MagnetisMM-3: Long-Term Update and Efficacy and Safety of Less Frequent Dosing of Elranatamab in Patients with Relapsed or Refractory Multiple Myeloma
Authors: Prince H. Miles , Bahlis Nizar J. , Rodríguez-Otero Paula , Karlin Lionel , Akard Luke , Varshavsky-Yanovsky Asya , Chu Michael P. , Nagai Yuya , Vesole David H. , Hickman Anne , Sullivan Sharon T. , Leip Eric , Conte Umberto , Viqueira Andrea , Lesokhin Alexander M. 
Published: December 2024

BACKGROUND
Elranatamab (ELRA) is a humanized, bispecific antibody that targets B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells. In the phase 2 registrational MagnetisMM-3 trial (NCT04649359), subcutaneous (SC) ELRA monotherapy induced deep and durable responses in patients with relapsed or refractory multiple myeloma (RRMM) naive to BCMA-directed therapy. Here, we report the long-term efficacy and safety of ELRA in BCMA-naive patients approximately 26 months after the last patient initiated treatment, including results after the switch to dosing once every 4 weeks (Q4W).
METHODS
Eligible patients had RRMM with disease refractory to ≥1 immunomodulatory drug, ≥1 proteasome inhibitor, and ≥1 anti-CD38 antibody. Patients were given SC ELRA as step-up priming doses followed by ELRA 76 mg QW for 6 cycles. Patients given QW dosing for ≥6 cycles who achieved partial response (PR) or better lasting ≥2 months were transitioned to Q2W dosing and to Q4W after ≥6 cycles of Q2W dosing. The primary endpoint was objective response rate (ORR), assessed by blinded-independent central review (BICR) per International Myeloma Working Group (IMWG) criteria. Adverse events (AEs) were graded using the National Cancer Institute Common Terminology Criteria for AEs (version 5.0).
Outcomes in patients who switched to Q4W dosing were assessed in a post-hoc analysis. The impact of Q4W dosing on efficacy was assessed by evaluating maintenance of response ≥6 months after the switch to Q4W. Patients were counted as responders if they had an assessment demonstrating response ≥6 months after the switch. The impact of switching to Q4W dosing on safety was assessed by comparing the incidence of TEAEs before and after the switch. New onset AEs for each participant were included for an equal time period before and after the switch (based on individual follow-up times after the switch), with a maximum time period of up to 6 months.
RESULTS
At the time of data cutoff (March 26, 2024), 23 of 123 patients (18.7%) remained on treatment, and 52 (42.3%) were still being followed in the study. After a median follow-up of 28.4 months per reverse Kaplan-Meier, the confirmed ORR was 61.0%, with 46 (37.4%) patients achieving complete response or better (≥CR), 23 (18.7%) VGPR, and 6 (4.9%) PR as best response. Median duration of response (DOR) was not reached (NR); the probability of maintaining a response at 24 months was 66.9% (95% CI, 54.4-76.7). Median DOR among patients with ≥VGPR and ≥CR were NR; the probability of maintaining response at 24 months was 71.5% (95% CI, 58.5-81.1) in patients with ≥VGPR and 87.9% (95% CI, 73.1-94.8) in patients with ≥CR. Median progression-free survival was 17.2 (95% CI, 9.8-NE) months. Median overall survival was 24.6 (95% CI, 13.4-NE) months. A total of 58 patients switched to Q2W dosing; 27 patients further decreased the dosing frequency to Q4W. Among the 58 patients who switched to Q2W dosing, the median time on the Q2W regimen was 13.4 (range, 0.03-22.2) months. In the 27 patients who further decreased the dosing frequency to Q4W, the median time since the switch to Q4W was 6.5 (range, 0.03-10.1) months. Among responders per BICR who switched to Q4W dosing ≥6 months before the data cutoff (n=25), 23 (92.0%) maintained their response ≥6 months after the switch, including 21 (84.0%) who maintained ≥CR. One (4.0%) patient had progressive disease (per IMWG criteria in ≥1 assessment), and 1 (4.0%) permanently discontinued ELRA within 6 months after the switch to Q4W. Among patients who switched to Q4W dosing overall (n=27), the most frequently reported (≥30% either before or after the switch) any grade TEAEs by system organ class (SOC), were infections (51.9% to 59.3%), hematologic disorders (40.7% to 25.9%), respiratory disorders (40.7% to 22.2%), and gastrointestinal disorders (37.0% to 22.2%). The most frequently reported (≥10% either before or after the switch) grade 3/4 TEAEs by SOC were hematologic disorders (33.3% to 25.9%) and infections (18.5% to 11.1%).
CONCLUSIONS
Overall, ELRA continues to demonstrate deep and durable responses and no new safety signals after long-term follow-up in a heavily pretreated population (median of 5 prior lines of therapy). These results suggest that reducing the dosing frequency of ELRA to Q4W may improve safety without compromising efficacy. Updated results with data from 32 months after the last patient's initial dose will be presented.