OBJECTIVES: Guidelines preferred (category 1) salvage therapies for relapsed/refractory multiple myeloma typically include bortezomib (BTZ) and lenalidomide. Since no randomized controlled trials (RCT) or relative effectiveness assessments comparing both drugs exist a comprehensive assessment of the cost-effectiveness of lenalidomide+dexamethasone (LEN/DEX) was performed in different drug sequencing (≥1 prior vs. 1 prior therapy) using indirect comparison. METHODS: A Markov-type model was designed to assess long-term cost-effectiveness of LEN/DEX vs BTZ (indirect), using patient-level data from the MM-009/MM-010 RCTs (LEN/DEX vs. DEX) and published APEX trial data (BTZ vs. DEX). Due to potential crossover-induced bias, overall survival (OS) was estimated using a quantitative relationship between time-to-progression/progression-free-survival and OS (censored normal weighted Tobit regression model, based on 153 studies containing 230 treatment arms and 22,696 MM patients). The indirect comparison was based on a mixed treatment comparison of time-to-progression from the aforementioned trials. The Portuguese societal perspective was assumed. Effectiveness was measured in life years (LY) and quality-adjusted life years (QALY). Annual discount rates were set at 5%. Probabilistic sensitivity analysis was conducted with Monte-Carlo simulations. RESULTS: LEN/DEX is estimated to add substantial clinical benefits to BTZ. In patients with ≥1 prior therapy incremental LY, QALY and costs with LEN/DEX were 1.1 LY (95%CI: 0.4;2.0), 0.8 QALY (95%CI: 0.3;1.5) and 49,266€ (95%CI: 37,730€;67,342€) and in patients with only 1 prior therapy 1.4 LY (95%CI: 0.4;2.9), 1.1 QALY (95%CI: 0.3;2.1) and 57,293€ (95%CI: 39,303€;84,809€), respectively. Corresponding ICERs (LEN/DEX vs BTZ) ranged from 39,770€/LY to 61,649/QALY. CONCLUSIONS: Lenalidomide plus dexamethasone can be regarded as a cost-effective choice compared to bortezomib monotherapy for relapsed/refractory multiple myeloma patients in Portugal.