The full potential of a graft-versus-myeloma effect after allogeneic hemato-poietic cell transplantation (HCT) for patients with multiple myeloma (MM) has not been realized because of excessive early transplantation-related mortality (TRM) with conventional HCT. Autolo-gous HCTs have been characterized by almost universal disease recurrences. The current trial combined autologous HCT with subsequent nonmyeloablative alloge-neic HCT to maintain the benefits of both approaches with acceptable toxicity. Fifty-four patients, 52 years of age (median; range, 29-71 years), with previously treated stage II or III MM (52% refractory or relapsed disease) were given melpha-lan 200 mg/m 2 and autologous HC transplants. Regimen-related toxicities after autologous HCT were moderate with a median of 6 days of neutropenia, 7 days of hospitalization, and 1 death from infection. Forty to 229 days later (median, 62 days), 52 patients received a single fraction dose of 2 Gy total body irradiation and HC transplants from HLA-identical siblings with postgrafting immunosup-pression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Patients experienced medians of 0 days of hospitalization , neutropenia, and thrombocytope-nia. Sustained engraftment was uniform. With a median follow-up of 552 days after allografting, overall survival is 78%. One patient (2%) died before day 100 from disease progression. Thirty-eight percent of patients developed acute graft-versus-host disease (GVHD; grade II in all but 4 cases) and 46% chronic GVHD requiring therapy. Tumor responses occurred slowly. Thus far, 57% of patients have achieved complete remissions and 26% have achieved partial remissions for an overall response of 83%. Despite being evaluated in elderly patients with MM, this 2-step approach has reduced the acute toxicities of allogeneic HCT while achieving potent antitumor activities. (Blood. 2003;102:3447-3454) Introduction High-dose therapy with autologous hematopoietic cell transplanta-tion (HCT) for advanced-stage myeloma in patients younger than 65 years of age has survival advantages compared with conventional therapy. 1,2 In the Intergroupe Francais du Myélome (IFM) 90 trial, the complete remission (CR) rate was higher and the 7-year event-free survival (EFS) 16% and overall survival (OS) 43% compared with 8% and 25% with conventional chemotherapy, respectively. 1,3 The use of tandem autografts is also superior to standard chemotherapy 4 and may be better than a single autograft. Recent data from the IFM94 trial, published in abstract form, comparing single dose of 140 mg/m 2 melphalan (Mel 140) plus total body irradiation (TBI; 8 Gy) versus tandem Mel 140 followed by Mel 140 TBI (8 Gy) in 399 patients found a similar CR rate of 34% versus 35% but 7-year EFS of 10% versus 20% and 7-year OS of 21% versus 42% favoring the tandem transplant arm. 3 Despite high response rates and relatively low transplantation-related mortality (TRM) of less than 10%, fewer than 30% of patients remain in remission 3 to 7 years later. 5-13 The high ...