Background
Phase 3, open-label, randomized controlled trial (AQUILA). N=390 patients with high-risk smoldering multiple myeloma defined by ≥2 of the 20/2/20 criteria: bone marrow plasma cells ≥20%, serum M-protein ≥2 g/dL, or serum free light-chain ratio ≥20. Patients with any SLiM or CRAB features were excluded. Daratumumab SC uses co-formulated recombinant human hyaluronidase (rHuPH20). Median follow-up 65.2 months.
Interventions and follow up
Arm A: Daratumumab SC 1800 mg: weekly × 8 doses, biweekly × 8 doses, then monthly up to 2 years total, then every 2 months until progression (N=195)
Arm B: Active monitoring with scheduled disease assessments every 8 weeks (N=195)
Primary endpoint: Progression-free survival (PFS)
Median follow-up: 65.2 months
Arm B: Active monitoring with scheduled disease assessments every 8 weeks (N=195)
Primary endpoint: Progression-free survival (PFS)
Median follow-up: 65.2 months
Results
5-yr PFS rate: 63.1% vs 40.8% (daratumumab vs active monitoring), HR 0.49 (95% CI 0.36–0.67), P<.001
ORR: 62.8% (daratumumab arm); ≥VGPR 25.1%; sCR 4.1%
OS (interim): HR 0.52 (95% CI 0.27–1.00), P=.049; immature, formal significance not established
ORR: 62.8% (daratumumab arm); ≥VGPR 25.1%; sCR 4.1%
OS (interim): HR 0.52 (95% CI 0.27–1.00), P=.049; immature, formal significance not established
Adverse events
Overall: Any-grade AEs 98% (daratumumab) vs 75% (monitoring); grade ≥3 39% vs 7%; discontinuation due to AEs 16%
Injection/cardiovascular: SC injection-site reactions any grade 12%, grade ≥3 <1%; hypertension grade ≥3 4.6%
Constitutional/other: Fatigue any grade 19%; second primary malignancies 8.7% (daratumumab) vs 4.6% (monitoring)
Injection/cardiovascular: SC injection-site reactions any grade 12%, grade ≥3 <1%; hypertension grade ≥3 4.6%
Constitutional/other: Fatigue any grade 19%; second primary malignancies 8.7% (daratumumab) vs 4.6% (monitoring)
Conclusions
Daratumumab SC significantly reduced the risk of progression from high-risk SMM to active myeloma compared with active monitoring at 5 years (63% vs 41%), supporting early intervention in patients meeting 20/2/20 criteria. This trial led to the first FDA approval of any agent specifically for SMM.
Key Limitations
PFS (progression to active MM) is a surrogate endpoint; patients in the monitoring arm can receive effective therapies at progression, making OS benefit essential and not yet established. The long daratumumab course (up to 5+ years of SC injections) is burdensome and exposes patients to therapy before confirmed survival benefit. Second primary malignancy rate was numerically higher with daratumumab (8.7% vs 4.6%) though not formally tested. Whether delaying progression translates to longer survival remains unknown.
Clinical Context
FDA approved daratumumab SC (Darzalex Faspro) for high-risk SMM in 2024 based on AQUILA — the first and only FDA-approved therapy for SMM. Clinical debate persists about treating SMM given available salvage options at progression; OS data will be decisive. Lenalidomide (E3A06) is the only agent with prior OS data in SMM but lacks FDA SMM approval. ESMO-MCBS: not assigned.
References