A Novel Necroptosis-Related Signature Can Predict Prognosis and Chemotherapy Sensitivity in Multiple Myeloma.

ABSTRACT

BACKGROUND: Necroptosis is an inflammatory cell death mode, and its association with multiple myeloma (MM) remains unclear. METHODS: This prospective study first analyzed the association between necroptosis-related signature as well as prognosis and chemotherapy sensitivity in MM using the necroptosis score. Consensus clustering was used to identify necroptosis-related molecular clusters. Least absolute shrinkage and selection operator analysis and multivariate Cox regression analysis were performed to establish the prognostic model of necroptosis-related genes (NRGs). RESULTS: A high necroptosis score was associated with poor prognosis and abundant immune infiltration. Two molecular clusters (clusters A and B) significantly differed in terms of prognosis and tumor microenvironment. Cluster B had a worse prognosis and higher tumor marker pathway activity than cluster A. The risk score model based on four NRGs can accurately predict the prognosis of patients with MM, which was validated in two validation cohorts. Receiver operating characteristic curve analysis showed that the area under the curves of the risk score in predicting the 1-, 3-, and 5-year survival rates were 0.710, 0.758, and 0.834, respectively. Further, the activity of pathways related to proliferation and genetic regulation in the high-risk group significantly increased. The drug prediction results showed that the low-risk score group was more sensitive to bortezomib, cytarabine, and doxorubicin than the high-risk score group. Meanwhile, the high-risk score group was more sensitive to lenalidomide and vinblastine than the low-risk score group. Finally, the upregulation of model genes CHMP1A, FAS, JAK3, and HSP90AA1 in clinical samples collected from patients with MM was validated via real-time polymerase chain reaction. CONCLUSION: A systematic analysis of NRGs can help identify potential necroptosis-related mechanisms and provide novel biomarkers for MM prognosis prediction, tumor microenvironment evaluation, and personalized treatment planning.