Background
Phase 3, open-label, randomized controlled trial (E3A06; ECOG-ACRIN). N=182 patients with intermediate- or high-risk smoldering multiple myeloma (SMM) defined by ≥2 of: bone marrow plasma cells 10–59%, serum M-protein ≥3 g/dL, or serum FLC ratio >8 (ECOG/SWOG criteria). Patients with osteolytic lesions or CRAB features were excluded. Results reflect a 6.5-year median follow-up analysis.
Interventions and follow up
Arm A: Lenalidomide 25 mg PO days 1–21 q28d for up to 2 years, then 10 mg/day continuous maintenance until progression (N=91)
Arm B: Observation with scheduled disease assessments (N=91)
Primary endpoint: Progression-free survival (time to progression to active MM)
mFollow up: 6.5 years
Arm B: Observation with scheduled disease assessments (N=91)
Primary endpoint: Progression-free survival (time to progression to active MM)
mFollow up: 6.5 years
Results
mPFS: Not reached vs 21 months (lenalidomide vs observation), HR 0.28 (95% CI 0.12–0.62), P=.002
3-yr PFS rate: 91% vs 66%
OS: HR 0.24 (95% CI 0.06–0.97), P=.047 — first SMM trial to demonstrate an OS benefit
3-yr PFS rate: 91% vs 66%
OS: HR 0.24 (95% CI 0.06–0.97), P=.047 — first SMM trial to demonstrate an OS benefit
Adverse events
Hematologic (grade ≥3, lenalidomide): Neutropenia 11%, thrombocytopenia 4.4%
Non-hematologic (grade ≥3): Fatigue 4.4%, DVT/PE 4.4%; second primary malignancies 6.6% (lenalidomide) vs 2.2% (observation); discontinuation due to AEs 25%
Non-hematologic (grade ≥3): Fatigue 4.4%, DVT/PE 4.4%; second primary malignancies 6.6% (lenalidomide) vs 2.2% (observation); discontinuation due to AEs 25%
Conclusions
Lenalidomide significantly delayed progression from high-risk SMM to active myeloma and demonstrated an OS benefit at 6.5-year follow-up, establishing the first phase 3 evidence for treating high-risk SMM. E3A06 is the only randomized SMM trial to report an OS benefit.
Key Limitations
SMM risk stratification has evolved substantially; the ECOG/SWOG criteria used do not align with current IMWG 20/2/20 risk stratification, and some enrolled patients might now be classified as active MM under updated criteria (e.g., 60% BMPC cutoff). The trial predates daratumumab SC availability for SMM (AQUILA). Small sample size (N=182) and few OS events (wide CI 0.06–0.97) require cautious interpretation of the survival benefit. Long-term lenalidomide increases the risk of second primary malignancies (6.6% vs 2.2%).
Clinical Context
E3A06 provided foundational evidence for treating high-risk SMM. AQUILA subsequently demonstrated daratumumab SC PFS HR 0.49 using contemporary 20/2/20 criteria, and the FDA approved daratumumab SC (Darzalex Faspro) for high-risk SMM in 2024 — the first and only FDA-approved SMM therapy. Lenalidomide remains the only agent with OS data in SMM but lacks an FDA SMM indication. ESMO does not assign MCBS scores for SMM prevention trials.