Multiple myeloma (MM) is the second most common hematologic malignancy and is characterized by abnormal monoclonal plasma cells in the bone marrow, extramedullary sites, or both (1, 2). In the United States (US), it is estimated that 35,780 new cases of MM will be diagnosed in 2024 and approximately 12,540 MM-related deaths will occur (3). Patients refractory to lenalidomide, often used continuously in front-line regimens, are unlikely to benefit from novel lenalidomide-based triplet chemotherapy regimens (4).

Ciltacabtagene autoleucel (cilta-cel) is a structurally differentiated B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapy (CAR T therapy) that received US Food and Drug Administration (FDA) approval in February 2022 for the treatment of patients with relapsed/refractory (RR) MM who have previously received four or more lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody, based on the results of the CARTITUDE-1 trial (NCT03548207) (5–7).

The follow-up phase III CARTITUDE-4 trial (NCT04181827) evaluated the efficacy and safety of cilta-cel vs. standard of care (SOC) therapy, consisting of either daratumumab, pomalidomide, and dexamethasone (DPd) or pomalidomide, bortezomib, and dexamethasone (PVd), in patients with MM refractory to lenalidomide who had received one to three prior lines of treatment, including a PI and an IMiD (8). Briefly, the CARTITUDE-4 trial was an open-label phase 3 randomized trial conducted at 81 sites in the US, Europe, Asia, and Australia. A total of 419 lenalidomide-refractory patients who had received between one and three lines of treatment for MM were randomized to receiving either a single cilta-cel infusion (n=208) or SOC (DPd [n=183, 87%] or PVd [n=28, 13%]) (8). Among patients assigned to receive cilta-cel, 10 (5.8%) never received cilta-cel as a trial treatment and 20 (9.6%) received cilta-cel after disease progression (8).

Progression-free survival (PFS) was significantly improved following cilta-cel infusion compared with trial SOC after a 16-month median follow-up (hazard ratio [HR], 0.26; P<0.01) (8). Cilta-cel also exhibited superior efficacy over SOC, with an overall response rate (ORR) of 84.6% vs. 67.3% and a complete response (CR) rate of 73.1% vs. 21.8%, respectively (8).

The process of administering cilta-cel involves many steps that are largely not required for SOC. First, patients’ blood is apheresed to collect mononuclear cells. Between the collection of patient cells and infusion of the CAR T product, bridging therapy may be administered if clinically indicated. Cilta-cel admistration is also preceded by lymphodepletion through a 3-day course of cyclophosphamide and fludarabine, as well as antipyretics and antihistamines administration 30 to 60 minutes prior to the infusion (5). Most CAR Ts are administered in the inpatient setting to monitor for the rapid onset of adverse events (AEs). However, cilta-cel’s generally predictable safety profile, including delayed onset of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) [median CRS onset: 7-8 days (9) vs. 1-3 days for idecabtagene vicleucel [ide-cel] and axicabtagene ciloleucel (10–13); median ICANS onset: 8-9.5 days (5, 8) vs. 2-3 days for ide-cel and tisagenlecleucel (10)] facilitates its administration in the outpatient setting compared to other CAR Ts from a clinical and US insurance payer perspective (5, 14, 15). As a result, the administration of cilta-cel in the outpatient setting is expanding (16–19), as it is associated with several benefits including financial savings, expanded treatment access for patients, increased patient comfort, and better alignment with patient preferences who desire a prompt return to normalcy (15, 20, 21).

While the clinical efficacy of CAR T is remarkable, the high upfront cost of acquisition, alongside extensive procedures and facility costs, emphasizes the importance of conducting cost-effectiveness analyses (22). Therefore, this study assessed the value of cilta-cel compared to the CARTITUDE-4 SOC (DPd/PVd) using a cost-per-responder (CPR) model that incorporated efficacy and total treatment costs.

The CPR analysis of data from the CARTITUDE-4 trial indicated that, among patients with lenalidomide-refractory MM, the cost per complete responder and cost per month in PFS with cilta-cel treatment were remarkably lower than those of SOC therapy (DPd/PVd) over 25.4 months. Additionally, cilta-cel treatment resulted in lower total costs per treated patient compared to SOC over the same period.

Cilta-cel treatment resulted in greater total costs pre-progression ($584,189) compared to SOC ($559,851), reflecting the additional resources associated with CAR T-cell therapy administration, including apheresis, bridging therapy, and post-infusion monitoring that are not required for SOC. However, total post-progression costs were substantially lower with cilta-cel treatment ($120,451) compared to SOC ($280,879) during the time period analyzed, due to the greater efficacy of CAR T and associated reduced need for subsequent treatments (8, 40). Indeed, the differentiating attribute of cilta-cel is its impressive response rate relative to other treatments available, which delays progression and helps patients avoid cycling through multiple lines of subsequent therapy (7, 8, 41).

