Linvoseltamab for Treatment of Relapsed/Refractory Multiple Myeloma

Abstract

Purpose: We present a phase I/II first-in-human trial evaluating the safety and efficacy of 50 mg and 200 mg doses of linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody in relapsed/refractory multiple myeloma (RRMM).

Methods: Phase II eligible patients had RRMM that either progressed on/after ≥three lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody or was triple-class (PI/IMiD/anti-CD38) refractory. Phase II treatment was once a week through week 14 and then once every 2 weeks. Phase II 200 mg patients who achieved a ≥very good partial response by week 24 received linvoseltamab once every 4 weeks. The primary end point in phase II was overall response rate (ORR).

Results: Among the 117 patients treated with 200 mg, the median age was 70 years, 39% had high-risk cytogenetics, and 28% had penta-refractory disease. At a median follow-up of 14.3 months, the ORR was 71%, with 50% achieving ≥complete response (CR). In 104 patients treated with 50 mg at a median follow-up of 7.4 months, the ORR was 48%, with 21% achieving ≥CR. The median duration of response (DOR) for 200 mg patients (n = 83) was 29.4 months (95% CI, 19.2 to not evaluable). Among 200 mg patients, the most common adverse events included cytokine release syndrome (35.0% Gr1, 10.3% Gr2, 0.9% Gr3), neutropenia (0.9% Gr2, 18.8% Gr3, 23.1% Gr4), and anemia (3.4% Gr1, 4.3% Gr2, 30.8% Gr3). Immune effector cell-associated neurotoxicity syndrome occurred in 7.7% of patients (2.6% each Gr1, Gr2, Gr3). Infections were reported in 74.4% of patients (33.3% Gr3, 2.6% Gr4); infection frequency and severity declined over time.

Conclusion: Linvoseltamab 200 mg induced deep and durable responses, with a median DOR of 29.4 months, in patients with RRMM with an acceptable safety profile.

Trial registration: ClinicalTrials.gov NCT03761108.

FIG 1.

Overall response to linvoseltamab in relapsed/refractory multiple myeloma. (A) The best overall response per IRC per IMWG criteria in patients treated at a full dose of 50 mg (n = 104 patients from phase II) or 200 mg (n = 105 phase II patients combined with n = 12 phase I patients, total N = 117 patients). The data cutoff for response assessment was January 6, 2024. (B) The evolution of responses over time among 83 patients who achieved a PR or better treated at 200 mg. (C) The evolution of responses over time among eight patients who underwent intrapatient dose escalation from 50 mg to 200 mg. Patients assigned to 50 mg dose in phase II were permitted to dose escalate to 200 mg if disease progression occurred between 4 and 12 weeks of treatment. Assessment of disease progression and response were determined by the investigator. CR, complete response; IMWG, International Myeloma Working Group; IRC, independent review committee; MR, minimal response; NE, not evaluable; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent CR; SD, stable disease; VGPR, very good partial response.

FIG 2.

KM analysis of DOR, PFS, and OS. (A) DOR to linvoseltamab among patients who had a PR or better at a full dose of 200 mg. (B) PFS in all patients treated at a full dose of 200 mg. Response assessment and progression was determined by an IRC. (C) OS in all patients treated at a full dose of 200 mg. Tick marks on the curve indicate censored data. DOR, duration of response; IRC, independent review committee; KM, Kaplan-Meier; NE, nonevaluable; OS, overall survival; PFS, progression-free survival; PR, partial response.

FIG 3.

Forest plot illustrating the response rate in prespecified subgroups among 200 mg treated patients. A solid circle denotes the response rate, as determined by the IRC in prespecified subgroups, and whiskers indicate the 95% CI. A vertical dashed line denotes the ORR. High-risk cytogenetics, presence of del(17p) and/or t(4;14) or t(14;16). BCMA, B-cell maturation antigen; BMPC, bone marrow plasma cells; EMP, extramedullary plasmacytoma; IRC, independent review committee; ISS, International Staging System; ORR, overall response rate.