OBJECTIVES:  To perform an adjusted comparison of overall survival (OS) for daratumumab monotherapy versus physician’s choice [PC]) as observed in a real-world historical control cohort from Czech Republic, using patient-level data. METHODS:  Patient-level data were pooled from daratumumab monotherapy clinical studies (patients treated with 16 mg/kg in the SIRIUS/GEN501 studies) and from the Czech Registry of monoclonal gammopathies (RMG), representing treatments observed in real-world cohort collected of MM-patients with at least 2 prior therapy lines and/or double refractory to a PI and an IMiD from 18 centres. For the Czech cohort, longitudinal follow-up in subsequent treatment lines was available for patients in 3^rd (n=206), 4^th (n=256), 5^th (n=203), and 6^th+ (n=307) lines; individual patients could contribute information to the analysis for multiple lines of therapy, with baseline defined as the date of initiation of the actual treatment line. A multivariate proportional hazards regression model was developed to compare OS between treatments, including age, gender, B2M, albumin, line of therapy, refractory status and prior pomalidomide/carfilzomib-exposure as co-variates. RESULTS:  Patients treated with daratumumab (N=148) and the CZ cohort (N= 463) differed in median age (64 vs. 62), median prior therapy lines (5 vs. 4), prior exposure to carfilzomib (41.2% vs 0.3%) and pomalidomide (55.4% vs 0.6%) and >=triple refractory status (64.2% vs. 5.3%). Median OS) for the DARA-patients was 20.1 [95% confidence interval: 16.6-NE] months versus 11.9 [11.2 - 13.1] months in the Czech database. The adjusted OS-HR for daratumumab versus PC was 0.35 [0.22-0.56] (versus unadjusted HR of 0.61 [0.48-0.78]). Impact of adjustment was mainly driven by refractory status and prior pomalidomide/carfilzomib-exposure. CONCLUSIONS:  This adjusted treatment comparison suggests improved OS for daratumumab compared to real-world historical control data in heavily pre-treated/refractory MM patients. Such comparisons can provide useful insights to clinicians and reimbursement-decision makers on relative treatment efficacies in the absence of head-to-head comparison studies.