WO2025094085A1 - Schémas combinés pour le traitement du myélome multiple - Google Patents

Schémas combinés pour le traitement du myélome multiple Download PDF

Info

Publication number
WO2025094085A1
WO2025094085A1 PCT/IB2024/060718 IB2024060718W WO2025094085A1 WO 2025094085 A1 WO2025094085 A1 WO 2025094085A1 IB 2024060718 W IB2024060718 W IB 2024060718W WO 2025094085 A1 WO2025094085 A1 WO 2025094085A1
Authority
WO
WIPO (PCT)
Prior art keywords
treatment
subject
bispecific antibody
administered
days
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2024/060718
Other languages
English (en)
Inventor
Colleen M. KANE
Marie-Anne Damiette SMIT
Brandi HILDER
Jaszianne TOLBERT
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Biotech Inc
Original Assignee
Janssen Biotech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Biotech Inc filed Critical Janssen Biotech Inc
Publication of WO2025094085A1 publication Critical patent/WO2025094085A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], 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 [IG], 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
    • 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
    • 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

  • multiple myeloma is characterized by production of monoclonal proteins (M-proteins) comprised of pathological immunoglobulins or fragments of such, which have lost their function.
  • M-proteins monoclonal proteins
  • the proliferation of multiple myeloma cells leads to subsequent displacement from the normal bone marrow niche, while overproduction of M-proteins causes characteristic osteolytic lesions, increased susceptibility to infections, hypercalcemia, renal insufficiency or failure, and neurological complications.
  • 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. 300658828v1 258199.061902 (JBI6857WOPCT1) [0006]
  • PIs proteasome inhibitors
  • IMDs immunomodulatory drugs
  • mAbs monoclonal antibodies
  • CAR chimeric antigen receptor
  • Embodiments of the present invention relate to combination regimens comprising a GPRC5DxCD3 bispecific antibody, such as talquetamab, for treatment of multiple myeloma.
  • An embodiment of the present invention provides a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a combination therapy comprising a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody and a therapeutically effective amount of pomalidomide.
  • Another embodiment of the present invention provides a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a combination therapy comprising a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody and a therapeutically effective amount of daratumumab.
  • Another embodiment of the present invention provides a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a combination therapy comprising a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody and a therapeutically effective amount of daratumumab and a therapeutically effective amount of pomalidomide.
  • Another embodiment of the present invention provides a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a combination therapy comprising a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody and a therapeutically effective amount of daratumumab and a therapeutically effective amount of lenalidomide.
  • the GPRC5DxCD3 bispecific antibody comprises a GPRC5D 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 300658828v1 258199.061902 (JBI6857WOPCT1) 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 GPRC5D 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 GPRC5DxCD3 bispecific antibody is an IgG1, an IgG2, an IgG3 or an IgG4 isotype.
  • the GPRC5DxCD3 bispecific antibody is an IgG4 isotype.
  • the GPRC5DxCD3 bispecific antibody comprises one or more substitutions in its Fc region.
  • the GPRC5DxCD3 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 GPRC5DxCD3 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 GPRC5D binding arm comprises Proline/Alanine/Alanine substitutions at amino acid positions 228/234/235, respectively, in its Fc region (according to EU index numbering).
  • the Fc region of the CD3 binding arm comprises S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region (according to EU index numbering).
  • the GPRC5DxCD3 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 GPRC5DxCD3 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 GPRC5DxCD3 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 GPRC5DxCD3 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 GPRC5DxCD3 bispecific antibody is talquetamab.
  • the subject has relapsed or refractory multiple myeloma.
  • the subject has received at least two prior lines of therapy. [0028] In certain embodiments, the subject has received at least three prior lines of therapy. [0029] In certain embodiments, the subject has received at least four prior lines of therapy. [0030] 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. [0031] 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 method comprises subcutaneously administering treatment doses of the GPRC5DxCD3 bispecific antibody in an amount of either (i) 0.4 mg/kg weekly (QW), or (ii) 0.8 mg/kg bi-weekly (Q2W). 300658828v1 258199.061902 (JBI6857WOPCT1) [0033] In certain embodiments, the method comprises subcutaneously administering to the subject one or more step-up doses of the GPRC5DxCD3 bispecific antibody prior to administering the first treatment dose of the GPRC5DxCD3 bispecific antibody.
  • FIG.4 provides a schematic overview of MonumenTAL-6, a Phase 3 Randomized Study Comparing Talquetamab in Combination with Pomalidomide (Tal-P), Talquetamab in Combination with Teclistamab (Tal-Tec), and Investigator’s Choice of Either Elotuzumab, Pomalidomide, and Dexamethasone (EPd) or Pomalidomide, Bortezomib, and Dexamethasone (PVd) in Participants with Relapsed or Refractory Myeloma who Have Received 1 to 4 Prior Lines of Therapy Including an Anti-CD38 Antibody and Lenalidomide.
  • Tal-P Phase 3 Randomized Study Comparing Talquetamab in Combination with Pomalidomide
  • Talquetamab in Combination with Teclistamab Talquetamab in Combination with Teclistamab
  • FIG.6a provides a table summary of pretreatment medication dosing schedules for Arm C (EPd) of the Phase 3 MonumenTAL-6 clinical study.
  • FIG.6b provides a table summary of study treatment dosing schedules for Arm C (EPd) of the Phase 3 MonumenTAL-6 clinical study.
  • FIG.6c provides a table summary of study treatment dosing schedules for Arm C (PVd) of the Phase 3 MonumenTAL-6 clinical study.
  • FIG.7 illustrates overall response rate (ORR) from the Phase 1b MonumenTAL-2 clinical study.
  • 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. WO1998/44001, WO1988/01649, WO1994/13804 and WO1992/01047.
  • Bispecific refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen.
  • the 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 together in a mixture, concurrently as single agents or sequentially as single agents in any order.
  • “Combination therapy,” also referred to as “combination regimen,” as used herein refers to a therapeutically effective regimen that comprises administration of two or more anti-multiple myeloma therapeutic agents to a subject to treat multiple myeloma.
  • the two or more therapeutics are administered to a subject on each therapeutic’s respective dosing schedule over a time period (e.g., a time period may comprise one or more treatment cycles, such as one or more 28-day treatment cycles); for example, a combination therapy may comprise administering to a subject (i) “therapeutic #1” on its weekly or bi-weekly or 300658828v1 258199.061902 (JBI6857WOPCT1) monthly dosing schedule starting on Day 1 of a treatment cycle and (ii) “therapeutic #2” on its weekly or bi-weekly or monthly dosing schedule starting on Day 1 of the same treatment cycle or a subsequent treatment cycle.
  • “Complementarity determining regions” are antibody regions that bind an antigen.
  • 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 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 Fc RI, Fc RIIa, Fc RIIb or Fc RIII. Activating Fc R includes Fc RI, Fc RIIa and Fc RIII.
  • GPRC5DxCD3 bispecific antibody refers to a bispecific antibody that specifically binds GPRC5D and CD3.
  • 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.
  • human antibody contains a constant region or a portion of the constant region, the constant region is also derived from human 300658828v1 258199.061902 (JBI6857WOPCT1) 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. 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 300658828v1 258199.061902 (JBI6857WOPCT1) instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN (DNAStar, Inc.) software.
  • 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., talquetamab treatment na ⁇ ve bone marrow sample).
  • Negative minimal residual disease status can be determined at a sensitivity of 300658828v1 258199.061902 (JBI6857WOPCT1) 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).
  • NGS next generation sequencing
  • 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 therapeutic 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, or three step-up doses followed by one treatment dose.
  • the step-up phase is 28 days, i.e., the step-up phase is a 28-day cycle of a therapeutically effective regimen.
  • Subject includes any human or nonhuman animal.
  • Nonhuman animal includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. 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 GPRC5D.
  • T cell antigen include, e.g., CD3. This dual/multi-target 300658828v1 258199.061902 (JBI6857WOPCT1) 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.
  • “Treat” or “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.
  • 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 patient diagnosed with multiple myeloma (MM) 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 300658828v1 258199.061902 (JBI6857WOPCT1) 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 present inventors have developed novel combination regimens comprising GPRC5DxCD3 bispecific antibodies , e.g., combination regimens comprising GPRC5DxCD3 bispecific antibodies and pomalidomide (pom), that provide deep and durable efficacy.
  • combination regimens comprising GPRC5DxCD3 bispecific antibodies and pomalidomide (pom)
  • pom pomalidomide
  • data from MonumenTAL-1 demonstrates that participants who switched to less frequent dosing after achieving response with talquetamab monotherapy have improved progression-free survival (PFS) compared with the overall pivotal population and experienced fewer study drug-related TEAEs and Grade 3 or 4 TEAEs after switching and experienced improve resolution of on-target-related toxicity (e.g., oral, skin, and rash AEs).
  • PFS progression-free survival
  • data from MonumanTAL-1 in which participants are receiving Q4W dosing demonstrated maintenance of response following switch, with a trend for improved resolution of GPRC5D-related oral, skin (rash and non- rash), and nail toxicities.
  • combination regimens of the present invention improve median progression free 300658828v1 258199.061902 (JBI6857WOPCT1) survival (PFS) in a population of subjects with relapsed or refractory multiple myeloma that have received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, wherein the improvement in median PFS is relative to median PFS of a reference population of subjects with relapsed or refractory multiple myeloma that have received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, said reference population having been administered either (i) elotuzumab,
  • CR or better rate refers to the percentage of subjects with best overall response of CR or better according to IMWG response criteria. 300658828v1 258199.061902 (JBI6857WOPCT1) [0106]
  • combination regimens of the present invention improve Very Good Partial Response (VGPR) or Better Rate in a population of subjects with relapsed or refractory multiple myeloma that have received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, wherein the improvement in VGPR or Better Rate is relative to VGPR or Better Rate of a reference population of subjects with relapsed or refractory multiple myeloma that have received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, said reference population having been administered either (
  • VGPR or better rate refers to the percentage of subjects with best overall response of VGPR or better according to IMWG response criteria.
  • combination regimens of the present invention e.g., talquetamab, pomalidomide and dexamethasone
  • MRD Minimal Residual Disease
  • the improvement in MRD-negative CR Rate is relative to MRD-negative CR Rate of a reference population of subjects with relapsed or refractory multiple myeloma that have received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide
  • said reference population having been administered either (i) elotuzumab, pomalidom
  • MRD- negative CR refers to the percentage of subjects who achieve both CR or better and MRD negativity at a threshold of 10 ⁇ -5 at any timepoint after the date of randomization and before disease progression or start of subsequent antimyeloma therapy (SST).
