Prof Keith Stewart (Mayo Clinic, Scottsdale, USA) chairs a discussion with Prof Gareth Morgan (The Royal Marsden Hospital, London, UK), Dr Leif L. Bergsagel (Mayo Clinic, Scottsdale, Arizona), and Prof Antonio Palumbo (University of Torina, Torina, Italy) at Myeloma 2014, about the treatment of myeloma. They discuss the clinical implications and strategies to overcome clonal heterogeneity, genomics and practice, early treatment, immune based therapy, and new insights in IMiD drug sensitivity and resistance.