A Window of Opportunity Trial to Learn if Linvoseltamab is Safe and Well Tolerated, and How Well it Works in Participants With Recently Diagnosed Multiple Myeloma Who Have Not Already Received Treatment.

Study Overview
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Brief Summary
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The primary objectives of the study are: For Phase 1 To find out if linvoseltamab is safe and well tolerated To find out what the most appropriate dosing schedule would be for future clinical trials For Phase 2 •To find out if it works to treat multiple myeloma The secondary objectives of the study are: For Phase 1 and 2 To find out how linvoseltamab moves throughout the body over time (pharmacokinetics) To find out how much B-cell maturation antigen (BCMA) participants have in their blood To find out if the participants' immune systems respond to linvoseltamab.

Official Title
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Phase 1/2 Study of Linvoseltamab (Anti-BCMA X Anti-CD3 Bispecific Antibody) in Previously Untreated Patients With Symptomatic Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Linvoseltamab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Confirmed diagnosis of symptomatic multiple myeloma (MM) by International Myeloma Working Group (IMWG) diagnosis criteria Measurable disease, according to the 2016 IMWG response criteria, as defined in the protocol No prior therapy for MM, with the exception of prior emergent or palliative radiation and up to 1 month of single-agent corticosteroids, with washout periods as per the protocol Participants must have evidence of adequate bone marrow reserves and hepatic, renal and cardiac function as defined in the protocol Participants must be age <70 and have adequate hepatic, renal, pulmonary and cardiac function to be considered transplant-eligible. The specific thresholds for adequate organ function are as per institutional guidance. Key Exclusion Criteria: Receiving any concurrent investigational agent with known or suspected activity against MM, or agents targeting the A proliferation-inducing ligand (APRIL)/ Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)/BCMA axis Known central nervous system (CNS) involvement with MM, as well as known neurocognitive conditions, CNS movement disorder, or history of seizure within 12 months prior to study enrollment Rapidly progressive symptomatic disease, (e.g. progressing renal failure or hypercalcemia not responsive to standard medical interventions), in urgent need of treatment with chemotherapy Diagnosis of non-secretory MM, active plasma cell leukemia, primary light-chain (AL) amyloidosis, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), or known POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Note: Other protocol-defined Inclusion/Exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Note: Phase 1 part B will be randomized 1:1. All other participants will be non-randomized.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 cohort<br>Linvoseltamab dose escalation (part A) and dose expansion (part B) for participants with NDMM who are treatment-naïve. | Drug: Linvoseltamab<br>* Linvoseltamab will be administered by intravenous (IV) infusion<br>* Other names: REGN5458;|
| Experimental: Phase 2 - transplant ineligible cohort<br>Transplant-ineligible participants, enrolled in dose expansion, will receive selected Linvoseltamab regimen until disease progression as per protocol. | Drug: Linvoseltamab<br>* Linvoseltamab will be administered by intravenous (IV) infusion<br>* Other names: REGN5458;|
| Experimental: Phase 2 - transplant eligible cohort<br>Transplant-eligible participants, enrolled in dose expansion, will receive selected linvoseltamab regimen for a fixed duration of treatment as per protocol | Drug: Linvoseltamab<br>* Linvoseltamab will be administered by intravenous (IV) infusion<br>* Other names: REGN5458;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) | Phase 1 | End of the Observation period; up to day 28 | 
| Incidence of treatment-emergent adverse events (TEAEs) | Phase 1 | Post-Last Linvoseltamab Dose, up to 90 days | 
| Severity of treatment-emergent adverse events (TEAEs) | Phase 1 | Post-Last Linvoseltamab Dose, up to 90 days | 
| Incidence of adverse events of special interest (AESIs) | Phase 1 | Post-Last Linvoseltamab Dose, up to 90 days | 
| Severity of adverse events of special interest (AESIs) | Phase 1 | Post-Last Linvoseltamab Dose, up to 90 days | 
