Background
Phase 3, open-label, randomized, two-stage trial (211 sites, 31 countries). N=939 randomized (stage 1 n=279, stage 2 n=660); primary MRD analysis ITT n=420. Adults with RRMM after 1–2 prior lines, PR or better to prior therapy, then progression; anti-CD38- and bortezomib-refractory excluded. Iberdomide is an oral cereblon E3 ligase modulator (CELMoD).
Results
Interventions and follow up: Arm A: Iberdomide 1.0 mg PO (stage 1 also 1.3 and 1.6 mg) + daratumumab 1800 mg SC + dexamethasone 40 mg (20 mg if >75 y) (IberDd), n=207 in primary analysis
Arm B: Daratumumab 1800 mg SC + bortezomib 1.3 mg/m² SC + dexamethasone 20 mg (DVd), n=213
Primary endpoints (dual): MRD-negative CR at any time (reported here) and PFS (ongoing, 800-pt confirmatory cohort)
mFollow up: 15.7 months (IQR 12.8–23.2)
Results: MRD-negative CR: 41% (85/207) vs 21% (44/213); difference 20.1% (95% CI 11.5–28.6), OR 2.8 (95% CI 1.8–4.3), P<.0001
PFS: NR (assessment ongoing)
OS: NR
Arm B: Daratumumab 1800 mg SC + bortezomib 1.3 mg/m² SC + dexamethasone 20 mg (DVd), n=213
Primary endpoints (dual): MRD-negative CR at any time (reported here) and PFS (ongoing, 800-pt confirmatory cohort)
mFollow up: 15.7 months (IQR 12.8–23.2)
Results: MRD-negative CR: 41% (85/207) vs 21% (44/213); difference 20.1% (95% CI 11.5–28.6), OR 2.8 (95% CI 1.8–4.3), P<.0001
PFS: NR (assessment ongoing)
OS: NR
Adverse events
Grade 3–4 (any): 92% vs 70%
Hematologic: neutropenia G3–4 84% vs 11%
Infection: G3–4 39% vs 22%; pneumonia SAE 18% vs 6%
Serious AEs: 58% vs 41%
Treatment-related deaths: 3 (1%) vs 2 (1%)
Hematologic: neutropenia G3–4 84% vs 11%
Infection: G3–4 39% vs 22%; pneumonia SAE 18% vs 6%
Serious AEs: 58% vs 41%
Treatment-related deaths: 3 (1%) vs 2 (1%)
Conclusions
IberDd significantly improved MRD-negative CR vs DVd in 1–2 prior line RRMM, with high but manageable hematologic toxicity. PFS, the second dual primary endpoint, is required to confirm clinical benefit.
Key Limitations
Interim analysis of the first dual primary endpoint only; PFS/OS not reported, and MRD-negative CR is a surrogate. Only the first 420 of 800 pts in the analysis; median follow-up 15.7 mo. Open-label. Excluded anti-CD38- and bortezomib-refractory patients, limiting relevance to the current setting where dara/len exposure is common. Markedly higher neutropenia (84% G3–4) and infection/pneumonia rates.
Clinical Context
Comparator DVd is a standard anti-CD38-based option in 1–2 prior line RRMM; competing regimens include DPd, Kd-based and CAR-T/bispecific therapy. Adds an oral CELMoD-based option, but no regulatory approval cited here and PFS confirmation is pending; guideline positioning to be determined after PFS.