SKY92
Identifies High‐Risk Newly Diagnosed Multiple Myeloma With Inferior Progression‐Free Survival and Implicates
NUF2
as a Candidate Driver
Roisin M. McAvera, Izabela Cymer, John Quinn, Phillip T. Murphy, Patrick Thornton, Niamh McAuley, Harmony Black, Omar Abdelzaher, Catherine Duane, Tatiana Cichocka, Eva Szegezdi, Meegahage Perera, Gerard M. Crotty, Michelle Connolly, Aileen Walsh, Ruth Clifford, Janusz Krawczyk, Teresa Meenaghan, Vitaliy Mykytiv, Ezzat Elhassadi, Mark Coyne, Robert J. Cummins, Rowan Kuiper, Michael O'Dwyer, Siobhan V. Glavey ABSTRACT
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.