The FDA's Oncologic Drug Advisory Committee (ODAC) has voted 6-2 that subcutaneous daratumumab (Darzalex Faspro) demonstrates a favorable benefit-risk profile for patients with high-risk smoldering multiple myeloma (SMM), potentially paving the way for the first approved therapy for this precursor condition.
The committee's decision was based on results from the phase 3 AQUILA trial (NCT03301220), which compared three years of daratumumab therapy versus active monitoring in patients with intermediate- and high-risk SMM. After a median follow-up of 65.2 months, the trial showed that daratumumab significantly delayed progression to active multiple myeloma.
Understanding Smoldering Multiple Myeloma
Smoldering multiple myeloma is an asymptomatic precursor condition to multiple myeloma. Patients with high-risk SMM have approximately an 80% risk of progression to symptomatic multiple myeloma within five years, according to recent models. Currently, there are no approved therapies for SMM, and the standard approach is watchful waiting.
"Patients with SMM feel like they're sitting on a ticking time bomb, waiting for a complication," said Sagar Lonial, MD, FACP, medical oncologist specializing in multiple myeloma at the Winship Cancer Institute of Emory University, during the applicant presentation.
AQUILA Trial Results
The phase 3 AQUILA study demonstrated that subcutaneous daratumumab significantly improved progression-free survival (PFS) compared to active monitoring. The median PFS was not reached with daratumumab monotherapy compared with 41.5 months with active monitoring. The 60-month PFS rates were 63.1% and 40.8%, respectively, representing a 51% reduction in the risk for disease progression or death (HR, 0.49; 95% CI, 0.36-0.67; P <.001).
The trial also showed that:
- Complete response or better was achieved by 8.8% of patients in the daratumumab group versus 0% in the monitoring group
- Very good partial response or better was experienced by 29.9% versus 1.0%, respectively
- At 5 years, overall survival was 93.0% in the daratumumab group compared to 86.9% in the active monitoring group
Additionally, fewer patients in the daratumumab group required initiation of first-line multiple myeloma treatment (33.2%) compared to the active monitoring group (53.6%).
Safety Profile
As expected, more adverse events were observed in the daratumumab arm, with 40.4% of patients experiencing grade 3 or 4 adverse events compared to 30.1% in the active monitoring group. The most common serious adverse event was hypertension (5.7% vs 4.6%, respectively).
The most common adverse events of any grade in the daratumumab group were fatigue (34.2%), upper respiratory tract infection (30.1%), and diarrhea (27.5%). Eleven patients discontinued daratumumab treatment due to treatment-emergent adverse events, while 90 patients required dose modifications.
Committee Deliberations
The ODAC discussion highlighted several areas of concern, including risk stratification accuracy, potential overtreatment of some patients, and undertreatment of others.
"It's crazy to say with a follow-up time of 5 and a half years that the data may be immature, but it might actually be a little immature here," said Christopher Lieu, MD, ODAC member and co-director of gastrointestinal medical oncology at the University of Colorado.
Several committee members expressed concerns about the classification of high-risk SMM, noting that the protocol-defined definition did not completely align with other available high-risk models. The FDA pointed out that when judged via the Mayo 2018 risk model, less than half of the trial participants would have been considered high-risk.
"I think these risk groups are phenomenal, but I think they're terrible for regulatory approval. These are prognostic risk groups. These are not predictive," said one ODAC member.
Another point of contention was whether SMM should be considered cancerous or precancerous. S. Vincent Rajkumar, MD, FRCPC, Edward W. and Betty Knight Scripps professor of medicine at Mayo Clinic, clarified that SMM is "asymptomatic but not premalignant," and patients with SMM are genomically indistinguishable from those with multiple myeloma.
The Decision
Despite the concerns, six committee members ultimately voted that the endpoint data was favorable and supported treatment in this indication.
"This was a very tough decision... I listened carefully to the sponsor, to the FDA, I did my homework, and I listened to the patients that are the real heroes here," said Toni Choueiri, MD, ODAC member and professor at Harvard Medical School, Dana-Farber Cancer Institute. "I have some concerns... we may be overtreating patients that have MGUS for 3 years, and we may have some real multiple myeloma patients that we are undertreating, but the thing today is that we do not have today an ideal classification on whom to treat for sure with high certainty."
Heidi McKean, MD, ODAC member and oncologist at Avera Health in Sioux Falls, South Dakota, explained her yes vote: "For me, the change was thinking of smoldering multiple myeloma as a malignancy and allowing the physician and the patient to look at this data and intervene earlier."
Implications for Treatment Landscape
If approved, daratumumab would be the first therapy specifically indicated for high-risk SMM, potentially changing the standard of care from watchful waiting to active intervention. This would represent a significant shift in the treatment paradigm for this patient population.
Johnson & Johnson, the applicant, had previously submitted regulatory applications to both the FDA and the European Medicines Agency in November 2025, seeking approval for daratumumab in high-risk SMM. Daratumumab is already approved for several multiple myeloma indications, including newly diagnosed or relapsed/refractory multiple myeloma and newly diagnosed AL amyloidosis.
The FDA will now consider the ODAC recommendation in its final decision on whether to approve daratumumab for high-risk SMM.
