starting in Cycle 7 (e.g., in Cycles 7-12 or Cycles 7-24), subcutaneously administering monthly (Q4W) doses of 3 mg/kg (e.g.,
  • the regimen comprises: in Cycle
  • the method achieves a clinical response in the subject that is a partial response (PR), a very good partial response (VGPR), a complete response (CR) or a stringent complete response (sCR), as defined by IMWG (2016) response criteria.
  • PR partial response
  • VGPR very good partial response
  • CR complete response
  • sCR stringent complete response
  • the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM of 70% or higher. In certain embodiments, the method achieves an overall response rate (ORR) in a population of subjects with HR- SMM of 75% or higher. In certain embodiments, the method comprises the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM of 80% or higher. In certain embodiments, the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM of 85% or higher. In certain embodiments, the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM of 90% or higher.
  • the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM of 95% or higher. In certain embodiments, the method achieves an overall response rate (ORR) of 100% in a population of subjects with HR-SMM.
  • the method achieves a CR in at least 25% of a population of subjects with HR-SMM. In certain embodiments, the method achieves a CR in at least 30% of a population of subjects with HR-SMM. In certain embodiments, the method achieves a CR in at least 35% of a population of subjects with HR-SMM. In certain embodiments, the method achieves a CR in at least 40% of a population of subjects with HR-SMM.
  • the method achieves MRD-negative disease in the subject.
  • the subject after the subject has received at least four 28-day cycles of treatment with the BCMAxCD3 bispecific antibody, the subject’s HR-SMM does not progress.
  • administration of the BCMAxCD3 bispecific antibody to the subject for a maximum of twenty-four (24) 28-day treatment cycles prevents the subject from developing multiple myeloma.
  • administration of the BCMAxCD3 bispecific antibody to the subject for a maximum of twelve (12) 28-day treatment cycles prevents the subject from developing multiple myeloma.
  • the method cures the HR-SMM and prevents the subject from developing MM.
  • the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM that is greater than an ORR achieved in a reference population of subjects with HR-SMM, said reference population having been administered lenalidomide and dexamethasone but not the BCMAxCD3 bispecific antibody.
  • ORR overall response rate
  • the method achieves a percentage of complete responses (CRs) in a population of subjects with HR-SMM that is greater than a percentage of CRs achieved in a reference population of subjects with HR-SMM, said reference population having been administered lenalidomide and dexamethasone but not the BCMAxCD3 bispecific antibody.
  • “About’’ when used in reference to numerical ranges, cutoffs, or specific values means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of an assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.
  • 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 CHI, 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 IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4.
  • Antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa (K) and lambda (X), based on the amino acid sequences of their constant domains.
  • K kappa
  • X lambda
  • 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.
  • dAb domain antibodies
  • 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. W01998/44001, WO1988/01649, WO1994/13804 and WO 1992/01047.
  • scFv single chain Fv
  • BCMA refers to human B-cell maturation antigen, also known as CD269 or TNFRSF17 (UniProt Q02223).
  • the extracellular domain of BCMA encompasses residues 1-54 of Q02223.
  • Human BCMA comprises the amino acid sequence of SEQ ID NO: 1
  • Bispecific antibody refers to an antibody that specifically binds two distinct antigens.
  • 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 Maccicci cynomolgus (cynomolgus, cyno) or 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. Unregulated cell division and growth results in the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream.
  • a “cancer” or “cancer tissue” can include a tumor.
  • 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.
  • Human CD3 epsilon comprises the amino acid sequence of SEQ ID NO: 2.
  • SEQ ID NO: 3 shows the extracellular domain of CD3 epsilon.
  • CH3 region or “CH3 domain” refers to the CH3 region of an immunoglobulin.
  • the CH3 region of human IgGl antibody corresponds to amino acid residues 341-446.
  • the CH3 region can also be any of the other antibody isotypes as described herein.
  • CDR complementarity determining regions
  • CDR CDR
  • HCDR1 CDR1
  • HCDR2 CDR3
  • LCDR1 CDR2
  • LCDR3 CDR3
  • Fc gamma receptor refers to well-known FcyRI, FcyRIIa, FcyRIIb or FcyRIII. Activating FcyR includes FcyRI, FcyRIIa and FcyRIII.
  • 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 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. W02009/085462.
