A Study to Examine the Effects of Novel Therapy Linvoseltamab in Combination With Other Cancer Treatments for Adult Participants With Multiple Myeloma That is Resistant to Current Standard of Care Treatments

• Linvoseltamab (Drug), also known as REGN5458, Lynozyfic™: Administered per the protocol
• Daratumumab (Drug), also known as Darzalex®; Darzalex Faspro™: Administered per the protocol
• Carfilzomib (Drug), also known as Kyprolis®: Administered per the protocol
• Lenalidomide (Drug), also known as Revlimid®: Administered per the protocol
• Bortezomib (Drug), also known as Velcade®: Administered per the protocol
• Pomalidomide (Drug), also known as Imnovid, Pomalyst®: Administered per the protocol
• Isatuximab (Drug), also known as Sarclisa®: Administered per the protocol
• Fianlimab (Drug), also known as REGN3767: Administered per the protocol
• Cemiplimab (Drug), also known as LIBTAYO, REGN2810: Administered per the protocol
• Nirogacestat (Drug), also known as PF-03084014: Administered per the protocol
• Cevostamab (Drug), also known as BFCR4350A, RO7187797: Administered per the protocol

Primary outcomes

• Incidence of Dose Limiting Toxicities (DLTs) for each study regimen during the observation period [Up to 28 Days]: Dose finding portion only
• Incidence of Treatment-Emergent Adverse Events (TEAEs) [Up to 5 Years]
• Severity of TEAEs [Up to 5 Years]
• Incidence of Serious Adverse Events (SAEs) [Up to 5 Years]
• Severity of SAEs [Up to 5 Years]
• Incidence of Adverse Events of Special Interest (AESIs) [Up to 5 Years]
• Severity of AESIs [Up to 5 Years]
• Incidence of laboratory abnormalities [Up to 5 Years]: ≥ grade 3 per National Cancer Institute-Common Terminology Criteria for Adverse Events \[NCI-CTCAE v5.0\]

Secondary outcomes

• Overall Response Rate (ORR) as measured by International Myeloma Working Group (IMWG) criteria [Up to 5 Years]
• Duration of Response (DOR) by IMWG criteria [Up to 5 Years]
• Progression-Free Survival (PFS) as measured by IMWG criteria [Up to 5 Years]
• Rate of Minimal Residual Disease (MRD) negative status by IMWG criteria [Up to 5 Years]
• Concentrations of total linvoseltamab in serum over time [Up to 5 Years]
• Incidence over time of Anti-Drug Antibodies (ADAs) to linvoseltamab [Up to 5 Years]
• Overall Survival (OS) [Up to 5 Years]

Sex: All, ages: 18 Years to any

General Key Inclusion Criteria:

1. Eastern Cooperative Oncology Group (ECOG) performance status ≤1
2. Participants must have measurable disease as defined in the protocol according to IMWG consensus criteria
3. Adequate creatinine clearance, hematologic function and hepatic function, as defined in protocol
4. Life expectancy of at least 6 months

Cohort Specific Inclusion Criteria:

For cohorts 1-6, each participant must have RRMM with progression following at least 3 lines of therapy, or at least 2 lines of therapy and either prior exposure to at least 1 anti-CD38 antibody, 1 immunomodulatory imide drug (IMiD) and 1 Proteasome Inhibitor (PI), or double-refractory to 1 PI and 1 IMiD, or the combination of 1 PI and 1 IMiD Cohort 1: Prior treatment with daratumumab is allowed if previously tolerated, as described in the protocol Cohort 2: Prior treatment with carfilzomib is allowed if previously tolerated at the approved full dose, as described in the protocol Cohort 3: Prior treatment with lenalidomide is allowed if previously tolerated at the approved full dose, as described in the protocol Cohort 4: Prior treatment with bortezomib is allowed if previously tolerated at the approved full dose, as described in the protocol Cohort 5: Prior treatment with pomalidomide is allowed if previously tolerated at the approved full dose, as described in the protocol Cohort 6: Prior treatment with isatuximab is allowed if previously tolerated, as described in the protocol

Cohort 7 and 8:

1. For participants without measurable disease by biochemical parameters \[serum or urine M-protein, or serum involved Free Light Chain (FLC)\], presence of at least 1 soft tissue plasmacytoma with a single diameter of ≥2 cm
2. RRMM with progressive disease and received at least 3 lines of therapy including exposure to at least 1 anti-CD38 antibody, 1 IMiD, and 1 PI or triple-class refractory disease (anti-CD38 antibody, IMiD, PI) Cohort 9: Progressive RRMM in participants with triple-class refractory disease (anti-CD38 antibody, IMiD, PI) after at least 3 lines of therapy Cohort 10: Progressive RRMM after at least 3 lines of therapy including exposure to at least 1 anti-CD38 antibody, 1 IMiD, and 1 PI