  • combination regimens of the present invention improve overall survival (OS) in a population of subjects with relapsed or refractory multiple myeloma that have received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, wherein the improvement in OS is relative to OS of a reference population of subjects with relapsed or refractory multiple myeloma that have received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide, said reference population having been administered either (i) elot
  • 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
  • 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 GPRC5DxCD3 bispecific antibody comprises any one of the GPRC5D binding domains described in U.S. Patent No.10,562,968, the content of 300658828v1 258199.061902 (JBI6857WOPCT1) which is incorporated herein by reference in its entirety.
  • the GPRC5DxCD3 bispecific antibody comprises any one of the CD3 binding domains described in U.S. Patent No.10,562,968.
  • the GPRC5DxCD3 bispecific antibody comprises any one of the GPRC5DxCD3 bispecific antibodies described in U.S. Patent No. 10,562,968. [0112] In some embodiments, the GPRC5DxCD3 bispecific antibody is chimeric, humanized or human. [0113] 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 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK [0114]
  • 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 Fc receptor (Fc R) and/or reduces Fc effector functions such as C1q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) or phagocytosis (ADCP).
  • Fc R Fc receptor
  • Fc positions that can be substituted to reduce binding of the Fc to the activating Fc R 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 IgG
  • 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 GPRC5DxCD3 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 GPRC5DxCD3 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 GPRC5DxCD3 bispecific antibody, according to the Kabat numbering system.
  • Table 3. Sequences of GPRC5D binding arm Region Sequence SEQ ID NO: HCDR1 GYTMN 4 HCDR2 LINPYNSDTNYAQKLQG 5 HCDR3 VALRVALDY 6 LCDR1 KASQNVATHVG 7 LCDR2 SASYRYS 8 LCDR3 QQYNRYPYT 9 VH QVQLVQSGAEVKKPGASVKVSCKASGYSF 10 TGYTMNWVRQAPGQGLEWMGLINPYNSD TNYAQKLQGRVTMTTDTSTSTAYMELRSL RSDDTAVYYCARVALRVALDYWGQGTLV TVSS VL DIQMTQSPSSLSASVGDRVTITCKASQNVA 11 THVGWYQQKPGKAPKRLIYSASYRYSGVP SRFSGSGSGTEFTLTISNLQP
  • Talquetamab is a GPRC5D-directed bispecific antibody in development for treatment of patients with relapsed or refractory multiple myeloma. See, e.g., Chari A, et al. Blood 2022; 140 (suppl 1): 384-387, which is incorporated by reference herein.
  • Talquetamab is a bispecific GPRC5D-directed CD3 T cell engager in development as a monotherapy for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least three or four prior therapies, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.
  • the GPRC5DxCD3 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 talquetamab.
  • Additional embodiments of GPRC5DxCD3 bispecific antibodies that may be used in combination regimens of the present invention are described below.
  • the GPRC5DxCD3 bispecific antibody comprises a GPRC5D 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 GPRC5D 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. 300658828v1 258199.061902 (JBI6857WOPCT1) [0130]
  • the GPRC5DxCD3 bispecific antibody is an IgG1, an IgG2, an IgG3 or an IgG4 isotype.
  • the GPRC5DxCD3 bispecific antibody is an IgG4 isotype. [0132] In certain embodiments, the GPRC5DxCD3 bispecific antibody comprises one or more substitutions in its Fc region. [0133] In certain embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A and L235A substitutions in its Fc region. [0134] In certain embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A, L235A F405L and R409K substitutions in its Fc region.
  • the GPRC5D binding arm comprises S228P, F234A and L235A substitutions in its Fc region (according to EU index numbering).
  • the Fc region of the CD3 binding arm comprises S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region (according to EU index numbering).
  • the GPRC5DxCD3 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 GPRC5DxCD3 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 GPRC5DxCD3 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 GPRC5DxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 300658828v1 258199.061902 (JBI6857WOPCT1) 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 GPRC5DxCD3 bispecific antibody is talquetamab.
  • the subject has relapsed or refractory multiple myeloma and received 1 to 4 prior lines of therapy including an anti-CD38 antibody and lenalidomide.
  • 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 1 to 11 prior lines of therapy, or from 1 to 10 prior lines of therapy.
  • the subject has previously received an autologous stem cell transplant (ASCT).
  • ASCT autologous stem cell transplant
  • the subject has received at least three prior lines of therapy.
  • the subject has received at least four prior lines of therapy. [0150] In certain embodiments, the subject has received at least five prior lines of therapy (penta-drug exposed). [0151] 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. [0152] 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 GPRC5DxCD3 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.
  • 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. 300658828v1 258199.061902 (JBI6857WOPCT1) [0158]
  • 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 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 subject is not relapsed/refractory to prior anti-myeloma treatment, but instead has newly diagnosed multiple myeloma according to IMWG diagnostic criteria and is ineligible or not intended for ASCT as initial therapy. 300658828v1 258199.061902 (JBI6857WOPCT1) [0165]
  • 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.
  • Chromosomal rearrangements can be identified using well known methods, for example fluorescent in situ hybridization, karyotyping, pulsed field gel electrophoresis, or sequencing.
  • Combination regimens comprising a GPRC5DxCD3 bispecific antibody
  • the inventors have developed novel combinations regimens comprising GPRC5DxCD3 bispecific antibodies and pomalidomide (pom) that provide deep and durable efficacy.
  • 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 GPRC5DxCD3 bispecific antibody such as talquetamab
  • a dosing schedule based on sequential 28-day cycles, for 300658828v1 258199.061902 (JBI6857WOPCT1) 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.
  • one or more step-up doses are administered prior to the first treatment cycle, i.e., prior to Cycle 1 Day 1.
  • a treatment cycle refers to a 28-day treatment cycle.
  • C1 refers to Cycle 1
  • C2 refers to Cycle 2
  • C3 refers to Cycle 3, and so on.
  • 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., “C5+” refers to from Cycle 5 and all subsequent cycles (i.e., C5, C6, C7, C8, C9, 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 may be 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 (QW) 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 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, “C1: 0.4 mg/kg QW” refers to administration of 0.4 mg/kg once per week in Cycle 1 of a therapeutically effective regimen, “C3-6: 0.8 mg/kg Q2W” refers to administration of 0.8 mg/kg once every two weeks from Cycle 3 through Cycle 6, “C7+: 0.8 mg/kg Q4W” refers to administration of 0.8 mg/kg once every four weeks starting in Cycle 7, etc.
  • a “GPRC5DxCD3 treatment cycle” refers to each treatment cycle in a therapeutically effective regimen in which at least one treatment dose of a GPRC5DxCD3 bispecific antibody is administered to the subject.
  • the first GPRC5DxCD3 treatment cycle in a therapeutically effective regimen is preceded by a step-up phase. 300658828v1 258199.061902 (JBI6857WOPCT1)
  • a “pomalidomide treatment cycle” refers to each treatment cycle in a therapeutically effective regimen in which at least one treatment dose of pomalidomide is administered to the subject.
  • IMWG criteria refers to IMWG (2016) criteria.
  • the methods of treatment are effective in eliciting a partial response, a very good partial response, a complete response or a stringent complete response, as determined by IMWG response criteria.
  • ORR 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.
  • IMWG criteria for response to Multiple Myeloma treatment are provided in Table 7 below.
  • IMWG criteria for coding CR and VGPR in subjects in whom the only measurable disease is by serum FLC levels CR in such subjects indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR in such subjects requires a >90% decrease in the difference between involved and uninvolved FLC levels.
  • 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.
  • the GPRC5DxCD3 bispecific antibody e.g., talquetamab
  • the GPRC5DxCD3 bispecific antibody may be subcutaneously administered according to one or both of the following weight-based dosing schedules (QW and/or Q2W) shown in Tables 9 and 10, wherein mg/kg refers to mg of talquetamab per kg of the patient’s body weight: 300658828v1 258199.061902 (JBI6857WOPCT1) Table 9 Phase Day Talquetamab Dose a Day 1 0.01 mg/kg Step-up Phase Day 3 b 0.06 mg/kg Day 5 b 0.4 mg/kg Treatment Phase Once a week thereafter c 0.4 mg/kg a Based on actual body weight.
  • QW and/or Q2W weight-based dosing schedules
  • Dose may be administered between 2 to 4 days after the previous dose and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions.
  • c Maintain a minimum of 6 days between weekly doses and a minimum of 12 days between biweekly (every 2 weeks) doses.
  • Table 10 Phase Day Talquetamab Dose a Day 1 0.01 mg/kg Day 3 b 0.06 mg/kg Step-up Phase Day 5 b 0.4 mg/kg Day 7 b 0.8 mg/kg T reatment Phase Once t h e e v r e e r a y f t 2 e r w c eeks 0.8 mg/kg a Based on actual body weight.
  • the method comprises subcutaneously administering treatment doses of the GPRC5DxCD3 bispecific antibody in an amount of either (i) 0.4 mg/kg weekly (QW), or (ii) 0.8 mg/kg bi-weekly (Q2W).
  • the method comprises subcutaneously administering treatment doses of the GPRC5DxCD3 bispecific antibody in an amount of 0.8 mg/kg bi- weekly (Q2W).
  • the method comprises subcutaneously administering treatment doses of the GPRC5DxCD3 bispecific antibody in an amount of 0.8 mg/kg on a bi- weekly (Q2W) dosing schedule, followed by monthly (Q4W) dosing schedule if the subject has achieved a certain clinical response.
  • the method comprises subcutaneously administering treatment doses of the GPRC5DxCD3 bispecific antibody in an amount of 0.8 mg/kg on a bi- weekly (Q2W) dosing schedule, followed by monthly (Q4W) dosing schedule if the subject has achieved a VGPR or better.
  • the method comprises subcutaneously administering treatment doses of the GPRC5DxCD3 bispecific antibody in an amount of 0.8 mg/kg on a bi- weekly (Q2W) dosing schedule, followed by monthly (Q4W) dosing schedule if the subject has achieved a PR or better.
  • the method comprises subcutaneously administering to the subject one or more step-up doses of the GPRC5DxCD3 bispecific antibody prior to administering the first treatment dose of the GPRC5DxCD3 bispecific antibody.
  • the method comprises subcutaneously administering 2 or 3 step-up doses of the GPRC5DxCD3 bispecific antibody prior to subcutaneously administering the first treatment dose.
  • the method comprises subcutaneously administering step- up doses of 0.01 mg/kg and 0.06 mg/kg of the GPRC5DxCD3 bispecific antibody prior to subcutaneously administering a treatment dose.
  • the method comprises subcutaneously administering step- up doses of 0.01 mg/kg, 0.06 mg/kg and 0.4 mg/kg of the GPRC5DxCD3 bispecific antibody prior to subcutaneously administering a treatment dose.
  • the method comprises subcutaneously administering step- up doses of the GPRC5DxCD3 bispecific antibody 2-4 days apart from each other.
  • the method comprises orally administering the pomalidomide in an amount of 2 mg daily or 4 mg daily.
  • the method comprises administering a combination regimen that includes the GPRC5DxCD3 bispecific antibody (e.g., talquetamab), pomalidomide and dexamethasone.
  • the combination therapy comprises sequential 28-day treatment cycles.
  • the pomalidomide is administered in an amount of 2 mg daily or 4 mg daily for Days 1-21 of each pomalidomide treatment cycle.
  • the combination therapy comprises sequential 28-day treatment cycles; administration of the GPRC5DxCD3 bispecific antibody starts in Cycle 1; and administration of the pomalidomide starts in Cycle 2.
  • the combination therapy comprises sequential 28-day treatment cycles; administration of the GPRC5DxCD3 bispecific antibody starts in Cycle 1; administration of the pomalidomide starts in Cycle 2; and administration of dexamethasone 300658828v1 258199.061902 (JBI6857WOPCT1) starts in Cycle 2.
  • the dexamethasone is administered during Cycles 2-4 only.
  • the combination therapy comprises sequential 28-day treatment cycles; Cycle 1 is a step-up phase comprising administration of one or more step-up doses and one or more treatment doses of the GPRC5DxCD3 bispecific antibody; and each subsequent treatment cycle (Cycle 2 onward) comprises oral administration of the pomalidomide in an amount of 2 mg daily on Days 1-21; and subcutaneous administration of the GPRC5DxCD3 bispecific antibody in an amount of either (i) 0.4 mg/kg weekly (QW), or (ii) 0.8 mg/kg bi-weekly (Q2W).
  • the combination therapy comprises sequential 28-day treatment cycles;
