Dr Landgren on Considerations Surrounding the Current Treatment Paradigm for Smoldering Multiple Myeloma

"The FDA has received the data, and approval of daratumumab for [smoldering myeloma] is anticipated in 2025.”

C. Ola Landgren, MD, PhD, a professor of medicine and chief of the Division of Myeloma in the Department of Medicine, director of the Sylvester Myeloma Institute, co-leader of the Translational and Clinical Oncology Program, and the Paul J. DiMare Endowed Chair in Immunotherapy at the University of Miami’s Sylvester Comprehensive Cancer Center, discussed how emerging clinical trial data may soon reshape the treatment paradigm for patients with smoldering multiple myeloma in 2025.

Smoldering multiple myeloma was first defined in the 1980s to describe patients whose disease did not meet diagnostic criteria for either monoclonal gammopathy of undetermined significance or symptomatic multiple myeloma. At the time, observation without treatment was the standard approach. However, as Landgren explained, subsequent research demonstrated that patients with smoldering multiple myeloma have a significantly higher rate of disease progression than those with monoclonal gammopathy of undetermined significance, raising questions about the role of early therapeutic intervention.

There are currently no FDA-approved therapies for smoldering multiple myeloma. However, findings from the phase 3 randomized registrational AQUILA study (NCT03301220) evaluating daratumumab (Darzalex) monotherapy in patients with high-risk smoldering multiple myeloma demonstrated a reduction in the risk of progression to symptomatic disease when compared with observation. This study also showed early signals of improved overall survival. The data have been submitted to the FDA, and a decision regarding the approval of daratumumab for this patient population is expected in 2025.

If approved, daratumumab would become the first FDA-approved therapy for smoldering multiple myeloma. Landgren noted that this shift would mark a departure from the longstanding observation-only model toward a more proactive, risk-adapted treatment strategy. For patients with high-risk features—like elevated serum M-protein levels, increased bone marrow plasma cell levels, or cytogenetic abnormalities—early treatment may help delay or prevent progression to symptomatic disease and associated end-organ damage.

Although the approval decision is still pending, Landgren emphasized that these findings support the use of risk stratification models to guide treatment selection and timing. The anticipated approval of daratumumab could prompt broader discussions about the optimal management of early disease states and encourage hematologists to consider therapeutic intervention prior to progression.

Landgren concluded that the expected regulatory decision and supporting clinical data may signal a new era in the management of smoldering multiple myeloma—one that moves beyond passive monitoring toward early, targeted therapy in appropriately selected patients.