| Proportion of participants with a very good partial response (VGPR) or better using the International Myeloma Working Group (IMWG) response criteria | Phase 2 | Up to 5 years | 
| Proportion of participants achieving Minimal Residual Disease (MRD) negative status (at 10^-5) after induction with consolidation therapy | Phase 2 Transplant-eligible cohort | Up to 5 years | 
| Proportion of participants achieving MRD-negative status (at 10^-5) after induction without consolidation therapy | Phase 2 Transplant-eligible cohort | Up to 5 years | 
| Proportion of participants achieving MRD-negative status as their best response after treatment period I with continuing to treatment period II | Phase 2 Transplant-ineligible cohort | Up to 5 years | 
| Proportion of participants achieving MRD-negative status as their best response after treatment period I without continuing to treatment period II | Phase 2 Transplant ineligible cohort | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of Linvoseltamab in serum | Phases 1 and 2 | Post-Last Linvoseltamab Dose, up to 12 weeks | 
| Concentrations of total soluble B-cell maturation antigen (BCMA) | Phases 1 and 2 | Post-Last Linvoseltamab Dose, up to 12 weeks | 
| Incidence of anti-drug antibodies (ADAs) to Linvoseltamab | Phases 1 and 2 | Post-Last Linvoseltamab Dose, up to 30 days | 
| Titer of ADAs to Linvoseltamab | Phases 1 and 2 | Post-Last Linvoseltamab Dose, up to 30 days | 
| Objective response rate (ORR) measured using the IMWG criteria | Phase 1 | Up to 5 years | 
| Duration of Response (DOR) measured using the IMWG criteria | Phase 1 | Post-Last Linvoseltamab Dose, up to 90 days | 
| Progression-free survival (PFS) measured using the IMWG criteria | Phase 1 | Post-Last Linvoseltamab Dose, up to 90 days | 
| Proportion of participants achieving MRD-negative status (at 10^-5) in participants with NDMM measured using the IMWG criteria | Phase 1 | Post-Last Linvoseltamab Dose, up to 90 days | 
| Incidence of treatment-emergent adverse events (TEAEs) | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| Severity of TEAEs | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| Incidence of adverse events of special interest (AESIs) | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| Severity of AESIs | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| ORR of participants deemed transplant-eligible and transplant-ineligible by the treating physician | Phase 2 | Up to 5 years | 
| MRD-negative status of participants deemed transplant-eligible and transplant-ineligible by the treating physician | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| DOR of participants deemed transplant-eligible and transplant-ineligible by the treating physician | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| PFS of participants deemed transplant-eligible and transplant-ineligible by the treating physician | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| Overall Survival (OS) of participants deemed transplant-eligible and transplant-ineligible by the treating physician | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| Time to response (TTR) as measured using the IMWG criteria | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| ORR by risk levels | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| MRD-negative rstatus by risk levels | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| DOR by risk levels | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| TTR by risk levels | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| PFS by risk levels | Phase 2 | Post-Last Linvoseltamab Dose, up to 90 days | 
| Incidence of MRD-negative status | Phase 2 | Up to 5 years | 
| Cluster of differentiation 34+ (CD34+) stem cell yield | Phase 2 Transplant-eligible cohort | At cycle 4 of induction (each cycle is 28 days long) | 
| Time to neutrophil engraftment | Phase 2 Transplant-eligible cohort | Up to 100 days post-transplant | 
| Time to platelet engraftment | Phase 2 Transplant-eligible cohort | Up to 100 days post-transplant | 
| PFS after ASCT followed by 3 cycles of linvoseltamab | Phase 2 Transplant-eligible cohort | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Newly diagnosed multiple myeloma (NDMM), Autologous stem cell transplantation (ASCT), Cluster of differentiation 3 (CD3), BCMA, High dose chemotherapy (HDT), International Myeloma Working Group (IMWG)