  • Cycle 1 is a step-up phase comprising administration of a first step-up dose of 0.01 mg/kg, a second step-up dose of 0.06 mg/kg, a third step-up dose of 0.4 mg/kg, and a first treatment dose of 0.8 mg/kg of the GPRC5DxCD3 bispecific antibody; and each subsequent treatment cycle (Cycle 2 onward) comprises oral administration of the pomalidomide in an amount of 2 mg daily on Days 1-21; and subcutaneous administration of the GPRC5DxCD3 bispecific antibody in an amount of 0.8 mg/kg bi-weekly (Q2W) (e.g., on Days 1 and 15).
  • Q2W 0.8 mg/kg bi-weekly
  • the GPRC5DxCD3 bispecific antibody is administered bi-weekly (Q2W) during treatment Cycles 2-4 or treatment Cycles 2-6 before switching to a monthly (Q4W) dosing regimen.
  • treatment doses of the GPRC5DxCD3 bispecific antibody are subcutaneously administered to the subject on a monthly dosing schedule (Q4W) either: (i) starting at treatment Cycle 5 if the subject has achieved a VGPR or better (a very good partial response, a complete response or a stringent complete response), as determined by IMWG response criteria; or (ii) starting at treatment Cycle 7, regardless of clinical response in the subject.
  • the method comprises treating the subject according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein: one or more step-up doses of the GPRC5DxCD3 bispecific antibody (e.g., talquetamab) are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject in an amount of 0.8 mg/kg, wherein the treatment doses of the GPRC5DxCD3 bispecific antibody are administered to the subject on a bi-weekly dosing schedule (Q2W) starting from treatment Cycle 2 (e.g., on Days 1 and 15), and then treatment doses of the GPRC5DxCD3 bispecific antibody are subcutaneously administered to the subject on a 300658828v1 258199.061902 (JBI6857WOPCT1) monthly dosing schedule (Q4W) either: (i) starting at treatment Cycle 5 if the subject has
  • the subject has received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide
  • the method comprises: treating the subject according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein: one or more step-up doses of the GPRC5DxCD3 bispecific antibody (e.g., talquetamab) are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject in an amount of 0.8 mg/kg, wherein the treatment doses of the GPRC5DxCD3 bispecific antibody are administered to the subject on a bi-weekly dosing schedule (Q2W) starting from treatment Cycle 2 (e.g., on Days 1 and 15), and then treatment doses of the GPRC5DxCD3 bispecific antibody are subcutaneously administered to the subject on a monthly dosing schedule (Q2W) starting from treatment Cycle 2
  • the subject achieves a clinical response that is a partial response, a very good partial response, a complete response, or a stringent complete response.
  • the GPRC5DxCD3 bispecific antibody e.g., talquetamab
  • pomalidomide are administered according to the dosing schedule illustrated in FIG.5b. 300658828v1 258199.061902 (JBI6857WOPCT1)
  • the GPRC5DxCD3 bispecific antibody e.g., talquetamab
  • pomalidomide and dexamethasone are administered according to the dosing schedule illustrated in FIG.5b.
  • the GPRC5DxCD3 bispecific antibody (e.g., talquetamab) and pomalidomide are administered according to the dosing schedule illustrated in FIG.5c.
  • the GPRC5DxCD3 bispecific antibody (e.g., talquetamab), pomalidomide and dexamethasone are administered according to the dosing schedule illustrated in FIG.5c.
  • pretreatment medications are administered according to the schedule illustrated in FIG.5a.
  • the subject has received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide
  • the method comprises: treating the subject according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein: one or more step-up doses of the GPRC5DxCD3 bispecific antibody (e.g., talquetamab) are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject in an amount of 0.8 mg/kg, wherein the treatment doses of the GPRC5DxCD3 bispecific antibody are administered to the subject on a bi-weekly dosing schedule (Q2W) starting from treatment Cycle 2 (e.g., on Days 1 and 15), and then treatment doses of the GPRC5DxCD3 bispecific antibody are subcutaneously administered to the subject on a monthly dosing schedule (Q2W) starting from treatment Cycle 2
  • the method further comprises administering dexamethasone to the subject.
  • the dexamethasone is administered orally or intravenously in an amount of 40 mg (or equivalent).
  • the dexamethasone is administered orally or intravenously in an amount of 40 mg (or equivalent) once per week (e.g., on Days 1, 8, 15 and 22) during treatment Cycles 2-4 only.
  • talquetamab, pomalidomide and dexamethasone are administered as follows, in 28-day treatment cycles: 300658828v1 258199.061902 (JBI6857WOPCT1) -
  • Cycle 1 the following doses of subcutaneous talquetamab are administered: o Talquetamab step-up dose 1 (SU1): 0.01 mg/kg, administered on Day 1; o Talquetamab step-up dose 2 (SU2): 0.06 mg/kg, administered 2d after SU1, between Days 3-6; o Talquetamab treatment dose (sometimes referred to as step-up dose 3): 0.4 mg/kg, administered 2d after SU2, between Days 5-10; o Talquetamab treatment dose: 0.8mg/kg, administered 2d after first treatment dose (step-up dose 3) of 0.4 mg/kg, between Days 7-15; -
  • the subcutaneous Talquetamab treatment dose of 0.8mg/kg are administered as follows: o Cycle 2
  • talquetamab, pomalidomide and dexamethasone are administered as follows, in 28-day treatment cycles: - In Cycle 1, the 2 or 3 step-up doses of subcutaneous talquetamab are administered 2-4 days apart from eather other, and then a 0.8 mg/kg treatment dose of subcutaneous talquetamab is administered 2 days after the previous dose; - In subsequent treatment cycles following Cycle 1, the subcutaneous Talquetamab treatment dose of 0.8mg/kg is administered as follows: 300658828v1 258199.061902 (JBI6857WOPCT1) - Cycle 2 – Cycle 4 (C2-C4), Talquetamab SC is administered bi-weekly (Q2W); - From Cycle 5 (C5), if confirmed VGPR or better, schedule can change to Q4W dosing (Day 1 of each 28-day cycle only ⁇ 3 days); - At Cycle 7 Day 1 ( ⁇ 3d), if confirmed PR or better, schedule changes to Q4W dosing;
  • talquetamab, pomalidomide and dexamethasone are administered as follows, in 28-day treatment cycles: - In Cycle 1, the following doses of subcutaneous talquetamab are administered: - Talquetamab step-up dose 1 (SU1): 0.01 mg/kg, administered on Day 1; - Talquetamab step-up dose 2 (SU2): 0.06 mg/kg, administered 2d after SU1, between Days 3-6; - Talquetamab treatment dose (sometimes referred to as step-up dose 3): 0.4 mg/kg, administered 2d after SU2, between Days 5-10; - Talquetamab treatment dose: 0.8mg/kg, administered 2d after first treatment dose (step-up dose 3) of 0.4 mg/kg, between Days 7-15, - In subsequent treatment cycles following Cycle 1, the subcutaneous Talquetamab treatment dose of 0.8mg/kg is administered as follows: - Cycle 2 – Cycle 4 (C2-C4), Talquetamab SC is administered bi-weekly (
  • a method of improving median progression free survival (PFS) in a population of subjects with relapsed or refractory multiple myeloma that have received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide comprises administering to the population of subjects a combination therapy comprising a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody (e.g., talquetamab), a therapeutically effective amount of pomalidomide and a therapeutically effective amount of dexamethasone, wherein the method comprises: treating the subject according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein one or more step-up doses of the GPRC5DxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject in an amount of 0.8 mg/
  • PFS median progression free survival
  • Another embodiment of the present invention provides a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a combination therapy comprising a GPRC5DxCD3 bispecific antibody described herein (e.g., talquetamab), pomalidomide and daratumumab according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein the subject has relapsed or refractory multiple myeloma and received at least 1 prior line of therapy including a PI and lenalidomide, and wherein: one or more step-up doses of the GPRC5DxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject in an amount of 0.8 mg/kg, and the treatment doses of the GPRC5DxCD
  • a combination therapy comprising a GPRC5DxCD3 bispecific antibody described
  • the subject achieves longer PFS compared to a subject that is administered a combination regimen comprising daratumumab, pomalidomide and dexamethasone (DPd) without a GPRC5DxCD3 bispecific antibody.
  • a combination regimen comprising daratumumab, pomalidomide and dexamethasone (DPd) without a GPRC5DxCD3 bispecific antibody.
  • Another embodiment of the present invention provides a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a combination therapy comprising talquetamab, pomalidomide and daratumumab according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein the subject has relapsed or refractory multiple myeloma and received at least 1 prior line of therapy including a PI and lenalidomide, and wherein: one or more step-up doses of the talquetamab are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the talquetamab is subcutaneously administered to the subject in an amount of 0.8 mg/kg, and the treatment doses of the talquetamab are administered to the subject on a bi- weekly dosing schedule (Q2W) starting from treatment Cycle 2 (e.g., on Days 1 and 15), and then treatment doses of the talquetamab are subcutaneously administered to
  • the subject achieves longer PFS compared to a subject that is administered a combination regimen comprising daratumumab, pomalidomide and dexamethasone (DPd) without talquetamab.
  • Another embodiment of the present invention provides a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a combination therapy comprising a GPRC5DxCD3 bispecific antibody described herein (e.g., talquetamab), pomalidomide and daratumumab according to a therapeutically effective 300658828v1 258199.061902 (JBI6857WOPCT1) regimen that comprises sequential 28-day treatment cycles, wherein the subject has relapsed or refractory multiple myeloma and received at least 1 prior line of therapy including a PI and lenalidomide, and wherein: one or more step-up doses of the GPRC5DxCD3 bispecific antibody are subcutaneously administered to the
  • the subject achieves longer PFS compared to a subject that is administered a combination regimen comprising daratumumab, pomalidomide and dexamethasone (DPd) without a GPRC5DxCD3 bispecific antibody.
  • a combination regimen comprising daratumumab, pomalidomide and dexamethasone (DPd) without a GPRC5DxCD3 bispecific antibody.
  • Another embodiment of the present invention provides a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a combination therapy comprising talquetamab and daratumumab according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein the subject has relapsed or refractory multiple myeloma and received at least 1 prior line of therapy including a PI and lenalidomide, and wherein: one or more step-up doses of the talquetamab are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the talquetamab is subcutaneously administered to the subject in an amount of 0.8 mg/kg, and the treatment doses of the talquetamab are administered to the subject on a bi- weekly dosing schedule (Q2W) starting from treatment Cycle 2 (e.g., on Days 1 and 15), and 300658828v1 258199.061902 (JBI6857WOPCT1) then
  • the subject achieves longer PFS compared to a subject that is administered a combination regimen comprising daratumumab, pomalidomide and dexamethasone (DPd) without talquetamab.
  • a dosing regimen of the present invention is provided below, in which talquetamab, daratumumab and pomalidomide are administered as a combination regimen in 28-day treatment cycles: - o Cycle 1: Step-up Dose 1: Day 2; Step-up Dose 2: Day 4 (+2 days); Step-up Dose 3: Day 8 (+2 days); treatment dose: Day 15 (+2 days)
  • Step-up Dose 2 and Step-up Dose 3 may be administered on Day 3 and Day 7 o Cycles 2-4: treatment dose on Days 1 and 15 o Cycles 5-6: Days 1 and 15 or if confirmed VGPR or better, may change to Q4W dosing (Day 1 only) o From Cycle 7: Q4W
  • Embodiments of the present invention also 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.
  • Subjects that are “not intended” for ASCT as initial therapy are clinically fit enough to undergo ASCT but defer this treatment option.
  • Tal- DR talquetamab, daratumumab and lenalidomide
  • PFS progression-free subjects with newly diagnosed multiple myeloma who are ineligible or not intended for ASCT as initial therapy.
  • talquetamab 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
  • An embodiment of the present invention provides a method of treating multiple myeloma in a subject in need thereof, comprising administering to the subject a combination therapy comprising talquetamab, lenalidomide and daratumumab according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein the subject has newly diagnosed multiple myeloma according to IMWG diagnostic criteria and is ineligible or not intended for ASCT as initial therapy, and wherein: one or more step-up doses of the talquetamab are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the talquetamab is subcutaneously administered to the subject in an amount of 0.8 mg/kg on a monthly dosing schedule (Q4W) starting in treatment cycle 2, and the lenalidomide is orally administered in an amount of 25 mg daily on Days 1-21 of each treatment cycle, starting in treatment Cycle 2, and 300658828v1 258199.061902 (JBI6857WOPCT1)
