Subcutaneous Darzalex Faspro Extends PFS in Smoldering Myeloma

Data from the AQUILA study support the use of fixed-duration subcutaneous Darzalex Faspro as an early treatment option in high-risk smoldering myeloma: © stock.adobe.com.

A poster presented at the 2025 Society of Hematologic Oncology Annual Meeting showed that subcutaneous Darzalex Faspro (daratumumab and hyaluronidase-fihj) significantly lowered the risk of disease progression or death compared with active monitoring in patients with high-risk smoldering multiple myeloma.

With a median follow-up of 65.2 months, the median progression-free survival (PFS) was not reached with Darzalex Faspro versus 41.5 months with monitoring, correlating with a 51% reduction in the risk of progressive disease or death. Per International Myeloma Working Group SLiM diagnostic criteria, investigators noted progression to multiple myeloma in 25.8% (50 of 194 patients) and 33.2% (65 of 196 patients) of each respective arm. Progression to multiple myeloma occurred in 6.2% (12 of 194 patients) and 17.3% (34 of 196 patients) of patients in each arm.

Investigators highlighted a PFS benefit with Darzalex Faspro across all pre-specified subgroups. An especially pronounced benefit occurred among patients with high-risk status; the median PFS was not reached with Darzalex Faspro versus 22.1 months with monitoring in this group.

“Darzalex Faspro demonstrated a favorable safety profile, with a low rate (5.7%) of treatment discontinuation due to treatment-emergent side effects. Patients maintained their health-related quality of life during Darzalex Faspro treatment compared with active monitoring,” lead study author, Dr. Meletios Athanasios Dimopoulos, professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine in Greece, wrote in the poster with coauthors. “Results from the phase 3 AQUILA study strongly support early intervention with subcutaneous Darzalex Faspro monotherapy for a fixed duration in patients with high-risk smoldering multiple myeloma, representing an opportunity to delay or avoid end-organ damage and progression to multiple myeloma although preserving quality of life and extending survival.”

In the open-label, multicenter phase 3 AQUILA study, 390 patients were randomly assigned to receive subcutaneous Darzalex Faspro at 1800 milligrams every week on cycles 1 and 2, every two weeks on cycles 3 to 6, and every four weeks thereafter for a maximum of 36 months (194 patients) or active monitoring, which consisted of no disease-specific therapy with side effect monitoring for up to 36 months (196 patients). During the study’s follow-up phase, investigators evaluated efficacy until progression and assessed survival every 6 months until the study’s conclusion.

The trial’s primary end point was independent review committee. Key secondary end points included objective response rate (ORR), time to first-line treatment for multiple myeloma, PFS on first-line treatment, and overall survival (OS).

Patients 18 years and older with a confirmed smoldering multiple myeloma diagnosis per International Myeloma Working Group criteria for no longer than 5 years, and an ECOG performance status of 0 or 1 were eligible for enrollment on the trial.

The median age was 63 years in the Darzalex Faspro arm and 64.5 years in the active monitoring arm, and most from each respective arm were women (51% versus 52.6%). In each arm, most patients had an ECOG performance status of 0 (85.1% versus 81.6%), fewer than thre risk factors for progression to multiple myeloma (79.4% versus 79.6%), and intermediate-risk (39.7% versus 38.8%) or high-risk status (37.1% versus 43.9%).

Data showed an ORR of 63.4% with Darzalex Faspro versus 2% with active monitoring. Among patients who received Darzalex Faspro, a very good partial response or better occurred in 29.9%, and 8.8% had a complete response or better.

The median time to initiating subsequent frontline therapy was not reached in the Darzalex Faspro arm and 50.2 months in the monitoring arm. The 60-month PFS rate on frontline therapy was 85.9% and 78% in each respective arm. The 60-month OS rates were 93% and 86.9%, respectively; data showed a strong positive trend toward longer OS with Darzalex Faspro.

Investigators noted no new safety signals among those who received Darzalex Faspro. In the Darzalex Faspro and monitoring arms, 96.9% versus 82.7% had side effects of any grade, 40.4% versus 30.1% had grade 3 or higher side effects, 29% versus 19.4% had serious side effects, and 1% versus 2% had grade 5 side effects. The most common grade 3 or higher side effect in each arm was hypertension (5.7% versus 4.6%), and the incidence of second primary malignancies was comparable between arms (9.3% versus 10.2%).

Health-related quality of life outcomes with Darzalex Faspro appeared to be consistent across multiple measures and domains. Similar mean changes between baseline and week 112 occurred in both treatment arms.

The European Commission approved subcutaneous Darzalex Faspro for this smoldering multiple myeloma population in July 2025 based on findings from the AQUILA trial. Additionally, the FDA’s Oncologic Advisory Drug Committee voted in favor of Darzalex Faspro’s benefit/risk profile for those with high-risk smoldering multiple myeloma in May 2025. 

References

1. “Phase 3 AQUILA study of daratumumab monotherapy versus active monitoring in patients with high-risk smoldering multiple myeloma,” by Dr. Meletios Athanasios Dimopoulos. Presented at the 2025 Society of Hematologic Oncology Annual Meeting (SOHO); Sept. 3-6, 2025; Houston, TX. MM-691.
2. “European Commission approves DARZALEX (daratumumab) as the first licensed treatment for patients with high-risk smouldering multiple myeloma,” by Johnson & Johnson. News release; July 23, 2025.
3. “May 20-21, 2025 Meeting of the Oncologic Drugs Advisory Committee (ODAC) - Day 1. Streamed live May 20, 2025,” by U.S. Food and Drug Administration. https://www.youtube.com/live/iSGFdhMgh1E

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