EMA Accepts Marketing Authorization Application for Linvoseltamab in R/R Multiple Myeloma

The European Medicines Agency (EMA) has accepted for review a marketing authorization application (MAA) seeking the approval of linvoseltamab (REGN5458) for the treatment of patients with relapsed/refractory multiple myeloma following disease progression on at least 3 prior therapies.¹

The MAA is supported by results from the pivotal phase 1/2 LINKER-MM1 trial (NCT03761108), in which treatment with linvoseltamab given at 200 mg (n = 117) led to an independent review committee–assessed objective response rate (ORR) of 71% in patients with relapsed/refractory multiple myeloma. Additional findings from the primary analysis, which were conducted with 11 months of median follow-up, showed that 46% of responders experienced a complete response (CR) or better.²

The agent is also under evaluation in the confirmatory phase 3 LINKER-MM3 trial (NCT05730036), in which patients will be randomly assigned to treatment with linvoseltamab or elotuzumab (Empliciti), pomalidomide (Pomalyst), and dexamethasone.¹

Linvoseltamab is an investigational bispecific antibody that is designed to lead to T-cell activation and cancer cell death by binding BCMA on multiple myeloma cells with CD3-expressing T cells.

In the ongoing, open-label, multicenter, phase 1/2 LINKER-MM1 trial, linvoseltamab is being evaluated in 282 patients with relapsed/refractory multiple myeloma. To be eligible for enrollment, patients must have received at least 3 prior lines of therapy or have triple refractory disease.

In the trial, linvoseltamab was administered intravenously with stepwise dosing followed by the full dose. The trial protocol also allowed response-adapted administration, which enabled patients who achieved a very good partial response (VGPR) or a CR to shift from every-2-week to every-4-week dosing after at least 24 weeks of therapy.

As part of the phase 1 dose-escalation portion of the trial, which is now complete, investigators evaluated the safety, tolerability, and dose-limiting toxicities of the agent across nine dose levels. The phase 2 dose-expansion portion is evaluating the safety and antitumor activity of linvoseltamab. The primary measure of efficacy is ORR, and secondary end points include duration of response (DOR), progression-free survival, rate of minimal residual disease negativity, and overall survival.

Regarding patient demographics, 27% were at least 75 years of age, 16% had extramedullary plasmacytomas, 23% had at least 50% of plasma cells in the bone marrow, and 39% had high-risk cytogenetics. Additionally, 17% of patients were Black or African American.²

Additional findings from an earlier analysis of the trial, which were presented at the 2023 ASH Annual Meeting & Exposition, demonstrated that with 8.0 months of median follow-up, the rates of stringent CR, CR, VGPR, and partial response (PR) were 33%, 6%, 20%, and 10%, respectively. Furthermore, the median DOR was not reached, and half of patients remained on treatment. The median times to PR or better, VGPR or better, and CR or better were 1.0, 2.6, and 7.6 months, respectively.^3,4

At the time of the latest data cutoff, all patients who received the 200-mg dose experienced an adverse effect (AE), 85% of which were grade 3 or greater in severity. The most frequent AE was cytokine release syndrome (CRS; 46%). Most cases of CRS were grade 1 (35%), 10% were grade 2; and 1 patient experienced a grade 3 event. Eight percent of patients experienced adjudicated immune effector cell–associated neurotoxicity syndrome (grade 3, 3%), and 73% of patients experienced infections (grade 3/4, 34%).²

Treatment-emergent AEs leading to death on treatment or within 30 days after the last dose of therapy occurred in 14 patients (12%), owing predominantly to infections (n = 11; 9%).²

In December 2023, Regeneron submitted a biologics license application for the agent in this population to the FDA.¹

References

1. Linvoseltamab receives EMA filing acceptance for treatment of relapsed/refractory multiple myeloma. News release. Regeneron. February 2, 2024. Accessed February 2, 2024. https://investor.regeneron.com/news-releases/news-release-details/linvoseltamab-receives-ema-filing-acceptance-treatment
2. Updated linvoseltamab pivotal data demonstrates strong rates and depth of response in patients with heavily pre-treated multiple myeloma. News release. Regeneron Pharmaceuticals, Inc. December 7, 2023. Accessed February 2, 2024. https://investor.regeneron.com/news-releases/news-release-details/updated-linvoseltamab-pivotal-data-demonstrated-strong-rates-and
3. Jagannath S, Richter J, Dhodapkar MV, et al. Patterns of response to 200 mg linvoseltamab in patients with relapsed/refractory multiple myeloma: longer follow-up of the Linker-MM1 study. Blood. 2023;142(suppl 1):4746. doi:10.1182/blood-2023-177968
4. American Society of Hematology 2023 investor event. Regeneron Pharmaceuticals, Inc. December 14, 2023. Accessed February 2, 2024. https://investor.regeneron.com/static-files/cb093452-9e37-41b0-9d52-c53b9275e99e