Subcutaneous Daratumumab Improves PFS in Smoldering Multiple Myeloma

"Results from the phase 3 AQUILA study strongly support early intervention with subcutaneous [daratumumab] 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] while preserving quality of life and extending survival," according to the study authors.

Subcutaneous daratumumab and hyaluronidase-fihj (Darzalex Faspro) significantly reduced the risk of disease progression or death compared with active monitoring among patients with high-risk smoldering multiple myeloma, according to a poster presentation on findings from the phase 3 AQUILA trial (NCT03301220) at the 2025 Society of Hematologic Oncology Annual Meeting (SOHO).1

With a median follow-up of 65.2 months, the median progression-free survival (PFS) was not reached with daratumumab vs 41.5 months with monitoring, correlating with a 51% reduction in the risk of progressive disease or death (HR, 0.49; 95% CI, 0.36-0.67; P <.001). Per International Myeloma Working Group (IMWG) SLiM diagnostic criteria, investigators noted progression to multiple myeloma in 25.8% (n = 50/194) and 33.2% (n = 65/196) of each respective arm. Based on CRAB criteria, progression to multiple myeloma occurred in 6.2% (n = 12/194) and 17.3% (n = 34/196) of patients in each arm.

Investigators highlighted a PFS benefit with daratumumab across all pre-specified subgroups. An especially pronounced benefit occurred among patients with high-risk status based on Mayo 2018 criteria; the median PFS was not reached with daratumumab vs 22.1 months with monitoring in this group (HR, 0.36; 95% CI, 0.23-0.58).

“[Daratumumab] demonstrated a favorable safety profile, with a low rate (5.7%) of treatment discontinuation due to treatment-emergent adverse effects [TEAEs]. Patients maintained their health-related quality of life during DARA treatment compared with active monitoring,” lead study author Meletios Athanasios Dimopoulos, MD, 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.1 “Results from the phase 3 AQUILA study strongly support early intervention with subcutaneous [daratumumab] 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] while preserving quality of life and extending survival.”

In the open-label, multicenter phase 3 AQUILA study, 390 patients were randomly assigned to receive subcutaneous daratumumab at 1800 mg every week on cycles 1 and 2, every 2 weeks on cycles 3 to 6, and every 4 weeks thereafter for a maximum of 36 months (n = 194) or active monitoring, which consisted of no disease-specific therapy with AE monitoring for up to 36 months (n = 196). During the study’s follow-up phase, investigators evaluated efficacy until progression per SLiM-CRAB criteria and assessed survival every 6 months until the study’s conclusion.

The trial’s primary end point was independent review committee (IRC)–evaluated PFS based on IMWG SLiM-CRAB criteria. 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 IMWG criteria for no longer than 5 years, and an ECOG performance status of 0 or 1 were eligible for enrollment on the trial. All patients needed to undergo CT or PET-CT and MRI imaging during screening.

The median age was 63.0 years (range, 31-86) in the daratumumab arm and 64.5 years (range, 36-83) in the active monitoring arm, and most from each respective arm were women (51.0% vs 52.6%). In each arm, most patients had an ECOG performance status of 0 (85.1% vs 81.6%), fewer than 3 risk factors for progression to multiple myeloma (79.4% vs 79.6%), and intermediate-risk (39.7% vs 38.8%) or high-risk status (37.1% vs 43.9%) per Mayo 2018 criteria.

Data showed an ORR of 63.4% with daratumumab vs 2.0% with active monitoring (OR, 83.80; 95% CI, 29.69-236.54; P <.001). Among patients who received daratumumab, 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 daratumumab arm and 50.2 months in the monitoring arm (HR, 0.46; 95% CI, 0.33-0.62). The 60-month PFS rate on frontline therapy was 85.9% and 78.0% in each respective arm (HR, 0.58; 95% CI, 0.35-0.96). The 60-month OS rates were 93.0% and 86.9%, respectively; data showed a strong positive trend toward longer OS with daratumumab (HR, 0.52; 95% CI, 0.27-0.98).

Investigators noted no new safety signals among those who received daratumumab. In the daratumumab and monitoring arms, 96.9% vs 82.7% had TEAEs of any grade, 40.4% vs 30.1% had grade 3 or higher TEAEs, 29.0% vs 19.4% had serious TEAEs, and 1.0% vs 2.0% had grade 5 TEAEs. The most common grade 3 or higher TEAE in each arm was hypertension (5.7% vs 4.6%), and the incidence of second primary malignancies was comparable between arms (9.3% vs 10.2%).

Health-related quality of life outcomes with daratumumab 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 daratumumab for this smoldering multiple myeloma population in July 2025 based on findings from the AQUILA trial.2 Additionally, the FDA’s Oncologic Advisory Drug Committee (ODAC) voted in favor of daratumumab’s benefit/risk profile for those with high-risk smoldering multiple myeloma in May 2025.3

References

1. Dimopoulos MA, Voorhees PM, Schjesvold F, et al. Phase 3 AQUILA study of daratumumab monotherapy versus active monitoring in patients with high-risk smoldering multiple myeloma. Presented at the 2025 Society of Hematologic Oncology Annual Meeting (SOHO); September 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. News release. Johnson & Johnson. July 23, 2025. Accessed September 4, 2025. https://tinyurl.com/bvhyv2vk
3. May 20-21, 2025 Meeting of the Oncologic Drugs Advisory Committee (ODAC) - Day 1. Streamed live May 20, 2025. Accessed September 4, 2025. https://tinyurl.com/25e3rr2x