Risk stratification and prognosis in smoldering MM

The Multiple Myeloma Hub spoke to Irene Ghobrial, Dana-Farber Cancer Institute, Boston, US. We asked about risk stratification and prognosis in smoldering multiple myeloma (MM).

During this interview, Ghobrial discussed risk stratification and prognosis in smoldering MM, with a focus on whether high-risk smoldering MM should be treated early. Ghobrial emphasized the heterogeneity of the condition, which ranges from indolent disease to high-risk cases with an approximately 50% likelihood of progression within 2 years.¹ High-risk smoldering MM is a true malignancy, with plasma cells actively proliferating despite the absence of symptoms or myeloma-defining events. Early treatment was highlighted as a potential opportunity to achieve long-term disease control, with supporting data from the AQUILA study and other clinical trials indicating that therapies such as daratumumab can improve progression-free and overall survival for these patients. Ghobrial concluded by noting that advances in immunotherapy, including bispecific antibodies and CAR T-cell therapy, may enable earlier, fixed-duration treatment strategies that prevent end-organ damage and potentially achieve cure in high-risk smoldering MM.

Key learnings

• Smoldering MM is a heterogeneous condition, with some patients never progressing and others rapidly progressing to a diagnosis of active MM.

• High-risk smoldering MM is characterized by approximately a 50% chance of progression within 2 years.¹

• Patients with high-risk smoldering MM do not meet criteria for active myeloma but possess malignant plasma cells that are actively proliferating despite the absence of symptoms.

• The biology of high-risk smoldering MM supports its classification as a malignancy rather than a benign precursor state, making it a potential target for early therapeutic intervention.

• Treating patients earlier in the disease course, before immune dysfunction accumulates, may improve the likelihood of durable disease control or cure.

• Data from the phase III AQUILA (NCT03301220) study demonstrate that treatment with daratumumab can significantly improve progression-free survival and overall survival compared with observation in high-risk smoldering MM, leading to European regulatory approval in July 2025 and U.S. Food and Drug Administration (FDA) consideration.²

• Early treatment strategies have potential for fixed-duration treatment with the goal of achieving deep responses, including measurable residual disease negativity which would then allow patients to discontinue treatment.

• Advances in immunotherapy, such as novel bispecific antibodies and chimeric antigen receptor T-cell therapies, provide additional opportunities for effective early intervention in high-risk smoldering MM.

• The long-term goals for smoldering MM are to detect high-risk disease through screening, intervene before end-organ damage occurs, and potentially prevent progression to active MM altogether.