TOPLINE:

In a cohort study, the AQUILA trial inclusion criteria placed more patients with smoldering multiple myeloma (SMM) in the high-risk group than the Mayo Clinic 2/20/20 risk stratification model but identified a group with a substantially lower 2-year risk for progression. These findings indicated that the 2/20/20 model detected a smaller, higher-risk subgroup that had a higher risk for progression and therefore more accurately identified patients more likely to benefit from early treatment.

METHODOLOGY:

• SMM is an asymptomatic precursor to multiple myeloma, and early treatment may benefit patients at a high risk for progression. Selecting an accurate risk stratification model is therefore essential to identify those most likely to benefit while avoiding overtreatment among lower-risk individuals. Since the AQUILA trial was first designed, the Mayo Clinic 2/20/20 risk stratification model has gained wide acceptance in clinical practice.
• Researchers compared two definitions of high-risk SMM by the AQUILA trial inclusion criteria and the Mayo Clinic 2/20/20 risk stratification model in two cohorts: 193 individuals (median age, 70 years) from the iStopMM screening study conducted in Iceland between 2016 and 2021 and 1147 individuals (median age, 72 years) from the DALY-CARE clinical cohort in Denmark between 2002 and 2025.
• According to the AQUILA criteria, high-risk SMM was defined as having immunoparesis, monoclonal protein (M-protein) concentration > 3.0 g/dL, immunoglobulin A isotype, 50% or more infiltration of bone marrow plasma cells, or a free light chain (FLC) ratio ≥ 8. According to the 2/20/20 model, high-risk SMM was defined as having an M-protein concentration > 2.0 g/dL, more than 20% infiltration of bone marrow plasma cells, or an FLC ratio > 20.
• Progression was defined as the initiation of treatment for multiple myeloma or amyloid light-chain amyloidosis in the DALY-CARE cohort; the cumulative incidence of progression was analyzed, with death treated as a competing risk. The median follow-up duration in the DALY-CARE cohort was 4.3 years.

TAKEAWAY:

• In the screened cohort, 34% vs 8% were classified as having high-risk SMM according to the AQUILA criteria vs the 2/20/20 model; in the clinical cohort, the corresponding proportions were 55% and 19%. This suggested that the AQUILA criteria classified substantially more patients at a high risk.
• Among individuals with AQUILA-defined high-risk disease in the clinical cohort, the 2-year risk for progression was 27.0%, and the estimated annual rate of progression was 14.5%. Among individuals with high-risk disease defined by the 2/20/20 model, the 2-year risk for progression was 44.1%, and the estimated annual rate of progression was 27.3%, indicating a higher concentration of short-term risk.
• The 5-year cumulative incidence of progression differed markedly between groups: 46.1% vs 66.5% for the AQUILA-defined high-risk group vs the 2/20/20 model-defined high-risk group.
• Substantial discordance existed between the models, with many AQUILA-defined high-risk patients classified as having low or intermediate risk by the 2/20/20 model. For instance, in the screened cohort, only 14 of 65 AQUILA-defined high-risk patients met the 2/20/20 high-risk criteria, whereas 51 were classified as having a low or intermediate risk. In the clinical cohort, 199 of 607 AQUILA-defined high-risk patients met the 2/20/20 high-risk criteria, and 408 were classified as having a low or intermediate risk.

IN PRACTICE:

In both the SMM cohorts, “the choice of SMM risk stratification model substantially determined how many individuals were classified as having high-risk disease,” the authors of the study wrote, noting that “the AQUILA trial criteria incorporate a larger fraction of patients as having high risk of progression than the 2/20/20 model, with a markedly lower risk of progression.” Given these results, as treatment of high-risk SMM moves into clinical practice, “using the 2/20/20 criteria is currently the most appropriate method” to define this population, minimizing overtreatment and improving the overall risk-benefit balance, leading to better outcomes for patients,” they concluded in a brief report.

SOURCE:

The brief report, led by Cecilie V. Maeng, MD, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, was published online in JAMA Oncology.

LIMITATIONS:

The iStopMM cohort was small, and the DALY-CARE cohort was retrospective, which increased the risk for misclassification and missing data. The 90-day restriction may have introduced potential immortal time bias. Additionally, cytogenetic data were unavailable, and both cohorts were predominantly of Northern European ancestry, which may have restricted generalizability.

DISCLOSURES:

One author reported receiving funding from the Danish Cancer Institute, and another author reported receiving support from the Rigshospitalet Research Foundation and the European Hematology Association. Maeng disclosed receiving a travel grant from Daiichi Sankyo during the conduct of the study. Several authors reported receiving grants or personal fees from various sources including Sanofi, Thermo Fisher Scientific, AbbVie, GSK, AstraZeneca, Janssen, and others. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.