Daratumumab Significantly Improves PFS, Extends OS in Smoldering Myeloma

Treatment with subcutaneous daratumumab (Darzalex Faspro) led to significant progression-free survival (PFS) benefit, with extended overall survival (OS), compared with active monitoring in patients with intermediate- or high-risk smoldering multiple myeloma, according to primary results from the phase 3 AQUILA study (NCT03301220) presented during the 2024 ASH Annual Meeting and simultaneously published in the New England Journal of Medicine.^1,2

Further, the greatest benefit was seen among patients with high-risk disease.

“We believe that with these data, 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,” Meletios-Athanasios Dimopoulos, MD, professor and chairman, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra General Hospital, in Athens, Greece, said during a press briefing at the meeting.

After a median follow-up of 65.2 months (range, 0-76.6), the median PFS was not reached (NR) with daratumumab monotherapy compared with 41.5 months with active monitoring. Further, 60-month PFS rates were 63.1% and 40.8%, respectively, reducing the risk for disease progression or death by 51% (HR, 0.49; 95% CI, 0.36-0.67; P < .001) with subcutaneous daratumumab.

“Furthermore, there were fewer patients in the daratumumab arm who progressed with CRAB criteria [12 vs 34, respectively] and with SLiM criteria [50 vs 65]. So not only [did] daratumumab [delay] progression, but [patients who received this agent] also avoided a clinically obvious and important type of progression,” Dimopoulos explained.

In total, 15 patients in the daratumumab arm (7.7%) and 26 patients in the active monitoring arm (13.3%) died. The 60-month OS rates were 93.0% with daratumumab compared with 86.9% with active monitoring, reducing the risk for death by 48% (HR, 0.52; 95% CI, 0.27-0.98). “The majority of deaths were due either to progressive disease during or after the study,” Dimopoulos added.

In addition, daratumumab monotherapy demonstrated a superior overall response rate (ORR) of 63.4% compared with 2.0% with active monitoring (P < .001), with an improved median time to first-line treatment for active myeloma (NR vs 50.2 months, respectively; [HR, 0.46; 95% CI, 0.33-0.62; P < .0001).³

Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 40.4% of patients in the daratumumab arm compared with 30.1% of those undergoing active monitoring, with the most common being hypertension (5.7% vs 4.6%, respectively). The most common serious TEAE was pneumonia (3.6% vs 0.5%, respectively).

“There were no new safety signals from what we know,” Dimopoulos said. “There was somehow an increased risk of infection, but these were well treated and reversible.”

Eleven patients discontinued daratumumab treatment due to TEAEs, whereas 90 patients underwent dose modifications as a result.

Although observation is the current standard of care for this patient population, Dimopoulos suggested that therapeutic intervention may benefit patients with high-risk disease.

At the 2024 ASH Annual Meeting, Dimopoulos presented on the primary analysis results from the phase 3 AQUILA study after 36 months of daratumumab monotherapy compared with active monitoring, aimed at assessing the effect of early intervention to prevent end-organ damage and progression to active disease.

“This is the largest phase 3 trial conducted in patients with high-risk smoldering myeloma,” Dimopoulos noted.

In the open-label, multicenter, randomized phase 3 trial, investigators randomly assigned patients 1:1 to receive either subcutaneous daratumumab monotherapy (n = 194) or active monitoring (n = 196) for 36 months or until confirmation of disease progression, whichever occurred first. Daratumumab was administered at a dose of 1800 mg on a weekly basis in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks thereafter in 28-day cycles.

Following treatment, patients underwent efficacy follow-up until progression by SLiM-CRAB criteria, with survival follow-up conducted every 6 months until the end of the study.

Patients were enrolled at 124 sites across 23 countries between December 10, 2017, and May 27, 2019.

Patients were eligible for the trial if they were 18 years of age or older; had received a confirmed diagnosis of smoldering multiple myeloma, in accordance with International Myeloma Working Group criteria, in the past 5 years; had measurable disease; had an ECOG performance status of 0 or 1; and were required to be at high risk for progression to active myeloma. High risk was identified with a percentage of clonal plasma cells in bone marrow of at least 10% and the presence of at least 1 of the following risk factors: serum M-protein level of at least 30 g/L, IgA disease, immunoparesis with reduced levels of 2 uninvolved immunoglobulin isotypes, serum involved/uninvolved free light chains between 8 and 100, or clonal plasma cells in bone marrow of more than 50% to less than 60%.

Patients were stratified by the number of risk factors for progression to multiple myeloma (more or less than 3).

PFS served as the primary end point, and secondary end points included ORR, time to first-line treatment for myeloma, PFS on first-line treatment for myeloma, and OS.

Median age was 64 years (range, 31-86), and 40.5% of patients were classified as having high-risk disease in accordance with the Mayo 2018 risk criteria. The median time from initial diagnosis of smoldering myeloma to randomization was 0.74 years.

By the clinical cutoff (May 1, 2024), 65.5% and 40.8% of patients in the daratumumab and active monitoring arms, respectively, completed 36 months of treatment. The most common reason for treatment discontinuation across both arms was progressive disease (21.8% vs 41.8%, respectively).

In November 2024, a supplemental biologics license application was submitted to the FDA, and an extension of indication application was submitted to the European Medicines Agency, for subcutaneous daratumumab to treat adult patients with high-risk smoldering multiple myeloma based on results from this trial.³

“I believe it is important to have an approved therapy, and then based on the practice of the physician and the patient they can make a joint decision whether [the patient] will get the treatment,” Dimopoulos said.¹

References

1. Dimopoulos MA, 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. Blood. 2024;144(supplement 1):773. doi:10.1182/blood-2024-201057
2. Dimopoulos MA, Voorhees PM, Schjesvold F, et al. Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma. The New Eng J Med. doi:10.1056/NEJMoa2409029
3. DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) shows 51 percent reduction in risk of progression to active multiple myeloma for patients with high-risk smoldering multiple myeloma. Johnson & Johnson. Published: December 8, 2024. Accessed: December 8, 2024. https://www.prnewswire.com/news-releases/darzalex-faspro-daratumumab-and-hyaluronidase-fihj-shows-51-percent-reduction-in-risk-of-progression-to-active-multiple-myeloma-for-patients-with-high-risk-smoldering-multiple-myeloma-302325567.html