A disulfidptosis‐related gene signature predicts prognosis and immune‐metabolic landscape in multiple myeloma

Summary Disulfidptosis is a newly recognized cell death induced by disulphide stress under glucose deprivation. However, its clinical implications in multiple myeloma (MM) remain largely unexplored. We identified disulfidptosis‐related genes via co‐expression analysis and developed a risk signature through univariate Cox, least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses. The model was internally and externally validated for overall survival prediction. Downstream analyses included functional enrichment, tumour mutation burden (TMB), tumour microenvironment (TME) characterization and immune‐metabolic profiling. Preliminary in vitro validation was conducted with PLEC ‐knockout KMS‐11 cells under glucose deprivation. A nine‐gene signature was established and validated, showing robust prognostic performance across cohorts. High‐risk patients displayed proliferative profiles, higher TMB, an immunosuppressive TME with neutrophils, eosinophils and exhausted T cells and activation of glycolysis and cystine/glutathione metabolism. This signature defines an aggressive MM subtype likely unresponsive to immune checkpoint therapy. Functional assays confirmed that PLEC mediates actin disulphide cross‐linking during metabolic stress. We present a novel disulfidptosis‐related gene signature with independent prognostic value in MM, offering insights into the molecular and immune landscape of MM and serving as a useful tool for risk stratification and therapeutic suggestion.