The remarkable genetic heterogeneity of Multiple Myeloma (MM) poses a significant challenge for proper prognostication and clinical management of patients. Accurate dissection of the genetic and molecular landscape of the disease and the robust identification of homogeneous classes of patients are essential steps to reliable risk stratification and the development of novel precision medicine strategies. Here we introduce MM-PSN, the first multi-omics Patient Similarity Network of newly diagnosed MM. MM-PSN has enabled the identification of three broad patient groups and twelve distinct sub-groups defined by five data types generated from genomic and transcriptomic patient profiling of 655 patients. The MM-PSN classification uncovered novel associations between distinct MM hallmarks with significant prognostic implications and allowed further refinement of risk stratification. Our analysis revealed that gain of 1q is the most important single lesion conferring high risk of relapse, and its association with an MMSET translocation is the most significant determinant of poor outcome. We developed a classifier and validated these results in an independent dataset of 559 pts. Our findings suggest that gain of 1q should be incorporated in routine staging systems and risk assessment tools. The MM-PSN classifier is available as a free resource to allow for an easy implementation in most clinical settings. ### Competing Interest Statement The authors have declared no competing interest.

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