The AQUILA trial compared daratumumab to active monitoring in high-risk smoldering multiple myeloma, demonstrating a significant improvement in progression-free survival (PFS) (84% vs 54% at 48 months) and a trend toward better overall survival (OS) (94% vs 86% at 48 months). Dara also achieved a higher rate of deep responses, with 60% of patients reaching minimal residual disease (MRD) negativity compared to none in the monitoring arm. This looks like a game-changer to delay progression, but we’ll need to weigh the toxicity profile carefully in practice and wait for survival data.
Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved.
In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria.
Daratumumab for High-Risk Smoldering Multiple Myeloma
Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified.
Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.)
Is the need to transplant declining? Salvage autologous transplant vs lenalidomide/dexamethasone offers no significant survival benefit in RRMM. Patients who relapsed were treated with high-dose chemotherapy followed by maintenance lenalidomide vs dexamethasone and lenalidomide and progression-free survival (PFS) was 20 vs 19 months.
Daratumumab continued to demonstrate single-agent clinical activity in patients with intermediate- or high-risk smoldering myeloma. No new safety concerns were observed after extended follow-up of approximately seven years, highlighting the tolerability of daratumumab. Will need phase III trials.
Direct comparison of Dara+len vs. len maintenance for those with +MMR after Auto-HSCT. MRD-neg conversion rates were higher in the combo arm. This is likely going to continue gaining traction in this group of patients.
Retrospective assessment of the SWOG0777 and SWOG 1211 studies showing that dose reductions in dexamethasone did not affect outcomes. Nice to see this does not have a negative impact, as I have been doing this for years in my elderly patients who would not tolerate the ultra-high dose steroids used in these trials.
MRD at year 1 can be prognostic in pt who had AutoBMT followed by maintenance linolidomide. Please use MRD wisely … it can be expensive.
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