OBJECTIVES: In this study a comprehensive assessment of the cost-effectiveness of lenalidomide-plus-dexamethasone compared to dexamethasone, as second-line or greater than second-line therapy in relapsed/refractory multiple myeloma (rrMM) patients was performed, from the perspective of the South Korean National Health System. METHODS: A Markov-type model was designed to assess the long-term costs and effectiveness of lenalidomide-plus-dexamethasone and dexamethasone, using patient-level data from the MM-009/MM-010 randomized controlled trials. Due to potential crossover-induced bias by subsequent therapies, overall survival (OS) was estimated using a quantitative relationship between progression-free-survival and OS (censored normal weighted Tobit regression model, based on 153 MM studies containing 230 treatment arms). Only direct costs were considered (drugs, adverse events and disease monitoring). Effectiveness was measured in life years (LY) and quality-adjusted life years (QALY). Costs were converted to United-States dollars (1USD=1,071.33WON). Annual discount rates were set at 5% for costs and effectiveness. Probabilistic sensitivity analysis (PSA) was conducted with Monte Carlo simulations. RESULTS: For the patient population with one previous therapy lenalidomide-plus-dexamethasone is estimated to add substantial benefits to dexamethasone, with expected gains of 1.83QALY and 2.50LY, offset by a mean incremental cost of $55,387. Corresponding incremental cost-effectiveness ratios are estimated at $30,195/QALY and $22,148/LY. PSA revealed a >95% probability of lenalidomide-plus-dexamethasone being cost-effective in comparison to dexamethasone at a $40,000 threshold. These results are robust against sensitivity analyses in turns of patient sub-populations and different crossover correction techniques (simulated treatment comparison; rank preserving structural failure time models). CONCLUSIONS: Lenalidomide-plus-dexamethasone can be regarded a valuable treatment option for second or greater line therapy in rrMM patients.