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

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.