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 (LINKER-MGUS1)

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

This study is researching an investigational drug called linvoseltamab ("study drug") in participants at moderate risk of developing multiple myeloma (about 3 to 10% average annual risk), a group that consists of patients with precancerous conditions called High-Risk Monoclonal Gammopathy of Undetermined Significance (HR-MGUS) and Non-High-Risk Smoldering Multiple Myeloma (NHR-SMM).

The primary purpose of the study is to understand how well the study drug can eliminate abnormal plasma cells and laboratory signs of HR-MGUS and NHR-SMM.

The study is looking at several other research questions, including:

• How many participants treated with linvoseltamab 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 the 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).

Study Overview

• Status: Recruiting
• Conditions: Monoclonal Gammopathy of Undetermined Significance (MGUS); Smoldering Multiple Myeloma (SMM)
• Intervention / Treatment: Drug: Linvoseltamab

• Study Type: Interventional
• Enrollment (Estimated): 116
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Clinical Trials Administrator; Phone Number: 844-734-6643; Email: clinicaltrials@regeneron.com

Study Locations

• Belgium
  • Antwerpen
    • Brasschaat, Antwerpen, Belgium, 2930
      • Recruiting
      • Algemeen Ziekenhuis (AZ) Klina
  • West-Vlaanderen
    • Roeselare, West-Vlaanderen, Belgium, 8800
      • Recruiting
      • Algemeen Ziekenhuis AZ Delta
• Ireland
  • Cork, Ireland, T12 EC8P
    • Recruiting
    • Cork University Hospital
• Italy
  • Forli-Cesena
    • Meldola, Forli-Cesena, Italy, 47014
      • Recruiting
      • Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori
  • Lombardy
    • Milan, Lombardy, Italy, 20142
      • Recruiting
      • San Paolo Hospital
• Poland
  • Kuyavian-Pomeranian Voivodeship
    • Torun, Kuyavian-Pomeranian Voivodeship, Poland, 87-100
      • Recruiting
      • Wojewodzki Szpital Zespolony - Ludwik Rydygier Provincial Hospital
  • Malopolska
    • Krakow, Malopolska, Poland, 30-510
      • Recruiting
      • Pratia McM Krakow
• Spain
  • Barcelona, Spain, 08041
    • Recruiting
    • Hospital Sant Pau
  • Madrid, Spain, 28006
    • Recruiting
    • Universitaru Hospital La Princesa
  • Murcia, Spain, 30008
    • Recruiting
    • Hospital General Universitario Morales Meseguer
  • Andalusia
    • Granada, Andalusia, Spain, 18014
      • Recruiting
      • Hospital Universitario Virgen de las Nieves
  • Barcelona
    • Terrassa, Barcelona, Spain, 08221
      • Recruiting
      • Hospital Universitari Mutua Terrassa
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Recruiting
      • Hospital Clinico Universitario Virgen de La Arrixaca
  • Principality of Asturias
    • Gijón, Principality of Asturias, Spain, 33203
      • Recruiting
      • Hospital de Cabueñes
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan Health
  • New York
    • Stony Brook, New York, United States, 11794
      • Recruiting
      • Stony Brook University Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Recruiting
      • Thomas Jefferson University Hospital
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Safety Run-In (Part 1); 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; Administered per the protocol; Other Names: REGN5458; Lynozyfic™
Experimental: Expansion (Part 2) - Dose regimen 1; Participants will be randomized in a 1:1:1:1 ratio across 4 dosing regimens	Drug: Linvoseltamab; Administered per the protocol; Other Names: REGN5458; Lynozyfic™
Experimental: Expansion (Part 2) - Dose regimen 2; Participants will be randomized in a 1:1:1:1 ratio across 4 dosing regimens	Drug: Linvoseltamab; Administered per the protocol; Other Names: REGN5458; Lynozyfic™
Experimental: Expansion (Part 2) - Dose regimen 3; Participants will be randomized in a 1:1:1:1 ratio across 4 dosing regimens	Drug: Linvoseltamab; Administered per the protocol; Other Names: REGN5458; Lynozyfic™
Experimental: Expansion (Part 2) - Dose regimen 4; Participants will be randomized in a 1:1:1:1 ratio across 4 dosing regimens	Drug: Linvoseltamab; Administered per the protocol; Other Names: REGN5458; Lynozyfic™

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Frequency of Adverse Events Interest (AEI) during the safety observation period	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	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
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
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
Sustained MRD negativity on an annual basis		Up to 3 years after achievement of CR
Concentration of linvoseltamab in serum over time		Up to 9 months
Frequency of Serious Adverse Events (SAEs)		Up to 5.5 years
Minimal Residual Disease (MRD) negativity among participants that achieve a response of CR		Up to 5.5 years
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
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

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Investigators: Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2024
• Primary Completion (Estimated): May 18, 2032
• Study Completion (Estimated): May 18, 2032

Study Registration Dates

• First Submitted: October 31, 2023
• First Submitted That Met QC Criteria: November 17, 2023
• First Posted (Actual): November 20, 2023

Study Record Updates

• Last Update Posted (Actual): April 8, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: immunotherapy; plasma cell disorders; linvoseltamab; monoclonal immunoglobulin (M-protein); cancer interception
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Hematologic Diseases; Immunoproliferative Disorders; Precancerous Conditions; Paraproteinemias; Blood Protein Disorders; Hypergammaglobulinemia; Hemic and Lymphatic Diseases; Smoldering Multiple Myeloma; Monoclonal Gammopathy of Undetermined Significance
• Other Study ID Numbers: R5458-ONC-2257; 2023-505242-25-00 (Ctis: EU CT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing.

IPD Sharing Time Frame

When Regeneron has:

• received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc.) for the product and indication or has globally discontinued development of the product for all indications on or after April 2020 and has no plans for future development
• made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry)
• the legal authority to share the data, and
• ensured the ability to protect participant privacy

• IPD Sharing Access Criteria: Qualified researchers can submit a proposal for access to individual patient or aggregate level data from a Regeneron-sponsored clinical trial through Vivli. Regeneron's Independent Research Request Evaluation Criteria can be found at: https://www.regeneron.com/sites/default/files/Regeneron-External-Data-Sharing-Policy-and-Independent-Research-Request-Evaluation-Criteria.pdf
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No