  • 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 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 naive 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% (IO -4 ), 0.001% (10 -5 ) or 0.0001% (10‘ 6 ). Negative minimal residual disease status can be determined using next generation sequencing (NGS).
  • NGS next generation sequencing
  • “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.
  • Refractory multiple myeloma refers to disease that is non-responsive to therapy or stops responding to therapy.
  • 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 the 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 therapeutic is administered to the subject.
  • a step-up phase may also include one or more treatment doses, z.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, z.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” or “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. This dual/multi-target binding ability recruits T cells to the target cell or tissue leading to the eradication of the target cell or tissue.
  • “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.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • 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 one or more step-up doses.
  • 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. These changes do not necessarily involve the uptake of new genetic material. Although transformation can arise from infection with a transforming virus and incorporation of new genomic nucleic acid, uptake of exogenous nucleic acid or it can also arise spontaneously or following exposure to a carcinogen, thereby mutating an endogenous gene.
  • 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.
  • the goal of therapy in high-risk SMM should be to deliver as highly effective therapy as possible to ultimately achieve cure or significant delay in progression-free survival (PFS) without compromising safety.
  • PFS progression-free survival
  • the present inventors have developed novel methods for treating high-risk SMM using BCMAxCD3 bispecific antibodies, which provide significant efficacy compared to patients with relapsed/refractory multiple myeloma that receive the same therapy.
  • Teclistamab (marketed 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.
  • BCMA bispecific B-cell maturation antigen
  • teclistamab The efficacy 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]).
  • the study has included patients who previously received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.
  • 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.
  • AEs hematologic adverse events
  • neutropenia 64.2 percent
  • anemia 37 percent
  • lymphopenia 32.7 percent
  • thrombocytopenia 21.2 percent
  • Infections occurred in 76.4 percent of patients (44.8 percent grade 3/4).
  • CRS cytokine release syndrome
  • any suitable BCMAxCD3 bispecific antibody known to those skilled in the art in view of the present disclosure can be used.
  • 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 (Medlmmune/AZ) and BsAb (Zymogenetics), HERCULES (Biogen personal) 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) (Immun
  • the BCMAxCD3 bispecific antibody comprises any one of the BCMA binding domains described in W02017/031104, the entire content of which is incorporated herein by reference. In some embodiments, the BCMAxCD3 bispecific antibody comprises any one of the CD3 binding domains described in W02017/031104. In some embodiments, the BCMAxCD3 bispecific antibody comprises any one of the BCMAxCD3 bispecific antibodies described in W02017/031104. [0079] In some embodiments, the BCMAxCD3 bispecific antibody is chimeric, humanized or human.
  • the bispecific antibody is an IgGl, 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.
  • the bispecific antibody can be of any allotype. It is expected that allotype has no influence on properties of the bispecific antibodies, such as binding or Fc-mediated effector functions. Immunogenicity of therapeutic antibodies is associated with increased risk of infusion reactions and decreased duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which therapeutic antibodies induce an immune response in the host can be determined in part by the allotype of the antibody (Stickler et al., (2011) Genes and Immunity 12:213-21). Antibody allotype is related to amino acid sequence variations at specific locations in the constant region sequences of the antibody. Table 2 shows select IgGl, IgG2 and IgG4 allotypes.
  • the bispecific antibody comprises one or more Fc substitutions that reduces binding of the bispecific antibody to a Fey receptor (FcyR) and/or reduces Fc effector functions such as Clq binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) or phagocytosis (ADCP).
  • FcyR Fey receptor
  • CDC complement dependent cytotoxicity
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • ADCP phagocytosis
  • Fc positions that can be substituted to reduce binding of the Fc to the activating FcyR and subsequently to reduce effector function are substitutions L234A/L235A on IgGl, 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 IgGl, H268Q/V309L/ A330S/P331S on IgG2, S267E/L328F on IgGl, L234F/L235E/D265A on IgGl, L234A
  • 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_Y4O7A/T366A_K4O9F, L351Y_Y4O7A/T366V_K4O9F, L351Y_Y4O7
  • 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 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.
  • the BCMAxCD3 bispecific antibody is CC-93269, BI 836909, JNJ-64007957 (teclistamab), or PF-06863135.
  • the BCMAxCD3 bispecific antibody is teclistamab (also referred to herein as Tec), which has the sequences described in Tables 3 and 4.
  • 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.
