An analysis of the results from the ongoing randomized phase III AQUILA study found that daratumumab monotherapy was well tolerated and demonstrated a clinically meaningful and significant benefit in preventing or delaying progression to active multiple myeloma compared with active monitoring in patients with high-risk smoldering multiple myeloma (SMM). The findings strongly support the benefit of early intervention with daratumumab monotherapy vs active monitoring, the current standard of care in these patients, according to the study authors. The study by Dimopoulos et al was presented during the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 773).

High-risk SMM is an asymptomatic precursor state of active disease and carries an average risk of progression from SMM to active myeloma of 10% per year. Recent studies have suggested that patients at high risk of disease progression may benefit from early intervention.

Study Methodology

A total of 390 eligible patients with a confirmed diagnosis of high-risk SMM were randomly assigned to receive either daratumumab (n = 194) or active monitoring (n = 196). Patients’ median age was 64 (range = 31–86 years). Daratumumab (once weekly in cycles 1 and 2, once every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter) was given in 28-day cycles until cycle 39, 36 months, or disease progression, whichever came first. Median treatment duration in the daratumumab group was 38 cycles (35 months).

The primary endpoint was progression-free survival, defined as progression to active multiple myeloma as assessed by an independent review committee and according to International Myeloma Working Group diagnostic criteria for multiple myeloma (SLiM-CRAB) or death. Major secondary endpoints included overall response rate, progression-free survival 2 (the time between the start of first-line therapy and the progression of the disease on second-line therapy), and overall survival.

Key Results

The researchers found that at a median follow-up of 65.2 months (0–76.6 months), progression-free survival was significantly improved with daratumumab vs active monitoring (hazard ratio [HR] = 0.49, 95% CI = 0.360.67; P < .0001). Median progression-free survival was not reached in the daratumumab group vs 41.5 months for active monitoring; estimated 60-month progression-free survival rates was 63.1% vs 40.8%, respectively.

Prespecified analyses showed generally consistent progression-free survival improvement with daratumumab vs active monitoring across subgroups. Overall response rate was 63.4% with daratumumab vs 2.0% with active monitoring (P < .0001). As of the clinical cutoff, 64 patients (33.0%) in the daratumumab group and 102 patients (52.0%) in the active monitoring group had started first-line multiple myeloma treatment.

The median time from randomization to the date of first-line treatment was not reached with daratumumab vs 50.2 months with active monitoring (HR = 0.46; 95% confidence interval [CI] = 0.33–0.62; nominal P < .0001). There was a positive trend in favor of daratumumab for progression-free survival 2 (HR = 0.58, 95% CI = 0.35–0.96) and overall survival (60-month rates = 93.0% with daratumumab, 86.9% with active monitoring; HR = 0.52; 95% CI = 0.27–0.98).

A total of 41 deaths were observed, including 15 in the daratumumab group and 26 in the active monitoring group. The researchers found that grade 3 or 4 treatment-emergent adverse events occurred in 40.4% and 30.1% of patients in the daratumumab and active monitoring groups, respectively. The most common (≥ 5% in either group) of these events was hypertension (5.7% with daratumumab, 4.6% with  active monitoring). The frequency of treatment-emergent adverse events leading to daratumumab discontinuation was low (5.7%), as was the incidence of fatal treatment-emergent adverse events in both groups (1.0% with daratumumab, 2.0% with active monitoring, 2.0%).

Clinical Significance

“[Daratumumab] monotherapy was well tolerated and demonstrated a clinically meaningful and significant benefit in preventing or delaying progression to active [multiple myeloma] compared with active monitoring in patients with high-risk SMM. Overall response rate was significantly higher and time to first-line [multiple myeloma] treatment was prolonged with [daratumumab] compared with active monitoring. This was accompanied by positive trends for [progression-free survival 2] and [overall survival] in favor of [daratumumab]. These results strongly support the benefit of early intervention with [daratumumab] monotherapy vs active monitoring, the current standard of care, in patients with high-risk SMM,” concluded the study authors.

Disclosure: For full disclosures of all study authors, visit ash.confex.com.