Linvoseltamab Receives EC Approval for Heavily Pretreated R/R Myeloma

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The European Commission (EC) has granted conditional marketing authorization to linvoseltamab (Lynozyfic) for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least 3 prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody, and have demonstrated disease progression on their last therapy.1

The approval was supported by findings from the pivotal phase 1/2 LINKER-MM1 trial (NCT03761108), which showed robust and durable responses in heavily pretreated patients. Among those who received linvoseltamab—a BCMA- and CD3-directed bispecific antibody—at the 200-mg dose (n = 117), the objective response rate (ORR) was 71%, and 50% of patients achieved a complete response (CR) or better, per independent review committee assessment. The minimal residual disease (MRD)–negativity rate among patients achieving a CR or stringent CR (n = 58) was 41% (95% CI, 29%-55%). The median duration of response (DOR) was 29 months (95% CI, 19-not estimable). Linvoseltamab is a bispecific antibody engineered to bridge B-cell maturation antigen (BCMA) on myeloma cells with CD3-expressing T cells, promoting T-cell activation and targeted tumor cell killing.

“We are excited by the potential of [linvoseltamab] and its differentiated clinical profile, dosing, and administration. Given the strength of the data, we are pursuing a robust clinical development program exploring its use—in earlier lines of therapy as monotherapy and in novel combinations—with the hope of further advancing care for patients,” George D. Yancopoulos, MD, PhD, board co-chair, president, and chief scientific officer of Regeneron, stated in a news release.

In August 2024, the FDA issued a complete response letter to the biologics license application (BLA) seeking the approval of linvoseltamab for the treatment of patients with relapsed/refractory multiple myeloma that has progressed following 3 or more prior therapies due to an issue associated with findings from a pre-approval inspection at a third-party fill/finish manufacturer for another company’s product candidate.2 In February 2025, the regulatory agency accepted a resubmitted BLA seeking approval of the bispecific antibody 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.3

LINKER-MM1 Trial Overview and Baseline Characteristics

The ongoing, open-label, multicenter phase 1/2 LINKER-MM1 trial is evaluating the safety, tolerability, and efficacy of linvoseltamab in patients with relapsed/refractory multiple myeloma.4

The completed phase 1 dose-escalation portion assessed the safety, tolerability, and dose-limiting toxicities of linvoseltamab across 9 escalating dose levels. This phase also explored different administration regimens to optimize dosing strategies.

The ongoing, phase 2 dose-expansion portion is focused on evaluating the safety and antitumor activity of linvoseltamab, with the ORR serving as the primary end point. Key secondary end points include duration of response (DOR), progression-free survival (PFS), minimal residual disease (MRD) negativity rate, and overall survival (OS).

Eligibility for the phase 2 cohort requires patients to have received at least 3 prior lines of therapy or to have triple-class refractory disease.

Linvoseltamab is administered using an initial step-up dosing regimen, followed by the full 200-mg dose given weekly. After week 14, patients transition to dosing every 2 weeks. Additionally, a response-adapted regimen allows patients who achieve a very good partial response or better after completing at least 24 weeks of therapy to shift to dosing once every 4 weeks. The protocol also requires a pair of 24-hour hospitalizations for safety monitoring during initial treatment.

Safety Analysis

The most frequently reported adverse effects included musculoskeletal pain (52%), cytokine release syndrome (CRS; 46%), neutropenia (43%), cough (42%), diarrhea (39%), anemia (38%), fatigue (36%), pneumonia (32%), and upper respiratory tract infection (30%).1

CRS was predominantly low grade; 35% of patients experienced grade 1 CRS, and 10% had grade 2 CRS. Only one case of grade 3 CRS (0.9%) was reported, and grade 4 or higher CRS were observed. The median time to CRS onset was 11 hours (range, –1.1 to 184 hours), and median time to CRS resolution was 16 hours (range, 1-96), with most cases resolving within 1 day.

Additionally, grade 3 immune effector cell–associated neurotoxicity syndrome occurred in 2.6% of patients. Infections were common, with grade 3 or 4 infections reported in 36% of patients, and fatal infections occurring in 4% of the study population.

References

1. Lynozyfic™ (linvoseltamab) approved in the European Union for the treatment of relapsed/refractory multiple myeloma. News Release. Regeneron. April, 28, 2025. Accessed April, 28, 2025. https://investor.regeneron.com/news-releases/news-release-details/lynozyfictm-linvoseltamab-approved-european-union-treatment
2. Regeneron provides update on biologics license application for linvoseltamab. News release. Regeneron Pharmaceuticals, Inc. August 20, 2024. Accessed April 28, 2025. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-biologics-license-application-0
3. Linvoseltamab BLA accepted for FDA review for the treatment of relapsed/refractory multiple myeloma.News release. Regeneron. February 11, 2025. Accessed April 28, 2025. https://investor.regeneron.com/news-releases/news-release-details/linvoseltamab-bla-accepted-fda-review-treatment
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