INTRODUCTION: The treatment of multiple myeloma (MM) remains a challenge as patients eventually progress through several lines of therapy (LOTs), requiring use of multiple MM drug classes. In this retrospective US claims-database study, we examined the healthcare costs of patients with MM who received ≥ 4 prior LOTs, including triple-class exposure (TCE). METHODS: Adult patients with MM were selected from the IBM MarketScan Commercial and Medicare claims databases (1 January 2012-30 June 2021). Eligible patients were required to have received at least four prior LOTs, and TCE (i.e., received a proteasome inhibitor, immunomodulatory drug, and anti-CD38-targeted monoclonal antibody) after the first-observed diagnosis of MM. The index date was defined as the initiation date of the first subsequent LOT after meeting the eligibility criteria for the study, and this date had to be after 1 January 2017 to capture contemporary cost estimates. The primary outcome measurements were all-cause and MM-related healthcare costs after the index date. RESULTS: The study population included 68 patients with MM (63% men), with a mean age of 59.8 years. Mean duration from first-observed MM diagnosis until index date averaged 46.7 months. During a mean follow-up of 21.9 months, total all-cause healthcare costs averaged US$757,386 per patient (equivalent to US$34,610 per patient per month). MM-related healthcare costs (US$670,561 per patient) contributed on average 88.5% to the total all-cause healthcare costs; the majority (67.2%) of MM-related healthcare costs were attributed to drug and infusion costs (US$450,952 per patient). CONCLUSIONS: In this retrospective US claims-database study, patients with MM with ≥ 4 prior LOTs, including TCE, continued to experience high healthcare costs that were mostly attributable to anti-myeloma drugs and their administration.