Bortezomib has significantly increased the response rates in multiple myeloma (MM), but optimal bortezomib-based regimens for initial MM therapy have not yet been defined. We retrospectively compared the outcomes of 128 patients newly diagnosed with symptomatic MM who received either bortezomib combined with dexamethasone (PD) or three-drug combinations of PD with liposomal doxorubicin (PAD) or thalidomide (PTD). The overall response rate (ORR), very good partial response (VGPR) rate, and complete remission CR/near-complete remission (nCR) results were better for the PAD and PTD regimens than for the PD group. Three-year overall survival (OS) was 80.1%, 72.5%, and 61.8% with PAD, PTD, and PD regimens, respectively. The 3-year OS rate of PAD and PTD was significantly higher than that of PD (80.1% vs 61.8%, P=0.024; 72.5% vs 61.8%, P=0.035), but the difference was not statistically significant between PAD and PTD (80.1% vs 72.5%, P=0.843). Similarly, the PAD and PTD regimens resulted in significantly superior 3-year progression-free survival (PFS) rates. The patients in the PTD arm were more frequently observed with grade 1-3 peripheral neuropathy (PN), compared to those in the PAD and PD groups, especially grade 2-3 PN. PN developed less frequently without sacrificing the efficacy when bortezomib was administered subcutaneously rather than intravenously. Our experience suggests that the three-drug combinations PAD and PTD produce a better outcome than PD, especially with respect to PAD, with fewer adverse events.