Daratumumab in SMM: ODAC Review Highlights Efficacy, Patient Definition Questions

In an interview with Targeted Oncology, George Mulligan, PhD, chief scientific officer of the Multiple Myeloma Research Foundation (MMRF), discusses the FDA's Oncologic Drugs Advisory Committee (ODAC) vote on the use of daratumumab (Darzalex) in patients with high-risk smoldering multiple myeloma (SMM). The Committee met in May 2025, and an official decision on the drug's approval in this disease state is still pending.

Daratumumab is a potent drug that has been approved for use in multiple myeloma, typically in relapsed settings. It is also used in complex, 3- or 4-drug combinations in the frontline setting and one of the first antibody drugs developed for this space.

The goal of using daratumumab in high-risk SMM is to treat patients who are expected to progress to myeloma soon and see if that progression can be delayed.

The challenge with this approach is severalfold. First, unlike its usual use in multidrug combinations, the AQUILA trial used daratumumab as a single agent in an observation arm. The goal was to see if the development of the disease could be delayed. A second challenge is accurately measuring this end point, and a third is recruiting a clean population of patients with high-risk SMM. The definition of high-risk SMM has evolved over the past decade, making it difficult to predict how quickly patients should progress.

The AQUILA study was a positive phase 3 trial, demonstrating a statistically significant delay in patients progressing to myeloma. ODAC, while not unanimous, supported the drug as being, on balance, potentially efficacious and reasonably safe in this setting. The key questions raised at the ODAC meeting centered on 2 main points:

1. Patient Definition: There was significant discussion and concern that a better, more research-backed definition of who is truly at high risk is needed.
2. Treatment Strategy: For patients at high risk of developing myeloma, should they receive a single agent, or should treatment begin with the standard, multidrug combinations typically used for active myeloma?