  • BCMAxCD3 bispecific antibodies that may be used in accordance with the methods are described below.
  • 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 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 IgGl, an IgG2, an IgG3 or an IgG4 isotype.
  • the BCMAxCD3 bispecific antibody is an IgG4 isotype.
  • the BCMAxCD3 bispecific antibody comprises one or more substitutions in its Fc region.
  • 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).
  • 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.
  • 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.
  • the inventors have developed novel methods of treating human subjects that have been diagnosed with high-risk smoldering multiple myeloma (HR-SMM). BCMAxCD3 bispecific antibodies disclosed herein are safe and highly effective in treating HR-SMM.
  • the diagnosis of smoldering (asymptomatic) multiple myeloma (SMM) is based on the demonstration of M-protein in serum (>3 gm/dL) or urine and/or the presence of 10-60% clonal bone marrow plasma cells (BMPC). Patients with SMM generally have an annual risk of progression of 10% for the first 5 years.
  • SMM is thought to comprise a mixture of high-risk patients, who may benefit from early therapeutic intervention before irreversible organ damage and symptoms appear.
  • These high-risk SMM patients are defined as having a 50% progression rate within 2 years.
  • the rationale is that early therapeutic interception of disease progression in these high-risk individuals will prevent/delay end-organ damage with all of its morbidities.
  • early intervention before clonal evolution with secondary acquisition of mutations along with immune-suppressive deregulation of the microenvironment may lead to a significant improvement in disease response, progression-free survival, and overall survival.
  • a patient with high-risk smoldering multiple myeloma generally meets either the Mayo 2018 Criteria (“20-2-20” critieria) or the International Myeloma Working Group Scoring System for SMM (see, e.g., Lakshman A, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J 2018;8:59; and Mateos MV, et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma. Blood Cancer J 2020; 10: 102, which are incorporated by reference herein).
  • a patient with high-risk smoldering multiple myeloma generally meets one of the following two diagnostic criteria (i.e., either Diagnostic Criteria #1 or Diagnostic Criteria #2 below) as shown in Table 7:
  • Embodiments provide methods of treating high-risk smoldering multiple myeloma (HR-SMM) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a BCMAxCD3 bispecific antibody.
  • HR-SMM high-risk smoldering multiple myeloma
  • the subject has not received prior SMM directed therapy.
  • the BCMAxCD3 bispecific antibody is administered as a monotherapy (i.e., without another concurrent SMM directed therapy).
  • methods of preventing or inhibiting development of HR-SMM into symptomatic multiple myeloma (MM) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a BCMAxCD3 bispecific antibody.
  • methods of curing HR-SMM in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a BCMAxCD3 bispecific antibody.
  • methods of achieving a complete response (CR) in a subject diagnosed with HR-SMM comprising administering to the subject a therapeutically effective amount of a BCMAxCD3 bispecific antibody.
  • methods of achieving an overall response rate (ORR) of 100% in a population of subjects diagnosed with HR-SMM comprising administering to each of the subjects a therapeutically effective amount of a BCMAxCD3 bispecific antibody.
  • the inventors have developed novel dosing regimens for the treatment of HR- SMM that achieve deep and durable clinical responses.
  • 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. Unless otherwise specified herein, when a dose is described in a unit of “mg/kg” or “pg/kg,” weight-based dosing is being employed.
  • a BCMAxCD3 bispecific antibody such as teclistamab
  • teclistamab is administered on a dosing schedule based on sequential 28-day 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 starts on Day 1 of Cycle 1 and ends on Day 28 of Cycle 1
  • Day 1 of Cycle 2 starts the day after Day 28 of Cycle 1 and ends on Day 28 of Cycle 2
  • 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.
  • 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 Cycle 3 and all subsequent cycles (i.e., C3, C4, C5, C6, C7, and so on).
  • Q4W means once every four weeks
  • Q2W also referred to as “bi-weekly” or “biweekly”
  • QW also referred to as “weekly”
  • Q4W is sometimes referred to herein as “monthly” but technically refers to once every 4 weeks or once every 28 days (e.g., in 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 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.
  • Administration of a treatment dose once every four weeks (Q4W) is also referred to herein as a monthly dosing schedule.
