Daratumumab Demonstrates Significant Benefit in High-Risk Smoldering Myeloma: Results from the Phase 3 AQUILA Study

Smoldering multiple myeloma (SMM), a common asymptomatic precursor to multiple myeloma (MM), affects an estimated 0.5% of adults over the age of 40 years, as demonstrated by a population study conducted in Iceland. However, there are currently no approved treatment options available for SMM. The standard practice for high-risk SMM has traditionally been close monitoring without intervention, but this approach can result in progression to active MM, marked by clinical manifestations of multiple myeloma, such as bone lesions, renal impairment, anemia, and hypercalcemia (CRAB).^1,2

An AI rendering of multiple myeloma. Image Credit: © Сергей Косилко - stock.adobe.com

The phase 3 AQUILA study(NCT03301220), the largest trial conducted in this patient population, evaluated whether early intervention with daratumumab (DARA, Darzalex; Janssen Biotech, Inc) could delay or prevent progression compared to active monitoring. Presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California by 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 Athens, Greece, the results of the AQUILA study demonstrate the benefit of early treatment of SMM.^1,2

DARA, a monoclonal antibody targeting CD38, has shown clinical activity and tolerability in SMM in earlier studies. The AQUILA trial enrolled 390 patients with high-risk SMM and randomized them 1 to 1 to receive DARA subcutaneously for 36 months or active monitoring. Eligible patients were staged using imaging techniques, such as PET-CT and MRI, to assess focal and lytic lesions prior to study enrollment. Regular evaluations included blood and urine analyses every 12 weeks, annual imaging, and biennial bone marrow assessments. Patients were retrospectively stratified using the Mayo Clinic 2018 risk model, with two-thirds classified as having high or intermediate risk.^1,2

The study's primary end point was progression-free survival (PFS), defined as the time to symptomatic MM development (per SLiM-CRAB criteria) or death. DARA significantly reduced the risk of progression or death by 51% compared to active monitoring, with median PFS not reached in the DARA group vs 41.5 months in the monitoring group. Moreover, fewer patients treated with DARA progressed with CRAB or SLiM criteria, highlighting its ability to delay clinically impactful progression. At 5 years, DARA maintained a significant PFS benefit even after treatment cessation.^1,2

“During the follow up period, there was a continuous improvement in favor of the DARA arm,” Dimopoulos said during the ASH presentation. “Despite the treatment being discontinued at 3 years, even at 5 or 6 years, there was a continuous benefit from treatment with DARA.”¹

Secondary outcomes also favored DARA. Time to first-line MM therapy (PFS2) was prolonged, and overall survival (OS) improved, with a 50% reduction in the risk of death compared to active monitoring. The 60-month OS rates were 93.0% for DARA and 86.9% for active monitoring. These benefits persisted beyond the treatment period, underscoring DARA’s long-term impact on disease progression.^1,2

“DARA prolonged PFS2, meaning the time from DARA treatment to progression after frontline therapy for myeloma, and also it improved the overall survival of patients,” Dimopoulos said.¹

DARA was well tolerated, with a manageable safety profile consistent with prior studies, Dimopoulos explained. Grade 3/4 treatment-emergent adverse events occurred in 40.4% of DARA patients, compared to 30.1% in the monitoring group. Infections were slightly increased but were effectively managed, according to Dimopoulos. Discontinuation due to adverse events was low at 5%, confirming DARA’s safety for long-term use.¹

The AQUILA study provides compelling evidence supporting early intervention with DARA in high-risk SMM. According to Dimopoulos, this treatment significantly delays progression to active MM, reduces the risk of symptomatic disease, and improves survival outcomes.¹

“We conclude that in this largest prospective, well-conducted study of patients with SMM, where patients were very carefully staged to make sure that patients with overt myeloma but without symptoms were not included, indicated that treatment with DARA for 36 months was associated with significant improvement of PFS,” Dimopoulos said.¹

These findings challenge the traditional observation-based approach for high-risk SMM, suggesting that immediate treatment with DARA may become the preferred standard of care for this patient subset.¹

“We believe that with these data, patients with high-risk SMM may benefit from immediate treatment with DARA, and that observation for this particular subset of patients may not be an adequate option,” Dimopoulos said.¹

REFERENCES

1. Dimopoulos MA. Diagnosing and Treating Blood Cancers and “Almost Cancers.” Presented at: 66th ASH Annual Meeting and Exposition; San Diego, California; December 7-10, 2024.

2. Dimopoulos MA, Voorhees PM, Schjesvold F, et al. 773 Phase 3 Randomized Study of Daratumumab Monotherapy Versus Active Monitoring in Patients with High-Risk Smoldering Multiple Myeloma: Primary Results of the Aquila Study. 2024. Accessed December 7, 2024. https://ash.confex.com/ash/2024/webprogram/Paper201057.html