A Study to Learn How Safe and How Well Linvoseltamab Works Compared to Standard Treatment in Adult Patients With Multiple Myeloma Who Are Not Eligible for Transplant

A Randomized, Open-Label, Controlled Phase 3 Study of Comparing Daratumumab, Lenalidomide and Dexamethasone Induction Followed by Linvoseltamab Versus Continued Daratumumab, Lenalidomide, and Dexamethasone in Newly Diagnosed Transplant Ineligible Multiple Myeloma Patients

This study is researching an experimental drug called linvoseltamab. The study is focused on participants with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplantation (transplant-ineligible).

The main purpose of this study is to compare the effect and safety of linvoseltamab with the effect and safety of the standard treatment.

Study Overview

• Status: Recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Daratumumab; Drug: Lenalidomide; Drug: Dexamethasone; Drug: Linvoseltamab

• Study Type: Interventional
• Enrollment (Estimated): 1000
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Silvia Villa; Phone Number: +31 10 268 70 65; Email: silvia.villa@emn.org

Study Locations

• Australia
  • Adelaide, Australia
    • Recruiting
    • Flinders Medical Centre
    • Contact: Sobieraj-Teague
  • Box Hill, Australia
    • Recruiting
    • Box Hill Hospital
    • Contact: Motorna
  • Canberra, Australia
    • Recruiting
    • Canberra Hospital
    • Contact: Joshi
  • Geelong, Australia
    • Recruiting
    • Barwon Health, University Hospital Geelong
    • Contact: Campbell
  • Heidelberg, Australia
    • Recruiting
    • Austin Hospital
    • Contact: Hocking
  • Kingswood, Australia
    • Recruiting
    • Nepean Cancer Centre
    • Contact: Ponraj
  • Melbourne, Australia
    • Recruiting
    • Northern Hospital
    • Contact: Cooke
  • Sunshine Coast, Australia
    • Recruiting
    • Sunshine Coast Health
    • Contact: Wallington-Gates
• Austria
  • Linz, Austria
    • Recruiting
    • Ordensklinikum Linz
    • Contact: Strassl
  • Vienna, Austria
    • Recruiting
    • Klinik Ottakring
    • Contact: Schreder
• Croatia
  • Zagreb, Croatia
    • Recruiting
    • University Hospital Centre Zagreb - Clinic for Internal Medicine
    • Contact: Basic-Kinda
• Czechia
  • Hradec Králové, Czechia
    • Recruiting
    • Fakultni nemocnice Hradec Kralove
    • Contact: Radocha
  • Olomouc, Czechia
    • Recruiting
    • University Hospital Olomouc
    • Contact: Minarik
  • Ostrava, Czechia
    • Recruiting
    • Fakultni Nemocnice Ostrava
    • Contact: Hajek
  • Pilsen, Czechia
    • Recruiting
    • Fakultni nemocnice Plzen
    • Contact: Jungova
• Denmark
  • Aarhus, Denmark
    • Recruiting
    • Aarhus Universitetshospital
    • Contact: Ølholm Vase
• Estonia
  • Tallinn, Estonia
    • Recruiting
    • North Estonia Medical Centre Foundation
    • Contact: Loigom
  • Tartu, Estonia
    • Recruiting
    • Tartu University Hospital
    • Contact: Pärnat
• Finland
  • Helsinki, Finland
    • Recruiting
    • Helsinki University Hospital Comprehensive Cancer Center
    • Contact: Söderholm
  • Kuopio, Finland
    • Recruiting
    • Kuopio University Hospital
    • Contact: Partanen
• Germany
  • Greifswald, Germany
    • Recruiting
    • Universitaetsmedizin Greifswald
    • Contact: Krönke
  • Lübeck, Germany
    • Recruiting
    • Universitaetsklinikum Schleswig-Holstein -Campus Luebeck - Klinik fuer Haematologie und Onkologie
    • Contact: Leitner
  • Würzburg, Germany
    • Recruiting
    • University Hospital of Würzburg
    • Contact: Waldschmidt
• Greece
  • Alexandroupoli, Greece
    • Recruiting
    • University Hospital of Alexandroupolis
    • Contact: Spanoudakis
  • Athens, Greece
    • Recruiting
    • Alexandra General Hospital -Department of Clinical Therapeutics N.K. Univ. of Athens
    • Contact: Evangelos Terpos
  • Athens, Greece
    • Recruiting
    • Evaggelismos Hospital
    • Contact: Delimpasi
  • Thessaloniki, Greece
    • Recruiting
    • Theagenion Cancer Hospital
    • Contact: Katodritou
