Background: MM patients undergo several lines of treatment (LOT), mainly involving ≥1 proteasome inhibitor (PI), immunomodulatory (IMiD), and novel agents such as daratumumab (dara). Research is underway to address the need of patients previously exposed to a PI, an IMiD, and dara (triple-exposed). This retrospective cohort analysis assessed costs and healthcare resource (HR) utilization in triple-exposed patients. Methods: A pooled cohort of patients from Optum’s Humedica Electronic Health Records and Clinformatics claims data with an index MM diagnosis between 2008-2018 and who 1) had ≥12 months of activity/insurance coverage prior to index MM diagnosis, 2) did not have any other cancer during this period, 3) were aged ≥18 years at index diagnosis, 4) were triple exposed and 5) had ≥1 LOT subsequent to triple-exposure were studied. Costs per LOT after triple-exposure, broken down into cost categories, were analyzed in patients from Optum claims data (N = 94), while HR utilization (hospitalization, ER/outpatient visits, lab tests and MM drugs) was analyzed in the pooled cohort (N = 517). Descriptive statistics are reported. Results: 53% of patients were male; mean follow-up was 8.9 months (272 days). At LOT1 following triple-exposure, mean age was 68 yrs, mean time from index MM diagnosis was 37 months, and median prior LOTs were 4. 50% were penta-exposed (2 PIs + 2 IMiDs + dara) following triple exposure. 42% received a pomalidomide-containing regimen in LOT1 after triple-exposure. 56% of patients had ≥2 LOTs after triple-exposure; 28% had ≥3. Mean duration of LOT1, LOT2, and LOT3 in claims data patients was 132, 102 and 101 days, respectively, with associated mean cost per LOT of $165,453, $131,759, and $116,915. Over the follow-up, patients had a mean of 1.75 hospitalizations, 0.92 ER visits, 32.1 outpatient/office visits and 28.8 lab tests; post triple-exposure mean cost per patient per month was $38,214 (Table). Conclusions: Substantial MM drug costs, inpatient stays and frequent outpatient visits contribute to high cost per month of post triple-exposure treatment, underscoring the need for effective MM treatments with durable response.