Tandem high-dose melphalan therapy with autologous peripheral stem cell support has emerged as the standard of care for patients without prohibitive comorbidities. Mucositis and gastrointestinal side effects are the most common extrahematologic side effects. Two previously published studies presented a triple transplant with a conditioning regimen of melphalan 100 mg/m(2) (MEL100) with peripheral stem cell support every 2 to 5 months for patients with prohibitive comorbidities for high-dose tandem transplantation. We present a novel approach that investigates the triple melphalan 100/m(2) approach on a dose-dense, every-3-weeks schedule in a patient population without significant comorbidities.Thirteen standard or high-risk patients with stage III multiple myeloma were prospectively treated. This population contained eight patients with immunoglobin G clonality, three immunoglobin A, one nonsecretory, and one light chain isotype. The induction regimens of the 13 patients were heterogenous and included five VAD, three DCIE, two Thal/Dex, two CIE, and one pulse decadron. Patients underwent peripheral blood leukopheresis, and these cells were divided into three equal sets and frozen. The patients were scheduled to receive melphalan at 100 mg/m(2) on days 1, 20, and 41, and then the autologous infusions occurred at days 0, 21, and 42.All patients were able to receive all three cycles of the MEL100 regimen. Seven patients (54%) received the treatments on the every-3-weeks schedule; three treatments (23%) during the second cycle and six treatments (46%) of the third cycle had to be delayed a median of 6 and 4 days, respectively. Three patients were managed completely in the outpatient setting, and the average total hospital stay for the three transplants was 18 days. Median progression-free survival was 854 days (range 73 to 1571), and the overall survival of this cohort has yet to be reached. No patient had worse than grade II mucositis, and no serious adverse events were recorded.Our regimen of three consecutive autologous peripheral stem cell transplants with a reduced dose of melphalan at 100 mg/m(2) given every 3 weeks was very well tolerated. The progression-free survival and overall survival are similar and can be compared favorably with the standard tandem myeloma regimens. Our data is intriguing, and further studies with larger numbers need to be performed to confirm these results.