Ongoing Debates in the Management of Smoldering Myeloma

During the recent HemOnc Pulse Live! event held in Austin, TX, a panel discussion led by Saad Z. Usmani, MD, MBA centers on clinical considerations and research questions related to precursor multiple myeloma, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma.

Panelists:

• Caitlin Costello, MD, UC San Diego Health
• Peter Voorhees, MD, Atrium Health Levine Cancer Institute
• Sham Mailankody, MBBS, Memorial Sloan Kettering Cancer Center

During the discussion, the panelists explore the inflammatory features of these early disease states and examine whether anti-inflammatory strategies may offer benefit in slowing or preventing progression to active multiple myeloma.

The conversation begins with the rationale behind reserving agents such as daratumumab for patients with symptomatic disease. Panelists suggest that in early stages, targeting inflammation may be more appropriate. They reference trials investigating agents such as canakinumab, luspatercept, and leflunomide to modulate inflammatory pathways without depleting critical therapeutic options for later use.

Despite these efforts, the panel notes that existing studies have not demonstrated consistent impact on the trajectory from precursor states to active disease. One explanation offered is the role of immune escape, in which genomic instability or disease-driven immune evasion triggers progression. Panelists discuss CD8-positive T-cell dysfunction, immunoparesis, and T-cell exhaustion as potential hallmarks of advancing disease. The importance of single-cell sequencing and spectral flow cytometry is emphasized in identifying immunologic changes from healthy marrow to MGUS, to smoldering, and ultimately to active myeloma.

The discussion also touches on non-pharmacologic interventions in early disease. Panelists highlight studies examining anti-inflammatory dietary strategies to modulate disease risk in precursor stages. These interventions are presented as low-toxicity options that may complement future preventive care models.

Overall, the panel underscores the need for continued investigation into immune biology, inflammation, and risk-modifying strategies in precursor myeloma, while maintaining a focus on preserving effective therapies for when disease becomes active and symptomatic.