Although therapeutic strategies have been adapted to age and comorbidities of myeloma patients for a long time, all patients currently experiment the same treatment whatever their genomic risk. However, high-risk patients should benefit right now from the most efficient drugs combinations. Herein, we review and discuss how to optimally define risk to adapt treatment and why a modern multiparametric definition of genomic risk is urgently needed. Minimal residual disease status will probably also take a growing place in patient's management, including in treatment adaptation. We also discuss how next-generation sequencing will definitively represent an essential tool to manage risk-based therapeutic strategies. Finally, despite an explosive knowledge of myeloma molecular landscape, targeted therapy perspectives remain poor, with only few exceptions.