Background Two chimeric antigen receptor-engineered T (CAR T) cell therapy drugs were recently approved for the treatment of patients with relapsed or refractory multiple myeloma (rrMM). Their financial impact, however, is poorly described. Objective The aim was to evaluate the economic burden of CAR T cell therapies ciltacabtagene autoleucel and idecabtagene vicleucel for the treatment of rrMM patients after at least four lines of therapy, and to compare the annual cost of these CAR T cell therapies over a hypothetical 1-million-member health plan from the US healthcare payer perspective. Patients and Methods The annual economic burden of ciltacabtagene autoleucel and idecabtagene vicleucel was estimated using data from pivotal clinical trials. The costs of drug acquisition, administration, and adverse event (AE) management were extracted from the IBM-Micromedex Red Book online, the Centers for Medicare & Medicaid Services fee schedules, and a review of the literature. We used descriptive statistics for the analysis. Results The annual costs (US dollars) of drug acquisition, administration, and AE management per patient were $465,000, $60,167, and $40,368 and $419,500, $61,250, and $47,270 for ciltacabtagene autoleucel and idecabtagene vicleucel, respectively. The total annual cost was higher for ciltacabtagene autoleucel ($565,534) than for idecabtagene vicleucel ($528,020). However, the total annual cost in a hypothetical 1-million-member plan was less with ciltacabtagene autoleucel, by $1.8 million. Conclusion This study found that the CAR T cell gene therapies ciltacabtagene autoleucel and idecabtagene vicleucel for rrMM represent a significant economic burden for healthcare payers in the USA.