• Ireland
  • Cork, Ireland
    • Recruiting
    • Cork University Hospital
    • Contact: Mykytiv
  • Dublin, Ireland
    • Recruiting
    • Beaumont Hospital
    • Contact: Quinn
  • Limerick, Ireland
    • Recruiting
    • University Hospital Limerick - Department of Haematology
    • Contact: Clifford
• Italy
  • Ancona, Italy
    • Recruiting
    • AOU Ospedali Riuniti di Ancona
    • Contact: Offidani
  • Cuneo, Italy
    • Recruiting
    • Azienda Ospedaliera Santa Croce e Carle - Ematologia
    • Contact: Celeghini
  • Florence, Italy
    • Recruiting
    • A.O.U. Careggi
    • Contact: Antonioli
  • Genova, Italy
    • Recruiting
    • IRCCS Ospedale Policlinico San Martino
    • Contact: Aquino
  • Legnano, Italy
    • Recruiting
    • Ospedale di Legnano, ASST Ovest Milanese
    • Contact: Rezzonico
  • Meldola, Italy
    • Recruiting
    • Meldola-Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.)
    • Contact: Cerchione
  • Milan, Italy
    • Recruiting
    • ASST Grande Ospedale Metropolitano Niguarda
    • Contact: Cafro
  • Milan, Italy
    • Recruiting
    • Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda - Oncologia
    • Contact: Bolli
  • Reggio, Italy
    • Recruiting
    • Azienda USL IRCCS Di Reggio Emilia
    • Contact: Gamberi
  • Rimini, Italy
    • Recruiting
    • Ospedale "Infermi" di Rimini
    • Contact: Rotondo
  • San Giovanni Rotondo, Italy
    • Recruiting
    • I.R.C.C.S. Ospedale Casa Sollievo della Sofferenza
    • Contact: Carella
• Netherlands
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus MC
    • Contact: Stege
• Norway
  • Stavanger, Norway
    • Recruiting
    • Stavanger University Hospital
    • Contact: Haukås
  • Trondheim, Norway
    • Recruiting
    • St. Olavs hospital HF
    • Contact: Slørdahl
  • Tønsberg, Norway
    • Recruiting
    • Vestfold Hospital Trust
    • Contact: Moksnes
• Portugal
  • Coimbra, Portugal
    • Recruiting
    • CHUC
    • Contact: Roque
  • Lisbon, Portugal
    • Recruiting
    • Hospital da Luz Lisboa
    • Contact: Pedrosa
• Spain
  • Badalona, Spain
    • Recruiting
    • Institut Catala D'oncologia (Badalona)
    • Contact: Ibarra
  • Barcelona, Spain
    • Recruiting
    • Hospital Clinic De Barcelona - Myeloma and Amyloidosis Unit
    • Contact: Laura Rosiñol Dachs, MD
  • Madrid, Spain
    • Recruiting
    • Hospital Quirón Salud Madrid
    • Contact: Martinez Chamorro
  • Santander, Spain
    • Recruiting
    • Hospital Universitario Marques De Valdecilla -Hematology and Hemotherapy Service
    • Contact: Enrique Ocio San Miguel, MD
  • Valencia, Spain
    • Recruiting
    • Hospital Universitario la Fe, Valencia
    • Contact: de la Rubia
• Sweden
  • Lund, Sweden
    • Recruiting
    • Skåne University Hospital, Region Skåne
    • Contact: Lemonakis
• Switzerland
  • Basel, Switzerland
    • Recruiting
    • Universitaetsspital Basel - Zentrum fur Hamato-Onkologie
    • Contact: Heim
  • Sankt Gallen, Switzerland
    • Recruiting
    • Kantonsspital St. Gallen
    • Contact: Lehmann
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye)
    • Recruiting
    • Liv Hospital Ankara
    • Contact: Beksac
  • Ankara, Turkey (Türkiye)
    • Recruiting
    • Ankara University Faculty of Medicine, Department of Hematology
    • Contact: Cengiz Seval
  • Izmir, Turkey (Türkiye)
    • Recruiting
    • Ege University Medicine Faculty, Izmir
    • Contact: Comert
  • Izmir, Turkey (Türkiye)
    • Recruiting
    • Ege Universitesi Tip Fakultesi - Hematology
    • Contact: Vural

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Participants must have confirmed diagnosis of symptomatic MM per IMWG criteria.
2. Participants must not be considered a candidate for high-dose chemotherapy (HDT) and ASCT, as described in the protocol.
3. Participants must have measurable disease as defined in the protocol.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
5. Participants must have clinical laboratory values within a prespecified range.

