Because interleukin-6 (IL-6) is considered important in the proliferation of early multiple myeloma (MM), we hypothesized that the addition of the anti-IL-6 monoclonal antibody siltuximab to the bortezomib-melphalan-prednisone (VMP) regimen would improve outcomes in transplant-ineligible patients with newly diagnosed MM. One hundred and six patients were randomized to receive 9 cycles of VMP or VMP plus siltuximab (11 mg/kg every 3 weeks) followed by siltuximab maintenance. Baseline characteristics were well balanced except for immunoglobulin A subtype and 17p deletions. With a complete response (CR) rate of 27 on siltuximab plus VMP (S+VMP) and 22 on VMP, the study did not confirm its hypothesis that the addition of siltuximab would increase the CR rate by at least 10 . Overall response rate was 88 on S+VMP and 80 on VMP, and at least very good partial response rates were 71 and 51 (P 5 .0382), respectively. Median progression-free survival (17 months) and 1-year overall survival (88 ) were identical in the 2 arms. Grade =3 adverse-event incidence was 92 on S1VMP and 81 on VMP ( P = .09), with trends toward more hematologic events and infections on S+VMP. Maintenance therapy with siltuximabwaswell tolerated. In conclusion, the addition of siltuximab toVMPdid not improve theCRrate or long-term outcomes. This study was registered at http://clinicaltrials.gov as NCT00911859. ? 2014 by The American Society of Hematology.