OBJECTIVES: Lenalidomide (LEN) and bortezomib (BORT) are both effective for the treatment of relapsed/refractory MM. The former is administered 25 mg/day orally on days 1-21 of repeated 28-day cycles.  The latter as a 1.3 mg/m2 intravenous dose on days 1, 4, 8 and 11 for eight, three week cycles.  Currently, there are no data from head to head randomized trials comparing LEN and BORT.  In the absence of such data, an indirect comparison between LEN and BORT was performed in the relapsed/refractory MM setting.  Such an analysis was feasible because comparable controls were used in the pivotal randomized trials and patients had similar baseline characteristics. METHODS: Three pivotal randomized trials with LEN (n=2) and BORT (n=1) in the relapsed/refractory setting were identified. Patients within each trial had similar disease characteristics.  Data in terms of response rate (RR), time to progression (TTP) and overall survival (OS) were extracted from the pivotal trials.  An indirect statistical comparison between LEN and BORT was then performed on these endpoints using the method of Bucher et al. (1997), which partly maintains the benefits of randomization on the magnitude of benefit.  RESULTS: The analysis identified significant differences in efficacy between these drugs.  Patients treated with LEN were significantly more likely to achieve a disease response (OR=1.92; 95%CI: 1.15 - 3.20) and to have a prolongation in TTP (HR = 0.64; 95%CI: 0.44 - 0.91).  The analysis also identified a trend for an OS benefit in patients receiving treatment with LEN over BORT (HR = 0.71; 95%CI: 0.46 - 1.11). CONCLUSIONS: Keeping in mind the caveats associated with cross trial comparisons, the analysis suggested increased effectiveness of LEN over BORT in MM patients with refractory/relapsed disease.  These findings, along with its oral route of administration and established safety profile suggest that LEN should be the preferred agent for refractory/relapsed MM.