Exclusion Criteria:

1. International Myeloma Working Group Frailty Index of 2 with the exception of participants who have a score of 2 based on age alone.
2. Participants who defer transplant due to personal preference.
3. Participants with non-secretory MM, active plasma cell leukemia, known light-chain (AL) amyloidosis in the presence of a concurrent diagnosis of myeloma, any other form of amyloidosis, Waldenström macroglobulinemia, or known POEMS syndrome.

4. Any prior therapy for monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or MM, with the exception of:

   • focal radiation and/or
   • a short course of corticosteroids as defined in the protocol.
5. Participants who have received or are receiving any investigational agent or cell therapy with known or suspected activity against MM
6. Participants who have known central nervous system (CNS) or meningeal involvement with MM or known or suspected progressive multifocal leukoencephalopathy (PML), a history of a neurocognitive condition or CNS movement disorder, OR a history of seizure, transient ischemic attack (TIA), stroke or seizure within 12 months prior to study C1D1.
7. Participants who have uncontrolled intercurrent illness.
8. Known contraindications to the use of daratumumab or lenalidomide per local prescribing information.
9. History of allogeneic hematopoietic stem cell transplantation or solid organ transplant at any time.

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
Active Comparator: Control arm DRd	Drug: Daratumumab; Administered per the protocol; Drug: Lenalidomide; Administered per the protocol; Drug: Dexamethasone; Administered per the protocol
Experimental: Experimental Arm DRd+ linvolsetamab	Drug: Daratumumab; Administered per the protocol; Drug: Lenalidomide; Administered per the protocol; Drug: Dexamethasone; Administered per the protocol; Drug: Linvoseltamab; Administered per the protocol; Other Names: REGN5458