General Key Exclusion Criteria:

1. Diagnosis of plasma cell leukemia, primary light-chain amyloidosis (excluding myeloma associated amyloidosis), Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), or POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, and Skin changes)
2. Participants with known MM brain lesions or meningeal involvement
3. Treatment with any systemic anti-myeloma therapy within 5 half-lives or within 21 days prior to first administration of study drug regimen, whichever is shorter
4. History of allogeneic and autologous stem cell transplantation, as described in the protocol
5. Unless stated otherwise in a specific sub-protocol, prior treatment with a T cell-based immunotherapy directed against B-Cell Maturation Antigen (BCMA) bispecific antibodies and Bispecific T-cell Engagers (BiTEs), and BCMA Chimeric Antigen Receptor (CAR) T cells (Note: BCMA antibody-drug conjugates are not excluded)
6. History of progressive multifocal leukoencephalopathy, neurodegenerative condition or Central Nervous System (CNS) movement disorder or participants with a history of seizure within 12 months prior to study enrollment are excluded
7. Live or attenuated vaccination within 28 days prior to first study drug regimen administration with a vector that has replicative potential
8. Cardiac ejection fraction <40% by Echocardiogram (Echo) or Multigated Acquisition (MUGA) scan

Cohort Specific Exclusion Criteria:

Cohort 2: Dose expansion: Prior treatment with a BCMA-directed CAR T-cell therapy will not be exclusionary if completed at least 12 weeks prior to first study treatment Cohort 3: Known malabsorption syndrome or pre-existing gastrointestinal (GI) condition that may impair absorption of lenalidomide; delivery of lenalidomide via nasogastric tube or gastrostomy tube is not allowed Cohort 4: Peripheral neuropathy grade ≥2 Cohort 5: Known malabsorption syndrome or pre-existing GI conditions that may impair absorption of pomalidomide; delivery of pomalidomide via nasogastric tube or gastrostomy tube is not allowed

Cohort 7:

1. Prior treatment with anti-Lymphocyte Activation Gene 3 (LAG-3) agents. Prior exposure to vaccine therapies or other immune checkpoint modulating therapies such as anti-Programmed cell Death Protein 1 (PD-1) antibodies is permitted, as described in the protocol
2. Ongoing or recent (within 2 years) evidence of an autoimmune disease that has required systemic treatment with immunosuppressive agents, as described in the protocol
3. Prior solid organ transplant
4. History of grade ≥3 immune-mediated adverse events (with the exclusion of endocrinopathies that are fully controlled by hormone replacement) from prior checkpoint inhibitor therapies

Cohort 8:

1. Prior treatment with anti-PD-1 or anti-PD-L1 agents. Prior exposure to vaccine therapies or other immune checkpoint modulating therapies such as anti-Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) antibodies is permitted, as described in the protocol
2. Encephalitis or meningitis in the year prior to enrollment
3. History of interstitial lung disease (eg, idiopathic pulmonary fibrosis or organizing pneumonia), of active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management, or of pneumonitis within the last 5 years. A history of radiation pneumonitis in the radiation field is permitted as long as pneumonitis resolved ≥6 months prior to enrollment
4. Ongoing or recent (within 2 years) evidence of an autoimmune disease that has required systemic treatment with immunosuppressive agents, as described in the protocol.
5. Prior solid organ transplant
6. History of grade ≥3 immune-mediated adverse events (with the exclusion of endocrinopathies that are fully controlled by hormone replacement) from prior checkpoint inhibitor therapies

Cohort 9:

1. Abnormal QT interval corrected by Fridericia's formula (QTcF), as described in the protocol
2. Use of concomitant medications that are known to prolong the QT/QTcF interval including Class Ia and Class III antiarrhythmics at the time of informed consent
3. Ongoing use or anticipated use of food or drugs that are known strong/moderate cytochrome P450 (CYP)3A4 inhibitors, or strong CYP3A inducers within 14 days prior to first dose of nirogacestat
4. Known malabsorption syndrome or existing gastrointestinal GI condition that may impair absorption of nirogacestat; delivery of nirogacestat via nasogastric tube or gastrostomy tube is not allowed

Cohort 10:

1. Known or suspected active Epstein-Barr Virus (EBV) infection
2. Known history of Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS)
3. Prior treatment with cevostamab or another agent with the same target \[Fragment crystallizable Receptor-like 5 (FcRH5)\]

Dose finding portion: Prior treatment with any BCMA-directed immunotherapy will not be exclusionary, as described in the protocol Dose expansion portion: Prior treatment with any T cell-engaging bispecific antibody directed against BCMA will be exclusionary, as described in the protocol

NOTE: Other protocol defined inclusion/exclusion criteria apply

• Clinical Trial Management, Study director, Regeneron Pharmaceuticals

NIH grants: 2023