Transitioning from SMM to MM

Smoldering myeloma (SMM) represents an important intermediate precursor stage between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). During the 2025 IMS meeting in Toronto, Prof Dr Sigurdur Kristinsson, haematologist at the University of Iceland in Reykjavik gave an educational talk on the factors determining the risk of progression, apart from genetics and the microenvironment. 

First of all, he emphasized that SMM is not a rare finding. In fact, screening of the Icelandic population demonstrated that about 0.5% of individuals over 40 have SMM, However, only ~8% of these individuals fall into the high-risk category where early intervention may be considered.¹ The risk of progression to MM is largely determined by clinical markers rather than baseline genetics or microenvironment.

The key predictors are captured in the “20-2-20 model”, which integrates the plasma cell percentage in bone marrow, the serum M-protein concentration, and the free light chain (FLC) ratio. Higher values in these parameters correspond to greater progression risk.² Additional cytogenetic abnormalities can further refine prediction. Importantly, monitoring SMM patients should focus on dynamics over time, such as rising M-protein, increasing plasma cells, or emerging early CRAB features (e.g., anemia), rather than static baseline values.

The management of SMM requires balancing vigilance with compassion. Most individuals with MGUS or SMM will not develop myeloma and should not be overburdened by unnecessary procedures or anxiety. In this regard, a bone marrow risk model, available at istopmm.com  helps physicians to determine whether a marrow biopsy is warranted, reducing unnecessary testing.³

Recent work has also refined definitions for light-chain MGUS and SMM. Unlike classic cases, these lack an M-protein spike and rely only on plasma cell counts and FLC ratios. The 20-2-20 framework remains useful for risk stratification in this subgroup.

In summary, the transition from SMM to MM is best predicted by quantitative markers and their evolution, with careful clinical follow-up and thoughtful patient communication being essential.