  • Dosing regimens may be described herein in terms of the dose amount and frequency; for example, “Cl: 1.5 mg/kg QW” refers to administration of 1.5 mg/kg once per week in Cycle 1 of a therapeutically effective regimen, “C3-6: 3 mg/kg Q2W” refers to administration of 3 mg/kg once every two weeks from Cycle 3 through Cycle 6, “C7+: 3 mg/kg Q4W” refers to administration of 3 mg/kg once every four weeks starting in Cycle 7, etc.
  • 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.
  • CR complete response
  • PR partial response
  • Q2W once every 2 weeks
  • Q4W once every 4 weeks
  • QW once weekly
  • RP2D recommended phase 2 dose
  • SUD step-up dose
  • methods of treating HR-SMM are effective in eliciting a clinical response in a subject as determined by International Myeloma Working Group (IMWG) 2016 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 2016 response criteria.
  • overall response rate refers to the percentage of patients in a population that achieve a partial response (PR) or better, i.e., a partial response, very good partial response, complete response or stringent complete response.
  • PR, VGPR, CR and sCR are as defined by the IMWG (2016) criteria.
  • IMWG (2016) response criteria are known in the art, and provided in Table A below. Table 8.
  • Clarifications to the criteria for coding progressive disease bone marrow criteria for progressive disease are to be used only in participants without measurable disease by M-protein and by FLC levels; “25% increase” refers to M-protein, and FLC, and does not refer to bone lesions, or soft-tissue plasmacytomas and the “lowest response value” does not need to be a confirmed value.
  • IMWG criteria for response to Multiple Myeloma treatment are also described, for example, in Durie et al., Kumar et al. and Rajkumar et al., which are incorporated by reference herein: Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9): 1467-1473; Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-346; Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical Trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 117(18):4691-4695.
  • Embodiments provide methods of treating high-risk smoldering multiple myeloma (HR-SMM) in a subject in need thereof, comprising treating the subject according to a therapeutically effective regimen that comprises sequential BCMAxCD3 treatment cycles.
  • HR-SMM multiple myeloma
  • each sequential BCMAxCD3 treatment cycle is 28 days.
  • the method comprises administering each dose of the BCMAxCD3 bispecific antibody subcutaneously.
  • one or more step-up doses of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase (e.g., wherein the step-up phase is Cycle 1 of a therapeutically effective regimen that comprises sequential 28-day BCMAxCD3 treatment cycles).
  • 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 or three treatment doses of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during the step-up phase, after the one or more step-up doses have been administered.
  • each of the treatment doses of the BCMAxCD3 bispecific antibody administered during the step-up phase is 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 is administered in an amount of 1.5 mg/kg.
  • the step-up phase comprises subcutaneously administering two step-up doses and three treatment doses of the BCMAxCD3 bispecific antibody.
  • the step-up phase comprises subcutaneously administering two step-up doses and two treatment doses of the BCMAxCD3 bispecific antibody.
  • two or three treatment doses of the BCMAxCD3 bispecific antibody are administered during the step-up phase on a weekly dosing schedule (QW).
  • QW weekly dosing schedule
  • 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, 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. In certain embodiments, 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 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 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 method comprises administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses, and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering weekly (QW) treatment doses.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses, and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering weekly (QW) treatment doses.
  • the method comprises administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses, and in one or more subsequent BCMAxCD3 treatment cycles (e.g., one BCMAxCD3 treatment cycle), subcutaneously administering weekly (QW) treatment doses, and then in one or more subsequent BCMAxCD3 treatment cycles (e.g., four BCMAxCD3 treatment cycles) subcutaneously administering bi-weekly (Q2W) treatment doses.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses, and in one or more subsequent BCMAxCD3 treatment cycles (e.g., one BCMAxCD3 treatment cycle), subcutaneously
  • the method comprises administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses, and in one or more subsequent BCMAxCD3 treatment cycles (e.g., one BCMAxCD3 treatment cycle), subcutaneously administering weekly (QW) treatment doses, and then in one or more subsequent BCMAxCD3 treatment cycles (e.g., four BCMAxCD3 treatment cycles) subcutaneously administering bi-weekly (Q2W) treatment doses, and then in one or more subsequent BCMAxCD3 treatment cycles (e.g., six, twelve or eighteen BCMAxCD3 treatment cycles), subcutaneously administering monthly (Q4W) treatment doses.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • the regimen comprises: in Cycle 1, subcutaneously administering one or more
  • each treatment dose of the BCMAxCD3 bispecific antibody is administered to the subject in an amount of 1.5 mg/kg or 3 mg/kg.
