Ultra high-risk myeloma can be defined as myeloma leading to death within 24 months. Despite tremendous improvements in the past decade (especially because of the availability of novel drugs such as thalidomide, bortezomib, and lenalidomide), these patients still represent 15% to 20% of the patients. Many prognostic factors can help to define these patients, including age, renal insufficiency, poor performance status, comorbidities, International Staging System (ISS) stage 3, high proliferation, leukemic presentation, and acquired genetic changes, as defined by interphase fluorescence in situ hybridization or genomics. Several combinations of these prognostic parameters can define ultra high-risk patients, making a universal therapeutic proposal almost impossible. However, focusing on fit patients with ISS 3, high proliferation, and poor-risk genetic changes, these patients should probably benefit from dose-dense and prolonged therapeutic schemas, ideally within prospective trials.