Bortezomib and melphalan have synergistic effects against multiple myeloma (MM) cells. We conducted a pilot study on the combination of bortezomib and high-dose melphalan (Bor-HDM) as a conditioning regimen followed by autologous stem cell transplant (ASCT) in 17 Japanese patients with newly diagnosed MM, in comparison with a historical control of patients who received high-dose melphalan (HDM) only followed by ASCT. Nine patients received a single dose of bortezomib 1.3 mg/m(2) on day -1 in combination with melphalan 100 mg/m(2) on days -3 and -2 (Bor1-HDM), and eight received two doses of bortezomib 1.3 mg/m(2) on days -4 and -1 (Bor2-HDM) in combination with HDM. Engraftment of autologous peripheral blood stem cells and regimen-related toxicities (RRT) were comparable among the HDM and Bor-HDM groups. Probability of upgrading from a less than very good partial response (VGPR) to VGPR after ASCT was approximately two times higher in the Bor-HDM group than in the HDM group. However, we observed no significant differences in engraftment, RRT, and response rates between the Bor1-HDM and Bor2-HDM groups. The present study showed that concurrent administration of at least two doses of bortezomib in combination with HDM can be safe in Japanese patients. Additional large prospective randomized trials are required to address the optimal dosages and schedules of bortezomib administration, as well as the efficacy of the Bor-HDM conditioning regimen for ASCT.