  • each weekly (QW) treatment dose is 1.5 mg/kg
  • each bi-weekly (Q2W) treatment dose is 3.0 mg/kg
  • each monthly (Q4W) treatment dose is 3.0 mg/kg.
  • the method comprises administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses of 1.5 mg/kg, and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering weekly (QW) treatment doses of 1.5 mg/kg.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses of 1.5 mg/kg, and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering weekly (QW) treatment doses of 1.5 mg/kg.
  • the method comprises administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses of 1.5 mg/kg, and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering weekly (QW) treatment doses of 1.5 mg/kg, and then in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering bi-weekly (Q2W) treatment doses of 3.0 mg/kg.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • the method comprises administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses of 1.5 mg/kg, and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering weekly (QW) treatment doses of 1.5 mg/kg, and then in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering bi-weekly (Q2W) treatment doses of 3.0 mg/kg, and then in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering monthly (Q4W) treatment doses of 3.0 mg/kg.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • the method comprises administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses of 1.5 mg/kg, in Cycle 2, subcutaneously administering weekly (QW) treatment doses of 1.5 mg/kg, in Cycles 3-6, subcutaneously administering bi-weekly (Q2W) treatment doses of 3.0 mg/kg; and [0141] starting in Cycle 7 (e.g., in Cycles 7-12 or Cycles 7-24), subcutaneously administering monthly (Q4W) treatment doses of 3.0 mg/kg.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • the method comprises administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses, and then two or more weekly (QW) treatment doses of 1.5 mg/kg (e.g., on Days 8, 15 and 22), in Cycle 2, subcutaneously administering weekly (QW) doses of 1.5 mg/kg (e.g., on Days 1, 8, 15 and 22), in Cycles 3-6, subcutaneously administering biweekly (Q2W) doses of 3 mg/kg (e.g., on Days 1 and 15); and starting in Cycle 7 (e.g., in Cycles 7-12 or Cycles 7-24), subcutaneously administering monthly (Q4W) doses of 3 mg/kg (e.g., on Day 1 of each cycle).
  • the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses, and then two or more weekly (QW) treatment doses
  • the method comprises administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering a first step-up dose of 0.06 mg/kg (e.g., on Day 1), a second step-up dose of 0.3 mg/kg (e.g., on Day 3), and then weekly (QW) treatment doses of 1.5 mg/kg (e.g., on Days 8, 15 and 22), in Cycle 2, subcutaneously administering weekly (QW) doses of 1.5 mg/kg (e.g., on Days 1, 8, 15 and 22), in Cycles 3-6, subcutaneously administering bi-weekly (Q2W) doses of 3 mg/kg (e.g., on Days 1 and 15); and starting in Cycle 7 (e.g., in Cycles 7-12 or Cycles 7-24), subcutaneously administering monthly (Q4W) doses of 3 mg/kg (e.g.,
  • the regimen comprises: in Cycle
  • Cycle 1 Dose is administered on Days 1, 3, 8, 15 and 22 of a 28-day treatment cycle. Step-up doses are given on Days 1 and 3 of Cycle 1; treatment doses are given on Days 8, 15 and 22 of Cycle 1.
  • Cycles 3-6 28-day cycles: treatment is administered on Days 1 and 15.
  • Treatment Cycle 1 step-up phase of an exemplary dosing regimen
  • one or more pretreatment medications are administered to the subject prior to administration of a dose of the BCMAxCD3 bispecific antibody.
  • one or more pretreatment medications are administered to the subject during Cycle 1 (step-up phase).
  • one or more pretreatment medications are administered to the subject during Cycle 1 (step-up phase) and Cycle 2.
  • one or more pretreatment medications are selected from the group consisting of dexamethasone, diphenhydramine, acetaminophen, and any combination thereof.
  • pretreatment medications are administered to the subject as shown in Table 13, in which “x” signifies administration of the pretreatment medication for the indicated day.
  • the methods achieve a clinical response in the subject that is a partial response (PR), a very good partial response (VGPR), a complete response (CR) or a stringent complete response (sCR), as defined by IMWG (2016) response criteria.
  • PR partial response
  • VGPR very good partial response
  • CR complete response
  • sCR stringent complete response
  • the methods achieve a CR, VGPR, or PR in the subject, as defined by IMWG (2016) response criteria.
