Exploring Biomarker-Based Risk Stratification in Smoldering Multiple Myeloma

The science around risk stratification in patients with smoldering multiple myeloma (SMM) has been evolving over the past 2 decades. A new study validates some, though not all, of the proposed biomarkers.

As methods continue to evolve for how best to identify patients with smoldering multiple myeloma (SMM) who are at risk of progression, a new retrospective analysis suggests that dynamic changes in monoclonal protein (MP) can be an effective identifier of progression risk.

The report also affirms that the percentage of bone marrow plasma cells (BMPC) at diagnosis and the relative increase of involved free light chain (eiFLC) could be significant predictors of progression at follow-up. The findings are contained in a letter to the editor published in the American Journal of Hematology.

Corresponding author Charlotte Gran, MD, and colleagues noted that several different models have been suggested to risk-stratify patients with SMM. First, the Mayo Clinic unveiled a prediction score that defined MP>30g/L and BMPC>10% as independent risk factors (RFs) for progression to MM within 5 years. In 2014, the International Myeloma Working Group issued guidance classifying the risk factors BMPCs>60%, FLC ratio>100 as myeloma defining events, rather than ultra high-risk SMM.

More recently, Gran and colleagues said, MP>20g/L, FLCr>20, and BMPCs>20% have been proposed as markers of progression.

Some reports have indicated that cumulative increase of MP during follow-up is an RF for SMM, and at least one study has shown that an increase of iFLC is a risk factor, though Gran and colleagues said FLC assessments are method-dependent, making it difficult to make comparisons.

In an effort to provide clarity to the situation, Gran and colleagues conducted a retrospective study assessing 126 SMM, 44 of whom progressed to MM, and 82 of whom did not). The investigators assessed patient biomarkers, with a median follow-up of 4.5 years. MP and FLC were assessed every 2 months, and the investigators then stratified patients according to previously published risk prediction models.

Their analysis showed that MP>20g/L at diagnosis was in fact an independent RF for progression, as was BMPC>20%. Further analysis showed that FLCr>8 was the optimal cut-off when stratifying patients, but they said it was not an independent RF.

Gran and colleagues found the median time to progression (TTP) was significant shorter in patients who met the two independent risk factors, though they said their model was not able to accurately discriminate between patients with one or two risk factors during the first 2 to 3 years, possibly because RFs at diagnosis do not account for the impact of evolving RFs.

Ten total patients (8%) died without evidence or progression, with a median follow-up of 25 months. Two patients were lost to follow-up.

The authors also identified two independent dynamic RFs using multivariate cox regression: evolving MP>5g/L and evolving FLCr>4.5. Those with either RF were classified in the analysis as high risk, and those patients had significantly shorter median TTPs compared with the low-risk patients.

Gran and co-authors noted that nailing down a meaningful risk profile is important because treatment of patients with high-risk SMM has been shown to increase both TTP and overall survival.

The investigators concluded by noting that their findings are exploratory in nature, and thus would need to be confirmed in larger studies. However, they said their data support MP and BMPC as valid predictors of risk at diagnosis, and evolving MP and FLCr as valid biomarkers at follow-up.

“With a median TTP of 5 months after an evolving pattern is observed, patients with evolving RF should be closely monitored,” they wrote.


Gran C, Luong, V, Bruchfeld JB, et al.Dynamic follow‐up of smoldering multiple myeloma identifies a subset of patients at high risk of progression. Am J Hematol. Published online December 2, 2020. doi: 10.1002/ajh.26062