AQUILA Phase 3 Trial Leads to European Commission Approval of Daratumumab for Smoldering Multiple Myeloma

Daratumumab has been approved by the European Commission for patients with high-risk smoldering multiple myeloma (MM). This approval was based on results from the phase 3 AQUILA study which demonstrated that fixed-duration subcutaneous daratumumab (DARA SC) significantly prolonged progression-free survival (PFS) and delayed treatment initiation compared with active monitoring. 

Half of patients diagnosed with smoldering MM progress to active MM. Researchers conducted a phase 3, randomized clinical trial to determine the efficacy and safety of daratumumab for patients with high-risk smoldering multiple myeloma. The primary end point is PFS, with secondary end points of time to progression, overall response rate (ORR), and overall survival (OS). 

A total of 390 patients with well-defined high-risk smoldering multiple myeloma were randomized to receive daratumumab SC (n=194) or active monitoring (n=196). The median follow-up was 65.2 months (range, 0 to 76.6), 63.1% of patients in the daratumumab arm remained alive and progression-free at 5 years, which was higher compared than patients in the active monitoring arm (40.8%; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.36 to 0.67; P < .001). Among patients reclassified with Mayo 2018 (20/2/20) criteria, the median PFS was not reached in the daratumumab group and was 22.1 months in the active monitoring group (HR, 0.36; 95% CI, 0.23 to 0.58).

At 5 years, the OS was higher in the daratumumab group (93.0%) than the active monitoring group (86.9%; HR, 0.52; 95% CI, 0.27 to 0.98). Patients in the daratumumab group also had a higher ORR (63.4% vs 2.0%; P < .001). Median time to first-line treatment for progression to symptomatic myeloma was not reached in the daratumumab group compared to 50.2 months with monitoring (HR, 0.46; 95% CI, 0.33 to 0.62; nominal P < .0001).

In terms of safety, grade 3 or 4 treatment-emergent adverse events occurred in 40.4% of patients receiving daratumumab and 30.1% of those active monitored. Hypertension was the most common grade 3 or 4 event for the daratumumab group (5.7%) and the active monitor group (4.6%). 

The researchers concluded, “the approval of daratumumab offers the potential to change this trajectory. By intervening earlier in the disease course, we have a meaningful opportunity to delay or prevent progression to symptomatic disease, reduce irreversible end-organ damage and extend the window of improved patient outcomes.”

Source:

European Commission approves DARZALEX® (daratumumab) as the first licensed treatment for patients with high-risk smouldering multiple myeloma. JNJ.com. Published July 23, 2025. Accessed July 24, 2025. https://www.jnj.com/media-center/press-releases/european-commission-approves-darzalex-daratumumab-as-the-first-licensed-treatment-for-patients-with-high-risk-smouldering-multiple-myeloma