Better Risk Stratification May Refine Early Myeloma Treatment

For defining high-risk smoldering disease in patients who have multiple myeloma (MM) and could potentially benefit from earlier treatment intervention, the 2/20/20 stratification model from the Mayo Clinic outperformed inclusion criteria from the phase 3 AQUILA trial (NCT03301220) in a recent cohort study.¹ The 2/20/20 criteria encompass classifying patient risk according to the presence of a serum M-protein level above 2 g/dL, bone marrow plasma cell infiltration of more than 20%.² and/or an involved-to-uninvolved serum free light chain ratio exceeding 20. The finding has immediate implications for how oncologists approach one of the trickiest decisions in blood cancer care: when to treat a condition that is not yet dangerous.

These results published in JAMA Oncology should not take away from the positive findings of the AQUILA trial, however, in which daratumumab administered early has demonstrated benefits for progression-free survival and overall survival in patients with high-risk smoldering MM.³ AQUILA’s estimated completion date is June 30, 2026.⁴

Two Screening Tools, Very Different Answers

Smoldering MM (SMM) is not yet active MM. These patients have abnormal plasma cells in their bone marrow that haven’t yet caused organ damage or symptoms.^5,6 Some will progress to active myeloma within a few years, but for many others, this is an extended timeline. Monitoring patients closely and treating only when the disease becomes active has been the watchful waiting approach for decades. But recent trials, including AQUILA and the QuiRedex study (NCT00480363), have raised the possibility that treating high-risk SMM early could improve outcomes.

The new research drew on data from 1340 patients across 2 large national cohorts, the Iceland Screens, Treats, and Prevents Multiple Myeloma study (iStopMM; n = 193) and the Danish Lymphoid Cancer Resource (DALY-CARE; n = 1147). Patients had median (IQR) ages of 70 years (63-72) and 72 years (64-79), respectively, and more than 50% of each cohort’s participants were female patients.

There was a dramatic gap in what the AQUILA criteria and the 2/20/20 model identified as high risk.

In DALY-CARE, the AQUILA criteria classified 55% of patients as high risk compared with the 2/20/20 model classifying 19% as high risk. The disparity was even starker in iStopMM: 34% vs 8%. What happened to those patients over time is even more telling. Among AQUILA-designated high-risk patients in the Danish cohort, only 27% (95% CI, 23.3%-30.7%) progressed to active myeloma within 2 years vs 44% (95% CI, 37.1%-51.1%) deemed high risk by the 2/20/20 model.

The study authors explained that the 2/20/20 criteria did a better job of identifying the patients most likely to progress, but that under the AQUILA criteria, substantially more patients were potentially identified as needing aggressive treatment than those who actually would; these were patients whose disease state would not progress within 2 years.

Looking Ahead

Early treatment with unnecessary drugs can carry financial, physical, and psychological costs, the authors argue, without meaningful benefit. At a population level, overclassifying patients as high risk strains health care systems and distorts the evidence base used to evaluate new treatments.

The study authors argued that a meaningful high-risk designation should point toward a roughly 50% progression risk within 2 years, a threshold that the AQUILA criteria fell well short of, but that the 2/20/20 model approaches. They concluded 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.”

There are some limitations on these results. Cytogenetic data were unavailable for most patients, and both cohorts skewed toward patients of Northern European descent, which could limit the findings’ generalizability. Still, with early intervention for smoldering MM increasingly entering clinical practice, the research offers an important corrective: not all high risk definitions are created equal, so patients and their doctors need to ask which risk tool is being used and why.

References

1. Maeng CV, Rögnvaldsson S, Brieghel C, et al. Identifying high-risk smoldering multiple myeloma for early intervention. JAMA Oncol. 2026:e260831. doi:10.1001/jamaoncol.2026.0831
2. What are monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma? International Myeloma Foundation. Accessed May 18, 2026. https://www.myeloma.org/what-are-mgus-smm-mm
3. Shaw ML, Voorhees P. Early intervention gains ground in smoldering myeloma: Peter Voorhees, MD. AJMC^®. March 4, 2026. Accessed May 18, 2026. https://www.ajmc.com/view/early-intervention-gains-ground-in-smoldering-myeloma-peter-voorhees-md
4. A study of subcutaneous daratumumab versus active monitoring in participants with high-risk smoldering multiple myeloma. Clinicaltrials.gov. Updated April 13, 2026. Accessed May 18, 2026. https://clinicaltrials.gov/study/NCT03301220
5. Smoldering multiple myeloma overview. Moffitt Cancer Center. Accessed May 18, 2026. https://www.moffitt.org/cancers/smoldering-multiple-myeloma-smm/
6. Smoldering multiple myeloma. Memorial Sloan Kettering Cancer Center. Accessed May 18, 2026. https://www.mskcc.org/cancer-care/types/multiple-myeloma/other-plasma-cell-diseases/smoldering-multiple-myeloma