Response-adapted randomization to Q2W vs Q4W isatuximab beyond cycle 6 in relapsed multiple myeloma: Results from a phase 2 Study of isa-pd in lenalidomide- and PI-exposed patients

Abstract

Abstract Introduction: Isatuximab (Isa), an anti-CD38 mAb, is approved with pomalidomide and low-dose dexamethasone (Isa-Pd) for RRMM after ≥2 prior therapies. This phase 2 trial evaluates Isa-Pd in RRMM after 1 prior Len+PI-based regimen. The trial employed a response-adapted design: all patients (pts) received 6 cycles of Isa-Pd, after which responders were randomized to standard or less frequent Isa dosing, while non-responders continued on standard dosing without randomization. This exploratory analysis focuses on the continuation phase, assessing outcomes by post-Cycle 6 assignment. Methods EAE115 (NCT05298683) is an investigator-initiated, phase 2, prospective, open-label, multicenter trial in RRMM after 1 prior Len+PI-based regimen. Key exclusions: prior anti-CD38 or pomalidomide exposure, or stem cell transplant ≤12 weeks prior. Pts initially receive six 28-day cycles of Isa 10 mg/kg IV (QW in Cycle 1, Q2W thereafter) plus Pd 4 mg/day PO (Days 1-21) and 40 mg (or 20 mg if ≥75y) PO/IV (QW) respectively. In the continuation phase (Cycle 7 onwards), pts with ≥very good partial response (VGPR) are randomized 1:1 to continue Isa Q2W or switch to Q4W plus Pd, while those with <VGPR continue Isa Q2W plus Pd. Endpoints include ORR, PFS, response improvement at continuation, treatment exposure and safety. Results As of 15 April 2025, 56 pts were enrolled; 11 [19.6%] discontinued before Cycle 7 and 11 [19.6%] had not reached randomization yet. Thus, 34 (60.7%) entered the continuation phase: 23/34 (67.6%) non-randomized (<VGPR), 6/34 (17.6%) randomized to Q2W and 5/34 (14.7%) to Q4W. At baseline, median age was 72.0y (range 48.0–87.0), 62.5% (35/56) were male and 58.9% (33/56) had ECOG PS 0. High-risk cytogenetics were reported in 17.9% (10/56) overall, with post-Cycle 7 non-randomized: 21.7% (5/23); Q2W-randomized: 33.3% (2/6), Q4W-randomized: 20.0% (1/5). Prior ASCT was performed in 23.2% (13/56), with post-Cycle 7 non-randomized: 21.7% (5/23); Q2W-randomized: 33.3% (2/6), Q4W-randomized: 20.0% (1/5). During the initial 6 cycles, median Isa dose intensity (DI) was 22.6 mg/kg/28-day cycle (range 1.4–40.0), corresponding to a median relative dose intensity (RDI) of 99.9% (range 5.7%–101.5%). Dose skips occurred in 22/56 (39.3%) pts. In the continuation phase, median Isa DI was 18.8 mg/kg (range 15.2–21.5) for non-randomized pts, 18.6 mg/kg (range 17.6–19.3) for Q2W-randomized, and 9.6 mg/kg (range 9.2–10.2) for Q4W-randomized, per 28-day cycle, with the corresponding median RDIs being 99.6% (range 82.0%–100.0%), 94.7% (91.7%–101.6%), and 99.9% (range 99.7%–100.0%), respectively. Dose skips occurred in 10/23 (43.5%) of non-randomized, 4/6 (66.7%) of Q2W-randomized pts; none in Q4W. At a median follow-up of 9.7 months (range 0.9–29.4), ORR was 67.9% (38/56), with ≥VGPR in 35.7% (20/56). Median time to first response was 1.0 month (range 0.9–13.8); median PFS was 15.4 months (95% confidence interval [CI]: 9.9–not reached), and median TTP was 17.5 months (95% CI: 10.8–not reached). Of the 18 patients with documented PD, 4 progressed prior to entering the continuation phase, and 14 (41.2%) during the continuation phase: 13 non-randomized and 1 Q4W-randomized. Among pts continuing to the continuation phase, ORR was 88.2% (30/34) overall and 82.6% (19/23) in the non-randomized; ≥VGPR in 50% (17/34) overall and 26.1% (6/23) of the non-randomized. At a median follow-up post-Cycle 6 of 10.0 months (range 0.2–23.3), one Q4W pt improved to CR; among non-randomized pts, 6/22 (27.3%) improved also response. TEAEs occurred in 91.1% (51/56) pts overall; Grade 3/4 in 66.1% (37/56) and Grade 5 in 8.9% (5/56). In the continuation phase, TEAEs occurred in 64.7% (22/34), with Grade ≥3 in 26.1% (6/23) of the non-randomized, 33.3% (2/6) of the Q2W-randomized and 20.0% (1/5) of the Q4W. Serious TEAEs occurred in 13.0% (3/23) of the non-randomized, 16.7% (1/6) of the Q2W-randomized, and none of the Q4W. Conclusion Isa-Pd showed robust efficacy with manageable safety and rapid responses in first-relapse RRMM pts after a Len+PI-based regimen. In pts with ≥VGPR, Isa Q4W provided comparable efficacy with improved safety and compliance versus Q2W, suggesting greater convenience without compromising efficacy. Pts with <VGPR benefited from continued Q2W dosing, with evidence of ongoing response improvement. These findings support a response-adapted strategy for optimizing Isa-based therapy in RRMM.