Abstract: Purpose: Early intervention in smoldering multiple myeloma (SMM) requires optimal risk stratification to avoid under and over-treatment. We hypothesized that replacing bone marrow (BM) plasma cells (PCs) for circulating tumor cells (CTCs), and adding immune biomarkers in peripheral blood (PB) for the identification of patients at risk of progression due to lost immune surveillance, could improve the International Myeloma Working Group 20/2/20 model. Experimental design: We report the outcomes of 150 SMM patients enrolled in the iMMunocell study, in which serial assessment of tumor and immune cells in PB was performed every 6 months for a period of three years since enrollment. Results: Patients with >0.015% vs ?0.015% CTCs at baseline had a median time-to-progression of 17 months vs not reached (hazard ratio: 4.9, P<.001). Presence of >20% BM PCs had no prognostic value in a multivariate analysis that included serum free light-chain ratio >20, >2g/dL M-protein, and >0.015% CTCs. The 20/2/20 and 20/2/0.015 models yielded similar risk stratification (C-index of 0.76 and 0.78). The combination of the 20/2/0.015 model with an immune risk-score based on the percentages of SLAN+ and SLAN- non-classical monocytes, CD69+HLADR+ cytotoxic NK cells, and CD4+CXCR3+ stem central memory T cells, allowed patient' stratification into low, intermediate-low, intermediate-high and high-risk disease with 0%, 20%, 39% and 73% rates of progression at two years. Conclusions: This study showed that CTCs outperform BM PCs for assessing tumor burden. Additional analysis in larger series are needed to define a consensus cutoff of CTCs for minimally invasive stratification of SMM.

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