The prognosis of patients with multiple myeloma has significantly improved after the introduction of novel concepts of immunomodulation and proteasome inhibition in myeloma therapies. In conjunction with the use of high-dose therapy and autologous stem cell transplantation, these newer antimyeloma agents facilitated the augmentation of deeper responses and as a result, enhanced survival outcomes. Despite mounting clinical evidence that novel therapies may mitigate the poor prognostic impact of some predictors historically considered “harbingers of doom” in myeloma such as t(4;14), the benefit of these advances is less evident in patients who present with genetically defined high-risk features such as presence of chromosomal abnormalities del17p, t(14;16), or t(14;20), or among patients presenting with plasma cell leukemia. With better understanding of the biology of the disease and further recognition of the genomic instability of the high-risk clonal plasma cell influencing both inherent and acquired therapeutic resistance, newer targeted treatment strategies will hopefully improve prognosis in future among this subset of patients with poorer outcomes. In this review, we not only focus on how to identify the genetically defined high-risk patients with myeloma but also describe the most optimal antimyeloma combination strategies that so far have shown to demonstrate long-term benefits for these patients.