Dr Krishnan on Risk-Stratification Factors in Smoldering Myeloma

Amrita Krishnan, MD, the Nason-Hollingsworth Chair in Multiple Myeloma, executive medical director of Hematology at City of Hope Orange County, director of the Judy and Bernard Briskin Multiple Myeloma Center, and professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, discussed risk stratification in smoldering myeloma and factors that define disease at high risk of progression to active multiple myeloma.

Krishnan explained the complexity of risk stratification and classification in smoldering multiple myeloma, emphasizing that multiple competing models existed, each incorporating overlapping but distinct variables. She noted that commonly used frameworks included the International Myeloma Working Group (IMWG) 2020 model, the PANGEA-SMM model, and the PETHEMA model, all of which attempt to quantify patients’ risk of progression to symptomatic disease.

Although these models shared core elements, such as tumor burden, Krishnan highlighted key differences, such as the incorporation of cytogenetic abnormalities and the measurement of longitudinal changes in markers like hemoglobin levels. She also acknowledged that the phase 3 AQUILA trial (NCT03301220), which supported the November 2025 FDA approval of daratumumab and hyaluronidase-fihj (Darzalex Faspro) for the treatment of adult patients with high-risk smoldering multiple myeloma, applied its own definition of high-risk disease per IMWG criteria. To enroll in the study, patients needed to have a clonal bone marrow plasma cells level of at least 10% and at least 1 of the following other risk factors: a serum M protein level of at least 30 g/L; immunoglobulin A smoldering multiple myeloma; immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes (only IgA, IgM, and IgG should be considered in determination for immunoparesis); a free light chain ratio of at least 8 and less than 100; or a clonal bone marrow plasma cell level of greater than 50% but less than 60% with measurable disease.

Krishnan framed high-risk smoldering myeloma primarily in terms of the likelihood of progression to active multiple myeloma. During the 2026 Bridging the Gaps in Leukemia, Lymphoma, and Myeloma meeting, Cristina Gasparetto, MD, of Duke Health, presented on risk-stratification factors in smoldering myeloma, which Krishnan explained related to traditional markers, such as tumor burden, serum M-protein level, degree of bone marrow plasmacytosis, and MRI-detected marrow abnormalities. Krishnan also underscored the importance of tumor-intrinsic biological features, such as cytogenetic abnormalities, genomic profiling, and proliferative capacity, when determining risk in smoldering myeloma.

Beyond tumor characteristics, Krishnan described additional contributors to disease progression risk, including patient-related factors and comorbidities. She also highlighted the role of immune dysregulation, noting that immunoparesis and the presence of circulating plasma cells may reflect impaired immune surveillance. Finally, she raised the question of the bone marrow microenvironment as a potential driver of risk of progression.