  • the method further comprises administering dexamethasone to the subject; for example, the dexamethasone may be administered orally or intravenously in an amount of 20 mg (or equivalent) once per week during treatment Cycles 2 and 3.
  • the subject achieves longer PFS compared to a subject that is administered a combination regimen comprising daratumumab, lenalidomide and dexamethasone (DRd) without talquetamab.
  • Embodiments of the present invention also provide alternative step-up dosing regimens for a GPRC5DxCD3 bispecific antibody such as talquetamab.
  • the inventors have developed shortened step-up dosing schedules that result in the same or similar adverse event profiles in patients (e.g., incidence and/or severity of CRS and/or ICANS) compared to patients that receive step-up dosing over a longer period of time.
  • a step-up dosing schedule comprises administering only two step-up doses of a GPRC5DxCD3 bispecific antibody (e.g., talquetamab) before the first treatment dose, wherein the two step-up doses are administered in an amount of 0.03 mg/kg followed by an amount of 0.2 mg/kg.
  • a GPRC5DxCD3 bispecific antibody e.g., talquetamab
  • a step-up dosing schedule comprises administering only two step-up doses of a GPRC5DxCD3 bispecific antibody (e.g., talquetamab) before the first treatment dose, wherein the two step- up doses are administered in an amount of 0.06 mg/kg followed by an amount of 0.4 mg/kg.
  • the time between the two step-up doses is between about 24 hours and about 72 hours.
  • the first treatment dose is 0.8 mg/kg.
  • the time between the second step- up dose and the first treatment dose is between about 24 hours and about 72 hours.
  • a method of treating multiple myeloma in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody (e.g., talquetamab), wherein the method comprises subcutaneously administering step-up doses on a compressed step-up dosing schedule, wherein the compressed step-up dosing schedule comprises administering only two step-up doses of the GPRC5DxCD3 bispecific antibody before subcutaneously administering a first treatment dose of 0.8 mg/kg, wherein the two step-up doses are administered either (i) in an amount of 0.03 mg/kg followed by an amount of 0.2 mg/kg, or (ii) in an amount of 0.06 mg/kg followed by an amount of 0.4 mg/kg.
  • a GPRC5DxCD3 bispecific antibody e.g., talquetamab
  • the time between the two step-up doses is between about 24 hours and about 72 hours.
  • the time between the second step-up dose and the first treatment dose is between about 24 hours and about 72 hours.
  • the subject is monitored (e.g., by a healthcare professional) for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) while receiving step- up doses, and administration of the compressed step-up dosing schedule shortens the amount of time the subject is monitored for CRS and ICANS.
  • CRS cytokine release syndrome
  • ICANS immune effector cell-associated neurotoxicity syndrome
  • administration of the compressed step-up dosing results in no difference, or minimal difference, in incidence and/or severity of CRS exhibited by the subject, compared to a subject that is administered three 300658828v1 258199.061902 (JBI6857WOPCT1) step-up doses (e.g., 0.01 mg/kg, 0.06 mg/kg, and 0.4 mg/kg with 2-4 days between the step- up doses and 2-4 days between the third step-up dose and first treatment dose).
  • the method comprises subcutaneously administering treatment doses of the GPRC5DxCD3 bispecific antibody (preferably talquetamab) in sequential 28-day treatment cycles.
  • the method comprises subcutaneously administering the step-up doses during a step-up phase in Cycle 1, and then subcutaneously administering a treatment dose of 0.8 mg/kg every two weeks (Q2W) (e.g., starting from Cycle 1 or Cycle 2).
  • the method further comprises subcutaneously administering a treatment dose of 0.8 mg/kg every two weeks (Q2W) and then subcutaneously administering a treatment dose of 0.8 mg/kg every four weeks (Q4W) either: (i) starting at treatment Cycle 5 if the subject has achieved a very good partial response, a complete response or a stringent complete response, as determined by IMWG response criteria; or (ii) starting at treatment Cycle 7, regardless of clinical response in the subject.
  • Embodiments of the present invention also provide methods of reducing the risk of CRS with a GPRC5DxCD3 bispecific antibody (e.g., talquetamab) by administering prophylactic tociluzimab.
  • the method comprises administering tocilizumab (e.g., intravenously) to the subject before administering a first step-up dose of the GPRC5DxCD3 bispecific antibody (e.g., talquetamab).
  • the tocilizumab is administered in an amount of 8 mg/kg.
  • the tocilizumab is administered about 3 hrs before the first step-up dose. tocilizumab.
  • dexamethasone is administered (e.g., orally or intravenously) after each step-up dose and after a first treatment dose of the GPRC5DxCD3 bispecific antibody (e.g., talquetamab).
  • the dexamethasone is administered in an amount of 8 mg. According to an embodiment, the dexamethasone is administered in an amount of 8 mg daily for two days after each step-up dose and first full treatment dose. According to an embodiment, administration of the tociluzimab results in reduced incidence and/or severity of CRS exhibited by the subject, compared to a subject that is not administered tociluzimab prior to administration of the GPRC5DxCD3 bispecific antibody.
  • administration of the tociluzimab and the dexamethasone results in reduced incidence and/or severity of CRS exhibited by the subject, compared to a subject that is not administered tociluzimab and dexamethasone prior to administration of the GPRC5DxCD3 bispecific antibody.
  • 300658828v1 258199.061902 JBI6857WOPCT1 EXEMPLARY EMBODIMENTS [0223]
  • JBI6857WOPCT1 JBI6857WOPCT1 EXEMPLARY EMBODIMENTS
  • a method of treating multiple myeloma in a subject in need thereof comprising administering to the subject a combination therapy comprising a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody and a therapeutically effective amount of pomalidomide.
  • the GPRC5DxCD3 bispecific antibody comprises a GPRC5D 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 GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain comprising 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 GPRC5DxCD3 bispecific antibody is an IgG1, an IgG2, an IgG3 or an IgG4 isotype. 5.
  • the GPRC5DxCD3 bispecific antibody is an IgG4 isotype. 6. The method of any of embodiments 1-5, wherein the GPRC5DxCD3 bispecific antibody comprises one or more substitutions in its Fc region. 7. The method of any of embodiments 1-6, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering). 300658828v1 258199.061902 (JBI6857WOPCT1) 8.
  • the GPRC5DxCD3 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 GPRC5D 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 GPRC5DxCD3 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 GPRC5DxCD3 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 GPRC5DxCD3 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 GPRC5DxCD3 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. 300658828v1 258199.061902 (JBI6857WOPCT1) 15.
  • the method of any of embodiments 1-10, wherein the GPRC5DxCD3 bispecific antibody is talquetamab. 16.
  • the method of any of embodiments 1-21 comprising subcutaneously administering treatment doses of the GPRC5DxCD3 bispecific antibody in an amount of 0.8 mg/kg bi-weekly (Q2W). 25. The method of any of embodiments 1-24 comprising subcutaneously administering to the subject one or more step-up doses of the GPRC5DxCD3 bispecific antibody prior to administering the first treatment dose of the GPRC5DxCD3 bispecific antibody. 26. The method of any of embodiments 1-25, comprising subcutaneously administering 2 or 3 step-up doses of the GPRC5DxCD3 bispecific antibody prior to subcutaneously administering the first treatment dose. 300658828v1 258199.061902 (JBI6857WOPCT1) 27.
  • any of embodiments 1-26, comprising (i) subcutaneously administering step-up doses of 0.01 mg/kg and 0.06 mg/kg of the GPRC5DxCD3 bispecific antibody prior to subcutaneously administering a treatment dose, or (ii) subcutaneously administering step-up doses of 0.03 mg/kg and 0.2 mg/kg of the GPRC5DxCD3 bispecific antibody prior to subcutaneously administering a treatment dose, or (iii) subcutaneously administering step-up doses of 0.06 mg/kg and 0.4 mg/kg of the GPRC5DxCD3 bispecific antibody prior to subcutaneously administering a treatment dose.
  • any of embodiments 1-29 comprising orally administering the pomalidomide in an amount of 4 mg daily.
  • the combination therapy comprises sequential 28-day treatment cycles.
  • 34. The method of any of embodiments 1-32, wherein the pomalidomide is administered in an amount of 2 mg daily or 4 mg daily for Days 1-21 of each pomalidomide treatment cycle.
  • 35. The method of any of embodiments 1-32, wherein the pomalidomide is administered in an amount of 2 mg daily for Days 1-21 of each pomalidomide treatment cycle.
  • 36. The method of any of embodiments 1-32, wherein the pomalidomide is administered in an amount of 4 mg daily for Days 1-21 of each pomalidomide treatment cycle. 37.
  • the combination therapy comprises sequential 28-day treatment cycles; administration of the GPRC5DxCD3 bispecific antibody starts in Cycle 1; and 300658828v1 258199.061902 (JBI6857WOPCT1) administration of the pomalidomide starts in Cycle 2. 38.
  • the combination therapy comprises sequential 28-day treatment cycles;
  • Cycle 1 is a step-up phase comprising administration of one or more step-up doses and one or more treatment doses of the GPRC5DxCD3 bispecific antibody;
  • each subsequent treatment cycle comprises oral administration of the pomalidomide in an amount of 2 mg daily on Days 1-21; and subcutaneous administration of the GPRC5DxCD3 bispecific antibody in an amount of either (i) 0.4 mg/kg weekly (QW), or (ii) 0.8 mg/kg bi-weekly (Q2W).
  • Cycle 1 is a step-up phase comprising (i) administration of a first step-up dose of 0.01 mg/kg, a second step-up dose of 0.06 mg/kg, a third step-up dose of 0.4 mg/kg, and a first treatment dose of 0.8 mg/kg of the GPRC5DxCD3 bispecific antibody, or (ii) administration of a first step-up dose of 0.03 mg/kg, a second step-up dose of 0.2 mg/kg, and a first treatment dose of 0.8 mg/kg of the GPRC5DxCD3 bispecific antibody, or (iii) administration of a first step-up dose of 0.06 mg/kg, a second step-up dose of 0.4 mg/kg, and a first treatment dose of 0.8 mg/kg of the GPRC5DxCD3 bispecific antibody; and each subsequent treatment cycle (Cycle 2 onward) comprises oral administration of the pomalidomide in
  • a method of improving median progression free survival (PFS) in a population of subjects with relapsed or refractory multiple myeloma that have received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide comprising administering to the population of subjects a combination therapy comprising a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody (e.g., talquetamab), a therapeutically effective amount of pomalidomide and a therapeutically effective amount of dexamethasone, wherein the method comprises: treating the subject according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein: 300658828v1 258199.061902 (JBI6857WOPCT1) one or more step-up doses of the GPRC5DxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the GPRC5DxCD3 bispecific
  • a method of improving overall response rate (ORR) in a population of subjects with relapsed or refractory multiple myeloma that have received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide comprising administering to the population of subjects a combination therapy comprising a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody (e.g., talquetamab), a therapeutically effective amount of 300658828v1 258199.061902 (JBI6857WOPCT1) pomalidomide and a therapeutically effective amount of dexamethasone, wherein the method comprises: treating the subject according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein: one or more step-up doses of the GPRC5DxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the GPRC5DxCD3 bi
  • step-up phase comprises (i) subcutaneously administering step-up doses of 0.01 mg/kg and 0.06 mg/kg of the GPRC5DxCD3 bispecific antibody 2-4 days apart from each other (e.g., on Days 1 300658828v1 258199.061902 (JBI6857WOPCT1) and 4, respectively), or (ii) subcutaneously administering step-up doses of 0.03 mg/kg and 0.2 mg/kg of the GPRC5DxCD3 bispecific antibody 24-72 hours apart from each other, or (iii) subcutaneously administering step-up doses of 0.06 mg/kg and 0.4 mg/kg of the GPRC5DxCD3 bispecific antibody 24-72 hours apart from each other.
  • step-up phase comprises (i) subcutaneously administering step-up doses of 0.01 mg/kg, 0.06 mg/kg and 0.4 mg/kg of the GPRC5DxCD3 bispecific antibody 2-4 days apart from each other (e.g., on Days 1, 4 and 8, respectively), or (ii) subcutaneously administering step-up doses of 0.03 mg/kg and 0.2 mg/kg of the GPRC5DxCD3 bispecific antibody 24-72 hours apart from each other, or (iii) subcutaneously administering step-up doses of 0.06 mg/kg and 0.4 mg/kg of the GPRC5DxCD3 bispecific antibody 24-72 hours apart from each other. 51.
