OBJECTIVES: The aim of this study was to investigate the cost-effectiveness of bortezomib, melphalan and prednisone with daratumumab (D-VMP) versus bortezomib, melphalan and prednisone (VMP) in patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for autologous stem-cell transplantation (ASCT). METHODS: A Markov model was established and three exclusive health states, progression-free survival (PFS), progressive disease (PD) and death were included. The cycle length was set at 1.5 months and the time horizon was set at 20 years. The efficacy data were derived from the ALCYONE trial, and the utility values were obtained from previously published studies. The discount rate in the model was 3% per annum, and the willingness-to-pay (WTP) threshold was set at 50 000.00/quality-adjusted life year (QALY) in the USA. Moreover, one-way and probabilistic sensitivity analyses were performed to evaluate the parameter uncertainty. RESULTS: D-VMP achieved an effectiveness of 6.91 QALYs at a cost of 58 695.42, while VMP achieved an effectiveness of 4.70 QALYs at a cost of 57 387.82. The incremental effectiveness and cost of D-VMP versus VMP were 2.21 QALYs and 01 307.6, yielding an incremental cost-effectiveness ratio (ICER) of US 26 836.02/QALY. The cost of daratumumab, utility for PFS, cost of subsequent therapies in the VMP group and cost of subsequent therapies in the D-VMP group were the most influential factors, and the probabilities of D-VMP and VMP as the cost-effective option were 0% and 100% at the WTP threshold of 50 000.00/QALY, respectively. CONCLUSIONS: Compared with VMP, D-VMP is unlikely to be a cost-effective regimen for patients with NDMM who are ineligible for ASCT from the US payer's perspective.