Twenty-seven patients with advanced multiple myeloma received high-dose therapy with 220 mg/m2 i.v. melphalan (HDM220) followed by autologous stem cell transplantation. At the time of HDM220, nine patients had primary refractory disease and 18 were in relapse after having responded to prior high-dose therapy. No toxic deaths were observed. The major adverse side-effect was grade 4 mucositis in 63% of patients. Two patients experienced reversible paroxysmal atrial fibrillation after HDM220. For the whole group of patients, the actuarial 3-year overall survival (OS) and event-free survival (EFS) are 36.1 and 16.9%, respectively. The probability of OS and EFS was significantly lower in patients treated for refractory relapse (22.9 and 0% at 2 years, respectively) as compared to primary refractory patients (66.7 and 64.3% at 2 years, respectively) or patients treated for chemosensitive relapse (42.9% at 2 years) (P = 0.0001). Low β2-microglobulin and CRP levels at the time of HDM220 were associated with a better OS and EFS. Our data suggest that HDM220 followed by ASCT should be considered in patients with primary refractory disease or chemosensitive disease relapsing after prior intensive therapy.