Understanding the mechanisms of drug resistance in multiple myeloma (MM) is vital in order to improve treatment. In this comprehensive discussion, the genomics, proteomics and signatures of therapy resistance in MM are covered, in addition to proteasome inhibitor, IMiD and CD38 resistance. Sagar Lonial, MD, of the Winship Cancer Institute of Emory University, Atlanta, GA, chairs a discussion with Brian Van Ness, PhD from the University of Minnesota, Minneapolis, MN, Florian Bassermann, MD, PhD, from the Technical University of Munich, Munich, Germany, and Anja Seckinger, MD, of the University of Heidelberg, Heidelberg, Germany. This video was recorded at the Myeloma 2018 meeting, held in San Diego, CA.