CO25 | P53 isoform diversity in multiple myeloma: unexplored risk factor beyond TP53 mutation and del(17p)

Introduction. In multiple myeloma (MM), TP53 abnormalities (deletions/mutations) confer high-risk disease. Beyond full-length p53 (p53FL), alternative isoforms modulate p53 activity and cellular stress responses, but their expression patterns and clinical impact remain largely unexplored. Defining isoform-specific biology may refine risk stratification and enable personalized therapy.Aim. To enhance MM risk stratification by integrating p53 isoforms expression profiles, improving prognostic accuracy, identify novel molecular subgroups, and ultimately supporting tailored therapeutic strategies.Patients and Methods. RNA-sequencing data from 659 newly diagnosed MM patients (pts) (CoMMpass) were analysed for major p53 isoforms. Expression levels were classified as absent, low, or high using median-based cut-offs. Associations with genomic features, treatment response and survival outcomes were evaluated. Isoform expression was combined with cytogenetic risk to define novel prognostic categories.Results. p53FL and p53β were widely expressed (95% and 99%), while p53γ, Δ40p53α and Δ133p53α/β showed heterogeneous patterns. High p53FL often co-occurred with high p53β and Δ133p53α, while absence of Δ133p53β was enriched in pts with high p53FL/p53β, suggesting functional interactions among isoforms. Del(17p) was detected in 10.8% of pts and associated with lower p53FL/p53β expression (p