Abstract The definition of high‐risk (HR) multiple myeloma (MM) is still a matter of debate. We prospectively evaluated the HR detection using FISH in combination with SKY92 gene expression profiling in 258 MM patients (newly diagnosed [ND] MM: n = 109; relapsed/refractory [RR] MM: n = 149). HR SKY92 was significantly enriched in RRMM (57/121, 47.1%) compared with NDMM (17/95, 17.9%) (p < 0.0001). RRMM patients with HR SKY92 showed significantly shorter progression‐free survival (PFS) (p < 0.0001) and overall survival (OS) (p < 0.0001) than SKY92 standard‐risk (SR). In NDMM, HR SKY92 also indicated a significantly inferior PFS (p < 0.0001) in comparison with SR. We combined SKY92 with FISH (HR: t(4;14), del17p, +1q21 according to R2‐ISS) in 181 patients (NDMM: n = 79; RRMM: n = 102). We found a discrepancy between both risk stratification systems, with only 49 (27.1%) patients being defined as HR by both SKY92 and FISH (“double HR”). In terms of survival outcomes, “double HR” presented a negative prognostic factor for PFS in both NDMM (p < 0.0001) and RRMM (p < 0.0001). Furthermore, “double‐HR” patients showed the worst OS (p = 0.000 13) in RRMM. Additionally, whole genome sequencing (WGS) revealed CRBN mutation (n = 3) and bi‐allelic events (mutation and/or deletion) in TP53 (n = 7) and TNFRSF17 (n = 1). Altogether, we provide the first prospective real‐world evidence that the combination SKY92 and FISH (according to R2‐ISS) identifies a subset of patients with ultra‐HR MM, and WGS complements SKY92 and FISH in MM risk stratification.
