High-quality response to multiple myeloma (MM) therapy can be predictive for improved outcomes. Novel agents may improve the depth of responses and therefore prolong survival. We report on the extended follow-up of a phase II study in frontline MM of bortezomib alone and in combination with dexamethasone. Forty-nine previously untreated, symptomatic MM patients received bortezomib 1.3 mg/m(2), days 1, 4, 8, 11, for up to six 3-week cycles. High-dose dexamethasone was added for patients not reaching either a partial response after cycle 2 or a complete response (CR) after cycle 4. The overall response rate in 48 evaluable patients was 90%, with 42% achieving at least a very good partial response, of which 19% were CR/near CR. Thirty-six patients received high-dose dexamethasone with 28 (77%) showing improved response. Twenty-seven patients have undergone successful stem-cell transplantation (SCT). After median follow-up of 49 months, 15 patients have died; median overall survival has still not been reached, with an estimated survival at 4 years of 67%. Overall survival with and without SCT was not different (P = 0.54). Grade 3/4 adverse events included neutropenia (10%), sensory neuropathy (6% grade 3), neuropathic pain (4% grade 3), and diarrhoea (4% grade 3). Bortezomib +/- dexamethasone is an effective and well-tolerated induction regimen for the frontline treatment of MM.