Identifying High-Risk Smoldering Multiple Myeloma for Early Intervention

Early treatment may benefit patients with high-risk smoldering multiple myeloma (SMM), a precursor of active multiple myeloma, but inconsistent high-risk definitions may capture different disease subsets.

To compare 2 high-risk SMM risk definitions: the AQUILA trial inclusion criteria and the 2/20/20 risk stratification model.

This cohort study included data from 2 separate SMM cohorts and a retrospective analysis assessing progression risk. The Iceland Screens, Treats, and Prevents Multiple Myeloma (iStopMM) is a large population-based screening study in Iceland, conducted from 2016 to 2021, while the Danish Lymphoid Cancer Resource (DALY-CARE) is a nationwide clinical data collection from Denmark from 2002 to 2025. From the iStopMM cohort, individuals with SMM were detected by screening. In DALY-CARE, individuals with SMM were identified in a clinical setting. Data were analyzed from March 2025 to January 2026.

High-risk SMM by the AQUILA criteria, defined by presence of immunoparesis, monoclonal protein (M-protein) greater than 3.0 g/dL, immunoglobin A isotype, bone marrow plasma cell infiltration greater than 50%, or free light chain ratio 8 or greater. High risk by the 2/20/20 model was defined by presence of more than 1 of: M-protein greater than 2.0 g/dL, bone marrow plasma cell infiltration greater than 20%, or free light chain ratio greater than 20.

Proportion of high-risk SMM in the 2 cohorts by both models and risk of progression as defined by initiation of treatment.

A total of 193 individuals (median [IQR] age, 70 [63-72] years; 116 [60%] female) from the iStopMM cohort and 1147 individuals (median [IQR] age, 72 [64-79] years; 598 [52%] female) from the DALY-CARE cohort were included. In the screened cohort (iStopMM), 65 participants (34%) had high-risk SMM according to the AQUILA criteria, and 15 participants (8%) had high-risk SMM according to the 2/20/20 model. In the clinical cohort (DALY-CARE), 607 participants (55%) met high-risk criteria according to AQUILA, and 219 participants (19%) had high-risk SMM according to the 2/20/20 model. For individuals with AQUILA-defined high-risk disease in the clinical cohort, the 2-year progression risk was 27.0% (95% CI, 23.3%-30.7%), with an annual progression rate of 14.5%. For individuals with high risk defined by 2/20/20, the 2-year progression risk was 44.1% (95% CI, 37.1%-51.1%), with an annual progression rate of 27.3%.

This cohort study found that the AQUILA trial criteria classified approximately 3 times more patients with SMM as having high risk compared with the 2/20/20 model and captured a group with substantially lower progression risk. These results suggest that the 2/20/20 model more accurately identifies a truly high-risk group with SMM, for whom early treatment is more likely to be beneficial.