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Between August 1993 and March 2003, 130 consecutive multiple myeloma (MM) patients eligible for high-dose treatment were offered a program including up-front autologous stem cell transplantation (ASCT) after conditioning with 200 mg/m2 melphalan followed by a second ASCT in case of relapse or progression. A total of 107 (82%) patients completed the first ASCT. The best response obtained after ASCT was complete response (CR) 23%, very good partial response (VGPR) 28%, partial response (PR) 42%, and minimal response (MR) 7%. Median overall survival (OS) and event-free survival (EFS) were 65.4 and 27.7 months, respectively. Relapse or progression occurred in 70 patients; 26 received a second ASCT (with a median time of 20.4 months from first ASCT). A major response (≥PR) was obtained in 69% of these patients. Median OS and EFS after the second ASCT were 38.1 and 14.8 months. Treatmentrelated mortality was 1.9% after the first ASCT but no deaths occurred after the second. Our experience suggests that elective up-front single ASCT followed by second ASCT after relapse or progression is a safe and effective global strategy to treat MM patients. Am. J. Hematol. 81:426-431, 2006. © 2006 Wiley-Liss, Inc.