Despite the superiority of high-dose (compared with standard) treatment in multiple myeloma, relapses still occur. We evaluated relapse patterns, salvage treatments employed and outcome in patients given tandem transplants on our total therapy I protocol. We focused on 146 patients (of 231 enrolled) who received tandem autotransplants < or =12 months apart and survived > or =2 months after the second transplant. With a median follow-up of 9 years after enrollment, 31 (21%) patients remain in complete or stable partial remission. Ninety-five (65%) patients received therapy for relapsing myeloma. The median time from the first transplant to relapse was 2.9 years. The median overall survival from relapse was 2.4 years. In one-quarter (23/95) of cases, the postrelapse interval exceeded the interval from the first transplant to relapse. On multivariate analysis, the presence of any cytogenetic abnormalities [P<0.001, Hazard Ratio (HR): 3.84] and beta-2 microglobulin levels >4 mg/l at relapse (P<0.001, HR: 2.87) were significant for poor survival after relapse. The median survival after relapse was 5.1, 1.3 and 0.7 years in patients with none (44%), one (46%) and two (10%) poor-risk factors, respectively. In conclusion, a sizeable fraction of myeloma patients relapsing after tandem autotransplants without poor-risk features enjoyed meaningful survival prolongation when appropriately treated.