  • step-up phase comprises (i) subcutaneously administering step-up doses of 0.01 mg/kg, 0.06 mg/kg and 0.4 mg/kg of the GPRC5DxCD3 bispecific antibody 2-4 days apart from each other (e.g., on Days 1, 4 and 8, respectively), or (ii) subcutaneously administering step-up doses of 0.03 mg/kg and 0.2 mg/kg of the GPRC5DxCD3 bispecific antibody 24-72 hours apart from each other, or (iii) subcutaneously administering step-up doses of 0.06 mg/kg and 0.4 mg/kg of the GPRC5DxCD3 bispecific antibody 24-72 hours apart from each other, and then subcutaneously administering the treatment dose of 0.8 mg/kg of the GPRC5DxCD3 bispecific antibody at least two days after the last step-up dose (e.g., between Days 7-15, such as Day 15).
  • step-up phase comprises (i) subcutaneously administering step-up doses of 0.01 mg/kg, 0.06 mg/
  • any of embodiments 1-42 comprising: treating the subject according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein: one or more step-up doses of the GPRC5DxCD3 bispecific antibody (e.g., talquetamab) are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject in an amount of 0.8 mg/kg, wherein the treatment doses of the GPRC5DxCD3 bispecific antibody are administered to the subject on a bi-weekly dosing schedule (Q2W) starting from treatment Cycle 2 (e.g., on Days 1 and 15), and then treatment doses of the GPRC5DxCD3 bispecific antibody are subcutaneously administered to the subject on a monthly dosing schedule (Q4W) either: (i) starting at treatment Cycle 5 if the subject has 300658828v1 258199.061902 (JBI6857WOP
  • Q2W
  • a method of improving median progression free survival (PFS) in a population of subjects with relapsed or refractory multiple myeloma that have received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide comprising administering to the population of subjects a combination therapy comprising a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody (e.g., talquetamab), a therapeutically effective amount of pomalidomide and a therapeutically effective amount of dexamethasone, wherein the method comprises: treating the subject according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein: one or more step-up doses of the GPRC5DxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject in an amount of 0.8 mg/kg, wherein the
  • a method of improving overall response rate (ORR) in a population of subjects with relapsed or refractory multiple myeloma that have received between 1-4 prior lines of therapy including an anti-CD38 antibody (e.g., daratumumab) and lenalidomide comprising administering to the population of subjects a combination therapy comprising a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody (e.g., talquetamab), a therapeutically effective amount of pomalidomide and a therapeutically effective amount of dexamethasone, wherein the method comprises: treating the subject according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein: one or more step-up doses of the GPRC5DxCD3 bispecific antibody are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject in an amount of 0.8 mg/kg, where
  • a method of treating multiple myeloma in a subject in need thereof comprising administering to the subject a combination therapy comprising talquetamab, pomalidomide and daratumumab according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein the subject has relapsed or refractory multiple myeloma and received at least 1 prior line of therapy including a PI and lenalidomide, and wherein: one or more step-up doses of the talquetamab are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the talquetamab is subcutaneously administered to the subject in an amount of 0.8 mg/kg, and the treatment doses of the talquetamab are administered to the subject on a bi- weekly dosing schedule (Q2W) starting from treatment Cycle 2 (e.g., on Days 1 and 15), and then treatment doses of the talquetamab are subcutaneously administered to the subject on a monthly dosing schedule
  • a method of treating multiple myeloma in a subject in need thereof comprising administering to the subject a combination therapy comprising talquetamab and daratumumab according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein the subject has relapsed or refractory multiple myeloma and received at least 1 prior line of therapy including a PI and lenalidomide, and wherein: one or more step-up doses of the talquetamab are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the talquetamab is subcutaneously administered to the subject in an amount of 0.8 mg/kg, and the treatment doses of the talquetamab are administered to the subject on a bi- weekly dosing schedule (Q2W) starting from treatment Cycle 2 (e.g., on Days 1 and 15), and then treatment doses of the talquetamab are subcutaneously administered to the subject on a monthly dosing schedule (Q4W)
  • a method of treating multiple myeloma in a subject in need thereof comprising administering to the subject a combination therapy comprising talquetamab, lenalidomide and daratumumab according to a therapeutically effective regimen that comprises sequential 28-day treatment cycles, wherein the subject has newly diagnosed multiple myeloma according to IMWG diagnostic criteria and is ineligible or not intended for ASCT as initial therapy, and wherein: one or more step-up doses of the talquetamab are subcutaneously administered to the subject during a step-up phase in Cycle 1, and then each treatment dose of the 300658828v1 258199.061902 (JBI6857WOPCT1) talquetamab is subcutaneously administered to the subject in an amount of 0.8 mg/kg on a monthly dosing schedule (Q4W) starting in treatment cycle 2, and the lenalidomide is orally administered in an amount of 25 mg daily on Days 1-21 of each treatment cycle, starting in treatment Cycle 2, and daratumumab is subcutaneous
  • any of embodiments 62-64 wherein the subject achieves longer PFS compared to a subject that is administered a combination regimen comprising daratumumab, lenalidomide and dexamethasone (DRd) without talquetamab.
  • a combination regimen comprising daratumumab, lenalidomide and dexamethasone (DRd) without talquetamab.
  • the step-up phase comprises subcutaneously administering two or three step-up doses of the talquetamab, e.g., 2-4 days apart from each other or 24-72 hours apart from each other. 68.
  • step-up phase comprises (i) subcutaneously administering step-up doses of 0.01 mg/kg, 0.06 mg/kg and 0.4 mg/kg of the talquetamab 2-4 days apart from each other, or (ii) subcutaneously administering step-up doses of 0.03 mg/kg and 0.2 mg/kg of the talquetamab 24-72 hours apart from each other, or (iii) subcutaneously administering step-up doses of 0.06 mg/kg and 0.4 mg/kg of the talquetamab 24-72 hours apart from each other. 69.
  • step-up phase comprises subcutaneously administering a treatment dose of 0.8 mg/kg after the step-up doses.
  • 70 The method of any of embodiments 1-69 comprising administering only two step-up doses of the GPRC5DxCD3 bispecific antibody (e.g., talquetamab), before the first treatment dose, wherein the two step-up doses are administered in an amount of 0.03 mg/kg followed by an amount of 0.2 mg/kg. 300658828v1 258199.061902 (JBI6857WOPCT1) 71.
  • GPRC5DxCD3 bispecific antibody e.g., talquetamab
  • any of embodiments 1-69 comprising administering only two step-up doses of the GPRC5DxCD3 bispecific antibody (e.g., talquetamab), before the first treatment dose, wherein the two step-up doses are administered in an amount of 0.06 mg/kg followed by an amount of 0.4 mg/kg.
  • the method of embodiment 70 or 71, wherein the time between the two step- up doses is between about 24 hours and about 72 hours.
  • 73 The method of embodiment 70 or 71, wherein the time between the two step- up doses is between about 2 days and about 4 days.
  • 74 The method of any of embodiments 70-73, wherein the first treatment dose is 0.8 mg/kg. 75.
  • a method of treating multiple myeloma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody (e.g., talquetamab), wherein the method comprises subcutaneously administering step-up doses on a compressed step-up dosing schedule, wherein the compressed step-up dosing schedule comprises administering only two step- up doses of the GPRC5DxCD3 bispecific antibody before subcutaneously administering a first treatment dose of 0.8 mg/kg, wherein the two step-up doses are administered either (i) in an amount of 0.03 mg/kg followed by an amount of 0.2 mg/kg, or (ii) in an amount of 0.06 mg/kg followed by an amount of 0.4 mg/kg.
  • a GPRC5DxCD3 bispecific antibody e.g., talquetamab
  • the method of any of embodiments 78-82, wherein the time between the second step-up dose and the first treatment dose is between about 24 hours and about 72 hours.
  • 84. The method of any of embodiments 78-82, wherein the time between the second step-up dose and the first treatment dose is between about 2 days and about 4 days.
  • 85. The method of any of embodiments 78-84, wherein the method comprises subcutaneously administering treatment doses in sequential 28-day treatment cycles.
  • the method further comprises subcutaneously administering the step-up doses during a step-up phase in Cycle 1, and subcutaneously administering a treatment dose of 0.8 mg/kg every two weeks (Q2W) (e.g., starting from Cycle 1 or Cycle 2).
  • Q2W subcutaneously administering 0.8 mg/kg every two weeks
  • the method further comprises subcutaneously administering a treatment dose of 0.8 mg/kg every two weeks (Q2W) and then subcutaneously administering a treatment dose of 0.8 mg/kg every four weeks (Q4W) either: (i) starting at treatment Cycle 5 if the subject has achieved a very good partial response, a complete response or a stringent complete response, as determined by IMWG response criteria; or (ii) starting at treatment Cycle 7, regardless of clinical response in the subject. 88.
  • the GPRC5DxCD3 bispecific antibody comprises a GPRC5D 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. 89.
  • the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain comprising 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. 300658828v1 258199.061902 (JBI6857WOPCT1) 90.
  • the GPRC5DxCD3 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. 98.
  • the GPRC5DxCD3 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. 99.
  • the GPRC5DxCD3 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% 300658828v1 258199.061902 (JBI6857WOPCT1) 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. 100.
  • HC1 first heavy chain having at least 95% identity to the amino acid sequence of SEQ ID NO: 12
  • LC1 having at least 95% 300658828v1 258199.061902
  • HC2 second heavy chain having at least 95% identity to the amino acid sequence of SEQ ID NO: 22
  • LC2 having at least 95% identity to the amino acid sequence of SEQ ID NO: 23.
  • the GPRC5DxCD3 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.
  • HC1 first heavy chain
  • LC1 first light chain
  • HC2 having at least 98% identity to the amino acid sequence of SEQ ID NO: 22
  • LC2 second light chain having at least 98% identity to the amino acid sequence of SEQ ID NO: 23.
  • any of embodiments 70-110 wherein the subject is monitored (e.g., by a healthcare professional) for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) while receiving step-up doses.
  • CRS cytokine release syndrome
  • ICANS immune effector cell-associated neurotoxicity syndrome
  • administration of two step-up doses instead of three step-up doses shortens the amount of time the subject is monitored for CRS and ICANS.
  • the method of embodiment 111 or 112 wherein administration of two step- up doses results in no difference, or minimal difference, in incidence and/or severity of CRS exhibited by the subject, compared to a subject that is administered three step-up doses. 114.
  • any of embodiments 1-110 wherein administration of compressed step-up dosing results in no difference, or negligible difference, in incidence and/or severity of CRS exhibited by the subject, compared to a subject that is administered three step-up doses, wherein said compressed step-up dosing comprises administration of two step-up doses of either (i) 0.03 mg/kg and 0.2 mg/kg, or (ii) 0.06 mg/kg and 0.4 mg/kg, with about 24-72 hours between the two step-up doses, and about 24-72 hours between the second step-up dose and first treatment dose, and wherein said three step-up doses comprise administration of 0.01 mg/kg, 0.06 mg/kg, and 0.4 mg/kg with 2-4 days between the step-up doses and 2-4 days between the third step-up dose and first treatment dose.
  • Example 1 Talquetamab + Pomalidomide in Patients with Relapsed/Refractory Multiple Myeloma: Safety and Preliminary Efficacy Results from the Phase 1b MonumenTAL-2 Study 300658828v1 258199.061902 (JBI6857WOPCT1) [0227] Antibodies [0228] Anti-GPRC5D/anti-CD3 antibody talquetamab (also called Tal) was made by Janssen Pharmaceuticals. Talquetamab comprises a GPRC5D binding arm and a CD3 binding arm, the amino acid sequences of which are shown in Table 5 and Table 6, respectively. Table 5.
