A Proof-of-Concept Study to Learn Whether Linvoseltamab Can Eliminate Abnormal Plasma Cells That May Lead to Multiple Myeloma in Adult Patients With High-Risk Monoclonal Gammopathy of Undetermined Significance or Non-High-Risk Smoldering Multiple Myeloma

• Linvoseltamab (Drug), also known as REGN5458, Lynozyfic™: Administered per the protocol

Primary outcomes

• Frequency of Adverse Events Interest (AEI) during the safety observation period [35 days]: Part 1 An AEI is a toxicity potentially related to study treatment that may preclude dose escalation or expansion according to the Bayesian Optimal Interval (BOIN) design decision rules
• Frequency of Treatment-Emergent Adverse Event (TEAEs) during the safety observation period [35 days]: Part 1 As assessed by the NCI-CTCAE grading system version 5 (for all grades)
• Severity of TEAEs during the safety observation period [35 days]: Part 1 As assessed by the NCI-CTCAE grading system version 5 (for all grades)
• Achievement of Complete Response (CR) as determined by the investigator [Up to 5.5 years]: Part 2

Secondary outcomes

• Frequency of TEAEs [Up to 5.5 years]: As assessed by the NCI-CTCAE grading system version 5 (for all grades)
• Severity of TEAEs [Up to 5.5 years]: As assessed by the NCI-CTCAE grading system version 5 (for all grades)
• Frequency of Serious Adverse Events (SAEs) [Up to 5.5 years]
• Severity of SAEs [Up to 5.5 years]
• Frequency of laboratory abnormalities [Up to 5.5 years]: As assessed by the NCI-CTCAE grading system version 5 (for all grades)
• Severity of laboratory abnormalities [Up to 5.5 years]: As assessed by the NCI-CTCAE grading system version 5 (for all grades)
• 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 the study duration [Up to 5.5. years]
• Magnitude of ADAs to linvoseltamab over the study duration [Up to 5.5. years]

Sex: All, ages: 18 Years to any

Key Inclusion Criteria:

1. HR-MGUS or NHR-SMM as defined in the protocol
2. Eastern Cooperative Oncology Group (ECOG) performance status ≤1
3. Adequate hematologic and hepatic function, as described in the protocol
4. Estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73 m\^2 by the Modification of Diet in Renal Disease (MDRD) equation

Key Exclusion Criteria:

1. High-risk SMM, as defined in the protocol
2. Evidence of any of myeloma-defining events, as described in the protocol
3. Diagnosis of systemic light-chain amyloidosis, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), solitary plasmacytoma, or symptomatic MM
4. Clinically significant cardiac or vascular disease within 3 months of study enrollment, as described in the protocol
5. Any infection requiring hospitalization or treatment with intravenous (IV) anti-infectives within 28 days of the first dose of linvoseltamab
6. Uncontrolled Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection; or other uncontrolled infection or unexplained signs of infection, as described in the protocol

NOTE: Other protocol defined inclusion/exclusion criteria apply

• Clinical Trial Management, Study director, Regeneron Pharmaceuticals

NIH grants: 2023