SLiM CRAB criteria revisited: temporal trends in prognosis of patients with smoldering multiple myeloma who meet the definition of ‘biomarker-defined early multiple myeloma’—a systematic review with meta-analysis

BACKGROUND: Biomarker-defined patients with smoldering multiple myeloma (SMM) were included in the diagnostic category of multiple myeloma (MM) by the International Myeloma Working Group (IMWG) in 2014. This includes ≥60% bone marrow plasma cells (BMPCs), free light chain ratio (FLCratio) ≥100, and >1 MRI-defined ≥5 mm focal lesion, also called SLiM CRAB MM. We examined whether the risk of progression of SLiM CRAB MM patients to CRAB positive MM described in recent studies differs from that reported in earlier studies published before the introduction of the new diagnostic criteria. METHODS: We conducted a systematic review with meta-analysis, and included studies on Embase and PubMed (01/01/2010–01/11/2022), selecting studies with digitizable progression curves. Inconsistent studies were excluded. We created forest plots using random effects models from digitized and published data and Kaplan–Meier curves. Main outcomes were median time to progression (TTP), 2-year progression risk, and odds ratios (ORs) comparing 2-year progression risks. FINDINGS: Our meta-analysis including 11 studies with 3482 patients found an approximately 3-fold longer TTP and 50% lower 2-year progression risk of SliM CRAB MM patients in recent (published after 2014) compared with earlier studies. Median TTP in patients with ≥60% BMPCs was 30.31 months [18.71–62.93] in recent compared with 9.20 months [6.02–15.56] in earlier studies; the 2-year progression risk was 45.45% [20.12–62.75] compared with 86.21% [65.74–94.45] in the respective time periods. In patients with a FLCratio ≥ 100, the median TTP was 48.06 months [40.51–64.91] vs. 15.33 months [9.38–19.10], and the 2-year progression risk was 31.61% [25.30–37.39] vs. 73.00% [62.39–80.62] in recent and earlier studies, respectively. Tests for heterogeneity showed that the two time periods differed significantly in their ORs when comparing patients who met the high-and low risk criteria. No appropriate recent studies on focal lesions have been published. INTERPRETATION: Recent studies show significantly improved prognosis of biomarker-defined MM with ≥60% BMPCs and FLCratio ≥ 100. This warrants careful evaluation for signs of progression before treatment initiation. FUNDING: Funding was provided by the Austrian Forum against Cancer.