Treatment with 3 years of subcutaneous daratumumab and hyaluronidase-fihj (Darzalex Faspro) significantly reduced the risk of progression from smoldering to active multiple myeloma without significantly impacting health-related quality of life (HRQOL), according to findings from the phase 3 AQUILA study (NCT03301220) that were presented at the 2024 ASH Annual Meeting.1
In the study, which had 5 years of follow-up data available, progression was measured using International Myeloma Working Group SLiM and CRAB criteria. At 5 years, 63.1% of patients were progression-free with daratumumab compared with 40.8% with active monitoring (HR, 0.49; 95% CI, 0.36-0.67; P < .001). In those with high-risk features, as identified by Mayo 2018 criteria, there was a 64% reduction in the risk of progression with daratumumab compared with active monitoring (HR, 0.36; 95% CI, 0.23-0.58). There was a trend toward improvement in HRQOL with daratumumab, according to lead investigator Meletios A. Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine.
Meletios A. Dimopoulos, MD
"We believe that with this data that patients with high-risk smoldering myeloma may benefit from immediate treatment with daratumumab, and that observation for this particular subset of patients may not be an adequate option," Dimopoulos said during a presentation of the findings during a press briefing. "Despite that the treatment was discontinued at 3 years, even at 5 or 6 years there was a continuous benefit from treatment with daratumumab."
In the study, investigators assigned patients in a 1:1 randomized fashion to receive daratumumab monotherapy (n = 194) or active monitoring (n = 196), with the number of risk factors used as a stratification factor. Daratumumab was administered subcutaneously at 1800 mg weekly for cycles 1 and 2 followed by every 2 weeks for cycles 3 to 6 and every 4 weeks thereafter. Treatment was stopped after 3 years. All patients were monitored using a combination of lab tests, CT/PET and MRI, and bone marrow biopsy, which was conducted at least every 2 years.
The baseline patient characteristics were balanced between the groups, with a few discrepancies. Overall, patients were slightly younger in the daratumumab arm, with a median age of 63 years vs 64.5 years in the active monitoring group. More than half (54.6%) of patients were below the age of 65 years in the daratumumab group compared with 50.0% in the control arm. Additionally, there were differences in the median time from diagnosis to randomization, which was 0.80 years in the daratumumab arm and 0.67 in the control arm.
During the study, which was initiated in 2017, the criteria for smoldering multiple myeloma risk assessment were updated. To accommodate this, the investigator adjusted their enrollment to use the 2018 Mayo Criteria, which examines serum M-protein > 2 g/L, involved:uninvolved free light chain ratio > 20, and clonal bone marrow plasma cells > 20%. Those with no factors were considered low risk, those with 1 were intermediate, and those with 2 or more were considered high risk. Overall, fewer patients were high risk in the daratumumab arm compared with the control (37.1% vs 43.9%).
At the median follow-up of 65.2 months, the median progression-free survival (PFS) was not yet reached with daratumumab compared with 41.5 months for active monitoring. There were 67 progression events with daratumumab and 99 with active monitoring. Death without disease progression was the same in both groups (n = 5) with the remaining progression events for daratumumab and active monitoring being related to CRAB criteria (19.4% vs 36.2%, respectively) and SLiM criteria (80.6% vs 69.1%, respectively).
At the 5-year analysis, 93.0% of patients remained alive in the daratumumab group compared with 86.9% with active monitoring, representing a significant improvement in overall survival (HR, 0.52; 95% CI, 0.27-0.98). "You can see that the deaths were essentially doubled [with active monitoring]," said Dimopoulos. "Of course, further follow up will be conducted in this."
Prolonged PFS was also seen with the first-line treatment for active multiple myeloma, Dimopoulos noted. In this group, which could include a variety of treatments, there was a 42% reduction in the risk of progression for those in the daratumumab arm (HR, 0.58; 95% CI, 0.35-0.96). This shows that using daratumumab earlier does not compromise the treatment for active myeloma down the road, which could be related to the fixed duration of treatment in the study, he said.
The median duration of adverse event (AE) reporting was 26 months with active monitoring and 35 months for daratumumab. A treatment-emergent AE (TEAE) of any grade occurred in 96.9% of patients with daratumumab and for 82.7% with active monitoring. The rate of grade 3/4 TEAEs were 40.4% and 30.1% for daratumumab and active monitoring, respectively. Treatment discontinuation due to a TEAE occurred in 5.7% of patients on daratumumab. Dose modifications were required for 46.6% of patients.
Based on an earlier assessment of AQUILA, the developer of daratumumab with hyaluronidase-fihj, Johnson & Johnson, applied for regulatory approval in both the United States and Europe.2 A decision timeline for the application has not yet been released.
References
1. Dimopoulos M-A, Voorhees PM, Schjesvold F, et al. Phase 3 Randomized study of daratumumab monotherapy versus active monitoring in patients with high-risk smoldering multiple myeloma: primary results of the AQUILA study. Presented at: ASH 2024 Annual Meeting & Exposition. December 7-10, 2024; San Diego, CA. Abstract #773.
2. Johnson & Johnson submits applications in the U.S. and EU seeking approval of DARZALEX FASPRO® / DARZALEX® as subcutaneous monotherapy for high-risk smoldering multiple myeloma. November 8, 2024. Accessed December 8, 2024. https://innovativemedicine.jnj.com/our-innovation/focus-areas/oncology/johnson-johnson-submits-applications-in-the-u-s-and-eu-seeking-approval-of-darzalex-faspro-darzalex-as-subcutaneous-monotherapy-for-high-risk-smoldering-multiple-myeloma