3 years of treatment with subcutaneous daratumumab and hyaluronidase-fihj (Darzalex Faspro) significantly reduced the risk of progression from latent multiple myeloma to active multiple myeloma without significant impact on health-related quality of life (HRQOL), according to results from the AQUILA Phase 3 study (NCT03301220) which were presented at the ASH Annual Meeting 2024.¹

In the study, which had 5 years of follow-up data, progression was measured using the International Myeloma Working Group SLiM and CRAB criteria. At 5 years, 63.1% of patients were progression-free with daratumumab, compared to 40.8% with active surveillance (HR: 0.49; 95% CI: 0.36-0.67; P. < 0.001). In people with high-risk characteristics, as identified by the May 2018 criteria, there was a 64% reduction in the risk of progression with daratumumab compared to active surveillance (HR: 0.36; 95% CI: 0.23-0.58). According to principal investigator Meletios A. Dimopoulos, MD, professor and chair of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, there was a trend toward improvement in HRQOL with daratumumab.

Meletios A. Dimopoulos, MD

“We believe that with these data, patients with high-risk latent myeloma may benefit from immediate treatment with daratumumab, and that observation of this particular subset of patients may not be an adequate option. ” Dimopoulos said during a presentation of the results during a study. press briefing. “Even if treatment was discontinued after 3 years, even after 5 or 6 years, treatment with daratumumab provided continued benefit.”

In the study, investigators randomized patients 1:1 to receive daratumumab monotherapy (n=194) or active surveillance (n=196), with the number of risk factors used as a stratification factor. . Daratumumab was administered subcutaneously at 1800 mg per week during cycles 1 and 2, followed by every 2 weeks during cycles 3 to 6 and every 4 weeks thereafter. Treatment was stopped after 3 years. All patients were monitored using a combination of laboratory tests, CT/PET, and MRI, as well as bone marrow biopsy, performed at least every 2 years.

Baseline patient characteristics were balanced between groups, with some discrepancies. Overall, patients were slightly younger in the daratumumab group, with a median age of 63 years compared to 64.5 years in the active surveillance group. More than half (54.6%) of patients were aged less than 65 years in the daratumumab group, compared to 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, launched in 2017, the criteria for assessing the risk of latent multiple myeloma were updated. To account for this, the investigator adjusted their recruitment to use the Mayo 2018 criteria, which looks at 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 at high risk in the daratumumab group compared to the control group (37.1% vs. 43.9%).

At a median follow-up of 65.2 months, median progression-free survival (PFS) had not yet been reached with daratumumab, compared to 41.5 months for active surveillance. There were 67 progression events with daratumumab and 99 with active surveillance. Deaths without disease progression were the same in both groups (n = 5), with the remaining progression events for daratumumab and active surveillance being related to CRAB criteria (19.4% vs. 36.2%, respectively) and SLiM criteria (80.6% versus 69.1%, respectively). ).

At the 5-year analysis, 93.0% of patients remained alive in the daratumumab group, compared to 86.9% on active surveillance, representing a significant improvement in overall survival (HR: 0.52; 95% CI, 0.27-0.98). “You can see the number of deaths has almost doubled (with active surveillance),” Dimopoulos said. “Of course, further follow-up will be carried out on this matter.”

Prolonged PFS was also observed with 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 early use of daratumumab does not compromise subsequent treatment of active myeloma, 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, regardless of grade, occurred in 96.9% of patients treated with daratumumab and in 82.7% of patients on active surveillance. The rate of grade 3/4 TEAEs was 40.4% and 30.1% for daratumumab and active surveillance, respectively. Discontinuation of treatment due to TEAE occurred in 5.7% of patients receiving daratumumab. Dose modifications were necessary for 46.6% of patients.

Based on an earlier assessment of AQUILA, the developer of daratumumab with hyaluronidase-fihj, Johnson & Johnson, has requested regulatory approval in the United States and Europe.² The timetable for a decision on the application has not yet been published.

References

1. Dimopoulos MA, Voorhees PM, Schjesvold F et al. Randomized phase 3 study comparing daratumumab monotherapy versus active surveillance in patients with high-risk latent multiple myeloma: main results of the AQUILA study. Presented at: ASH 2024 Annual Meeting & Exhibition. December 7-10, 2024; San Diego, California. Summary #773.

2. Johnson & Johnson submits applications in the United States and the European Union for approval of DARZALEX FASPRO®/DARZALEX® as subcutaneous monotherapy for high-risk latent multiple myeloma. November 8, 2024. Accessed December 8, 2024.