  • GPRC5D is a novel antigen that is highly expressed on malignant plasma cells but has low expression on B cells and normal plasma cells. Tal has demonstrated deep and durable responses, including in high-risk populations, and a clinically manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (RRMM) in the MonumenTAL-1 study (NCT03399799/NCT04634552).
  • Pomalidomide (pom) is an immunomodulatory drug (IMiD) that has direct on-tumor apoptotic activity and enhances immune activity. This example reports initial efficacy and safety results of tal + pom from the MonumenTAL-2 study.
  • the tal + pom results represent the first clinical results from a combination therapy comprising a GPRC5D-targeted therapy and an IMiD.
  • Methods [0232] MonumenTAL-2 (NCT05050097) is a multi-arm, phase 1b study of tal in combination with antimyeloma agents in pts with MM. A schematic summary of the MonumenTAL-2 study design is provided in FIG.1. [0233] A summary of the patient characteristics of the Tal + Pom cohort of MonumenTAL-2 is provided in FIG.2.
  • Pts received the recommended phase 2 doses of subcutaneous tal 0.4 mg/kg weekly (QW) or 0.8 mg/kg every other week (Q2W), with step- up dosing, + oral pom 2 mg daily (dose escalation to 4 mg daily permitted) starting in cycle prior T-cell redirection therapies including BsAbs and chimeric antigen receptor (CAR)-T along with prior pom exposure were permitted.
  • CRS and ICANS were graded by ASTCT criteria; all other adverse events (AEs) were graded by CTCAE v5.0. Response was assessed by IMWG criteria. Efficacy endpoints are presented as individual cohorts (QW and Q2W); safety is presented across both cohorts.
  • Cytopenias were mostly grade 3/4 and generally limited to the first few cycles. ICANS occurred in 3 pts; all were grade 1. Taste-, skin-, nail-, and rash- related GPRC5D AEs were mainly grade 1/2, with few discontinuations. Nine pts had AEs that led to treatment discontinuation. AEs led to dose reduction of tal or pom in 37.1% and 48.6% of pts, respectively; 65.7% and 77.1% of pts skipped doses of tal and pom due to AEs, respectively. The most common AEs that led to dose reduction of pom included neutropenia, peripheral neuropathy, and fatigue. Dose reductions and schedule changes were used to manage AEs.
  • Example 2 A Study Comparing Talquetamab Plus Pomalidomide, Talquetamab Plus Teclistamab, and Elotuzumab, Pomalidomide, and Dexamethasone or Pomalidomide, Bortezomib, and Dexamethasone in Participants with Relapsed or Refractory Myeloma who Have Received an Anti-CD38 Antibody and Lenalidomide (MonumenTAL-6) [0250] This is a randomized, Phase 3, active-controlled, parallel, multicenter, interventional, open-label study in participants with relapsed or refractory multiple myeloma who have received 1 to 4 prior lines of therapy including an anti-CD38 mAb and lenalidomide.
  • the primary objective of this study is to compare the effectiveness of either talquetamab plus pomalidomide (Tal-P) or talquetamab plus teclistamab (Tal-Tec) with elotuzumab, pomalidomide, and dexamethasone (EPd) or pomalidomide, bortezomib, and dexamethasone (PVd).
  • Secondary objectives include to further compare the efficacy of either Tal-P or Tal-Tec with EPd or PVd and to assess the safety and tolerability of Tal-P and Tal- Tec.
  • Tal-P or Tal-Tec will improve PFS compared with EPd or PVd in participants with relapsed or refractory multiple myeloma who have received 1 to 4 prior lines of therapy including an anti-CD38 mAb and lenalidomide.
  • Study Arms and Duration [0256] Study treatment will be administered in 28-day cycles for Tal-P (Arm A), Tal-Tec (Arm B), and EPd (Arm C).
  • Talquetamab INITIAL Arm A dosing schedule, which was later updated: [0260] In Cycle 1 (28-day cycle) of Arm A, the following doses of subcutaneous talquetamab will be administered: - Talquetamab step-up dose 1 (SU1): 0.01 mg/kg, administered on Day 1; - Talquetamab step-up dose 2 (SU2): 0.06 mg/kg, administered 2d after SU1, between Days 3-6; - Talquetamab treatment dose (sometimes referred to as step-up dose 3): 0.4 mg/kg, administered 2d after SU2, between Days 5-10; - Talquetamab treatment dose: 0.8mg/kg, administered 2d after first treatment dose (step-up dose 3) of 0.4 mg/kg, between Days 7-15.
  • SU1 0.01 mg/kg, administered on Day 1
  • - Talquetamab step-up dose 2 (SU2) 0.06 mg/kg, administered 2d after SU1, between Days 3-6
  • - Talquetamab treatment dose (sometimes referred
  • the subcutaneous Talquetamab treatment dose of 0.8mg/kg will be administered as follows in Arm A: - Cycle 2 – Cycle 4 (C2-C4), Talquetamab SC is administered bi-weekly (Q2W), i.e., 14 days ( ⁇ 3d) after prior treatment dose; - From Cycle 5 (C5), if confirmed VGPR or better, schedule can change to Q4W dosing (Day 1 of each 28-day cycle only) per investigator discretion; - Q4W from Cycle 7 (C7) for all participants.
  • Q2W bi-weekly
  • Q4W bi-weekly
  • schedule can change to Q4W dosing (Day 1 of each 28-day cycle only) per investigator discretion
  • Q4W from Cycle 7 (C7) for all participants.
  • Talquetamab UPDATED Arm A dosing schedule: [0263] In Cycle 1 (28-day cycle) of Arm A, the following doses of subcutaneous talquetamab will be administered: - Talquetamab step-up dose 1 (SU1): 0.01 mg/kg, administered on Day 1; - Talquetamab step-up dose 2 (SU2): 0.06 mg/kg, administered 2d after SU1, between Days 3-6; - Talquetamab treatment dose (sometimes referred to as step-up dose 3): 0.4 mg/kg, administered 2d after SU2, between Days 5-10; 300658828v1 258199.061902 (JBI6857WOPCT1) - Talquetamab treatment dose: 0.8mg/kg, administered 2d after first treatment dose (step-up dose 3) of 0.4 mg/kg, between Days 7-15.
  • SU1 0.01 mg/kg
  • SU2 0.06 mg/kg
  • SU1 0.06 mg/kg
  • SU1 0.06 mg/kg
  • the selected dose regimen for pomalidomide is based on standard doses used in clinical practice for the treatment of multiple myeloma, as detailed in respective product information. Participants can continue therapy with pomalidomide beyond Cycle 26 if no discontinuation criteria are met.
  • Arm B (Tal-Tec) Dosing Schedule [0270] In Arm B, participants will receive therapy with Tal/Tec for up to 26 cycles if they have no sign of progressive disease or toxicity. An initial Arm B dosing schedule was later updated in a protocol amendment, as a result of developing data from other clinical studies involving Tal and Tec.
  • a reduction in talquetamab dose frequency after response does not compromise efficacy and may ameliorate GPRC5D specific AEs.
  • Talquetamab Arm B dosing schedule [0272] Talquetamab will be administered as follows, in 28-day treatment cycles: - In Cycle 1, the following doses of subcutaneous talquetamab are administered: o Talquetamab step-up dose 1 (SU1): 0.01 mg/kg, administered on Day 1; o Talquetamab step-up dose 2 (SU2): 0.06 mg/kg, administered 2d after SU1; o Talquetamab treatment dose (sometimes referred to as step-up dose 3): 0.4 mg/kg, administered 2d after SU2; o Talquetamab treatment dose: 0.8 mg/kg, administered 2d after first treatment dose (step-up dose 3) of 0.4 mg/kg, between Days 7-15; - In subsequent treatment cycles following Cycle 1, the subcutaneous Talquetamab treatment doses of 0.8mg/kg are administered as follows: o Cycle 2 – Cycle 4 (C2-C4), Talquetamab SC is administered bi-weekly (Q2W), i.e., 14
  • Teclistamab Arm B dosing schedule [0274] Teclistamab will be administered as follows, in 28-day treatment cycles: - In Cycle 1, the following doses of subcutaneous teclistamab are administered: o Tec step-up dose 1 (SU1): 0.06 mg/kg, administered on Day 1; o Tec step-up dose 2 (SU2): 0.3 mg/kg, administered 2d after SU1; o Tec treatment dose (sometimes referred to as step-up dose 3): 1.5 mg/kg, administered 2d after SU2; 300658828v1 258199.061902 (JBI6857WOPCT1) o Tec treatment dose: 1.5 mg/kg, administered 2d after first treatment dose (step-up dose 3) of 1.5 mg/kg, between Days 7-15.
  • o Tec step-up dose 1 SU1
  • SU2 0.06 mg/kg
  • o Tec treatment dose (sometimes referred to as step-up dose 3): 1.5
  • Efficacy Evaluations will occur per IMWG criteria (2016) as defined in the protocol using data from serum, urine, bone marrow, and imaging (if applicable). Responses or progression will be evaluated by investigators, use of a computerized algorithm, and by an IRC; assessment by the IRC will be used as the primary analysis.
  • Primary Outcome Measures Progression Free Survival (PFS) [ Time Frame: Up to 7 years 2 months ] PFS is defined as the duration from the date of randomization to either progressive disease or death, whichever comes first.
  • ORR Overall Response Rate
  • PR partial response
  • IMWG international myeloma working group
  • VPR Very Good Partial Response
  • JBI6857WOPCT1 Very Good Partial Response
  • MRD Magnetic Reduction
  • MRD-negative CR is defined as the percentage of participants who achieve both CR or better and MRD negativity at a threshold of 10 ⁇ -5 at any timepoint after the date of randomization and before disease progression or start of subsequent antimyeloma therapy (SST).
  • OS Overall Survival
  • PFS2 Progression Free Survival on Next-line Therapy
  • PFS2 is defined as time from randomization to progression on the next line of therapy or death, whichever comes first.
  • TTNT Time to Next Treatment [ Time Frame: Up to 7 years 2 months ]
  • TTNT is defined as the time from randomization to the start of SST.
  • Serum Concentration of Talquetamab and Teclistamab [ Time Frame: Up to 7 years 2 months ] Serum concentration of talquetamab and teclistamab will be reported.
  • Time Frame: Up to 7 years 2 months Number of participants with Anti-drug Antibodies (ADAs) to Talquetamab and Teclistamab will be reported.
  • Time to Sustained Worsening in Symptoms, Functioning, and Health-related Quality of Life (HRQoL) as Assessed by Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q) [ Time Frame: Up to 7 years 2 months ] Time to sustained worsening in symptoms, functioning and HRQoL is defined as the interval from the date of randomization to the start date of meaningful change.
  • the MySIm-Q is a disease-specific patient-reported outcome (PRO) assessment complementary to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 item (EORTC-QLQ-C30). It includes 17 items resulting in a symptom subscale and an impact subscale. 300658828v1 258199.061902 (JBI6857WOPCT1) Time to Sustained Worsening in Symptoms, Functioning, and Health-related Quality of Life (HRQoL) as Assessed by EORTC-QLQ-C30 [ Time Frame: Up to 7 years 2 months ] Time to sustained worsening in symptoms, functioning and HRQoL is defined as the interval from the date of randomization to the start date of meaningful change.
  • EORTC-QLQ-C30 Version 3 includes 30 items that make up 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (pain, fatigue, and nausea or vomiting), and 5 single symptom items (dyspnea, insomnia, appetite loss, constipation, and diarrhea) and a single impact item (financial difficulties).
  • the recall period is 7 days ("past week"), and responses are reported using a verbal and numeric rating scales.
  • the item and scale scores are transformed to a 0 to 100 scale. A high scale score represents a higher response level.
  • Time to Sustained Worsening in Symptoms, Functioning, and Health-related Quality of Life is assessed by EuroQol Five Dimension Questionnaire 5-Level (EQ-5D-5L) [ Time Frame: Up to 7 years 2 months ]
  • Time to sustained worsening in symptoms, functioning and HRQoL is defined as the interval from the date of randomization to the start date of meaningful change.
  • the EQ-5D-5L is a 5- item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain or discomfort, and anxiety or depression plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).
  • PGI-S will be used as an anchor, external criterion, to determine meaningful change in scores for the MySIm-Q and EORTC-QLQ-C30 in this population.
  • the response options are presented as a 5-point verbal rating scale from “none” to “very severe.”
  • Time to sustained worsening in symptoms, functioning and HRQoL is defined as the interval from the date of randomization to the start date of meaningful change.
  • the epstein taste 300658828v1 258199.061902 (JBI6857WOPCT1) survey consists of 17 items from the full 71 item PRO instrument, specific to taste changes. developed for use in patients with head and neck cancer as a composite of the Vanderbilt Head and Neck Symptom Survey.
  • the MySIm-Q is a disease-specific patient-reported outcome (PRO) assessment complementary to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 item (EORTC-QLQ-C30). It includes 17 items resulting in a symptom subscale and an impact subscale.
  • the recall period is 7 days ("past week"), and responses are reported using a verbal and numeric rating scales.
  • the item and scale scores are transformed to a 0 to 100 scale.
  • a high scale score represents a higher response level.
  • a high score for a functional scale represents a high or healthy level of functioning and a high score for the global health status represents high HRQoL, but a high score for a symptom scale or item represents a high level of symptomatology or problems.
  • HRQoL Health-related Quality of Life
  • the EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain or discomfort, and anxiety or depression plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). Change from Baseline in Symptoms, Functioning, and Health-related Quality of Life (HRQoL) as Assessed by PGI-S [ Time Frame: Up to 7 years 2 months ] 300658828v1 258199.061902 (JBI6857WOPCT1) Change from baseline in symptoms, functioning, and HRQoL as assessed by PGI-S will be reported.