  • the methods achieve a VGPR or PR in the subject, as defined by IMWG (2016) response criteria.
  • the methods achieve an overall response rate (ORR) in a population of subjects with HR-SMM of 70% or higher.
  • the methods achieve an overall response rate (ORR) in a population of subjects with HR-SMM of 75% or higher.
  • the methods achieve an overall response rate (ORR) in a population of subjects with HR-SMM of 80% or higher.
  • the methods achieve an overall response rate (ORR) in a population of subjects with HR-SMM of 85% or higher.
  • the methods achieve an overall response rate (ORR) in a population of subjects with HR-SMM of 90% or higher.
  • the methods achieve an overall response rate (ORR) in a population of subjects with HR-SMM of 95% or higher.
  • the methods achieve an overall response rate (ORR) of 100% in a population of subjects with HR-SMM.
  • the methods achieve a CR in at least 25% of a population of subjects with HR-SMM.
  • the methods achieve a CR in at least 30% of a population of subjects with HR-SMM.
  • the methods achieve a CR in at least 35% of a population of subjects with HR-SMM.
  • the methods achieve a CR in at least 40% of a population of subjects with HR-SMM.
  • the methods achieve MRD-negative disease in the subject.
  • the subject after the subject has received at least four 28 -day cycles of treatment with the BCMAxCD3 bispecific antibody, the subject’s HR-SMM does not progress.
  • administration of the BCMAxCD3 bispecific antibody to the subject for a maximum of twenty-four (24) 28-day treatment cycles prevents the subject from developing multiple myeloma.
  • administration of the BCMAxCD3 bispecific antibody to the subject for a maximum of twelve (12) 28-day treatment cycles prevents the subject from developing multiple myeloma.
  • the method cures the HR- SMM and prevents the subject from developing MM.
  • the method achieves an overall response rate (ORR) in a population of subjects with HR-SMM that is greater than an ORR achieved in a reference population of subjects with HR-SMM, said reference population having been administered Lenalidomide and Dexamethasone but not the BCMAxCD3 bispecific antibody.
  • the method achieves a percentage of complete responses (CRs) in a population of subjects with HR-SMM that is greater than a percentage of CRs achieved in a reference population of subjects with HR-SMM, said reference population having been administered Lenalidomide and Dexamethasone but not the BCMAxCD3 bispecific antibody.
  • HR-SMM high-risk smoldering multiple myeloma
  • 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.
  • 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).
  • BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises F405L and R409K substitutions in its Fc region (according to EU index numbering).
  • 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.
  • 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.
  • 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.
  • step-up doses of the BCMAxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase (e.g., wherein the step-up phase is Cycle 1 of a therapeutically effective regimen that comprises sequential 28-day BCMAxCD3 treatment cycles).
  • step-up phase comprises a first step-up dose of 0.06 mg/kg of the BCMAxCD3 bispecific antibody.
  • 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.
  • step-up phase comprises subcutaneously administering two step-up doses and two 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.
  • 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.
  • 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.
  • 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.
  • any of embodiments 1-48 comprising administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses, and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering weekly (QW) treatment doses.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • any of embodiments 1-48 comprising administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses, and in one or more subsequent BCMAxCD3 treatment cycles (e.g., one BCMAxCD3 treatment cycle), subcutaneously administering weekly (QW) treatment doses, and then in one or more subsequent BCMAxCD3 treatment cycles (e.g., four BCMAxCD3 treatment cycles) subcutaneously administering bi-weekly (Q2W) treatment doses.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses, and in one or more subsequent BCMAxCD3 treatment cycles (e.g., one BCMAxCD3 treatment
  • any of embodiments 1-48 comprising administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses, and in one or more subsequent BCMAxCD3 treatment cycles (e.g., one BCMAxCD3 treatment cycle), subcutaneously administering weekly (QW) treatment doses, and then in one or more subsequent BCMAxCD3 treatment cycles (e.g., four BCMAxCD3 treatment cycles) subcutaneously administering bi-weekly (Q2W) treatment doses, and then in one or more subsequent BCMAxCD3 treatment cycles (e.g., six, twelve or eighteen BCMAxCD3 treatment cycles), subcutaneously administering monthly (Q4W) treatment doses.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • the regimen comprises: in Cycle 1, subcutaneously
  • any of embodiments 1-48 comprising administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses, in Cycle 2, subcutaneously administering weekly (QW) treatment doses, in Cycles 3-6, subcutaneously administering bi-weekly (Q2W) treatment doses; and starting in Cycle 7 (e.g., in Cycles 7-12 or Cycles 7-24), subcutaneously administering monthly (Q4W) treatment doses.
