OBJECTIVES: As with many types of cancer, treatment of multiple myeloma (MM) is characterised by sequential treatment lines consisting of innovative expensive drugs such as thalidomide, bortezomib and lenalidomide. While cost-effectiveness of single treatments has been studied, a full disease model evaluating treatments sequentially is currently lacking, consequently, high uncertainty exists on incremental cost-effectiveness ratios. Therefore, we aimed to take a look at the big picture and calculate real-world costs and effects for commonly used treatment pathways for MM. METHODS: We developed a patient-level simulation (PLS) for elderly (>65) MM patients diagnosed since 2004. Real-world data (N=621) including patient and disease characteristics, treatment information as well as resource use was collected from hospital registrations and medical files. Five treatment categories per line were observed resulting in 19 commonly used treatment pathways. Parametric survival models including patient characteristics such as age, performance status, comorbidities and laboratory values were used to predict time to an event, i.e. the start of a new treatment or death. Logistic regression determined which of the two competing events occurred.  The sensitivity of parameters was explored through sensitivity analyses. RESULTS: In total, the costs and effects of 19 treatment pathways were calculated.  Depending on the treatment sequencing, total costs ranged from €40,810 (Melphalan/Prednison-Thalidomide-Other) to €132,613 (Bortezomib-Lenalidomde-Other) while overall survival ranged from 28 to 50 months for Bortezomib-Lenalidomide-Thalidomide and Lenalidomide-Bortezomib-Other, respectively. Costs per quality-adjusted-life-year (QALY) were between €21,881 (Melphalan/Prednison-Thalidomide-Other) and €57,743 (Bortezomib-Lenalidomide-Other). Compared to real-world prescription, QALYs could be increased at a cost of €33,785 per QALY (Lenalidomide-Thalidomide-Other). CONCLUSIONS: The cost-effectiveness of 19 treatment pathways for MM patients was calculated and revealed that real-world treatment could be improved at a cost of €33,785 per QALY. Our PLS model proved to be a reliable and robust approach to study entire treatment pathways for MM.