  • HRQoL Health-related Quality of Life
  • the EORTC-QLQ-C30 Version 3 includes 30 items that make up 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (pain, fatigue, and nausea or vomiting), and 5 single symptom items (dyspnea, insomnia, appetite loss, constipation, and diarrhea) and a single impact item (financial difficulties).
  • the recall period is 7 days ("past week"), and responses are reported using a verbal and numeric rating scales.
  • the item and scale scores are transformed to a 0 to 100 scale. A high scale score represents a higher response level.
  • a high score for a functional scale represents a high or healthy level of functioning and a high score for the global health status represents high HRQoL, but a high score for a symptom scale or item represents a high level of symptomatology or problems.
  • Active Comparator Arm C: Elotuzumab+ Drug: Pomalidomide Pomalidomide+Dexamethasone (EPd) or Pomalidomide will be administered orally.
  • Drug Elotuzumab intravenous (IV) injection in combination Elotuzumab will be administered with pomalidomide and dexamethasone intravenously.
  • Dexamethasone dexamethasone orally as per investigator Dexamethasone will be administered either or intravenously. 300658828v1 258199.061902 (JBI6857WOPCT1) choice. Dexamethasone will be administered Drug: Bortezomib as a pretreatment medication. Bortezomib will be administered as a SC injection.
  • Example 3 A Phase 3 Randomized Study Comparing Talquetamab SC in Combination With Daratumumab SC and Pomalidomide (Tal-DP) or Talquetamab SC in Combination With Daratumumab SC (Tal-D) Versus Daratumumab SC, Pomalidomide and Dexamethasone (DPd), in Participants With Relapsed or Refractory Multiple Myeloma who Have Received at Least 1 Prior Line of Therapy (MonumenTAL-3; NCT05455320) [0286] Objectives [0287] The primary objective of this study is to compare the efficacy of talquetamab SC in combination with daratumumab SC and pomalidomide (Tal-DP; Arm A) and talquetamab SC in combination with daratumumab SC (Tal-D; Arm C) with that of daratumumab SC in combination with pomalidomide and de
  • PFS primary endpoint
  • key secondary endpoints overall response, CR or better, MRD-negative CR and OS
  • data will be collected to evaluate VGPR or better; PFS2; safety profile (ie, incidence and severity of AEs); PK and 300658828v1 258199.061902 (JBI6857WOPCT1) immunogenicity for talquetamab SC and daratumumab SC; PROs; MRU; and other exploratory endpoints.
  • An Independent Data Monitoring Committee will be commissioned for this study to review data from the interim analyses and cumulative safety data. Approximately 810 participants will be randomized in a 1:1:1 ratio to Tal-DP (Arm A), DPd (Arm B) and Tal-D (Arm C).
  • Step-up Dose 1 Day 2; Step-up Dose 2: Day 4 (+2 days); Step-up Dose 3: Day 8 (+2 days); treatment dose: Day 15 (+2 days) o
  • Step-up Dose 2 and Step-up Dose 3 may be administered on Day 3 and Day 7, respectively with Sponsor Approval - Cycles 2-4: treatment dose on Days 1 and 15 - Cycles 5-6: Days 1 and 15 or if confirmed VGPR or better, may change to Q4W dosing (Day 1 only) - From Cycle 7: Q4W dosing (Day 1 only) for participants with response of confirmed PR or better.
  • PK results showed that talquetamab trough levels maximum EC90 values identified in an ex vivo cytotoxicity assay.
  • This assay assessed the ability of talquetamab to induce killing using mononuclear cells from the bone marrow samples of multiple myeloma patients in co-culture with T cells from healthy donors.
  • the trough concentrations at steady state were also comparable to or higher than the maximum weekly dose schedule.
  • Response data in this study are preliminary but suggest a promising effect of talquetamab in combination with daratumumab SC.
  • the frequency of dosing may be decreased at the investigator's discretion to Q4W for talquetamab starting at C5D1 for participants with response of confirmed VGPR or better.
  • talquetamab dosing must be switched to Q4W starting at C7D1.
  • the median concentration-time profile following Q4W dosing at C5D1 or C7D1 is estimated to be above the maximum concentration associated with the EC90 value identified in an ex vivo cytotoxicity assay and is expected to be sufficient to maintain efficacy in a low tumor burden setting.
  • PFS is defined as time from the date of randomization to the first documentation of disease progression, or death due to any cause, whichever is reported first.
  • Secondary outcome measures include the following: Overall Response (Partial Overall response (PR or better) is defined as Response [PR] or Better) percentage of participants who have a PR or better per International Myeloma Working Group (IMWG) criteria.
  • Very Good Partial VGPR or better rate is defined as the percentage of Response (VGPR) or participants who achieve a VGPR or better according Better Rate to IMWG response criteria.
  • Complete Response (CR) CR or better rate is defined as the percentage of or Better Rate participants who achieve CR or better according to IMWG response criteria.
  • Overall Minimal Residual MRD-negative CR is defined as proportion of Disease (MRD) Negative participants with CR or stringent CR who achieve CR MRD negativity at a threshold of 10 ⁇ -5 at any timepoint after the first dose of study drug and before disease progression or start of subsequent antimyeloma therapy. 300658828v1 258199.061902 (JBI6857WOPCT1) Overall Survival (OS) OS is defined as the time from the date of randomization to the date of the participant's death.
  • MRD proportion of Disease
  • OS Overall Survival
  • Progression-free Survival PFS2 is defined as the time interval between the date on Next-line Therapy of randomization and date of event, which is defined (PFS2) as progressive disease as assessed by investigator on the first subsequent line of antimyeloma therapy, or death from any cause, whichever occurs first.
  • Time to Next Therapy TTNT is defined as the time from randomization to (TTNT) the start of subsequent antimyeloma treatment.
  • lenalidomide-refractory Participants who have received only 1 prior line of antimyeloma therapy must be considered lenalidomide-refractory (that is, have 300658828v1 258199.061902 (JBI6857WOPCT1) demonstrated progressive disease by IMWG criteria on or within 60 days of completion of lenalidomide-containing regimen).
  • Plasma cell leukemia per IMWG criteria
  • Tec-DR Tec-DR
  • DRd Talquetamab in Combination with Daratumumab SC and Lenalidomide
  • Tal-DR Talquetamab in Combination with Daratumumab SC and Lenalidomide
  • the study will be conducted in 3 phases: Screening (up to 28 days), Treatment (until confirmed progressive disease, death, intolerable toxicity, loss to follow-up, withdrawal of consent, or end of the study, whichever occurs first), and Follow-up (until withdrawal of consent, loss to follow-up, death, or end of study, whichever occurs first).
  • the primary objective is to compare the efficacy of Tec-DR versus DRd and Tal-DR versus DRd in terms of PFS and 12-month MRD-negative CR.
  • Efficacy assessments will occur per IMWG criteria (2016) as defined in the protocol, using data from serum, urine, bone marrow, and imaging.
  • 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
  • Dexamethasone (16 mg) will be administered as pretreatment medication on Days 1, 2, 4, and 8 of Cycle 1.
  • Talquetamab SC C1 3 step-up doses (0.01, 0.06, and 0.4 mg/kg) on Days 2, 4, and 8 followed by treatment dose (0.8 mg/kg) on Day 15 C2+: Q4W treatment doses (0.8 mg/kg) on Day 1
  • Dexamethasone oral/IV 20 C2-3: weekly on Days 1, 8, 15, and 22 mg** * Lenalidomide dose may need to be adjusted for participants with reduced CrCl.
  • Talquetamab and daratumumab will be initiated in Cycle 1 and lenalidomide only added in Cycle 2 after the step-up phase.
  • the talquetamab dose schedule for the Randomized Part of the study will consist of 3 step-up doses (0.01, 0.06, and 0.4 mg/kg) on Cycle 1 Days 2, 4, and 8 followed by the treatment dose of 0.8 mg/kg dose at Cycle 1 Day 15. Starting from Cycle 2, dosing will be 0.8 mg/kg on Day 1 of each cycle.
  • the proposed dose for talquetamab SC was selected based on the PK, pharmacodynamic, safety,and efficacy findings from the a subset of the pivotal RP2D population in MonumtanTAL-1 who switched to less frequent dosing and the Phase 1 portion of the study (monotherapy), the Phase 1b TriMM-2 clinical study (combination therapy in the relapsed/refractory population), and early data from MonumenTAL-2 (combination therapy in the relapsed/refractory and newly diagnosed populations).
  • TEAEs were tolerable and manageable.
  • CRS was generally low grade and neurotoxicity events were rare.
  • This assay assessed the ability of talquetamab to induce killing using mononuclear cells from the bone marrow samples of multiple myeloma patients in co-culture with T cells from healthy donors.
  • the trough concentrations at steady state were also comparable to or higher than the maximum EC90.
  • Exclusion Criteria include the following: Received any prior therapy for multiple myeloma or smoldering myeloma other than a short course of corticosteroids (not to exceed 40 milligrams [mg] of dexamethasone, or equivalent per day for a maximum of 4 days, total of 160 mg dexamethasone or equivalent).
  • AEs were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Responses were assessed per IMWG criteria.
  • CRS cytokine release syndrome
  • ICANS immune effector cell–associated neurotoxicity syndrome
  • There dysgeusia 79.2%; gr 3/4: NA
  • neutropenia 77.9%; gr 3/4: 68.8%
  • CRS 74.0%; all gr 1/2
  • dry mouth 64.9%; gr 3/4: 2.6%
  • fatigue 57.1%; gr 3/4: 5.2%).
  • CRS events predominantly occurred during SUDs across all cohorts, as shown in the following table: SUDs C1D1 Global Q2W cohort a pproved SUDs, mg/kg 0.01 0.06 0.4 0.8 63/154 56/154 2 n (%) 41 2/154 CRS, /154 ( 26.6) (40.9) (36.4) (14.3) Cohort 34 SUDs, mg/kg NA 0.03 0.2 0.8 3/6 CRS, n (%) NA 4/6 ( 66.7) (50.0) 0 Cohort 35 SUDs, mg/kg NA 0.06 0.4 0.8 ) N 9/12 5/12 1/12 CRS, n (% A (75.0) (41.7) (8.3) [0338] Most CRS events occurred during the first SUD for the alternative SUD cohorts (66.7% and 75.0%) vs during the second SUD for the global Q2W cohort (40.9%).
  • Example 7 Prophylactic Tocilizumab (“Toci”) to Mitigate Cytokine Release Syndrome in Patients Receiving Talquetamab for Relapsed/Refractory Multiple Myeloma: Results From the Phase 1/2 MonumenTAL-1 Study [0343] Introduction: In the MonumenTAL-1 study, at 25.6–34.6 months median follow- up across cohorts, cytokine release syndrome (CRS) occurred in 73.1–79.0% of patients, among whom, 35.0–47.4% were treated with tocilizumab (toci; ⁇ other interventions). Data suggest that prophylactic toci before BsAb treatment may reduce the incidence and severity of CRS, which may facilitate outpatient administration of step-up doses (SUDs) and improve patient experience.
  • CRS cytokine release syndrome
  • Eligible patients were from phase 2 of MonumenTAL-1 [0345] Patients received subcutaneous tal 0.8 mg/kg every other week (Q2W) preceded by step-up (priming) doses of 0.01, 0.06, and 0.3 mg/kg in the prospective exploratory cohort. Toci (8 mg/kg IV dose) was given ⁇ 3 hrs before the first tal step-up dose together with 300658828v1 258199.061902 (JBI6857WOPCT1) required pretreatments (glucocorticoid, antihistamine, and antipyretic).
  • Dexamethasone (dex; 8 mg PO/IV) was given daily for 2 days after each step-up dose and first full treatment dose. If posttreatment dex was scheduled on a day when premedication with dex was required, only the premedication dose was given.
  • CRS and ICANS were graded by American Society for Transplantation and Cellular Therapy criteria; other adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
  • Results Twelve (12) patients were included in the analysis, with median follow- up (range) of 4.4 months (0.3–8.8). Most patients were male (75.0%), and ⁇ 42% were Black or African American; patients had a median (range) of 3 (3–10) prior LOT.
  • Grade 3/4 neutropenia occurred early in the prophylactic toci cohorts, consistent with early timing in the global cohorts (plateauing around 5–6 months), although numbers are small.
  • ICANS grade 2; concomitant with CRS.
  • One patient (8.3%) discontinued treatment due to AEs (skin desquamation).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Des modes de réalisation de la présente invention concernent des procédés de traitement du myélome multiple chez un sujet en ayant besoin par l'administration de schémas combinés thérapeutiquement efficaces comprenant un anticorps bispécifique GPRC5DxCD3 et un ou plusieurs éléments parmi le pomalidomide, le daratumumab ou le lénalidomide.
PCT/IB2024/060718 2023-10-31 2024-10-30 Schémas combinés pour le traitement du myélome multiple Pending WO2025094085A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US202363594804P 2023-10-31 2023-10-31
US63/594,804 2023-10-31
US202363607918P 2023-12-08 2023-12-08
US63/607,918 2023-12-08
US202463621741P 2024-01-17 2024-01-17
US63/621,741 2024-01-17
US202463654497P 2024-05-31 2024-05-31
US63/654,497 2024-05-31
US202463698140P 2024-09-24 2024-09-24
US63/698,140 2024-09-24

