FDA Approves Linvoseltamab for Relapsed/Refractory Multiple Myeloma

FDA

The FDA has granted accelerated approval to linvoseltamab-gcpt (Lynozyfic) for use in adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody.1-3

The regulatory decision is supported by findings from the phase 1/2 LINKER-MM1 trial (NCT03761108), in which the BCMA-directed CD3 T-cell engager elicited an objective response rate (ORR) of 70% (95% CI, 59%-80%), which included a complete response (CR) rate of 45% (95% CI, 34%-57%), a very good partial response (VGPR) rate of 15%, and a partial response (PR) rate of 5%.1,3

The median time to first response was 0.95 months (range, 0.5-6), and the median duration of response (DOR) was not reached (NR; 95% CI, 12-not evaluable [NE]). At a median follow-up of 11.3 months, the estimated 9- and 12-month DOR rates were 89% (95% CI, 77%-95%) and 72% (95% CI, 54%-84%).

“The FDA approval of Lynozyfic represents meaningful progress for the multiple myeloma community. Lynozyfic demonstrated early, deep and durable responses in heavily pre-treated patients, which I saw firsthand in clinical trials,” Sundar Jagannath, MD, network director of the Center of Excellence for Multiple Myeloma at Mount Sina and a trial investigator, stated in a news release.3 “Lynozyfic has a convenient response-adapted dosing regimen, which provides the potential to extend time between doses. This is a significant patient-centric advancement that could help reduce treatment burden.”

Looking at LINKER-MM1

The open-label, multicenter, multicohort study enrolled patients who had previously received 3 or more therapies, including a PI, IMiD, and an anti-CD38 antibody.3 Patients had an ECOG performance status no higher than 1 and acceptable hematologic, renal, and hepatic function at baseline.

If they had brain lesions or meningeal involvement, they were excluded. Other exclusion criteria include a history of a neurodegenerative condition or history of seizure within 1 year of enrollment, as well as active infection or prior receipt of a BCMA-directed bispecific antibody therapy, bispecific T-cell engaging therapy, or a BCMA-targeted CAR T-cell therapy.

Linvoseltamab was intravenously administered at a step-up dose of 5 mg on day 1, 25 mg on day 8, and 200 mg on day 15. From weeks 4 to 13, the agent was administered weekly at a dose of 200 mg; thereafter, the agent was given at the same dose every other week. After at least 24 weeks of treatment, patients in the phase 2 portion of the trial who experienced a VGPR or better were given linvoseltamab at 200 mg every 4 weeks. Treatment continued until progressive disease or intolerable toxicity.

A total of 80 patients comprised the efficacy population. The median patient age was 71 years (range, 27-83), with one-third of patients aged 75 years or older. More than half of the patients were male (64%) and White (69%). At the time of study entry, 39% of patients had stage I disease, 36% had stage II disease, and 19% had stage III disease per International Staging System criteria. Forty percent of patients had high-risk cytogenetics, and 18% had baseline extramedullary disease.

Patients were heavily pretreated, having received a median of 5 prior lines of therapy (range, 4-13), and the majority (83%) were refractory to their last line of therapy. Moreover, 79% of patients were triple-class refractory, and 13% had prior exposure to a BCMA-targeted antibody-drug conjugate.

Efficacy of linvoseltamab was established based on ORR per blinded independent review committee (IRC) assessment and the International Myeloma Working Group criteria.

Examining Earlier Data

Results previously 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 ORR of 71%.4 The CR or better rate was 50%, and the VGPR or better rate was 63% per IRC assessment.

The median DOR was 29 months for all responders; however, the median DOR was NRfor those who achieved a CR or better. In non-prespecified analyses, the estimated probability of maintaining a response at 1 year was 81% among all patients who experienced a PR or better and 95% among those who achieved a CR or better. The median progression-free survival was NR. However, the estimated likelihood of being progression free at 1 year was 70% in all patients and 96% among those who achieved a CR or better.

Additionally, the median overall survival (OS) was 31 months (95% CI, 22-NE) 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% in all patients and 100% in those who achieved a CR or better.

