Hyperdiploid multiple myeloma: A heterogeneous entity requiring refined risk stratification-Insights from chromosome...

Hyperdiploidy (HRD) is the most common genetic subtype in multiple myeloma (MM) but with significant prognostic heterogeneity. In this integrated Single Nucleotide Polymorphism (SNP-array) and Fluorescence In Situ Hybridization (FISH) analysis of 694 newly diagnosed Chinese MM patients, a modal chromosome count >49 predicted superior overall survival (OS, p = 0.0062) and progression-free survival (PFS, p = 0.00037), outperforming other metrics. Gain of chromosome 3 was favourable for OS (p = 0.0024) and PFS (p = 0.00078). Notably, HRD improved OS in patients with isolated 1q21⁺ (p = 0.011) but not in those harbouring high-risk abnormalities (t(4;14), t(14;16), 17p^- or 1p32^-). The prognostic value of modal count was cytogenetic abnormality (CA)-dependent: in HRD without high-risk CAs, >49 conferred better OS (p = 0.01) and PFS (p = 0.001); in isolated 1q21⁺, a favourable trend was observed; but no discrimination in other high-risk CAs. Autologous haematopoietic stem cell transplantation (AHSCT) significantly improved OS (p = 0.014) and showed a PFS trend (p = 0.062) only in HRD patients without high-risk CAs and with >49 chromosomes. In conclusion, modal chromosome count >49 and chromosome 3 gain are robust favourable markers in HRD. HRD provides survival benefit in isolated 1q21⁺. FISH-based detection of trisomy 3 may offer a rapid, economical alternative for risk assessment of HRD. AHSCT benefit is restricted to low-risk HRD with higher ploidy.