A Proof-of-Concept Trial to Study the Safety and Activity of Linvoseltamab in Participants With Smoldering Multiple Myeloma at High Risk of Developing Multiple Myeloma

Study Overview
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Brief Summary
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This study is researching an investigational drug called linvoseltamab (study drug) in participants at high risk of developing multiple myeloma (MM), a group commonly labeled as high-risk smoldering multiple myeloma (HR-SMM). The aim of the study is to understand the safety and tolerability (how your body reacts to linvoseltamab) as well as the effectiveness (how well linvoseltamab eliminates plasma cells and prevents the development of MM) of the study drug. There are 2 parts to the study. In Part 1, linvoseltamab will be given to a small number of participants to study the early side effects (safety) of the study drug and make sure the treatment is acceptable. In Part 2, linvoseltamab will be given to more participants to continue to assess the side effects of the study drug and to evaluate the ability of linvoseltamab to treat HR-SMM and prevent progression to MM. The study is looking at several other research questions, including: How many participants treated with linvoseltamab (study drug) have improvement of their HR-SMM? What side effects may happen from taking the study drug? How much study drug is in your blood at different times? Whether the body makes antibodies against the study drug (which could make the drug less effective or could lead to side effects)

Official Title
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Phase 2 Study of Linvoseltamab in Patients With Smoldering Multiple Myeloma at High Risk of Progression to Multiple Myeloma

Conditions
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Smoldering Multiple Myeloma (SMM)

Intervention / Treatment
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* Drug: Linvoseltamab


Participation Criteria
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Eligibility Criteria
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KEY Inclusion Criteria: High-risk SMM diagnosis within 5 years of study enrollment Eastern Cooperative Oncology Group (ECOG) performance status ≤1 Adequate hematologic and hepatic function, as described in the protocol Estimated glomerular filtration rate ≥30 mL/min/1.73 m^2 KEY Exclusion Criteria: Evidence of myeloma defining events *SLiM CRAB, as described in the protocol *SLiM (greater than or equal to Sixty percent clonal plasma cells in the bone marrow, involved/uninvolved free Light chain ratio of ≥100 with the involved free light chain (FLC) being ≥100 mg/L, MRI with >1 focal lesion) CRAB (hyperCalcemia, Renal insufficiency, Anemia, or lytic Bone lesions) Diagnosis of systemic light chain amyloidosis, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), soft tissue plasmacytoma, or symptomatic multiple myeloma Clinically significant cardiac or vascular disease within 3 months of study enrollment, as described in the protocol Any infection requiring hospitalization or treatment with IV anti-infectives within 28 days of first dose of study drug Uncontrolled human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection; or other uncontrolled infection or unexplained signs of infection History of severe allergic reaction attributed to compounds with a similar chemical or biologic composition as the study drug or excipient 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Run-In (Part 1)<br>Evaluation of initial safety and tolerability of the step-up regimen leading up to the start of full dose linvoseltamab. | Drug: Linvoseltamab<br>* Administration by intravenous (IV) infusion<br>* Other names: REGN5458;|
| Experimental: Expansion (Part 2)<br>Linvoseltamab monotherapy according to the same dosing schedule established in the safety run-in part. | Drug: Linvoseltamab<br>* Administration 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 |
| --- | --- | --- |
| Frequency of adverse events of special interest (AESI) during the safety run-in observation period | AESI include grade 2 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) | Up to 35 days | 
| Frequency of treatment-emergent adverse events (TEAEs) during the safety run-in observation period |  | Up to 35 days | 
| Severity of TEAEs during the safety run-in observation period |  | Up to 35 days | 
| Complete response (CR) as determined by the investigator |  | Up to 7 years | 
| Minimal residual disease (MRD) negativity |  | At 12 months | 
| MRD negativity |  | At 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of TEAEs during expansion part | As assessed by the NCI-CTCAE grading system version 5 (for all grades) | Up to 7 years | 
| Severity of TEAEs during expansion part | As assessed by the NCI-CTCAE grading system version 5 (for all grades) | Up to 7 years | 
| Frequency of serious adverse events (SAEs) |  | Up to 7 years | 
| Severity of SAEs |  | Up to 7 years | 
| Frequency of laboratory abnormalities |  | Up to 7 years | 
| Severity of laboratory abnormalities |  | Up to 7 years | 
| Overall response of partial response (PR) or better |  | Up to 7 years | 
| Duration of response (DOR) |  | Up to 7 years | 
| Biochemical progression-free-survival (PFS) |  | Up to 7 years | 
| MRD negativity among participants that achieve very good partial response (VGPR) or better |  | Up to 3 years after end of treatment | 
| Sustained MRD negativity |  | Up to 3 years after end of treatment | 
| Time from treatment initiation to date of any myeloma-defining event |  | Up to 7 years | 
| Time from start of treatment to date of progression to MM or death |  | Up to 7 years | 
| Time to initiation of first-line treatment for MM |  | Up to 7 years | 
| Overall survival (OS) |  | Up to 7 years | 
| Concentration of linvoseltamab in serum over time |  | Up to 2 years | 
| Incidence of anti-drug antibodies (ADAs) to linvoseltamab over time |  | Up to 2 years | 
| Titer of ADAs to linvoseltamab over time |  | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Linvoseltamab, Multiple Myeloma (MM), B cell maturation antigen (BCMA), Bispecific antibody