OBJECTIVES: To fully evaluate the potential benefit of novel agents for the treatment of heavily pretreated/refractory patients with multiple myeloma (MM) understanding the outcomes of this patient population based on current real-world experience is important. The objective of this study was to perform an adjusted comparison of patients’ clinical outcomes from daratumumab monotherapy clinical studies versus real-world US data to establish the comparative efficacy of daratumumab versus real-world historical control (physician’s choice [PC]) using patient-level data. In the absence of head-to-head trials, indirect treatment comparisons (ITCs) can provide useful insights to clinicians and reimbursement-decision makers on relative treatment efficacies. METHODS: Patient-level data were available for pooled daratumumab monotherapy clinical studies (patients treated with 16 mg/kg in the MMY2002/GEN501 studies) and pooled US databases (IMS-LifeLink/OPTUM), representing treatments observed in real-world cohort of patients with MM with at least 3 prior therapy lines or double refractory. Pooled daratumumab studies demonstrated median overall survival (OS) of 19.9 [95% confidence interval: 15.1-NE] months versus 7.9 [6.9-8.9] months for the pooled US database (Usmani. Blood 2015:126(23): Abstracts 29/4498). The relative treatment effect of daratumumab versus PC was estimated using a multivariate proportional hazards regression model, including age, gender, number of prior therapies, albumin, hemoglobin, refractory status, and prior pomalidomide/carfilzomib-exposure as co-variates. RESULTS: Patients treated with daratumumab (N=148) and the US cohort (N=658) differed in median age (64 vs 69), median prior therapy lines (5 vs 4), prior exposure to carfilzomib (41% vs 28%) and pomalidomide (55% vs 15%) and triple/quadruple refractory status (64% vs 14%). The adjusted OS-HR for daratumumab versus PC was 0.32 [0.22-0.46] (versus 0.44 [0.33-0.58] unadjusted). Impact of adjustment was mainly driven by refractory status and prior pomalidomide/carfilzomib-exposure. CONCLUSIONS: In absence of direct evidence, this ITC suggests improved OS for daratumumab compared to real-world historical control data in heavily pretreated/refractory MM patients.