Pre-Infusion Ferritin: A Predictive Biomarker for CAR T-Cell Therapy Response in Multiple Myeloma
Authors: Moreno Eider , Arribas Mariano , Martinez David A. , Figueroa Aguirre Juana , Patel Rohan S , Yadav Udit , Wiedmeier-Nutor Erin J , Bergsagel Leif , Fonseca Rafael , Chhabra Saurabh , Castro Januario E. 
Published: December 2024

Background
Clinical biomarkers are essential for optimizing CAR T-cell therapy in multiple myeloma (MM). Clinicians can anticipate patient responses by evaluating predictive biomarkers, particularly earlier during treatment, tailoring treatments to enhance efficacy and survival outcomes. Ferritin, a general inflammation marker, appears to be a promising predictor of clinical outcome in MM patients receiving therapy with CAR T-cells. Our goal was to evaluate this and other biomarkers in this patient population.
Methods
We retrospectively analyzed MM-patients treated with idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) at Mayo Clinic Arizona between September/2019 and November/2023. We evaluated the demographic characteristics, pre-infusion bone marrow samples, adverse events, mortality, and clinical response after CAR T-cell therapy infusion, and clinical laboratory data were interpreted using reference limits established by Mayo Clinic laboratories. Statistical calculations using parametric tests were performed, and survival curves were estimated using the Kaplan-Meier analysis and compared statistically using the log-rank test and Pearson's correlation.
Results
Forty patients with MM received CAR T cells, and 23 and 17 patients received cilta-cel and Ide-cel, respectively. The median age was 64 years [IQR 40-80], and 62.5% were male. All patients received inpatient CAR T-cell infusions; the median vein-to-vein was 54 days (IQR: 39-109), and the median length of hospital stay was ten days (IQR: 7-25). Cytokine release syndrome (CRS) was observed in 90% of patients (3% grade ≥3), while immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 23% of patients (3% grade ≥3).
At day 90, the overall response rate (ORR) was 87.5%, with 21 patients (52.5%) having a complete response (CR), 9 (22.5%) with a very good partial response (VGPR), 5 (12.5%) had a partial response (PR), 1 (2.5%) had stable disease (SD), and 4 (10%) had progressive disease (PD). 35 patients was evaluated for minimal residual assessment (MRD) using flow cytometry cut-off 10-5. Of the total population eligible (PR, VGPR, and CR) for MRD evaluation, 97% were MRD negative.
The median progression-free survival (PFS) was 13.5 months on ide-cel and has not been reached on cilta-cel. The mortality rate was 23.5% Ide-cel vs 8.6% with cilta-cel. In terms of PFS, we did not find any association with age, disease risk, number of previous lines of therapy, time from last treatment to CAR T-cell infusion, absolute lymphocyte counts at leukapheresis, % of plasma cells in bone marrow pre-infusion, vein-to-vein time, use of tocilizumab, or steroids for CRS/ICANS management. However, univariate analyses showed that a ferritin level &lt;337 mcg/L at baseline pre-CAR T-cell infusion strongly correlated independently with improved PFS (median non-reached) compared with patients with ferritin levels &gt;337 mcg/L that had a PFS of 13.50 months HR 0.2 (95% CI 0.07 - 0.83); p=0.0245. In addition, ferritin levels &lt;337 mcg/L pre-infusion correlated with improved overall survival (OS) (median non-reached) compared with 22.23 months in patients with higher ferritin levels HR 0.2 (95% CI 0.02 - 0.53), p=0.0069.
Conclusions
In conclusion, our analysis shows that ferritin levels pre-CAR T-cell infusion are independent predictive biomarkers of PFS and OS in MM-patients regardless of the CAR T-cell product received. Our cohort of MM-patients treated with the two FDA-approved CAR T-cell products showed the expected PFS, OS, and adverse events. Moreover, our results showed no significant association between clinical response and age, risk stratification, number of previous therapy lines, or other evaluated factors with disease progression. Future prospective studies will help to validate these findings and explore the mechanisms associated with high ferritin levels and their potential implications in the heightened immune-activation state in patients that express high ferritin levels and their correlation with CAR T-cell efficacy.