FDA approves first treatment for smoldering multiple myeloma

Abstract

The FDA has approved the subcutaneous injection of anti-CD38 monoclonal antibody daratumumab and hyaluronidase-fihj for patients with high-risk smoldering multiple myeloma (SMM), a precursor to multiple myeloma.¹ This is the first FDA-approved drug for adults with high-risk SMM.

The antibody gained approval based on results of the phase 3 AQUILA trial, which were published in The New England Journal of Medicine by Meletios A. Dimopoulos, MD, a professor and chairman of clinical therapeutics at the School of Medicine of the National and Kapodistrian University of Athens, and his colleagues.²

AQUILA randomly assigned 390 patients with high-risk SMM to either subcutaneous daratumumab monotherapy or active monitoring. Patients assigned to daratumumab had a 51% reduction in the risk for progression or death in comparison with patients assigned to active monitoring (hazard ratio, 0.49; 95% CI, 0.36–0.67; p < .001). The 5-year progression-free survival rate was 63.1% with daratumumab and 40.8% with active monitoring. The overall survival rates at 5 years were 93.0% with daratumumab and 86.9% with active monitoring; although the results were numerically better with daratumumab, the difference was not statistically significant.

“These are very impressive results,” says Ajay K. Nooka, MD, MPH, a professor at Emory University School of Medicine in Atlanta, Georgia. “Although the survival difference was not statistically significant, it serves as an indicator of the natural history of the disease, where an intervention may yield improved outcomes as we continue to follow patients over a longer period of time.” Dr Nooka adds that despite this being the first treatment approved by the FDA for SMM, it is still unclear exactly which patients would benefit.

In the AQUILA trial, high risk was defined as a clonal bone marrow plasma cell (BMPC) level ≥10% and one or more of the following risk factors: a serum M protein level ≥30 g/L, immunoglobulin A SMM, immunoparesis with a reduction of two uninvolved immunoglobulin isotypes, a serum involved/uninvolved free light chain ratio ≥8 but <100, and a clonal BMPC level of >50% to <60%.

Since the trial was designed, the definition of high-risk SMM has evolved. A current agreement defines it with the 20/2/20 model, Dr Nooka says. Patients with high-risk disease have two or more of the following: a BMPC level >20%, an M protein level >2 g/dL, an involved/uninvolved free light chain ratio >20, and a fluorescence in situ hybridization abnormality.

“The FDA states that the drug was approved for high-risk SMM but did not specify what high-risk SMM is,” says Dr Nooka. “That leaves the burden on societies like the International Myeloma Society to figure it out.”

So far, he says, there seems to be a general agreement to use the 20/2/20 criteria to define these patients, but even these criteria need more refinement with the use of genomics.

“Not every 20/2/20 patient has disease that behaves the same way,” Dr Nooka says, “but there is an opportunity for us to use the currently available techniques to figure out who is at higher risk for progression, even among the high-risk SMM population, so that they can benefit from early intervention.”