  • the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses, in Cycle 2, subcutaneously administering weekly (QW) treatment doses, in Cycles 3-6, subcutaneously administering bi-weekly (Q2W) treatment doses; and starting in Cycle 7 (e.g., in Cycles 7-12 or Cycles
  • each treatment dose of the BCMAxCD3 bispecific antibody is administered to the subject in an amount of 1.5 mg/kg or 3 mg/kg (e.g., wherein each weekly treatment dose is 1.5 mg/kg, each biweekly treatment dose is 3.0 mg/kg, and each monthly treatment dose is 3.0 mg/kg).
  • any of embodiments 1-53 comprising administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses of 1.5 mg/kg, and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering weekly (QW) treatment doses of 1.5 mg/kg.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • any of embodiments 1-54 comprising administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses of 1.5 mg/kg, and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering weekly (QW) treatment doses of 1.5 mg/kg, and then in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering bi-weekly (Q2W) treatment doses of 3.0 mg/kg.
  • the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses of 1.5 mg/kg, and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering weekly (QW) treatment doses of 1.5 mg/kg, and then in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering bi-week
  • any of embodiments 1-55 comprising administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses of 1.5 mg/kg, and in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering weekly (QW) treatment doses of 1.5 mg/kg, and then in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering bi-weekly (Q2W) treatment doses of 3.0 mg/kg, and then in one or more subsequent BCMAxCD3 treatment cycles, subcutaneously administering monthly (Q4W) treatment doses of 3.0 mg/kg.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses of 1.5 mg
  • any of embodiments 1-56 comprising administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses and then two or more weekly (QW) treatment doses of 1.5 mg/kg, in Cycle 2, subcutaneously administering weekly (QW) treatment doses of 1.5 mg/kg, in Cycles 3-6, subcutaneously administering bi-weekly (Q2W) treatment doses of 3.0 mg/kg; and starting in Cycle 7 (e.g., in Cycles 7-12 or Cycles 7-24), subcutaneously administering monthly (Q4W) treatment doses of 3.0 mg/kg.
  • the BCMAxCD3 bispecific antibody e.g., teclistamab
  • any of embodiments 1-57 comprising administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses, and then two or more weekly (QW) treatment doses of 1.5 mg/kg (e.g., on Days 8, 15 and 22), in Cycle 2, subcutaneously administering weekly (QW) doses of 1.5 mg/kg (e.g., on Days 1, 8, 15 and 22), in Cycles 3-6, subcutaneously administering bi-weekly (Q2W) doses of 3 mg/kg (e.g., on Days 1 and 15); and starting in Cycle 7 (e.g., in Cycles 7-12 or Cycles 7-24), subcutaneously administering monthly (Q4W) doses of 3 mg/kg (e.g., on Day 1 of each cycle).
  • the regimen comprises: in Cycle 1, subcutaneously administering one or more step-up doses, and then two or more weekly (
  • any of embodiments 1-58 comprising administering the BCMAxCD3 bispecific antibody (e.g., teclistamab) according to a regimen comprising 28-day cycles, wherein the regimen comprises: in Cycle 1, subcutaneously administering a first step-up dose of 0.06 mg/kg (e.g., on Day 1), a second step-up dose of 0.3 mg/kg (e.g., on Day 3), and then weekly (QW) treatment doses of 1.5 mg/kg (e.g., on Days 8, 15 and 22), in Cycle 2, subcutaneously administering weekly (QW) doses of 1.5 mg/kg (e.g., on Days 1, 8, 15 and 22), in Cycles 3-6, subcutaneously administering bi-weekly (Q2W) doses of 3 mg/kg (e.g., on Days 1 and 15); and starting in Cycle 7 (e.g., in Cycles 7-12 or Cycles 7-24), subcutaneously administering monthly (Q4W) doses of 3 mg/kg (e.
  • the regimen comprises:
  • Anti-BCMA/anti-CD3 antibody teclistamab also called Tec
  • 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.
