Background
Phase 3, open-label, randomized controlled trial (ICARIA-MM). N=307 patients with relapsed or refractory multiple myeloma after ≥2 prior lines including both a PI and an IMiD. Randomized 1:1. Key eligibility: prior lenalidomide and PI required; ECOG PS ≤2. Evaluated a pomalidomide-based combination against the Pd doublet.
Interventions and follow up
Arm A (Isa-Pd): Isatuximab 10 mg/kg IV (weekly cycle 1, then every 2 weeks) + pomalidomide 4 mg PO (days 1–21) + dexamethasone 40 mg PO/IV (days 1, 8, 15, 22), 28-day cycles until progression.
Arm B (Pd): Pomalidomide 4 mg PO (days 1–21) + dexamethasone 40 mg PO/IV, 28-day cycles until progression.
Primary endpoint: Progression-free survival (by BICR)
Median follow-up: 11.6 months
Arm B (Pd): Pomalidomide 4 mg PO (days 1–21) + dexamethasone 40 mg PO/IV, 28-day cycles until progression.
Primary endpoint: Progression-free survival (by BICR)
Median follow-up: 11.6 months
Results
mPFS: 11.53 vs 6.47 months, HR 0.596 (95% CI 0.44–0.81), P=.001
ORR: 60.4% vs 35.3%
≥VGPR rate: 31.8% vs 8.9%
mOS: 24.6 vs 17.7 months, HR 0.687 (95% CI 0.52–0.90), P=.0084 (updated)
ORR: 60.4% vs 35.3%
≥VGPR rate: 31.8% vs 8.9%
mOS: 24.6 vs 17.7 months, HR 0.687 (95% CI 0.52–0.90), P=.0084 (updated)
Adverse events
Hematologic (Isa-Pd vs Pd): Grade ≥3 neutropenia 84.9% vs 70.1%.
Infection: Grade ≥3 infections 42.8% vs 28.3%; upper respiratory infections 57.1% vs 46.6%; pneumonia grade ≥3 17.9% vs 7.3%.
Administration: Infusion reactions any grade 38.2% (grade ≥3 1.9%).
Infection: Grade ≥3 infections 42.8% vs 28.3%; upper respiratory infections 57.1% vs 46.6%; pneumonia grade ≥3 17.9% vs 7.3%.
Administration: Infusion reactions any grade 38.2% (grade ≥3 1.9%).
Conclusions
Isatuximab added to pomalidomide + dexamethasone (Isa-Pd) significantly improved PFS (HR 0.596) and OS (HR 0.687) in 2+ prior line RRMM refractory to prior lenalidomide and PI, establishing Isa-Pd as an effective option in this heavily pretreated setting.
Key Limitations
The control arm (Pd doublet) is a relatively modest comparator; the incremental benefit of isatuximab over Pd may appear less impressive vs a triplet control. The high rate of grade ≥3 neutropenia (85%) and infections (43%) reflects the heavily pretreated population but requires careful management. Follow-up was short at primary analysis. In the current era, many patients have already received anti-CD38 antibody frontline, limiting applicability.
Clinical Context
Isa-Pd was FDA-approved in 2020 for RRMM after ≥2 prior lines including lenalidomide and a PI, and is recommended in ASCO and ESMO relapse guidance. It competes with daratumumab + Pd (APOLLO) and pomalidomide + bortezomib + dex (OPTIMISMM) in this space. The updated OS benefit (HR 0.687) is clinically meaningful. Isa-Pd is preferred in anti-CD38-naïve patients who have progressed on lenalidomide and a PI.