In Vivo Anti-BCMA CAR T-Cell Expansion Kinetics Correlate with Early IMWG Response in RRMM: A Single Institution Study with Comparative Analysis of Idecabtagene Vicleucel and Ciltacabtagene Autoleucel
Authors: Kocoglu Mehmet H. , Rapoport Aaron P. , Luetkens Tim , Gebru Etse , Omili Destiny , Yared Jean A. , Hardy Nancy M. , Bentzen Soren M , Badros Ashraf Z. , Atanackovic Djordje 
Published: December 2023

Introduction: The most recent breakthrough in the treatment of relapsed/refractory MM (RRMM) is chimeric antigen receptor (CAR) T-cell (CAR T) therapy which led to high overall response rates with acceptable toxicity. Here we present our single-institution experience with MM-specific CAR T performing a comparative analysis of clinical data and expansion kinetics after infusion of two commercially available myeloma CAR-T products.
Methods: Out of 76 RRMM patients treated with CAR T, 23 patients provided consent, enrolled, apheresed and treated with commercial CAR-T between 6/20/2022 and 4/24/2023. Majority of patients had relapsed and multi-refractory MM. 11 patients received idecabtagene (idecel) and 12 received ciltacabtagene (ciltacel). Manufacturing slot availability was the primary deterministic factor for CAR T-type assignment. Study was IRB approved and informed consent was obtained to collect blood and clinical data. Blood samples were obtained at apheresis, pre-lymphodepleting (LD) chemotherapy, and on days 0, +7, +14, +21, +28 and +3 months post CAR T-cell infusion. PBMCs were generated from whole blood using density gradient centrifugation and were stained using BCMA or control CAR detection reagents and monoclonal antibodies against T-cell surface antigens. Samples were analyzed using MacsQuant-10 flow cytometer, gating on CD3+ and CAR+ cells. Fisher's Exact Test and Pearson Chi-Square tests were used for assessment of categorical variables whereas Independent-Samples Median Test was employed for non-categorical variables. Mann-Whitney U test was used for CAR T cell expansion analyses at individual timepoints.
Results: As of July 10, 2023, 23 commercial patients were enrolled. Baseline clinical characteristics were comparable between the idecel and ciltacel cohorts with regard to age (median 66, p=0.827), prior lines of treatment, ASCT history (Table 1). Two patients in each cohort were penta-refractory. Three patients in each cohort had EMD (27.3%). There was balanced distribution of del 17p and t(4;14) across cohorts (p=1.000, p=0.175). Each cohort had 1 RISS-3 patient (p=0.476). Seven patients (30.4%) were previously treated with belantamab. Pre-apheresis and pre-LD absolute lymphocyte count (ALC) were comparable across cohorts. (Table 1). There were no G3 CRS events whereas G1/2 CRS events were not statistically significant between cohorts (p=0.256). Three G3 ICANS were observed, 2 in idecel and 1 in ciltacel cohorts (18.2% and 8.3%). Distribution of all-grade ICANS across cohorts were not statistically significant (p=0.676). Post-CAR T ferritin max correlated with the baseline b2m (p&lt;0.001) and tocilizumab dose number (p=0.009) but none correlated with peak CAR T expansion (p=0.315). Responses were assessed by IMWG criteria at months 1,3,6,9 for efficacy-evaluable patients at that timepoint (n=19,14,8 and 2 in grand cohort (82.6%, 60.9%, 34.8% and 8.7%)). Global cohort ORR was 78.3% (n=18) and 60.9% (n=14) at days 30 and 90 respectively. +1 month IMWG responses were comparable with 72.7% (8/11) in idecel and 83.3% (10/12) in ciltacel cohort (p=0.625). Similarly, there was no statistically significant ORR difference between cohorts at 3, 6, and 9 months. Two-way ANOVA revealed a trend towards an effect of treatment type on CAR-T expansion (p=0.0595) (Figure 1A). Time-to-peak analysis reached statistical significance (p=0.0127) between two products (Figure 1B). Despite its delayed peak, ciltacel had significantly higher magnitude of expansion (p=0.043) (Figure 1C). Peak CAR-T expansion was associated with clinical responses across cohorts at +1 (p=0.034) and +3 months (p=0.050) but not at +6 months (p=0.449). Day +30 responses were indicative of Day +90 and Day +180 responses (p&lt;0.001, p=0.011).
Conclusions: In our single-center study of comparative analysis of commercial BCMA targeting CAR T-cell treatments, peak CAR T-cell expansion showed a positive correlation with +1 and +3 month post-CAR-T clinical responses. Despite the delayed peak expansion with ciltacel, the expansion was more robust with a higher level of circulating CAR T-cells. Baseline ALC or fludarabine dose reduction did not have an impact on overall CAR T expansion in combined cohort. Studies are underway at our institution investigating anti-BCMA CAR T cell responses in more detail and larger numbers of patients and functional studies will be further presented.