  • teclistamab also referred to as “TEC” or “Tec”
  • HR- SMM high-risk smoldering multiple myeloma
  • This study has an initial, safety run-in cohort of 6 patients treated with TEC. All patients receive 2 step-up doses of subcutaneous TEC. In the safety run-in, patients receive a dose lower than the recommended phase 2 dose (RP2D) of TEC. If no dose limiting toxicities (DLTs) are observed, the next cohort receives the RP2D of TEC.
  • RP2D recommended phase 2 dose
  • DLTs dose limiting toxicities
  • TEC is given at a dose of 1.5 mg/kg weekly for cycles 1 and 2 followed by 3 mg/kg on days 1 and 15 for cycles 3 to 6, and monthly starting with cycle 7 for a total of 24 cycles (2 years).
  • lenalidomide is given at a dose of 25 mg orally on days 1-21 and dexamethasone 40mg is given weekly during the 28-day cycle for 24 cycles. All eligible patients undergo stem cell collection after 4 cycles of therapy.
  • the primary objective is complete response rate. Secondary objectives include PFS, ORR, MRD negativity rates, pharmacokinetics of TEC, and safety. Exploratory objectives include mass spectrometry quantification of M protein, molecular evolution of tumor cells, and immune biomarkers of response. Eligibility Criteria:
  • BMPC Bone Marrow Plasma Cell
  • BMPC Bone Marrow Plasma Cell
  • FISH Fluorescence In Situ Hybridization
  • Evolving pattern o Evolving M-Protein (eMP: >10% increase in Serum Mi- Protein) over a 6 month period OR; o Evolving change in hemoglobin (eHb) > 0.5 g/dl decrease over a 12 month period OR; o Progressive Involved light chain increase > 10% over a 6 month period along with a light chain ratio > 8
  • Bone lesions lytic lesions or generalized osteoporosis with compression fractures
  • Serum involved/uninvolved FLC ratio >100 is not considered a MDE if urinary monoclonal protein is ⁇ 200mg/24 hours.
  • Symptomatic Multiple Myeloma or any evidence of CRAB criteria including presence of myeloma defining events (MDE). Any prior therapy for active Myeloma should also be excluded. Prior therapy for smoldering myeloma is not an exclusion criterion. Bisphosphonates are not excluded.
  • Prior therapy with bisphosphonate is allowed.
  • Prior radiation therapy to a solitary plasmacytoma is allowed but had to be at least 6 months prior to enrollment on the trial.
  • Prior clinical trials or therapy for smoldering MM or MGUS are allowed per exclusion criteria described above. Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant or breast-feeding or planning to become pregnant while enrolled in this study or within 90 days after receiving the last dose of study drug are preferred.
  • HIV human immunodeficiency virus
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • hepatitis B virus vaccine Participants who are seropositive because of hepatitis B virus vaccine are eligible. Participants who are positive for HIV 1 and 2 antibody, hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug or its excipients (refer to the teclistamab Investigator’s Brochure and appropriate package inserts).
  • PCR polymerase chain reaction
  • N0M0 Localized prostate cancer
  • o With a Gleason score of ⁇ 6, treated within the last 24 months, or untreated and under surveillance o With a Gleason score of 3+4 that has been treated >6 months prior to full study screening and considered to have a very low risk of recurrence, or • History of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence.
  • Breast cancer adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence.
  • the ORR is 100% with 42% achieving a CR, 25% VGPR, 33% PR.
  • Four patients with high-risk FISH receiving TEC have achieved a CR within 5 cycles.
  • the ORR is 66% without any complete responses to date.
  • the MRD negative rate at 10‘ 6 is 100%, including 2 patients with VGPR-MRD negative disease.
  • Average time to MRD negativity observed among evaluable patients was 4.25 cycles. No patients have progressed on treatment. Stem cell collection was successful in all eligible patients with an average stem cell yield of 9.06 x 10 6 CD34+ cells/kg.

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Abstract

Des modes de réalisation concernent des méthodes de traitement du myélome multiple indolent à haut risque chez un sujet en ayant besoin, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un anticorps bispécifique anti-BCMAxCD3.
PCT/IB2024/060769 2023-11-01 2024-10-31 Méthodes de traitement du myélome multiple indolent à haut risque Pending WO2025094107A1 (fr)

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