Abstract
SMM is a precursor condition to multiple myeloma (MM) without approved treatment options. Therapeutic intervention before MM diagnosis and onset of end-organ damage may benefit patients with high-risk SMM.
The phase 3 AQUILA study (NCT03301220) evaluated whether daratumumab delays progression to MM vs active monitoring in high-risk SMM.
Adults with high-risk SMM who provided informed consent were randomized 1:1 to active monitoring or subcutaneous daratumumab monotherapy for 36 months or until disease progression, whichever came first. The primary endpoint was progression-free survival (PFS), defined as progression to MM per independent review committee according to the IMWG diagnostic criteria for MM (SLiM-CRAB) or death.
A total of 390 patients were randomized (daratumumab, n = 194; active monitoring, n = 196). Baseline characteristics were generally balanced. Median daratumumab duration was 35.0 months. Median follow-up was 65.2 months. Daratumumab significantly reduced the risk of progression toMMor death by 51% vs active monitoring (60-month rates: 63.1% vs 40.8%; HR, 0.49 [95% CI, 0.36–0.67]; P < 0.0001), with consistent PFS benefits across prespecified subgroups, including retrospective analysis of high-risk SMM per the Mayo 2018 criteria. Overall response rate was 63.4% with daratumumab vs 2.0% with active monitoring (P < 0.0001). First-line MM treatment was initiated by 33.2% of daratumumab patients and 53.6% of active monitoring patients; median time to initiation was not reached vs 50.2 months, respectively (HR, 0.46 [95% CI, 0.33–0.62]). Daratumumab also improved progression after the next line of therapy including first-line MM treatment (60-month rates: 85.9% vs 78.0%; HR, 0.58 [95% CI, 0.35–0.96]) and overall survival (60-month rates: 93.0% vs 86.9%; HR, 0.52 [95% CI, 0.27–0.98]). Forty-one deaths occurred (daratumumab, n = 15; active monitoring, n = 26). A low (5.7%) frequency of daratumumab discontinuation due to treatment-emergent adverse events (TEAEs) was reported. Grade 3/4 TEAEs occurred in 40.4% and 30.1% of daratumumab and active monitoring patients, respectively; hypertension was the most frequent event (5.7% vs 4.6%). Quality of life was maintained and similar between arms across multiple measures/domains.
These results demonstrate the benefit of early intervention with daratumumab monotherapy in high-risk SMM, representing an opportunity to delay or even prevent end-organ damage and progression toMMwhile maintaining quality of life and improving survival.
