Evolving diagnostic criteria for high-risk smoldering MM

The Multiple Myeloma Hub spoke with María-Victoria Mateos, University Hospital of Salamanca, Salamanca, ES. We asked about evolving diagnostic criteria for high-risk smoldering multiple myeloma (MM).

During this interview, Mateos discussed the latest updates in the diagnosis, prognosis, and management of high-risk smoldering MM. The discussion covered the diagnostic criteria that distinguish smoldering MM from monoclonal gammopathy of undetermined significance and active MM, with emphasis on the role of myeloma-defining events. Mateos outlined updates to risk stratification models, including the International Myeloma Working Group 2/20/20 model and its integration with cytogenetics, along with alternative approaches such as flow cytometry, positive emission tomography imaging, genomic profiling, and dynamic models like PANGEA. Mateos highlighted the importance of identifying patients with high-risk smoldering MM, given the significantly higher risk of progression among these patients, and reviewed data from clinical trials supporting therapeutic intervention in this setting. Mateos concluded with an overview of more novel approaches under investigation, including CAR T-cell therapies and bispecific antibodies.

Key learnings

• Smoldering MM is defined by the presence of a monoclonal protein ≥3 g/dL and/or bone marrow plasma cell infiltration between 10% and 59%, without myeloma-defining events.¹
• Myeloma-defining events include CRAB symptoms or one or more biomarkers: ≥60% clonal bone marrow plasma cells, free light chain ratio ≥100, or >1 focal lesion on MRI.¹
• The risk of progression in smoldering MM is approximately 10% per year during the first 5 years, 3% annually during the next 5 years, and 1% per year thereafter.²
• The IMWG 2/20/20 risk model stratifies patients based on M-protein ≥2 g/dL, free light chain ratio >20, and bone marrow plasma cells >20%. Presence of two or more factors predicts 46% progression risk at 2 years.³
• Cytogenetic abnormalities, including t(4;14), t(14;16), gain(1q), and del(13q)/monosomy 13, indicate higher risk status and can increase 2-year progression risk to 59%.³
• Other risk models incorporate factors including flow cytometry, PET positivity without lytic lesions, and specific laboratory features such as 24-hour proteinuria or IgA/IgG phenotype.
• Future directions may include dynamic models, such as the PANGEA model and assessment of evolving M-protein kinetics, providing an option for ongoing risk reassessment and can identify “ultra-high-risk” patients.
• The management of smoldering MM is risk-adapted. Lower-risk patients are typically monitored, while high-risk patients may be considered for clinical trials or early treatment with daratumumab.⁴
• Early treatment studies, including E3A06 (NCT01169337) and QuiRedex (NCT00480363), showed benefits of lenalidomide-based therapy in high-risk smoldering MM, improving progression-free survival and, in some cases, overall survival.^5,6
• Intensive strategies such as carfilzomib, lenalidomide, and dexamethasone-based induction with or without autologous transplant followed by maintenance, have demonstrated deep responses, with measurable residual disease negativity associated with a numerically reduced risk of progression.⁷
• The phase III AQUILA (NCT03301220) study evaluated daratumumab monotherapy versus active monitoring in smoldering MM, showing a significant progression-free survival benefit (HR, 0.36; 95% CI, 0.23–0.58), particularly in patients meeting high-risk 2/20/20 criteria.⁴
• Daratumumab has now been approved for the treatment of high-risk smoldering MM by the European Commission; based on data from the phase II AQUILA study.⁸
• Future directions include exploring novel immunotherapies such as CAR T-cell therapy and bispecific antibodies in this earlier disease state.

CAR, chimeric antigen receptor; CRAB, calcium levels, renal dysfunction, anemia, and bone lesions; CT, computed tomography; Ig, immunoglobin; IMWG, International Myeloma Working Group; MM, multiple myeloma; M-protein, monoclonal protein; MRI, magnetic resonance imaging; PET, positron emission tomography.