A Study to Learn How Linvoseltamab (REGN5458) Will Work Compared to the Elotuzumab, Pomalidomide and Dexamethasone (EPd) Combination, in Participants With Relapsed/Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The study is researching an experimental drug called linvoseltamab, also called REGN5458. Linvoseltamab has previously been studied by itself (without other cancer drugs) in participants who had advanced multiple myeloma that returned and needed to be treated again after many other therapies had failed. These participants were no longer benefiting from standard medications and had no good treatment options. In that study, some participants who were treated with linvoseltamab had improvement of their myeloma (shrinkage of their tumors), including some participants who had complete responses (that is, the treatment got rid of all evidence of myeloma in their bodies). This study is focused on participants who have multiple myeloma that has returned or needs to be treated again after one to four prior treatments and have standard cancer treatment options available to them. The aim of the study is to see how safe and effective linvoseltamab is compared to a combination of three cancer drugs: elotuzumab, pomalidomide and dexamethasone (called EPd in this form), one of these standard treatment options. Half of the participants in this study will get linvoseltamab, and the other half will get EPd. Both linvoseltamab and EPd will be referred to as study drugs in this form. The study is looking at several other research questions, including: How long participants benefit from receiving linvoseltamab compared with EPd How many participants treated with linvoseltamab or EPd have improvement of their multiple myeloma and by how much What side effects happen from taking linvoseltamab compared to EPd How long participants live while receiving treatment or after treatment with linvoseltamab compared to EPd If there is any improvement in pain after treatment with linvoseltamab compared to EPd

Official Title
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An Open-label, Randomized, Phase 3 Study of Linvoseltamab (REGN5458; Anti- BCMA x Anti-CD3 Bispecific Antibody) Versus the Combination of Elotuzumab, Pomalidomide, and Dexamethasone (EPd), in Patients With Relapsed/Refractory Multiple Myeloma (LINKER-MM3)

Conditions
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Relapsed Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: Linvoseltamab
* Drug: Elotuzumab
* Drug: Pomalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age 18 years or older (or legal adult age in the country) at the time of the screening visit. Eastern Cooperative Oncology Group (ECOG) performance status ≤1. Patients with ECOG 2 solely due to local symptoms of myeloma (eg. pain) may be allowed after discussion with the Medical Monitor. Received at least 1 and no more than 4 prior lines of anti-neoplastic MM therapies, including lenalidomide and a proteasome inhibitor and demonstrated disease progression on or after the last therapy as defined by the 2016 IMWG criteria. Participants who have received only 1 line of prior line of antimyeloma therapy must be lenalidomide refractory, as described in the protocol. Patients must have measurable disease for response assessment as per the 2016 IMWG response assessment criteria, as described in the protocol Adequate hematologic, hepatic, renal and cardiac function, as well as evidence of adequate bone marrow reserves Life expectancy of at least 6 months Key Exclusion Criteria: Diagnosis of plasma cell leukemia, amyloidosis, Waldenström macroglobulinemia, or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes). Prior treatment with elotuzumab and/or pomalidomide Participants with known MM brain lesions or meningeal involvement Treatment with any systemic anti-cancer therapy within 5 half-lives or within 28 days before first administration of study drug, whichever is shorter History of allogeneic stem cell transplantation within 6 months, or autologous stem cell transplantation within 12 weeks of the start of study treatment Prior treatment with B-cell maturation antigen (BCMA) directed immunotherapies Any infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first administration of study drug Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV); or another uncontrolled infection, as defined in the protocol. 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Linvoseltamab<br>Randomization 1:1 | Drug: Linvoseltamab<br>* REGN5458 will be administered by intravenous (IV) infusion<br>* Other names: REGN5458;|
| Active Comparator: Elotuzumab/Pomalidomide/Dexamethasone (EPd)<br>Randomization 1:1 | Drug: Elotuzumab<br>* Elotuzumab will be administered by IV infusion<br>* Other names: Empliciti;Drug: Pomalidomide<br>* Pomalidomide capsules will administered by mouth (PO)<br>* Other names: Pomalyst;Drug: Dexamethasone<br>* Dexamethasone tablets/capsules will be administered PO and/or by IV infusion<br>* Other names: Decadron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) per International Myeloma Working Group (IMWG) response criteria determined by Independent Review Committee (IRC) |  | Up to approximatively 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) greater or equal to Partial Response (PR) per IMWG response criteria as determined by the IRC |  | Up to approximatively 5 years | 