Safety Spotlight

Safety was evaluated in 117 patients, and the median duration of treatment with linvoseltamab was 47 weeks (range, 1-151).3 Slightly more than half of patients (55%) were exposed to the agent for at least 9 months, and about one-third (36%) were exposed for at least 12 months.

Serious adverse effects (AEs) were reported in 74% of patients. Moreover, 74% of patients experienced AEs that led to dose interruptions or delays, and 16% had AEs that resulted in permanent discontinuation of the agent.

The most common AEs occurring in at least 10% of patients included musculoskeletal pain (all grade, 53%; grade 3/4, 3.4%), cytokine release syndrome (CRS; 46% 0.9%), cough (39%; 0%), upper respiratory tract infection (35%; 6%), diarrhea (35%; 1.7%), fatigue (34%; 0%), pneumonia (28%; 21%), nausea (23% 0%), headache (22%; 0.9%), dyspnea (21%; 0.9%), vomiting (19%; 0%), edema (19%; 0.9%), encephalopathy (18%; 3.4%), COVID-19 (17%; 5%), constipation (17%; 0%), pyrexia (17%; 0%), nasal congestion (16%; 0%), urinary tract infections (16%; 8%), decreased appetite (15%; 0.9%), rash (15%; 1.7%), hypogammaglobulinemia (13%; 0.9%), sensory neuropathy (13%; 0.9%), insomnia (13%; 0%), sepsis (10%; 6%), and hypertension (10%; 4.3%).

The most common select laboratory abnormalities that worsened from baseline in patients included decreased lymphocyte count (all grade, 97%; grade 3/4, 92%), decreased hemoglobin (72%; 42%), decreased platelet count (64%; 19%), decreased white blood cell count (63%; 31%), decreased neutrophil count (62%; 47%), increased aspartate aminotransferase (61%; 10%), decreased phosphorus (55%; 24%), and increased creatinine (47%; 7%), and increased alanine aminotransferase (46%; 6%).

The prescribing information for the agent includes a Boxed Warning for life-threatening CRS and neurologic toxicity.1 Forty-six percent of those who received linvoseltamab on the trial at the recommended dose experienced CRS; 54% experienced neurologic toxicities such as immune effector cell–associated neurotoxicity. Grade 3 or 4 CRS was reported in less than 1% of patients; 8% of patients experienced grade 3 or 4 neurologic toxicity.

The Path to Approval

In February 2025, the regulatory agency accepted the resubmission of a biologics license application seeking the approval of the drug for use in 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.5 The acceptance followed 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 2024.6 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.5

References

1. FDA grants accelerated approval to linvoseltamab-gcpt for relapsed or refractory multiple myeloma. FDA. July 2, 2025. Accessed July 2, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-linvoseltamab-gcpt-relapsed-or-refractory-multiple-myeloma
2. Lynozyfic™ (linvoseltamab-gcpt) receives FDA accelerated approval for treatment of relapsed or refractory multiple myeloma. News release. Regeneron Pharmaceuticals, Inc. July 2, 2025. Accessed July 2, 2025. https://newsroom.regeneron.com/news-releases/news-release-details/lynozyfictm-linvoseltamab-gcpt-receives-fda-accelerated-approval
3. Lynozyfic. Prescribing information. Regeneron Pharmaceuticals, Inc.; 2025. Accessed July 2, 2025. https://www.regeneron.com/downloads/lynozyfic_fpi.pdf
4. Updated linvoseltamab pivotal data showcase continued deepening of responses in patients with heavily pre-treated multiple myeloma. News Release. Regeneron. June 16, 2024. Accessed July 2, 2025. https://investor.regeneron.com/news-releases/news-release-details/updated-linvoseltamab-data-showcase-continued-deepening
5. Linvoseltamab BLA accepted for FDA review for the treatment of relapsed/refractory multiple myeloma.News release. Regeneron. February 11, 2025. Accessed July 2, 2025. https://investor.regeneron.com/news-releases/news-release-details/linvoseltamab-bla-accepted-fda-review-treatment
6. Regeneron provides update on biologics license application for linvoseltamab. News release. Regeneron. August 20, 2024. Accessed July 2, 2025. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-biologics-license-application-0