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minimal Residual Disease (MRD)	Minimal Residual Disease (MRD) negative Complete Remission (CR) status at 10^-5 per International Myeloma Working Group (IMWG) criteria	up to 11 years
MRD negative CR status by BICR	MRD negative CR status at 10^-5 as determined by the Blinded Independent Central Review (BICR)	up to 11 years
Progression Free Survival (PFS) per IMWG criteria	defined as the time from the date of randomization until the first occurrence of disease progression or death from any cause, whichever occurs earlier, where disease progression is determined per IMWG criteria.	up to 11 years
PFS as determined by BICR	defined as the time from the date of randomization until the first occurrence of disease progression or death from any cause, whichever occurs earlier, where disease progression is determined per by BICR.	up to 11 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Overall Survival (OS), measured from the date of from randomization to the date the subject's death	up to 11 years
Objective Response (OR) of Complete Response (CR)	To compare the proportion of patients who achieve an objective response per International Myeloma Working Group (IMWG) response criteria between the two study arms for Complete Response (CR) or better	up to 11 years
OR of Very Good Partial Response (VGPR)	To compare the proportion of patients who achieve an objective response per International Myeloma Working Group (IMWG) response criteria between the two study arms for VGPR or better	up to 11 years
OR of Partial Response (PR)	To compare the proportion of patients who achieve an objective response per International Myeloma Working Group (IMWG) response criteria between the two study arms for PR or better	up to 11 years
Sustained MRD	Sustained MRD negative CR (sMRD) at 10^-5 per IMWG criteria	up to 11 years
Duration of response (DOR) of stringent (s)CR	duration of response to best overall response of stringent sCR, per IMWG response criteria	up to 11 years
Duration of response (DOR) of CR	duration of response to best overall response of CR, per IMWG response criteria	up to 11 years
Duration of response (DOR) of VGPR	duration of response to best overall response of VGPR, per IMWG response criteria	up to 11 years
Duration of response (DOR) of PR	duration of response to best overall response of PR, per IMWG response criteria	up to 11 years
Time to response ≥CR	Time from randomization to objective response (≥CR) as per IMWG response criteria	up to 11 years
Time to response ≥VGPR	Time from randomization to objective response (≥VGPR) as per IMWG response criteria	up to 11 years
Time to response ≥PR	Time from randomization to objective response (≥PR) as per IMWG response criteria	up to 11 years
Disease progression	Time to disease progression per IMWG response criteria	up to 11 years
Incidence of TEAEs	Incidence of treatment emergent adverse events (TEAEs)	up to 11 years
Severity of TEAEs	Severity of treatment emergent adverse events (TEAEs)	up to 11 years
Serious Adverse Events	Incidence of Serious Adverse Events (SAE)	up to 11 years
Concentrations of linvoseltamab	Concentrations of linvoseltamab in serum over time	up to 11 years
Incidence antidrug antibodies	Incidence of antidrug antibodies (ADAs) to linvoseltamab	up to 11 years
Titer of ADA	Titer of ADA to linvoseltamab	up to 11 years
EORTC QLQ-C30 Global Health Status / Quality of Life	Change in European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) The EORTC QLQ-C30 is a 30-item validated questionnaire developed to measure patient-reported quality of life using one global health status/quality of life (GHS/QoL) scale, 5 functioning scales (physical, role, emotional, cognitive, and social) ranging from from 1 = "very poor" to 7 = "excellent" and 9 symptom scales/items (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) among patients with cancer, ranging from 1 = "not at all" to 4 = "very much" higher scores indicate higher symptom burden.	up to 11 years
EORTC QLQ-C30 Physical Functioning (PF)	Change in European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire functioning scale Physical Functioning (PF). PF scale consist of 5 items, ranging from from 1 = "not at all" to 4 = "very much" higher scores indicate higher ("better") level of functioning	up to 11 years
EORTC QLQ-C30 Role Functioning (RF)	Change in European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire functioning scale Role Functioning (RF). RF scale consist of 2 items, ranging from from 1 = "not at all" to 4 = "very much" higher scores indicate higher ("better") level of functioning	up to 11 years
EORTC QLQ-C30 Pain	Change in European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire symptom scale Pain. Pain scale consist of 2 items, ranging from from 1 = "not at all" to 4 = "very much" higher scores indicate higher symptom burden	up to 11 years
EORTC QLQ-C30 Fatigue	Change in European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire symptom scale Fatigue. Fatigue scale consist of 3 items, ranging from from 1 = "not at all" to 4 = "very much" higher scores indicate higher symptom burden	up to 11 years
EQ-5D-5L VAS	Change in EuroQoL-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Visual Analogue Score (VAS) (EQ-5D-5L VAS). The EQ-5D-5L is a generic questionnaire that measures Health-Related Quality of Life (HRQoL) across 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) across 5 levels (1= no problems, 2= slight problems, 3= some problems, 4= severe problems and 5= extreme problems), higher scores indicate lower health states And a visual analogue scale (VAS). VAS scale ranging from 0 = "worst" to 100 = "best" higher score indicate higher health status	up to 11 years

Collaborators and Investigators

• Sponsor: European Myeloma Network B.V.
• Collaborators: Regeneron Pharmaceuticals
• Investigators: Principal Investigator: Roberto Mina, A.O.U. Città della Salute e Della Scienza di Torino; Principal Investigator: Claudia Stege, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): December 23, 2025
• Primary Completion (Estimated): December 1, 2036
• Study Completion (Estimated): December 1, 2036

Study Registration Dates

• First Submitted: April 10, 2025
• First Submitted That Met QC Criteria: April 10, 2025
• First Posted (Actual): April 17, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Lenalidomide; Newly diagnosed; Multiple Myeloma (MM); Transplant ineligible; Linvoseltamab; CD38 antibody; BCMA X CD3 bispecific antibody
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Neoplasms, Plasma Cell; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Hemic and Lymphatic Diseases; Multiple Myeloma; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Carboxylic Acids; Polycyclic Compounds; Piperidines; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Pregnadienetriols; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Piperidones; Isoindoles; Lenalidomide; Dexamethasone; daratumumab
• Other Study ID Numbers: EMN39; 2024-519827-16-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes