Background: Targeting CD38 in multiple myeloma (MM) using daratumumab-based regimens can prolong remission in both the newly diagnosed and relapsed settings. However clinical trials have excluded patients with creatinine clearances (CrCl) <30 mL/min, warranting real-world analysis of daratumumab use in MM patients with renal insufficiency. Methods: Following IRB approval, we performed a retrospective chart review of relapsed MM patients at our institution who had reduced CrCl and received at least one dose of either daratumumab between October 2018 and January 2022. All subjects received IV daratumumab, 52% went on to receive SQ. Outcomes included change in CrCl during treatment, adverse events, and survival. Survival was estimated using product-limit estimates. CrCl groups at daratumumab initiation of more or less than 30 were compared using the chi-square test or Fisher’s exact test, as deemed appropriate, for categorical variables and the two-sample t-test or Mann-Whitney test for continuous data (SAS Institute Inc., Cary, NC). Results: 101 MM patients were included, with median age of 74 (54-92); 46 (45.5%) were female. 14% were on hemodialysis. Patients had a median of 2 prior lines of therapy. Distribution of R-ISS stages were I (20%), II (35%), and III (45%). High-risk cytogenetics were present in 20%. A median of 23 daratumumab infusions (1-60) were delivered over a median of 18 months (median IV=16, SQ=10). Daratumumab regimens included DRD (32%), DPD (35%), DKD (13%), and DVD (35%). Median CrCl at MM diagnosis and at daratumumab initiation was 45 (7.3-101) and 40 (5.3-107), respectively, with 33% having CrCl <30. Following 3, 6, and 12 months (n = 95, 89, 69) on daratumumab-based regimens, median CrCl were 45, 43, and 41, respectively. There were no differences in renal function in patients who went on to receive SQ daratumumab. 16 patients had died at the time of data collection, and the median survival was 63 months. Of the 101 patients, 16 subjects were deceased at the time of data collection, and 23% of subjects had gone on to subsequent treatments. Analysis showed that there was a progression-free survival of 54% at 5 years. The most common adverse events reported were anemia (37%) and neutropenia (15%). Infusion-related reactions were reported in 19% of patients. Conclusions: This is the largest real-world assessment of outcome for MM patients treated with daratumumab-containing regimens in the setting of renal insufficiency. There was no significant impact of the treatment on renal function at 12 months. Compared to published data on patients treated with CrCl>30, there does not appear to be a detriment to survival or an increase in adverse events when using daratumumab regimens in patients with more advanced renal insufficiency.