The management of smoldering multiple myeloma (MM) is undergoing a significant transformation, driven by growing evidence that early intervention can meaningfully delay progression to active disease. Historically, active monitoring has been the standard of care for these patients; however, data from several randomized studies have steadily challenged that long-standing approach—particularly for individuals at higher risk of progression.
Two earlier trials helped lay the groundwork for this shift. The QuiRedex study (NCT00480363) from the Spanish Myeloma Group demonstrated both progression-free survival (PFS) and overall survival (OS) benefits with lenalidomide and dexamethasone in high-risk patients. Similarly, an Easter Cooperative Oncology Gourp–led study (NCT01169337) showed that lenalidomide monotherapy provided a PFS advantage in this same population. Together, these studies suggested that treatment prior to symptomatic disease could alter the natural course of smoldering myeloma.
Now, a phase 3 registrational study [the phase 3 AQUILA trial (NCT03301220)] evaluating daratumumab monotherapy has added further momentum. The trial demonstrated an improvement in PFS, along with an early signal suggesting a favorable OS advantage. This development marks a pivotal moment, as it represents the first regulatory-approved therapy specifically for smoldering MM.
Although active monitoring remains a conversation to have with patients, the availability of an approved treatment fundamentally changes that discussion. Clinicians must now weigh the advantages and disadvantages of intervention vs observation, tailoring recommendations to each patient’s risk profile and preferences. In this interview with Peter Voorhees, MD, hematologist, Medical Oncology, Atrium Health Levine Cancer Institute, he emphasizes, “Really, it’s a shared decision-making model that we have to follow,” underscoring the importance of guiding patients through an increasingly complex set of options.
The November 6 approval of daratumumab also has implications for future research. With an established therapy now in place, designing clinical trials with active monitoring as a control arm may no longer be feasible. Important questions remain, and investigators are now considering whether multidrug regimens traditionally used in active myeloma might offer additional benefit in this earlier setting, and whether immunotherapy or T-cell–redirecting therapies could play a role. For now, however, daratumumab represents a clear step forward—reshaping both clinical practice and the research agenda in smoldering MM.
