Bendamustine is a bifunctional alkylating agent with proven activity in myeloma. In this study 60 newly diag- nosed myeloma patients were given bendamustine plus bortezomib and prednisone in a regimen consisting of one cycle of bortezomib twice weekly for 6 weeks (1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32), plus bendamus- tine (90 mg/m2 on days 1 and 4) and prednisone. The following cycles included bortezomib once weekly. Patients who were transplant candidates proceeded to stem cell collection after four cycles and the transplant was per- formed after six cycles. Patients who were not candidates for transplantation received up to nine cycles. Forty-two patients were transplant candidates and after six cycles, 50% achieved at least a very good partial response, with 24% having complete responses; 35 proceeded to a transplant, and the complete response rate was 54%. Seventeen patients continued up to nine cycles, and 57% achieved at least a very good partial response, including 26% with complete responses. The 2-year progression-free survival and overall survival rates were 62% and 86%, respectively. The safety profile was manageable, but stem cell mobilization was compromised in 35% of patients. In summary, this combination is effective in untreated patients, with an acceptable toxicity profile, but given the introduction of second-generation novel agents and monoclonal antibodies, the combination will probably be bet- ter reserved for relapsing patients, in whom stem cell collection is not needed, while cost-effective combinations with non-cross-resistant drugs continue to represent a medical need. This trial was registered with ClinicalTrials.gov, number NCT01376401.