Linvoseltamab Displays Durable Efficacy in Relapsed/Refractory Multiple Myeloma

Naresh Bumma, MD

Treatment with linvoseltamab (REGN5458) led to deep and durable responses in patients with relapsed/refractory multiple myeloma, according to findings from the phase 1/2 LINKER-MM1 study (NCT03761108) published online in the Journal of Clinical Oncology.

At a median follow-up of 14.3 months (range, 0.2-38.4), patients who received linvoseltamab 200 mg (n = 117) achieved an overall response rate (ORR) of 70.9%, with 49.6% experiencing a complete response (CR) or a stringent CR. Additionally, at a median follow-up of 7.4 months (range, 0.4-42.0), patients who were treated at the 50 mg dose level (n = 104) achieved an ORR of 48.1%, with 21.2% experiencing at least a CR. Responders treated at the 200 mg dose level (n = 83) achieved a median duration of response (DOR) of 29.4 months (95% CI, 19.2-not evaluable [NE]), with an estimated 12-month DOR rate of 80.9% (95% CI, 70.3%-88.0%).

“In this phase 1/2 clinical trial, a full dose of 200 mg intravenous [IV] linvoseltamab led to deep and durable responses in patients with relapsed/refractory multiple myeloma,” Naresh Bumma, MD, an assistant professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center—James in Columbus, and coauthors wrote. “On the basis of the totality of the safety and efficacy data in this clinical trial comparing 50 mg and 200 mg dosing, including results from patients who underwent intrapatient dose-escalation, 200 mg was selected as the optimal dose of linvoseltamab.”

The open-label LINKER-MM1 trial was the first-in-human study examining the safety and efficacy of the anti-BCMA/anti-CD3 bispecific antibody linvoseltamab in patients with relapsed/refractory multiple myeloma. In order to be eligible for the trial, patients needed to be at least 18 years of age, have an ECOG performance status of 1 or less, and have measurable serum or urine markers per the International Myeloma Working Group (IMWG) criteria. In phase 1, patients were required to have disease that was refractory to both an immunomodulatory agent and a proteasome inhibitor; in phase 2 patients were required to have disease that was refractory to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.

During the dose escalation portion of the trial, patients received linvoseltamab via a modified 3 + 3 (4 + 3) dose-escalation design, including a 28-day dose-limiting toxicity observation period. In the phase 2 portion, investigators examined full IV doses of linvoseltamab given at 50 mg or 200 mg once a week for weeks 3 through 14, then patients received the agent once every 2 weeks starting on week 16. Patients who received linvoseltamab 200 mg transitioned to a once every 4 weeks dosing schedule if they achieved at least a very good partial response (VGPR) after at least 24 weeks of therapy.

The primary end point in phase 2 was ORR per independent review committee by IMWG criteria. Secondary end points included DOR, progression-free survival (PFS), investigator-assessed ORR, overall survival (OS), and safety, among others.

The baseline patient characteristics were generally well balanced between the 50 mg and 200 mg groups; the median age was 65 years (range, 45-90) and 70 years (range, 37-91), respectively. Most patients in both groups were male (53.8% vs 54.7%), White (72.1% vs 70.9%), had an ECOG performance status of 1 (64.4% vs 72.6%), received prior autologous transplant (79.8% vs 65.8%), had at least quad-refractory disease (82.7% vs 65.8%), and were refractory to the last line of treatment (89.4% vs 85.5%). The median number of prior lines of therapy received was 6 (range, 3-14) and 5 (range, 2-16), respectively.

Additional findings from LINKER-MM1 demonstrated that 39.4% of patients in the 50 mg group experienced at least a VGPR vs 63.2% in the 200 mg group. Patients who received linvoseltamab 200 mg achieved a median time to response, at least VGPR, and at least CR of 1 month (range, 0.5-6.3), 2.6 months (range, 0.7-15.7), and 8.5 months (range, 1.6-14.1), respectively. The estimated median PFS was not reached (95% CI, 17.3-NE) and the estimated median OS was 31.4 months (95% CI, 21.6-NE), respectively; the estimated 12-month PFS and OS rates were 70.0% (95% CI, 60.1%-78.0%) and 75.3% (95% CI, 66.0%-82.3%), respectively.

In terms of safety, patients in the 50 mg and 200 mg groups experienced an any-grade treatment-emergent adverse effect (TEAE) at rates of 98.1% and 100%, respectively; grade 3 to 4 TEAEs occurred at rates of 72.1% and 73.5%, respectively. Patients in both groups experienced any-grade cytokine release syndrome (54.8% vs 46.2%), anemia (42.3% vs 38.5%), cough (34.6% vs 36.8%), and diarrhea (30.8% vs 37.6%), among other TEAEs. In the 200 mg group, 6 patients experienced TEAEs leading to death within 30 days of the last dose of linvoseltamab, 5 of which were due to infection, and 35 patients died over the course of the study.

“In summary, 200 mg linvoseltamab demonstrated high efficacy in patients with late-stage relapsed/refractory multiple myeloma, including patients with high disease burden and high-risk features which is noteworthy in the context of other approved drugs in this class,” Bumma and coauthors wrote in conclusion. “A response-adapted regimen allowed patients treated at 200 mg who experience deep responses [≥ VGPR] to shift to once every 4-week dosing after 24 weeks on study; this regimen maximized patient convenience, and was associated with both sustained efficacy, and a decrease in infection rate over time, particularly among patients with deep responses. These data suggest that linvoseltamab offers substantial clinical benefit for treatment of relapsed/refractory multiple myeloma.”

Reference

Bumma N, Richter J, Jagannath S, et al. Linvoseltamab for treatment of relapsed/refractory multiple myeloma. J Clin Oncol. Published online June 16, 2024. doi:10.1200/JCO.24.01008