Daratumumab marks shift toward early intervention in smoldering multiple myeloma
FDA approval of daratumumab for high-risk smoldering multiple myeloma marks a shift from observation to early intervention. In a Phase II trial in earlier-stage disease, the overall response rate was 54% and the primary endpoint was not met.
The recent FDA approval of daratumumab for high-risk SMM marks a historic turning point. For the first time, early intervention is not only feasible but clinically validated. The approval of daratumumab for high-risk SMM in 2025 represents a key moment in early MM clinical management.
Smoldering multiple myeloma (SMM) has long been viewed as an intermediate precursor state, monitored until symptoms or organ dysfunction signaled the transition to active multiple myeloma (MM). For decades, SMM occupied a middle ground in hematology; biologically aligned with MM, yet clinically silent. Patients were monitored but not treated, based on the belief that therapy prior to organ damage offered no survival advantage and carried unnecessary toxicity.
The evolution of SMM – from a passive observation state to an actionable disease stage – reflects a broader shift toward detection and proactive treatment of early malignant clones. This evolving framework challenges long-standing assumptions regarding diagnostic boundaries, risk stratification, and the traditional “watch-and-wait” paradigm.
Daratumumab is approved for patients with multiple myeloma (MM) and high-risk smoldering MM (HR-SMM). We report on a Phase II trial of single-agent daratumumab in patients with earlier-stage disease, including high-risk monoclonal gammopathy of undetermined significance and low-risk SMM, to test if earlier treatment can induce deep responses and prevent progression to MM (D-PRISM/NCT03236428, n = 41). As primary outcome, the rate of Very Good Partial Response or better is 17% (95% CI: 7–32), which is comparable to what was observed in HR-SMM and does not meet the study’s primary endpoint. The overall response rate is 54%, with two patients developing MM and 51% biochemical progression.
Grade 3 or higher toxicities include hypertension (7%), diarrhea (2%), flu-like symptoms (2%), and headache (2%). This study demonstrates that, although less effective than expected, daratumumab is safe and can induce deep responses in certain early-stage patients, highlighting the importance of adopting genomic and immune profiling to improve patient selection and maximize the benefit/risk ratio in trials of early intervention.
Risk stratification remains critically important to the management of patients with SMM, identifying individuals most likely to progress to MM. The so-called “20/2/20 model” (based on serum M-protein ≥2 g/dL, free light chain ratio ≥20, and bone marrow plasma cells ≥20%) has gained widespread adoption for its practicality. It provides a simple clinical framework to enrich high-risk disease.
The 20/2/20 model has inherent limitations. It is grounded in clinical data and laboratory features detectable by earlier-generation technologies and does not incorporate biological data such as genomics or host immune status. By integrating next-generation sequencing, ctDNA assays, single-cell immune profiling, advanced imaging and other approaches, the field will continue to advance.