A Proof-of-concept Study to Learn Whether Linvoseltamab Can Prevent Multiple Myeloma in Adult Patients With High-Risk Monoclonal Gammopathy of Undetermined Significance or Non-High-Risk Smoldering Multiple Myeloma

Study Overview
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Brief Summary
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The primary purpose of the study is to investigate whether early treatment with the study drug can prevent the development of multiple myeloma. This requires understanding the safety and tolerability of the study drug (how your body reacts to linvoseltamab) as well as the effectiveness of the study drug (how well linvoseltamab eliminates plasma cells and prevents the development of multiple myeloma). All participants will start treatment with gradually increasing doses of linvoseltamab (step-up doses) before they start receiving the assigned full dose. The study is split into 2 parts. In Part 1, separate groups of 3-6 patients will receive different full doses of linvoseltamab to evaluate the short-term side effects (safety) observed within the first 35 days after starting treatment, to make sure the study drug is well tolerated, and to help make a decision about the dosing regimens chosen for Part 2. In Part 2, a larger number of participants will be randomized to different dosing regimens to further assess the side effects of linvoseltamab, and to evaluate the ability of linvoseltamab to treat HR-MGUS and NHR-SMM and prevent progression to multiple myeloma. The study is looking at several other research questions, including: How many participants treated with linvoseltamab (study drug) have improvement of their HR-MGUS or NHR-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 Dose-Ranging and Interception Study of Linvoseltamab in Patients With High-Risk Monoclonal Gammopathy of Undetermined Significance or Non-High-Risk Smoldering Multiple Myeloma

Conditions
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Monoclonal Gammopathy of Undetermined Significance (MGUS), 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: HR-MGUS or NHR-SMM as defined in the protocol Eastern Cooperative Oncology Group (ECOG) performance status ≤1 Adequate hematologic and hepatic function, as described in the protocol Estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 by the modification of diet in renal disease (MDRD) equation. Key Exclusion Criteria: High-risk SMM according to the 20-2-20 risk stratification model (Mayo criteria), as defined in the protocol Evidence of any of myeloma-defining events, as described in the protocol Diagnosis of systemic light-chain amyloidosis, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), soft tissue plasmacytoma, or symptomatic MM 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 the first dose of linvoseltamab Uncontrolled human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection; or other uncontrolled infection or unexplained signs of infection. 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Run-In (Part 1)<br>Sequential groups of participants will be enrolled to assess the initial safety and tolerability of the step-up regimen leading up to the start of different full doses of linvoseltamab. | Drug: Linvoseltamab<br>* Administration by intravenous (IV) infusion<br>* Other names: REGN5458;|
| Experimental: Expansion (Part 2) - Dose regimen 1<br>Participants will be randomized in a 1:1:1:1 ratio across 4 dosing regimens | Drug: Linvoseltamab<br>* Administration by intravenous (IV) infusion<br>* Other names: REGN5458;|
| Experimental: Expansion (Part 2) - Dose regimen 2<br>Participants will be randomized in a 1:1:1:1 ratio across 4 dosing regimens | Drug: Linvoseltamab<br>* Administration by intravenous (IV) infusion<br>* Other names: REGN5458;|
| Experimental: Expansion (Part 2) - Dose regimen 3<br>Participants will be randomized in a 1:1:1:1 ratio across 4 dosing regimens | Drug: Linvoseltamab<br>* Administration by intravenous (IV) infusion<br>* Other names: REGN5458;|
| Experimental: Expansion (Part 2) - Dose regimen 4<br>Participants will be randomized in a 1:1:1:1 ratio across 4 dosing regimens | 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 (AEI) during the safety observation period | Part 1 As assessed by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading system version 5 (for all grades). AESI include grade 2 or higher cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), grade 3 or higher tumor lysis syndrome (TLS), infusion-related reaction (IRR), allergic reactions, infections and hepatitis B virus (HBV) reactivation | 35 days | 
| Frequency of treatment-emergent adverse event (TEAEs) during the safety observation period | Part 1 As assessed by the NCI-CTCAE grading system version 5 (for all grades) | 35 days | 
| Severity of TEAEs during the safety observation period | Part 1 As assessed by the NCI-CTCAE grading system version 5 (for all grades) | 35 days | 
| Achievement of complete response (CR) as determined by the investigator | Part 2 | Up to 5.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of TEAEs | As assessed by the NCI-CTCAE grading system version 5 (for all grades) | Up to 5.5 years | 
| Severity of TEAEs | As assessed by the NCI-CTCAE grading system version 5 (for all grades) | Up to 5.5 years | 
| Frequency of serious adverse events (SAEs) |  | Up to 5.5 years | 
| Severity of SAEs |  | Up to 5.5 years | 
| Frequency of laboratory abnormalities | As assessed by the NCI-CTCAE grading system version 5 (for all grades) | Up to 5.5 years | 
| Severity of laboratory abnormalities | As assessed by the NCI-CTCAE grading system version 5 (for all grades) | Up to 5.5 years | 
| Minimal residual disease (MRD) negativity among participants that achieve a response of CR |  | Up to 5.5 years | 
| Sustained MRD negativity on an annual basis |  | Up to 3 years after achievement of CR | 
| Overall response of partial response (PR) or better as determined by the investigator |  | Up to 5.5 years | 
| Duration of response (DOR) as determined by the investigator |  | Up to 5.5 years | 
| Biochemical progression-free survival (PFS) as determined by the investigator |  | Up to 5.5 years | 
| Concentration of linvoseltamab in serum over time |  | Up to 9 months | 
| Incidence of anti-drug antibodies (ADAs) to linvoseltamab over time |  | Up to 9 months | 
| Titer of ADAs to linvoseltamab over time |  | Up to 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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linvoseltamab, monoclonal immunoglobulin (M-protein), cancer interception, immunotherapy, plasma cell disorders