Leif Bergsagel, MD, Mayo Clinic, Phoenix, AZ, and Francesco Maura, MD, Sylvester Comprehensive Cancer Center, discuss genomics of high-risk and smoldering multiple myeloma. Topics cover next-generation sequencing (NGS), del(17p) and TP53 mutations, high-risk factors, controversy surrounding 17P deletion and TP53 mutation, challenges in determining and targeting cancer cells.