CHMP Recommends Conditional Approval of Linvoseltamab for R/R Multiple Myeloma

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended the conditional marketing authorization of linvoseltamab (REGN5458) for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody, and have experienced disease progression on their last therapy.1

This recommendation was based on findings from the phase 1/2 LINKER-MM1 trial (NCT03761108), which demonstrated that at a median follow-up of 14 months, patients treated with linvoseltamab at a dose of 200 mg (n = 117) experienced an objective response rate (ORR) of 71%, including 50% of patients achieving a complete response (CR) or better and 63% achieving a very good partial response (VGPR) or better.2

Among all responders, the median duration of response (DOR) was 29 months; the median DOR was not reached for those who achieved a CR or better. The median overall survival (OS) was 31 months (95% CI, 22-not evaluable) for all patients. At 12 months, an estimated 75% of all patients were alive, and 100% of those who achieved a CR or better remained alive.

In February 2025, the FDA accepted a resubmission of a biologics license application for linvoseltamab for the treatment of adults with relapsed/refractory multiple myeloma who have received at least 3 prior lines of therapy.3 A regulatory decision is expected by July 10, 2025.

LINKER-MM1 Trial Design

The phase 1/2, open-label, multicenter LINKER-MM1 trial enrolled 282 patients with relapsed/refractory multiple myeloma.2 In the phase 2 portion of the study, patients were required to have received at least 3 prior lines of therapy or have triple-class refractory disease.

The completed phase 1 dose-escalation portion assessed safety, tolerability, and dose-limiting toxicities. The ongoing phase 2 dose-expansion portion is evaluating ORR as the primary end point; secondary end points include DOR, progression-free survival, OS, and minimal residual disease (MRD)–negative status.

In the phase 2 portion, linvoseltamab is being administered with an initial step-up dosing regimen followed by a full 200-mg weekly dose. At week 16, patients transition to every-2-week dosing. Patients achieving VGPR or better after 24 weeks of therapy may transition to dosing once every 4 weeks. The regimen includes two 24-hour hospitalizations for safety monitoring.

Safety Observations

The safety profile of linvoseltamab was generally manageable and consistent with prior reports. At a 14-month median follow-up, the most common treatment-emergent adverse effect (TEAE) was cytokine release syndrome (CRS), which occurred in 46% of patients (grade 1, 35%; grade 2, 10%; grade 3, 1%).

Any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) was observed in 8% of patients, including three patients who had grade 3 ICANS; no cases were grade 4 or higher.

Any-grade infections occurred in 74% of patients, with 36% experiencing grade 3 or 4 infections. The frequency and severity of infections decreased after 6 months.

The most common grade 3 or 4 TEAEs were neutropenia (42%) and anemia (31%). Six deaths considered related to treatment occurred during the trial, with 5 due to infection and 1 due to renal failure.

Ongoing and Future Studies

Linvoseltamab is being investigated in a broad clinical development program for multiple myeloma across different treatment settings.1 In addition to LINKER-MM1, the investigational bispecific antibody is being evaluated in two ongoing trials.

The phase 1b LINKER-MM2 trial (NCT05137054) is evaluating the safety and efficacy of linvoseltamab in combination with agents such as daratumumab (Darzalex) or carfilzomib (Kyprolis) for adult patients with relapsed/refractory multiple myeloma.

The phase 3 LINKER-MM3 trial (NCT05730036) is an open-label, randomized study comparing linvoseltamab monotherapy to the combination of elotuzumab (Empliciti), pomalidomide (Pomalyst), and dexamethasone in patients with relapsed/refractory multiple myeloma.

References

1. Linvoseltamab recommended for EU approval by the CHMP to treat relapsed/refractory multiple myeloma. Regeneron. February 28, 2025. Accessed February 28, 2025. https://investor.regeneron.com/news-releases/news-release-details/linvoseltamab-recommended-eu-approval-chmp-treat
2. Updated linvoseltamab pivotal data showcase continued deepening of responses in patients with heavily pre-treated multiple myeloma. News Release. Regeneron. June 16, 2024. Accessed February 28, 2025. https://investor.regeneron.com/news-releases/news-release-details/updated-linvoseltamab-data-showcase-continued-deepening
3. Linvoseltamab BLA accepted for FDA review for the treatment of relapsed/refractory multiple myeloma. News release. Regeneron. February 11, 2025. Accessed February 28, 2025. https://investor.regeneron.com/news-releases/news-release-details/linvoseltamab-bla-accepted-fda-review-treatment