Multiple myeloma (MM) is characterized by notable inter-patient and intra-clonal heterogeneity that is gradually decoded over the last decade. Despite the deeper and better understanding of its biology and the development of novel therapeutic strategies that have prolonged overall survival, MM still retains a poor prognosis in patient subgroups with certain high-risk features. Areas covered: This article summarizes currently identified features that stratified patients in high-risk myeloma with impaired prognosis and discusses available therapeutic options that may partially overcome the impact of these adverse factors in patients' outcome. Numerous molecular and genetic assays such as detection by fluorescent in situ hybridization (FISH) of cytogenetic aberrations, gene expression profiling, minimal residual disease assessment by flow cytometry, or next-generation sequencing as well as novel imaging modalities such as magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT) have considerably increased available tools for recognizing in advance patients with unfavorable outcome. In parallel, many novel agents, particularly in combination treatments, have significantly improved the natural evolution of high-risk disease. Expert commentary: Moving forward to the same direction, a more accurate identification of patients with high-risk MM will allow a more individualized and intensive approach in their management directly after diagnosis.