EVALUATION of CYTOKINE RELEASE SYNDROME in PATIENTS with RELAPSED or REFRACTORY MULTIPLE MYELOMA RECEIVING STEP-UP PRIMING DOSES and LONGER DOSING INTERVALS of ELRANATAMAB: MAGNETISMM-9

Document Type

Conference Proceeding

Publication Date

6-1-2024

Publication Title

HemaSphere

Keywords

B cell maturation antigen, bispecific antibody, elranatamab, adult, adverse drug reaction, conference abstract, controlled study, cytogenetics, cytokine release syndrome, dosing interval, drug dose regimen, drug therapy, female, follow up, human, incidence, major clinical study, male, multiple myeloma, neurotoxicity, neutropenia, pharmacokinetics, prevalence, refractory disease, side effect, subcutaneous tissue

Abstract

Background: Elranatamab (ELRA) is a humanized, B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the phase 2 registrational MagnetisMM-3 (MM-3) trial, subcutaneous ELRA was given as 2 step-up priming doses (12 mg on Day 1 and 32 mg on Day 4 of Cycle 1, respectively) followed by 76 mg once weekly (QW) in patients with relapsed or refractory multiple myeloma (RRMM). Overall, 56.3% of patients had cytokine release syndrome (CRS; grade 2, 14.3%; no grade ≥3). Most events occurred after doses 1 (44.5%), 2 (20.2%), and 3 (5.9%); 0.8% (1 patient) had CRS with doses 4+. Recurrent CRS (>1 CRS event) occurred in 15.1% of patients (Lesokhin, Nat Med 2023). Aims: To report the overall safety and CRS profile associated with an alternative priming regimen and longer dosing intervals of ELRA in patients with RRMM. Methods: MagnetisMM-9 (NCT05014412) is a phase 1/2, open-label, nonrandomized study of ELRA in patients with RRMM and disease refractory to ≥1 immunomodulatory drug, ≥1 proteasome inhibitor, and ≥1 anti-CD38 antibody. Patients were given subcutaneous ELRA as step-up priming doses of 4 and 20 mg on Day 1 and Day 4 of Cycle 1, respectively. After the priming doses, ELRA 76 mg was given QW for 6 cycles (Part 1) or for 1 cycle followed by 116 or 152 mg every two weeks for 5 cycles (Part 2A). The recommended phase 2 dose (RP2D) from Part 2A (152 mg) was evaluated in Part 2B (dose expansion). The rate of grade ≥2 CRS per American Society for Transplantation and Cellular Therapy criteria during Cycle 1 is the primary endpoint for both parts. Secondary endpoints include evaluation of adverse events (AEs) and pharmacokinetics. Results: For 85 treated patients, the median age was 64.0 years; 49.4% were male; 23.5% had extramedullary disease, and 31.8% had high-risk cytogenetics. Patients had a median of 5.0 (range, 1-12) prior lines of therapy; 85.9% had triple-class refractory disease. After a median follow-up of 7.4 months, the most common (>50%) AEs were CRS (63.5%; grade ≥2, 15.3%) and neutropenia (54.1%; all grade ≥2). Immune effector cell-associated neurotoxicity (ICANS) occurred in 4.7% of patients (all grade ≤2). The median time to onset of ICANS was 2.0 days (range, 2.0-7.0), and the median time to resolution was 1.0 day (range, 1.0-2.0 days). The overall grade ≥2 CRS rate in Cycle 1 was 14.1% (90% CI, 8.4-21.9). CRS rates by grade for step-up doses as well as doses 3, 4, and ≥5 are shown in the Figure. For doses 4+, any grade CRS was observed in 10.6% (grade ≥2, 3.5%) of patients overall, including 12.1% (grade ≥2, 3.0%) of patients continuing to receive 76 mg in Part 1 (n=33), 25.0% (grade ≥2, 0%) of patients receiving 116 mg (n=12), and 5.0% (grade ≥2, 5.0%) of patients receiving 152 mg (RP2D; n=40). Overall, recurrent CRS was observed in 20.0% of patients. The geometric means (CV%) of free ELRA concentrations 24 hours (Cmax-24h) after step-up doses 1 and 2 were 85.64 (48%) and 242.8 (55%), respectively. Summary/Conclusion: The 4/20 mg step-up priming regimen and alternative dosing schedules resulted in similar safety and incidence of overall and grade ≥2 CRS events vs the regimen used in MM-3 (12/32 mg), with no new safety signals identified. However, the CRS profile in this study differed, with more CRS after doses 2, 3, and 4+ and a higher prevalence of recurrent CRS. The Cmax-24h of free ELRA (CV%) after the priming doses were lower than those in MM-3 (107.4 [47%] and 405.1 [72%], respectively). Thus, the priming regimen used in MM-3 remains the optimal regimen for mitigating CRS. Future analyses of ongoing studies will be used to confirm these results. (Figure present).

Volume

8

First Page

1751

Last Page

1752

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