A Study to Compare Linvoseltamab and Daratumumab Treatment in High-Risk Smoldering Multiple Myeloma (HR-SMM) (LINKER-SMM2)

A Phase 3, Randomized, Open-Label Study of Linvoseltamab Versus Daratumumab in Participants With Smoldering Multiple Myeloma at High Risk of Developing Multiple Myeloma

This study is researching an experimental drug called linvoseltamab (also called "study drug") compared to another drug called daratumumab, in participants with Smoldering Multiple Myeloma (SMM), who are at a High Risk (HR) of developing active multiple myeloma.

The aim of this study is to find out whether linvoseltamab is better than daratumumab in delaying the development of MM.

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

• 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: Not yet recruiting
• Conditions: High Risk Smoldering Multiple Myeloma (HR-SMM)
• Intervention / Treatment: Drug: Daratumumab; Drug: Linvoseltamab

• Study Type: Interventional
• Enrollment (Estimated): 270
• Phase: Phase 3

Contacts and Locations

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

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

1. Eastern Cooperative Oncology Group performance status score ≤1
2. SMM diagnosis per IMWG criteria as defined in the protocol
3. Meets HR-SMM criteria by 1 of the risk models as defined in the protocol

Key Exclusion Criteria:

1. Evidence of myeloma-defining events attributable to the underlying plasma cell dyscrasia, as defined in the protocol
2. Diagnosis of systemic light chain amyloidosis, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), plasma cell leukemia, or soft tissue plasmacytoma
3. History of neurodegenerative condition, progressive multifocal leukoencephalopathy, or Central Nervous System (CNS) movement disorder
4. History of a seizure within the 12 months of randomization
5. Prior exposure to any approved or investigational treatments directed against a clonal plasma cell disorder (including but not limited to conventional chemotherapies, radiotherapy, immunomodulatory drugs, proteasome inhibitors, anti-CD38 antibodies). Ongoing treatment with other monoclonal antibodies (eg, infliximab, rituximab) or other treatments likely to interfere with study procedures or results, 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: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Linvoseltamab	Drug: Linvoseltamab; Administered per the protocol; Other Names: REGN5458; Lynozyfic™
Active Comparator: Daratumumab	Drug: Daratumumab; Administered per the protocol; Other Names: Darzalex®; Darzalex Faspro®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Clinical Progression Free Survival (PFS) per International Myeloma Working Group (IMWG) criteria	Up to 5 years
Biochemical PFS per IMWG criteria	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of TEAEs		Up to 3 years
Time to death		Up to 9 years
Duration Of Response (DOR) per IMWG criteria		Up to 5 years
Functional Assessment of Cancer Therapy (FACIT)- Item Global Population 5 (GP5) responses	FACIT-Item GP5 will be used to assess the patient-reported impact of treatment toxicity that uses a single item "I am bothered by side effects of treatment" on a 5-point scale (0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, 4 = very much).	Up to 5 years
Change from baseline in FACIT- Item GP5 score		Up to 5 years
Achievement of Minimal Residual Disease (MRD) Complete Response (CR) at 10^-5 per IMWG criteria		Up to 3 years
Achievement of Overall Response Rate (ORR) of Partial Response or better (≥PR) per IMWG criteria		Up to 3 years
Best Overall Response (BOR) per IMWG criteria		Up to 3 years
Achievement of MRD-negativity		Up to 3 years
Sustained MRD-negativity		Up to 3 years
Duration of MRD-negative CR		Up to 3 years
Occurrence of Treatment-Emergent Adverse Events (TEAEs)		Up to 3 years
Occurrence of Serious Adverse Events (SAEs)		Up to 3 years
Change from baseline score in European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) Global Health Status (GHS)/Quality of Life (QoL) scale	The EORTC QLQ-C30 is a 30-item validated questionnaire developed to measure patient-reported QoL using 1 GHS/QoL scale, 5 functioning scales (physical, role, emotional, cognitive and social) and 9 symptom scales / items (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) among patients with cancer. For the functioning scales and global health status / QoL, scores range from 1 = "very poor" to 5 = "excellent" with higher scores indicating better functioning and positive changes from baseline indicate improvement.	Up to 5 years
Change from baseline score in EORTC QLQ-C30 physical functioning scale		Up to 5 years
Change from baseline score in EORTC QLQ-C30 role functioning scale		Up to 5 years
Change from baseline score in EORTC QLQ-C30 emotional functioning scale		Up to 5 years
Change from baseline score in EORTC QLQ-C30 pain scale	The EORTC QLQ-C30 is a 30-item validated questionnaire developed to measure patient-reported QoL using 1 GHS/QoL scale, 5 functioning scales (physical, role, emotional, cognitive and social) and 9 symptom scales / items (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) among patients with cancer. For the 9 symptom scales, scores range from 1 = "not at all" to 9 = "very much" higher scores indicate higher symptom burden and negative changes from baseline indicate improvement.	Up to 5 years
Change from baseline score in EORTC QLQ-C30 fatigue scale		Up to 5 years
Change from baseline score in EORTC IL478 future perspectives scale	EORTC IL478 corresponds to the EORTC QLQ-Multiple Myeloma Module 20 (MY20) future Perspective Scale. This is a is a self-administered instrument to assess QoL in persons with MM. For the future perspective 3 items are analyzed. A high score for an item represents a high level of symptomatic problem.	Up to 5 years
Change from baseline score in EuroQoL-5 Dimensions 5-Level Questionnaire Visual Analogue Scale (EQ-5D-5L VAS )	The EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-5L descriptive system comprises the following 5 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". The EQ VAS records the participant's self-rated health on a vertical visual analogue scale where the endpoints are labeled "Best imaginable health state" and "Worst imaginable health state".	Up to 5 years
Concentrations of linvoseltamab in serum		Up to 5 years
Occurrence of Anti-Drug Antibodies (ADAs) to linvoseltamab in serum		Up to 5 years
Magnitude of ADA to linvoseltamab in serum		Up to 5 years

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Estimated): March 25, 2026
• Primary Completion (Estimated): July 22, 2033
• Study Completion (Estimated): July 22, 2033

Study Registration Dates

• First Submitted: January 29, 2026
• First Submitted That Met QC Criteria: February 5, 2026
• First Posted (Actual): February 6, 2026

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 12, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Bispecific antibody; Darzalex; Smoldering Myeloma; Multiple Myeloma (MM); Smoldering Multiple Myeloma (SMM); Linvoseltamab; B Cell Maturation Antigen (BCMA); HR-SMM; Linozyfic
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Precancerous Conditions; Neoplasms, Plasma Cell; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Hypergammaglobulinemia; Hemic and Lymphatic Diseases; Smoldering Multiple Myeloma; Multiple Myeloma; daratumumab
• Other Study ID Numbers: R5458-HM-24145; 2025-523252-31-00 (Ctis)

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