The achievement of CR is the crucial step for a prolonged PFS and OS after an autologous SCT in multiple myeloma (MM). Unfortunately, even with the use of new regimens and the current high CR rates, most, if not all, patients will ultimately relapse or progress. We analyzed the type of relapse or progression (asymptomatic vs symptomatic), clinical features including the presence of extramedullary involvement and time to next treatment in 211 patients who underwent melphalan-based autologous SCT over an 18-year period at our institution. After autologous SCT, serological or asymptomatic relapse/progression was observed in about one half of the patients. The treatment-free interval was significantly longer in patients relapsing from CR than in those progressing from PR (P=0.017). Patients with serological relapse/progression had a significantly longer OS than those relapsing from symptomatic disease (P=0.002). The relapse pattern was similar to the initial clinical presentation. Survival after relapse/progression was shorter in those patients with a 24-h urine M-protein excretion of at least 200 mg (P=0.048). Extramedullary involvement was frequent (24%), being the highest risk in patients with extramedullary involvement at diagnosis (P=0.001).