PURPOSE OF REVIEW:Bortezomib-based combinations are being investigated in relapsed or refractory multiple myeloma with the aim of improving outcomes. This review presents recent data from clinical trials of these combinations and discusses their implications. RECENT FINDINGS:Preclinical findings indicating additive or synergistic activity of bortezomib plus conventional and novel agents for multiple myeloma appear to be supported by clinical studies of bortezomib-based combinations. Bortezomib combined with a broad set of active agents results in enhanced response rates, including high complete response rates. Encouraging responses to bortezomib and its combinations are also seen in elderly patients, patients with adverse prognostic factors such as refractory disease and increased beta2-microglobulin, patients with cytogenetic abnormalities such as chromosome 13 deletion, advanced bone disease, extramedullary involvement, and patients with renal impairment, including patients with renal failure requiring dialysis. Toxicities are predictable and manageable and comparable to those seen with bortezomib monotherapy. SUMMARY:Bortezomib-based combinations show promising activity in relapsed or refractory multiple myeloma, including reversal of chemoresistance to previously used agents. As high complete and overall response rates translate into longer survival, bortezomib-based combinations appear likely to have a significant impact on the multiple myeloma treatment algorithm and on the course of the disease itself.