FDA Accepts BLA Resubmission for Linvoseltamab in R/R Multiple Myeloma

The FDA has accepted the resubmission of a biologics license application (BLA) seeking the approval of linvoseltamab (REGN5458) for the treatment of patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy or those who received 3 prior lines of therapy and are refractory to the last line of therapy.1

Acceptance of this BLA resubmission follows the resolution of issues with third-party fill/finish manufacturing issues cited in the FDA’s complete response letter issued for the initial BLA in August 2024.2 Regeneron Pharmaceuticals, the drug’s developer, identified this finding as the sole barrier to approvability and announced that the issue has since been resolved, enabling BLA resubmission.

The FDA has set a new target action date of July 10, 2025, for linvoseltamab under the Prescription Drug User Fee Act.1

The investigational agent is also under review by the European Medicines Agency (EMA) for the same patient population. It has yet to receive approvals from any regulatory authorities.

Data from the phase 1/2 LINKER-MM1 trial (NCT03761108) supported the earlier BLA submission. Updated results presented at the 2024 EHA Congress showed that, at a median follow-up of 14.3 months, patients who received the 200-mg dose of linvoseltamab (n = 117) achieved an overall response rate of 71%.3 The complete response (CR) or better rate was 50%, and the very good partial response (VGPR) or better rate was 63% per independent review committee (IRC) assessment.

LINKER-MM1: Overview

The open-label, multicenter, dose-escalation and -expansion trial evaluated linvoseltamab inpatients at least 18 years of age with relapsed or refractory multiple myeloma who had an ECOG performance status of 0 or 1 and measurable serum or urine markers per International Myeloma Working Group (IMWG) criteria.4 In phase 1, patients had to have disease refractory to an immunomodulatory agent (IMiD) and proteasome inhibitor (PI); in phase 2, their disease also had to be refractory to an anti-CD38 antibody.

The trial followed a modified 3+3 (4+3) dose-escalation design, including a 28-day observation period for dose-limiting toxicities. In phase 2, patients received intravenous linvoseltamab at 50 mg or 200 mg weekly from weeks 3 to 14, followed by every 2 weeks starting at week 16. Notably, patients treated with the 200-mg dose transitioned to every-4-week dosing if they achieved a VGPR or better after at least 24 weeks of treatment.

The primary end point in phase 2 was ORR by IRC assessment per IMWG criteria. Secondary end points included duration of response (DOR), progression-free survival (PFS), ORR by investigator assessment, overall survival (OS), and safety.

Additional Efficacy and Safety Data

Further data presented at the 2024 EHA Congress demonstrated that the median DOR was 29 months for all responders; however, the median DOR was not reached for those who achieved a CR or better.3 In non-prespecified analyses, the estimated probability of maintaining a response at 12 months was 81% among all patients who had a partial response (PR) or better and 95% among those who achieved a CR or better. The median PFS was not reached (NR). However, the estimated likelihood of being progression-free at 12 months was 70% among all patients and 96% among those who achieved a CR or better.

The median OS was 31 months (95% CI, 22-not estimable) for all patients. Prespecified analyses showed that the median OS was NR for patients who achieved a CR or better, with estimated 12-month survival probabilities of 75% among all patients and 100% among those who achieved a CR or better.

Regarding safety, the agent’s toxicity profile remained consistent with findings at 11 months. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse effect (TEAE), occurring in 46% of patients; this included 35% with grade 1 CRS, 10% with grade 2 CRS, and one patient (1%) with grade 3 CRS. Adjudicated immune effector cell–associated neurotoxicity syndrome (ICANS) of any grade occurred in 8% of patients; 3 patients had grade 3 ICANS, and there were no grade 4 or higher events. Infections were reported in 74% of patients, including 36% who had grade 3/4 infections; the incidence of infections decreased in frequency and severity after 6 months. The most common grade 3 or 4 TEAEs were neutropenia (42%) and anemia (31%).

Six treatment-related deaths occurred during treatment or within 30 days of the last dose, 5 of which were due to infection, plus 1 due to renal failure.

References

1. Linvoseltamab BLA accepted for FDA review for the treatment of relapsed/refractory multiple myeloma.News release. Regeneron. February 11, 2025. Accessed February 11, 2025. https://investor.regeneron.com/news-releases/news-release-details/linvoseltamab-bla-accepted-fda-review-treatment
2. Regeneron provides update on biologics license application for linvoseltamab. News release. Regeneron. August 20, 2024. Accessed February 11, 2025. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-biologics-license-application-0
3. 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 11, 2025. https://investor.regeneron.com/news-releases/news-release-details/updated-linvoseltamab-data-showcase-continued-deepening
4. Bumma N, Richter J, Jagannath S, et al. Linvoseltamab for treatment of relapsed/refractory multiple myeloma. J Clin Oncol. 2024;42(22):2702-2712. doi:10.1200/JCO.24.01008