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ABSTRACT Introduction Multiple myeloma (MM) is plasma cell dyscrasia with marked variability in its clinical presentation and outcome, both of which are dictated by its underlying genetics. Next-generation sequencing techniques (NGS) have become essential to understanding the genomics of multiple myeloma. The exploitation of these advances in the clinic will require new clinical trial designs with endpoints that facilitate rapid readouts of success or failure and capture the impact of rare mutational events on outcomes. An understanding of NGS and its applications in multiple myeloma is therefore significant for both researchers and clinicians alike. Areas covered In this review, we summarize the significant advances that NGS has yielded in our understanding of the prognosis, clonal evolution, treatment and response assessment of multiple myeloma and its precursor conditions. We synthesize the relevant literature related to both genomics and the clinical management of MM, with articles selected based on our experience in the field. Expert opinion In the opinion of these authors, NGS will play a significant role in the future of precision medicine in multiple myeloma, especially as disease-specific panels and response adapted approaches to therapy gain traction. In the process, challenges related to cost, quality control, and standardization will need to be overcome.