The Phase 3 AQUILA study investigated daratumumab monotherapy versus active monitoring in patients with high-risk smoldering multiple myeloma (SMM) to assess its efficacy in delaying progression to active multiple myeloma (MM). During the ASH 2024 Annual Meeting, Meletios Dimopoulos, MD, presented the results of the study.
High-risk SMM is an asymptomatic precursor to MM with no approved treatments the authors noted, although early intervention may benefit patients at high risk of progression. daratumumab, a monoclonal antibody targeting CD38, has shown promising efficacy and tolerability in earlier studies, prompting this large-scale evaluation.
The trial enrolled 390 patients randomized 1:1 to receive either subcutaneous daratumumab or active monitoring. Eligibility required a diagnosis of high-risk SMM (≤5 years) with specific clinical markers, including elevated clonal bone marrow plasma cells or abnormal serum protein levels. daratumumab was administered in 28-day cycles until 39 cycles, 36 months, or disease progression.
After a median follow-up of 65.2 months, daratumumab demonstrated significant improvement in progression-free survival (PFS) compared to active monitoring. The median PFS was not reached in the daratumumab group, while it was 41.5 months in the active monitoring group (hazard ratio [HR], 0.49; P<0.0001). Estimated 60-month PFS rates were 63.1% for daratumumab versus 40.8% for active monitoring. Additionally, the overall response rate (ORR) was 63.4% with daratumumab compared to 2.0% in the active monitoring group (P<0.0001). Median time to first-line MM treatment was significantly extended in the daratumumab group, with a positive trend for improved PFS2 (HR, 0.58) and overall survival (OS). The 60-month OS rates were 93.0% for daratumumab versus 86.9% for active monitoring (HR, 0.52).
daratumumab was well tolerated, with grade 3/4 treatment-emergent adverse events (TEAEs) occurring in 40.4% of the daratumumab group and 30.1% of the active monitoring group. Hypertension was the most common grade 3/4 TEAE (daratumumab, 5.7%; active monitoring, 4.6%). Discontinuation due to TEAEs was rare (5.7% in the daratumumab group), and fatal TEAEs were low in both groups (1.0% for DARA; 2.0% for active monitoring).
Overall, daratumumab monotherapy significantly delayed progression to MM, improved response rates, and extended the time to first-line treatment compared with active monitoring in high-risk SMM patients, according to the study authors. It was well tolerated and showed favorable trends for PFS2 and OS, strongly supporting early intervention with daratumumab in this population.
“These results strongly support the benefit of early intervention with [daratumumab] monotherapy versus active monitoring, the current standard of care, in patients with high-risk SMM,” the study authors concluded.