Publications (1)

Publication Number Publication Date
WO2025094085A1 true WO2025094085A1 (fr) 2025-05-08

Family

ID=93648647

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/060718 Pending WO2025094085A1 (fr) 2023-10-31 2024-10-30 Schémas combinés pour le traitement du myélome multiple

Country Status (1)

Country Link
WO (1) WO2025094085A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988001649A1 (fr) 1986-09-02 1988-03-10 Genex Corporation Molecules de liaison de chaines de polypeptide simples
WO1992001047A1 (fr) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Procede de production de chainon de paires a liaison specifique
WO1994013804A1 (fr) 1992-12-04 1994-06-23 Medical Research Council Proteines de liaison multivalentes et multispecifiques, leur fabrication et leur utilisation
WO1998044001A1 (fr) 1997-03-27 1998-10-08 Commonwealth Scientific And Industrial Research Organisation Reactifs polyvalents presentant une avidite elevee et une specificite multiple
WO2009085462A1 (fr) 2007-12-19 2009-07-09 Centocor, Inc. Conception et génération de banques d'exposition sur phage humain pix de novo au moyen d'une fusion vers pix ou pvii, vecteur, anticorps et procédés
WO2018017786A2 (fr) 2016-07-20 2018-01-25 Janssen Pharmaceutica Nv Anticorps anti-gprc5d, molécules bispécifiques de liaison à l'antigène qui se lient à gprc5d et cd3 et leurs utilisations
WO2022058445A1 (fr) 2020-09-16 2022-03-24 Janssen Pharmaceutica Nv Méthodes de traitement d'un myélome multiple

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988001649A1 (fr) 1986-09-02 1988-03-10 Genex Corporation Molecules de liaison de chaines de polypeptide simples
WO1992001047A1 (fr) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Procede de production de chainon de paires a liaison specifique
WO1994013804A1 (fr) 1992-12-04 1994-06-23 Medical Research Council Proteines de liaison multivalentes et multispecifiques, leur fabrication et leur utilisation
WO1998044001A1 (fr) 1997-03-27 1998-10-08 Commonwealth Scientific And Industrial Research Organisation Reactifs polyvalents presentant une avidite elevee et une specificite multiple
WO2009085462A1 (fr) 2007-12-19 2009-07-09 Centocor, Inc. Conception et génération de banques d'exposition sur phage humain pix de novo au moyen d'une fusion vers pix ou pvii, vecteur, anticorps et procédés
WO2018017786A2 (fr) 2016-07-20 2018-01-25 Janssen Pharmaceutica Nv Anticorps anti-gprc5d, molécules bispécifiques de liaison à l'antigène qui se lient à gprc5d et cd3 et leurs utilisations
US10562968B2 (en) 2016-07-20 2020-02-18 Janssen Pharmaceutica Nv Anti-GPRC5D antibodies, bispecific antigen binding molecules that bind GPRC5D and CD3, and uses thereof
WO2022058445A1 (fr) 2020-09-16 2022-03-24 Janssen Pharmaceutica Nv Méthodes de traitement d'un myélome multiple

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Record History | ver. 29: 2023-10-10 | NCT05050097 | ClinicalTrials.gov", 11 October 2023 (2023-10-11), XP093249550, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT05050097?tab=history&a=29#version-content-panel> *
BAERT ET AL., N ENGL J MED, vol. 348, 2003, pages 602 - 08
CHAMESBATY, CURR OPIN DRUG DISC DEV, vol. 12, 2009, pages 276
CHARI A ET AL., BLOOD, vol. 140, 2022, pages 384 - 387
CHARI AJAI ET AL: "Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 387, no. 24, 15 December 2022 (2022-12-15), US, pages 2232 - 2244, XP093183744, ISSN: 0028-4793, DOI: 10.1056/NEJMoa2204591 *
CHOTHIA ET AL., J MOL BIOL, vol. 196, 1987, pages 901 - 17
DURIE BGHAROUSSEAU JLMIGUEL JS ET AL.: "International uniform response criteria for multiple myeloma", LEUKEMIA, vol. 20, no. 9, 2006, pages 1467 - 1473, XP037780658, DOI: 10.1038/sj.leu.2404284
HONEGGERPLUCKTHUN, J MOL BIOL, vol. 309, 2001, pages 657 - 70
KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1991, NATIONAL INSTITUTES OF HEALTH
KNAPPIK ET AL., J MOL BIOL, vol. 296, 2000, pages 57 - 86
KUMAR SPAIVA BANDERSON KC ET AL.: "International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma", LANCET ONCOL, vol. 17, no. 8, 2016, pages e328 - 346, XP029663519, DOI: 10.1016/S1470-2045(16)30206-6
LEFRANC ET AL., DEV COMP IMMUNOL, vol. 27, 2003, pages 55 - 77
MARTINTHORNTON, J BMOL BIOL, vol. 263, 1996, pages 800 - 15
MATOUS JEFFREY ET AL: "Talquetamab + Pomalidomide in Patients with Relapsed/Refractory Multiple Myeloma: Safety and Preliminary Efficacy Results from the Phase 1b MonumenTAL-2 Study", BLOOD, vol. 142, no. Supplement 1, 2 November 2023 (2023-11-02), AMSTERDAM, NL, pages 1014 - 1014, XP093249553, ISSN: 0006-4971, DOI: 10.1182/blood-2023-187706 *
NUNEZ-PRADO ET AL., DRUG DISCOVERY TODAY, vol. 20, no. 5, 2015, pages 588 - 594
RAJKUMAR SVHAROUSSEAU JLDURIE B ET AL.: "Consensus recommendations for the uniform reporting of clinical Trials: report of the International Myeloma Workshop Consensus Panel 1", BLOOD, vol. 117, no. 18, 2011, pages 4691 - 4695
SCHINKE CAROLINA D. ET AL: "Pivotal phase 2 MonumenTAL-1 results of talquetamab (tal), a GPRC5DxCD3 bispecific antibody (BsAb), for relapsed/refractory multiple myeloma (RRMM).", JOURNAL OF CLINICAL ONCOLOGY, vol. 41, no. 16_suppl, 1 June 2023 (2023-06-01), pages 8036 - 8036, XP093259773, ISSN: 0732-183X, DOI: 10.1200/JCO.2023.41.16_suppl.8036 *
SHI ET AL., J MOL BIOL, vol. 397, 2010, pages 385 - 96
STICKLER ET AL., GENES AND IMMUNITY, vol. 12, 2011, pages 213 - 21
VERKLEIJ CHRISTIE P. M. ET AL: "Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma", BLOOD ADVANCES, vol. 5, no. 8, 27 April 2021 (2021-04-27), pages 2196 - 2215, XP055880142, ISSN: 2473-9529, DOI: 10.1182/bloodadvances.2020003805 *
WU ET AL., J EXP MED, vol. 132, 1970, pages 211 - 50
ZANDER THILO ET AL: "Alternate-day dosing of pomalidomide in relapsed/ refractory multiple myeloma: a multicenter, single-arm phase 2 trial", BLOOD CANCER JOURNAL, vol. 37, no. 3, 12 January 2023 (2023-01-12), London, pages 699 - 701, XP093259807, ISSN: 0887-6924, Retrieved from the Internet <URL:https://www.nature.com/articles/s41375-023-01809-z> DOI: 10.1038/s41375-023-01809-z *

Similar Documents

Publication Publication Date Title
US12098210B2 (en) Methods of treating cancers and enhancing efficacy of BCMAxCD3 bispecific antibodies
US20220177584A1 (en) Methods for treating multiple myeloma
US20250242019A2 (en) Methods for treating multiple myeloma
WO2024095173A1 (fr) Méthodes de traitement de cancers
IL323989A (en) Methods for treating multiple myeloma
WO2025094085A1 (fr) Schémas combinés pour le traitement du myélome multiple
IL324993A (en) Methods of treating multiple myeloma
WO2025096717A1 (fr) Méthodes de traitement du myélome multiple
CA3212336A1 (en) Methods for treating multiple myeloma
US20230295292A1 (en) Methods of treating cancers and enhancing efficacy of gprc5dxcd3 bispecific antibodies
US20260041768A1 (en) Methods for treating multiple myeloma with car-t cells and bispecific antibodies
WO2025019733A2 (fr) Procédés de traitement du myélome multiple
WO2025243241A1 (fr) Méthodes de traitement d&#39;un myélome multiple
WO2025094107A1 (fr) Méthodes de traitement du myélome multiple indolent à haut risque
TW202608482A (zh) 用於治療多發性骨髓瘤之方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24812224

Country of ref document: EP

Kind code of ref document: A1