FDA ODAC: AQUILA Trial Supports Favorable Benefit-Risk of SQ Daratumumab in SMM

Results from the international AQUILA clinical trial support a favorable benefit-risk profile for subcutaneous daratumumab in patients with high-risk smoldering multiple myeloma (SMM), the FDA’s Oncologic Drugs Advisory Committee (ODAC) has decided.¹ The ODAC convened on May 20, 2025, at the Center for Drug Evaluation and Research (CDER) on the FDA White Oak Campus in Silver Spring, Maryland, to hear arguments on and discuss this topic.^1,2

The discussion is relevant to a supplemental Biologics License Application (sBLA) currently before the FDA, submitted by Janssen Biotech, Inc., for use of injection daratumumab and hyaluronidase as monotherapy for high-risk SMM in adult patients.^2,3 Daratumumab and hyaluronidase, manufactured by Janssen as DARZALEX FASPRO, is already FDA-approved for several indications in multiple myeloma (MM).^1,3,4 There are currently no FDA-approved therapies for SMM and the standard of care for high-risk disease is a clinical trial or active monitoring.^1,4

The primary clinical trial evidence Janssen has marshalled in their submitted sBLA for the monotherapy’s efficacy and safety is the results from the AQUILA trial. Launched in 2017, AQUILA is a randomized, open-label, phase 3 study that enrolled 390 patients with high-risk SMM who received either subcutaneous daratumumab monotherapy or active monitoring without treatment. The trial thus was a comparison of the treatment injection against active monitoring.^1,4

Representatives from Johnson & Johnson, led by the company’s vice president for oncology research and development Sen Zhuang, MD, PhD, argued that the trial met its primary endpoint of a statistically significant improvement in progression-free survival (PFS), defined as time from randomization to progression to MM or death. Furthermore, regarding secondary endpoints, there was early evidence of overall survival (OS) benefit and positive trends in overall response rate (ORR) and progression-free survival 2 (PFS2). They described the safety results as also favorable and as expected.^1,4

The FDA has raised concerns about the design of AQUILA which, it argued, makes the trial results’ applicability to patients with high-risk SMM questionable. According to the FDA, the endpoints chosen to measure efficacy in the trial might not have been appropriate in high-risk SMM. Moreover, regarding AQUILA’s having met its primary endpoint in PFS, the FDA said this was primarily due to delaying diagnosis of emergent MM. It also cited inconsistencies in the criteria used to clinically define MM, and when patients began MM therapy after MM diagnosis, of what type, or if at all.^1,3

“The clinical meaningfulness of the PFS endpoint as defined in the AQUILA trial, and the impact of treatment prior to the development of multiple myeloma, and the effect on long-term outcomes, is unknown,” stated Payal Aggarwal, DO, MS, a hematologist-oncologist from the multiple myeloma team at the FDA’s division of hematologic malignancies II.¹

Regarding secondary endpoints of efficacy, the FDA said AQUILA was underpowered for measuring OS results and that PFS2 results are easily confounded. Of the safety findings, the FDA said the patient-reported outcomes (PROs) data were not sufficiently informative and there remained high rates of clinically relevant toxicities shown with the treatment.^1,3

The FDA pointed out that clinical definitions and risk assessment models of MM and SMM have been revised in the time since AQUILA commenced, and enrollees who were categorized in the trial as having SMM might not be by current standards now. For instance, SMM in less than half of the cohort had a high-risk for progression according to the Mayo 2018 risk criteria. The FDA noted that the high-risk criteria in the trial’s protocol did not completely match any particular established model.^1,3

“While the AQUILA trial was conducted prior to the establishment of the Mayo 2018 model, the criteria used in the protocol did not completely align with any of the available models, but instead incorporated criteria from multiple models and additional criteria, such as IGA smoldering multiple myeloma and clonal bone marrow plasma cells greater than 50% to 60%, to define patients with high-risk smoldering multiple myeloma,” Dr. Aggarwal continued.¹

Johnson and Johnson maintained that AQUILA’s design and cohort applied to real-world patient populations and that the trial’s results showed a meaningful benefit from the study treatment. The company also emphasized daratumumab and hyaluronidase as able to meet an unmet need in patients with high-risk SMM.^1,4 Testimony then followed at the ODAC meeting from patients with SMM and clinicians who manage the disease, expressing a desire for more options than only “watchful waiting.”¹

“There’s nothing premalignant in smoldering myeloma. Waiting for further cancer progression and genomic evolution until patients develop fractures in their bones or renal failure only harms our patients because it allows for evolution and drug resistance. It is like waiting for metastatic cancer to happen before we treat our patients,” said Irene Ghobrial, MD, professor of medicine at Dana-Farber Cancer Institute in Boston, Massachusetts, who stated having received no financial support from the presentation sponsor.¹

In the final vote, six members of the Committee voted “Yes” and two “No” to the discussion question of whether the AQUILA results support a conclusion that subcutaneous daratumumab has a favorable benefit-risk profile in high-risk SMM.¹

Several of the “yes”-voting committee members found the PFS and OS improvements to be promising but still had critiques about the data, such as its potential immaturity.¹

“I think these risk groups are phenomenal, but I think they are terrible for regulatory approval. These are prognostic risk groups. These are not predictive,” noted Committee member Daniel Spratt, MD, of University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland, Ohio, who voted “Yes” on the discussion question.¹

The two Committee members who voted “No” on the discussion question both expressed a concern that the data showed that certain patients were over- or undertreated. Moreover, it is unclear which patients benefit from the treatment and by how much.¹

“We’re probably overtreating more than 50% of patients at three years. Out of the patients getting treated, 40% of them are having grade three-four toxicity, and that didn’t translate to any real clear signal in PFS or overall survival, there clouding my view of what the early treatment is really doing,” elaborated Ravi Madan, MD, of medical oncology at the National Cancer Institute, who voted “No” on the discussion question.¹

An issue that was repeatedly raised in the Committee discussion was safety and the risk for over-management in a patient population that is asymptomatic. There was a concern about whether management approach for SMM truly treats the disease or if it merely delays a diagnosis of MM.¹

“Make no doubt about it, this is going to lead to overtreatment for a population of patients. And those patients may experience toxicity, particularly infection from this,” said Christopher Lieu, MD, professor at the University of Colorado in Aurora. However, he voted “Yes” on the discussion question, explaining that he would like patients and clinicians to be able to have the benefit-risk discussions of this treatment.¹

“I think that conversation includes the fact that there are toxicities from this drug. That there’s a chance that you can prevent a life-altering fracture. That you might be able to prevent, or delay, at least, the onset of treatment. That you might be able to delay or prevent end-organ damage,” Dr. Lieu clarified.¹

The FDA is not legally bound to follow the recommendations it receives from ODAC but typically has done so.²