FDA Panel Supports Darzalex for Early Myeloma

Regulatory Backing for Landmark Use in Smoldering Myeloma

Johnson & Johnson’s (J&J) Darzalex Faspro has secured a crucial recommendation from the U.S. Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee. In a 6-2 vote, the panel endorsed the benefit-risk profile of Darzalex Faspro for the treatment of high-risk smoldering multiple myeloma (SMM)—a precursor to active multiple myeloma that currently lacks FDA-approved therapies.

This outcome places Darzalex Faspro, the subcutaneous version of Darzalex, on track to become the first approved treatment for SMM. While the FDA is not obligated to follow its advisory committee's recommendations, it usually does so in practice.

Clinical Trial Concerns and Favorable Endpoints

Regulatory concerns emerged during the advisory meeting, primarily centered around findings from J&J’s phase 3 Aquila trial. The trial compared Darzalex Faspro against standard surveillance in patients with high-risk SMM. Despite FDA skepticism, the consistent positive results across multiple endpoints, including a potential early survival benefit, convinced most panelists to vote in favor of approval.

Quoting panelist Dan Spratt, M.D., of Case Western Reserve University: “My vote comes down to all the endpoints effectively are favoring the intervention here.”

Regulatory Debate: Risks and Relevance of Early Treatment

However, not all committee members were aligned. Ravi Madan, M.D., from the National Cancer Institute, voiced reservations about the broader implications of early treatment strategies. He emphasized a need for caution: “We have to really step back and ask ourselves, just because we can treat earlier, should we?”

The FDA outlined three key concerns: the applicability of patient selection criteria, the ambiguous clinical meaning of delayed disease progression, and potential long-term impacts on future treatment options and toxicity.

Patient Selection and Trial Design Limitations

One major point of contention was that over half of the Aquila trial participants did not meet the updated criteria for high-risk SMM, which were revised after the trial began in 2017. Only 41% of patients conformed to the new definition. Nonetheless, Mayo Clinic’s Vincent Rajkumar, M.D., a contributor to SMM risk stratification guidelines, defended the trial cohort’s risk profile:

“When people ask me, 'what is high-risk smoldering myeloma,' we say any criteria that gets you that 40%, 50% risk at two or three years is the high-risk group.”

Efficacy: Progression-Free Survival and Overall Benefit

Darzalex Faspro demonstrated a 51% reduction in the risk of SMM progressing to active multiple myeloma compared to monitoring. Still, the FDA questioned whether merely postponing progression was enough, given the inevitability of SMM advancing to full disease. Additional concerns centered around progression-free survival 2 (PFS2) and overall survival (OS) outcomes, especially within the subgroup meeting the revised high-risk criteria, where PFS2 improvement was just 9%.

At the five-year mark, overall survival showed a six-percentage-point difference, a margin not considered statistically significant due to the trial’s limited power. Nonetheless, Dr. Spratt argued that this was “pretty profound” for a slow-progressing disease like SMM.

Concerns Over Treatment Impact and Safety Profile

Another layer of concern involved whether early use of Darzalex could compromise future responsiveness to anti-CD38 therapies such as Sanofi’s Sarclisa. Due to a small sample size, meaningful survival or progression analyses for these patients were not conducted. Yet, J&J pointed out that all patients who transitioned to CD38-containing regimens remained responsive and continued treatment.

In terms of safety, Darzalex treatment was associated with more frequent adverse events. J&J highlighted similar patient-reported outcomes between groups, but the FDA deemed the data inadequate. Still, committee member Mark Conaway, Ph.D., from the University of Virginia, stated: “A sizable portion of a population whose perception of benefit would outweigh the risk” might still benefit from the treatment.

Next Steps and Need for Caution

Several advisory committee members called for the FDA to impose strict eligibility criteria in any potential approval and urged ongoing monitoring of the Aquila trial data. The panel’s decision underscores both the promise and the complexity of treating early-stage cancers and the challenges of interpreting long-term benefits from early interventions.

Highlights

• FDA advisory committee voted 6-2 in favor of J&J’s Darzalex Faspro for high-risk smoldering multiple myeloma (SMM).
• The recommendation marks potential first FDA-approved therapy for SMM, an asymptomatic precursor to multiple myeloma.
• FDA raised concerns about trial design, including outdated risk stratification and limited evidence for long-term efficacy.
• Darzalex Faspro reduced risk of disease progression by 51% compared to monitoring but showed only modest survival benefit.
• Experts debated ethical implications of early treatment and need for stricter patient selection moving forward.
• Higher incidence of adverse events in Darzalex arm noted, with questions about long-term impact on future treatments.