There exists a need for effective salvage regimens for multiple myeloma patients being considered for reduced-intensity allogeneic hematopoietic SCT (RI-alloHSCT). We developed EPOCH-F, a regimen consisting of infusional etoposide, VCR and adriamycin with prednisone, CY and fludarabine to achieve both tumor control and host lymphocyte depletion to facilitate engraftment before RI-alloHSCT. In all, 22 multiple myeloma patients were treated with EPOCH-F before RI-alloHSCT. The median age was 53 years (range 36-65), and the median number of previous therapies was 2 (range 1-8). Patients received a median of three cycles (range 1-5) of EPOCH-F. Toxicities were primarily hematologic and manageable. Median lymphocyte counts decreased from 1423/μL (range 335-2788) to 519/μL (range 102-1420; P=0.0002). The overall response (≥PR) to EPOCH-F was 22 with 13% achieving a CR/near-complete response (nCR); only 1 patient progressed while on therapy. A total of 20 patients underwent RI-alloHSCT. Median day +100 donor chimerism was 100% (range 60-100). In all, 70% of patients achieved very good partial response or better response after transplant; 40% of patients achieved CR/nCR. TRM at 100 days and 5 years was 5 and 30%, respectively. Median OS after RI-alloHSCT was 46.1 months. EPOCH-F provides disease control and host lymphocyte depletion with consistent full donor engraftment in multiple myeloma patients undergoing RI-alloHSCT.