Bortezomib is a novel proteasome inhibitor that has shown marked antitumor effects in patients with multiple myeloma (MM). We evaluated the feasibility and efficacy of bortezomib plus dexamethasone (BD) therapy and assessed bone metabolism in relapsed or refractory MM. Fourteen patients received 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 along with 20 mg/dose of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 in a 21-day cycle. After 1 to 3 cycles of BD therapy, 9 patients (64%) achieved an objective response (5 very good partial responses and 4 partial responses). Notably, a rapid increase in the serum concentration of alkaline phosphatase (ALP) was observed in 6 of the treatment-responsive patients. Moreover, serum levels of bone-formation markers (bone-specific ALP and osteocalcin) significantly increased in 5 and 2 responsive patients, respectively. Radiographic examination showed improvement in bone lesions, suggesting that BD therapy induces osteoblast activation in responders. Adverse events included thrombocytopenia of grades 1 to 3, peripheral neuropathy of grades 1 to 2, and grade 3 ileus and were transient and manageable. Although severe lung injury has been reported among Japanese patients treated with bortezomib, no pulmonary complications were observed during BD therapy. Our results suggest that BD therapy is a safe and promising therapeutic approach for Japanese patients with MM.