OBJECTIVES: Published cost-effectiveness evidence on the various treatments used for relapsed or relapsed and refractory multiple myeloma (R or RRMM) has not been explored in a systematic literature review (SLR). We therefore investigated this topic using such an approach.  METHODS: We searched MEDLINE, EMBASE, The Cochrane Library and EconLit databases for English-language economic evaluations of pharmaceuticals for directly managing R or RRMM published after 2003. Publication quality was assessed using standard Drummond criteria. RESULTS: Overall, 14 publications on nine primary economic models met the inclusion criteria. These involved comparisons between lenalidomide + dexamethasone and dexamethasone (n=3) and between lenalidomide +/- dexamethasone and bortezomib (n=7), of which some compared all these options (n=2); and between bortezomib and best supportive care (n=1). The studies varied in their geographical focus and economic perspective and, accordingly, the willingness-to-pay thresholds used. Bortezomib was cost-effective compared with dexamethasone in Sweden (moderate-quality study) and the United Kingdom (UK; abstract-only data), but neither study reported the perspective used. From a UK payer’s perspective, lenalidomide + dexamethasone was cost-effective compared to dexamethasone (but only 50% of the time in a probabilistic sensitivity analysis). Comparisons between lenalidomide + dexamethasone and bortezomib had varied results. Lenalidomide was dominant to bortezomib in a model for Russia (abstract-only data) and lenalidomide + dexamethasone was cost-effective compared with bortezomib in studies for Portugal (societal perspective; abstract-only data), Greece (payer’s perspective; high-quality study) and Norway (payer’s perspective; moderate-quality study). However, bortezomib was dominant to lenalidomide + dexamethasone in evaluations for Sweden (moderate-quality study) and the UK (abstract-only data), with neither clearly reporting the perspective used. CONCLUSIONS: The published cost-effectiveness evidence on lenalidomide versus bortezomib – the two most commonly used drugs for R or RRMM – is inconsistent. Our review suggests that none of the drugs available for this population represent an economically dominant option.