SKY92 Identifies High-Risk Newly Diagnosed Multiple Myeloma With Inferior Progression-Free Survival and Implicates NUF2 as a Candidate Driver

Objectives: To determine the prevalence and prognostic significance of the SKY92 gene-expression signature, evaluate minimal/measurable residual disease (MRD), and identify molecular drivers of high-risk disease in transplant-eligible newly diagnosed multiple myeloma (TE-NDMM) patients in the Republic of Ireland. Methods: Baseline genomic risk was assessed using the MMprofiler microarray in 114 TE-NDMM patients. MRD was evaluated 100 days after autologous stem cell transplantation using next-generation sequencing at the International Myeloma Working Group-recommended sensitivity of 10⁻⁵. Differential gene expression and copy number analyses were performed and compared with digital MLPA and retrospective fluorescence in situ hybridisation (FISH). Results: SKY92 classified 25.4% (29/114) of patients as high-risk and was associated with inferior progression-free survival and other adverse disease features. MRD assessment achieved 10⁻⁵ sensitivity, although MRD negativity was not associated with SKY92 risk status. High-risk disease demonstrated enrichment of pathways involved in chromosomal stability and DNA repair. NUF2 emerged as a key independent prognostic marker, showing strong association with high-risk biology and identifying a potential molecular driver of aggressive disease. Copy number abnormality detection showed high concordance between MMprofiler, digital MLPA, and retrospective FISH. Conclusions: This first characterisation of SKY92-defined high-risk multiple myeloma in Ireland supports integrated genomic profiling for clinical risk stratification and identifies NUF2 as a promising candidate driver, demonstrating that deep profiling of high-risk disease may help to discover new targets for this challenging entity.