The CAR T-cell infusion setting also impacts cost-effectiveness of treatment, largely due to the high hospitalization costs associated with inpatient monitoring for common post-infusion AEs including CRS and ICANS (16). The improved safety profile of novel CAR T-cell therapies, delayed onset of CRS and ICANS relative to earlier CAR T-cell treatments, and enhanced ability to manage common post-infusion AEs have all increased the interest and feasibility of outpatient CAR T-cell infusion (40). In the current study, a scenario analysis in which 30% of patients received CAR T-cell infusion in the outpatient setting (assuming an outpatient setting of care immediately following the infusion and the same payer mix as the base-case analysis) resulted in a $7,418 reduction in the cost per complete responder relative to the base-case analysis. Similarly, post-treatment costs based on the CARTITUDE-1 trial were estimated over a 12-month period for outpatient cilta-cel administration, with subsequent cost reductions of $2,838 and $5,677 per patient when 15% or 30% of patients received outpatient infusion, respectively (14). This reduced economic burden can be achieved while maintaining safety and efficacy outcomes, with a recent systematic review identifying similar safety and efficacy rates following CAR T-cell infusion in either the inpatient or outpatient setting for patients with MM, lymphoma, or acute lymphoblastic leukemia (16). To note, our study assumed that “outpatient administration” of cilta-cel consisted of one day in the inpatient setting followed by 11 days in the outpatient setting (as opposed to seven days inpatient followed by seven outpatient days for the base-case model). However, the exact distribution of days in the inpatient and outpatient settings associated with an outpatient administration is expected to differ based on several patient-, physician- and facility-specific factors (42). Therefore, the magnitude of the economic benefit of outpatient administration of cilta-cel may also differ accordingly.

While, to the best of our knowledge, no other CPR analysis has been conducted for cilta-cel, an evaluation of CAR T-cell therapy ide-cel, the only other CAR T approved for patients with relapsed or refractory MM, estimated a cost of $1,710,000 per complete responder and $50,000 per month in PFS (43). This may be partially explained by a greater proportion of patients achieving CR or better when on cilta-cel as observed in clinical trials (73.1% at median follow-up time of 15.9 months) (8) than on ide-cel (39% at median follow-up time of 18.6 months) (44). This hypothesis is also supported by a recent matching-adjusted indirect comparison of cilta-cel vs. ide-cel, which found that patients in the cilta-cel group were significantly more likely to achieve complete response or better (response ratio: 1.91 [95% CI: 1.56, 2.34]) and less likely to progress or die than patients in the ide-cel group (HR: 0.51 [95% CI: 0.31, 0.84]) (45).

This study was subject to some limitations, most of which are inherent to cost modeling studies. First, inputs and assumptions used in the study model were based on published literature and therefore may be subject to some level of uncertainty or may not be applicable to all situations. For example, patients receiving cilta-cel were assumed to be consistently seen bi-weekly during the first 112 days and monthly thereafter based on published data (14), but variations of this frequency may occur. In addition, for most AEs (including cytopenias), AE-related costs were based on inpatient costs for these AEs (including costs specific to grade 1-2 and grade ≥3 CRS/ICANS), but some costs for services and treatments received outside of the inpatient setting (e.g., for patients remaining cytopenic for several months and requiring transfusion support) may not be captured. Second, clinical inputs, including PFS, OS, CR, and AE rates, were based on results from the CARTITUDE-4 trial and are not necessarily fully reflective of real-world outcomes, potentially limiting generalizability of the study findings. Third, as the time period considered was 25.4 months (the maximum observed follow-up for patients in the SOC arm), we had limited visibility into the cost-effectiveness of cilta-cel vs. SOC over a longer time horizon. However, since the cost-effectiveness of CAR T seems to increase over time due to its prolonged PFS (46), we would expect the difference in costs between arms would likewise increase. Finally, the model assumed that one line of subsequent treatment was considered for each patient post progression. However, it is possible that some patients did not receive any subsequent treatment after progression, and that others received more than two subsequent regimens during the 25.4-month follow-up period. Therefore, the impact of this assumption on our findings is unclear.

Using a CPR analysis, this study demonstrated the cost-effectiveness of cilta-cel compared to CARTITUDE-4 trial’s SOC, identifying remarkably lower costs per treated patient, costs per complete responder, and costs per month in PFS for patients treated with cilta-cel. These findings highlight the importance of considering treatment effectiveness, as well as long-term cost, when evaluating treatment options for patients with RRMM.