Background: Daratumumab (Dara) was recently FDA approved for the treatment of relapsed/refractory multiple myeloma (RRMM). We evaluated a real-world single-center experience of Dara salvage therapy for RRMM.Methods: Patients treated at the University of Florida with Dara for RRMM between January 2016 and February 2018 were included. Data was collected by chart review and analyzed for patient demographics, disease characteristics, treatment, and outcomes.Results: 25 patients (13 as monotherapy and 12 in combination) were included, with a median age of 63 (range, 42-86) years. Median time from MM diagnosis to Dara initiation was 51.3 (range, 8.4 -162.3) months. The median duration of Dara therapy was 72 days (range, 7 - 622). The median number of Dara doses was 7 (range, 2- 49). The best response to DARA was Very Good Partial Response (VGPR) in 1 (4%), Partial Response (PR) in 17 (68%), while 7 (28%) had Progressive Disease (PD). Overall Response Rate (ORR) to Dara was 72%. By the end of the study period, another 11 (44%) patients progressed while on DARA with a total of 18 (72%) patients having PD at the time of analysis. Estimated median progression free survival (PFS) after starting Dara was 155 days (95% CI: 21 - 289) and estimated median overall survival (OS) in the entire cohort was 11.7 months (95% CI: 4.2 - 19.2). Post DARA, 1 (4%) patient with VGPR underwent ASCT, while 9 (36%) went on to have other therapies which included HyperCVAD, Melphalan, and clinical trials, and 8 (32%) were treated with only best supportive care.Of 18 patients who had PD, 10 (40%) patients had a progressive extramedullary disease (EMD), of whom 6 (24%) had EMD prior to starting Dara, while another 4 (16%) patients developed new EMD while on Dara. PFS in the EMD cohort was 63 days (95% CI: 23 - 103), which was shorter than patients with no EMD (333 days; 95% CI: 42 - 624) (P= 0.08). Estimated median OS in patients with EMD was 5.4 months while in patients with no EMD was 16.1 months (p =0.16).Conclusions: DARA therapy does have good ORR (72%) in RRMM, however, there was an unusually high incidence of progressive or newly diagnosed EMD in RRMM patients treated with Dara/Dara-containing regimens, suggesting that Dara may not be effective in treating or preventing EMD. Moreover, we noticed patients who have EMD or develop new EMD tends to have worse outcomes. The underlying escape mechanism for EMD remains unknown and warrants further investigation. DisclosuresNo relevant conflicts of interest to declare.