| Objective Response Rate (ORR) greater or equal to Very Good Partial Response (VGPR) per IMWG response criteria as determined by IRC |  | Up to approximatively 5 years | 
| Objective Response Rate (ORR) greater or equal to Complete Response (CR) per IMWG response criteria as determined by IRC |  | Up to approximatively 5 years | 
| Incidence of minimal residual disease (MRD) negative status |  | Up to approximatively 5 years | 
| Overall Survival (OS) |  | Up to approximatively 5 years | 
| Mean change from baseline in the worst pain score measured by Brief Pain Inventory-Short Form (BPI-SF) Item 3 | The BPI-SF is a validated, self-administered questionnaire designed to measure a participant's perceived level of pain. The BPI-SF Item 3 uses a numeric rating scale to assess pain severity and pain interference in the past 24 hours. The numeric rating scale ranges from 0 (no pain) to 10 (worst imaginable pain), where higher scores indicate greater intensity of pain. | Baseline to week 12 | 
| Progression-free Survival (PFS) per IMWG response criteria as determined by the investigator |  | Up to approximatively 5 years | 
| Incidence of treatment emergent adverse events (TEAEs) |  | Up to approximatively 5 years | 
| Severity of treatment emergent adverse events (TEAEs) |  | Up to approximatively 5 years | 
| Incidence of adverse events of special interest (AESI) |  | Up to approximatively 5 years | 
| Severity of adverse events of special interest (AESI) |  | Up to approximatively 5 years | 
| Incidence of Serious Adverse Events (SAE) |  | Up to approximatively 5 years | 
| Severity of Serious Adverse Events (SAE) |  | Up to approximatively 5 years | 
| ORR greater or equal to PR per IMWG response criteria as determined by the investigator |  | Up to approximatively 5 years | 
| ORR greater or equal to VGPR per IMWG response criteria as determined by the investigator |  | Up to approximatively 5 years | 
| ORR greater or equal to CR per IMWG response criteria as determined by the investigator |  | Up to approximatively 5 years | 
| Duration of Response (DoR) as per IMWG response criteria as determined by the investigator |  | Up to approximatively 5 years | 
| DoR as per IMWG response criteria as determined by the IRC |  | Up to approximatively 5 years | 
| Duration of MRD negative status in the bone marrow |  | Up to approximatively 5 years | 
| Time from randomization to objective response (≥PR) as per IMWG response criteria as determined by the IRC |  | From randomization to objective response, up to approximatively 5 years | 
| Time from randomization to objective response (≥PR) as per IMWG response criteria as determined by the investigator |  | From randomization to objective response, up to approximatively 5 years | 
| Concentration of linvoseltamab in the serum over time |  | Up to approximatively 5 years | 
| Incidence of antidrug antibodies (ADAs) |  | Up to approximatively 5 years | 
| Titer of antidrug antibodies (ADAs) |  | Up to approximatively 5 years | 
| Incidence of neutralizing antibodies (Nabs) to linvoseltamab over time |  | Up to approximatively 5 years | 
| Proportion of Pain Responders | Defined by at least a 2-point reduction from baseline in the BPI-SF Item 3 without an increase in analgesic use | At week 12 | 
| Change from baseline in patient-reported global health status/quality of life (QoL), per European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | The EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including global health status/quality of life, functional Scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Participants rate items on a 4-point scale, with 1 as not at all and 4 as very much. | Baseline to week 12 | 
| Change from baseline in patient reported disease symptoms per EORTC Quality of Life Questionnaire-Multiple Myeloma (MM) module 20 [QLQ-MY20]) | The EORTC QLQ-MY20 is a self -administered instrument to assess QoL in persons with MM. This 20-item questionnaire measures the following domains: symptom scales, including disease symptoms (6 items) and symptoms related to side effects of treatment (10 items); function scale and future perspective (3 items); and body image (1 item). A high score represents a high level of symptoms or problems. | Baseline to week 12 | 
| Patient-Reported Outcomes in Patient Global Impression of Symptom Severity (PGIS) | The PGIS is a single 1-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time by using a 4-point Likert scale that ranges from (1) = none (no symptoms) to (4) = severe. The global anchor, PGIS will be used for interpretation of EORTC QLQ-C30, EORTC QLQ-MY20, and BPI-SF. | Baseline to week 12 | 
| Patient-Reported Outcomes in Patient Global Impression of Change (PGIC) | The PGIC is a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change since starting treatment as rated on a 5-point Likert scale anchored by (1) much better to (5) much worse, with (4) = no change. The global anchor, PGIC will be used for interpretation of EORTC QLQ-C30, EORTC QLQ-MY20, and BPI-SF. | Baseline to week 12 | 
| Change from baseline in patient-reported general health status per EuroQoL-5 Dimension-5 Level Scale [EQ-5D-5L]) | The EQ-5D-5L consists of EQ-5D descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. | Baseline to week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BCMA X CD3 Bispecific Monoclonal Antibody