Risk factors and their contributions to prognosis in multiple myeloma

Despite improvements in clinical outcomes for multiple myeloma (MM), some patients still experience short survival, and identifying high-risk (HR) MM patients early remains a substantial challenge. In this study, we collected recently published International Myeloma Society (IMS) / International Myeloma Working Group (IMWG) recommendation and four additional risk factors of diverse nature (APOBEC mutational activity, chromothripsis, EMC92 gene expression signature, proliferation index (PR)) and examined their predictive utility on CoMMpass data. All factors were highly associated with survival even when the treatment heterogeneity in CoMMpass data was adjusted. 27% of the patients harbored the IMS/IMWG lesion, but only 21% of them were implicated uniquely by it. As a whole, 68% of the patients harbored HR lesions, 62% of them with multiple lesions. "Multi-hit" effect was profound with median survival reduced drastically while the hazard ratio (HzR) increased sharply from single to quadruple-or-more HR factor inflicted groups compared with those without any HR lesions. The concordance, C-statistic, of patient's risk prediction starting from a baseline model with patient age and sex (C=0.63) increased slightly to C=0.65 with IMS/IMWG factor only but improved further to C=0.72 with additional HR factors. Interestingly, EMC92 turned out essential in the reliable prediction of a patient's risk of overall survival. Most functional high risk (FHR) patients also harbored additional HR lesions although a quarter of them were free of other lesions but still had very poor outcomes. These results provide a solid rationale for expanding HR factors beyond IMS/IMWG recommendation utilizing diverse genomic technologies.