Understanding the mutations and whole-genome interactions taking place in multiple myeloma (MM) is crucial for disease understanding and therapy research. In this video, recorded at the 23rd Congress of European Hematology Association (EHA) 2018, held in Stockholm, Sweden, Nikhil Munshi, MD, of the Dana-Farber Cancer Institute, Boston, MA, discusses how his group has used whole genome sequencing to identify two key mutational signals in MM: age-related mutation signatures and DNA repair pathway signatures. He explains how these data were combined with epigenetic analysis and RNA sequencing to explore the impact of these mutations on gene expression, which revealed an impact on transcription. Finally, he touches upon how this information might be used to develop therapies to halt MM progression by targeting such mechanisms.