Linvoseltamab in Relapsed/Refractory Multiple Myeloma

Presentation

The patient is a 43-year-old male with a long history of IgG kappa multiple myeloma with t(11;14) initially diagnosed in 2008 after presenting with anemia and back pain. He had no other comorbidities and was on no medication at diagnosis. As part of a clinical trial, he underwent induction therapy of lenalidomide, bortezomib, doxorubicin, and dexamethasone (RVDD), followed by a lenalidomide maintenance per protocol. Stem cells were collected after 4 cycles of therapy. In February 2016, he had confirmed progressive disease (PD) and received ixazomib, lenalidomide, and dexamethasone (IRd) and then moved forward to an autologous stem cell transplant, conditioned with 200 mg/m² of melphalan. He achieved a very good partial remission (VGPR). He did have grade 1 to 2 peripheral neuropathy in both feet at this point. At day 100, he went on to receive 3 mg ixazomib on maintenance days 1, 8, and 15. He did well and then had noted PD in December 2019. As a result, he was started on venetoclax with dexamethasone off-label.

In July 2020, he had an increase in his myeloma numbers, and a restaging PET noted increased activity. His treatment was changed to daratumumab, pomalidomide, and dexamethasone (DPd), and he completed 12 cycles before he again progressed.

Treatment

At this point, the patient has had 5 lines of therapy and is progressing after 2 years on DPd. He had an increase in his IgG paraprotein to 3.21 g/dL and his free kappa light chain (FKLC) to 356 mg/L, with new bone lesions on PET/CT. A bone marrow biopsy noted 40% plasma cells with FISH positive for t(11;14), normal cytogenetics. His neuropathy remained grade 1 in both feet.

It was at that point that we discussed the available options and felt the phase 1/2 FIH Study of REGN5458 (Anti-BCMA x Anti CD3 Bispecific Antibody) in Patients with Relapsed or Refractory Multiple Myeloma clinical trial would be a good option. In June 2021, the patient was admitted for step-up dosing. This dosing schedule called for a week 1 initial dose of 5 mg, a week 2 intermediate dose of 25 mg, a week 3 split dosing, with a total of 200 mg over 2 days, and then a week 4 dose of 200 mg over 4 hours. He had grade 1 cytokine release syndrome (CRS) during the step-up, but his course was otherwise uncomplicated. The patient went on to receive a weekly dosing of 200 mg and then dosing every other week starting at week 12. He experienced grade 1 diarrhea and grade 2 neutropenia that resolved with every-other-week dosing. He initially achieved a partial response, and with time went on to a stringent complete response (sCR).

To date, he continues with every-other-week dosing of 200 mg in sCR and is tolerating very well. He was also restarted on zoledronic acid (now discontinued), an antiviral with valacyclovir, and Pneumocystis jirovecii pneumonia prophylaxis, along with monthly intravenous immunoglobulin (IVIG).

REGN5458 is now known as linvoseltamab. On July 2, 2025, the Food and Drug Administration (FDA) granted accelerated approval to linvoseltamab (Lynozyfic, Regeneron Pharmaceuticals, Inc.).

Discussion

Linvoseltamab is a fully human BCMAxCD3 bispecific antibody (BsAb) that was created using the Veloci-Bi platform.¹ It was approved for relapsed/refractory myeloma patients who have had at least 4 lines of prior therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Approval was based on results from the phase 1/2 LINKER-MM1 trial, which found that an intravenous dose of 200 mg demonstrated durable responses in this heavily pretreated population of myeloma patients.^2,3 The trial’s overall response rate of achieving a complete response or better was 45%. The median time to first response was .95 months. The estimated median duration of response at 9 months was 89% and at 12 months it was 72%. Linvoseltamab’s approved dosing is weekly after step-up dosing and then every 2 weeks after week 16. For patients achieving a VGPR or better after 24 weeks, dosing is reduced to every 4 weeks.^1,3

Rates of neutropenia were 42.7% with infection rates of about 74%. Opportunistic infections, including cytomegalovirus, occurred about 10% of the time and decreased over time. CRS occurred in 46% of patients.^1,2 CRS typically occurred in the step-up dosing as it did with our patient, and most were mild and quickly resolved. The median onset of CRS on trial was 11 hours¹ and resolved within a median of 14.7 hours.³ Other common adverse events included musculoskeletal pain, cough, upper respiratory tract infections, pneumonia and nausea, and headache and dyspnea.^1,3

For our patient, this was a logical choice at the time of relapse and what was approved at the time. He continues to do well on trial and with a new amendment, will potentially be moving to monthly dosing which helps with less frequent visits to our infusion center. He remains in sCR and we continue IVIG monthly. This is an IV infusion. There are trials underway looking at subcutaneous dosing. For our cancer center, we use a team approach when choosing and educating on next lines of therapy. Our advanced practice providers and clinical pharmacists play a huge role in the treatment and management of myeloma patients.

References

1. 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
2. Phase 1/​2 study of REGN5458 in adult patients with relapsed or refractory multiple myeloma (LINKER-MM1). Clinicaltrials.gov. Updated May 15, 2025. Accessed August 27, 2025. https://clinicaltrials.gov/study/NCT03761108
3. Lynozyfic (linvoseltamab-gcpt) receives FDA accelerated approval for treatment of relapsed or refractory multiple myeloma. Regeneron. News release. July 2, 2025. Accessed August 27th, 2025. https://investor.regeneron.com/news-releases/news-release-details/lynozyfictm-linvoseltamab-gcpt-receives-fda-accelerated-approval