Daratumumab and hyaluronidase-fihj, a monotherapy for high-risk smoldering multiple myeloma: a shift in preventing...

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder with heterogeneous risk of progression to active multiple myeloma. Most patients are managed with observation, but selected high-risk patients may benefit from early intervention. Daratumumab, an anti-CD38 monoclonal antibody, has recently emerged as a promising therapeutic option in this setting.

This review summarizes the biological rationale for targeting CD38 in SMM, including the immune-mediated and direct antimyeloma effects of daratumumab. It discusses current approaches to SMM risk stratification, with an emphasis on the Mayo 20/2/20 and IMWG 2020 models. The review also covers clinical evidence supporting daratumumab, particularly the phase III AQUILA trial, which showed that fixed-duration subcutaneous daratumumab delayed progression to active multiple myeloma compared with active monitoring. Ongoing studies of daratumumab-based combinations and other anti-CD38 strategies are also discussed.

Daratumumab marks an important step toward early, disease-modifying therapy for high-risk SMM. Future strategies may include triplets, quadruplets, and immune-based combinations to achieve deeper responses and a possible functional cure. However, these approaches must be balanced against the risks of toxicity, infection, immunosuppression, and overtreatment. Precise patient selection remains the key challenge.