OA-45: Pharmacokinetic and correlative analysis of ciltacabtagene autoleucel in patients with lenalidomide-refractory multiple myeloma in the CARTITUDE-4 trial

Introduction: CARTITUDE-4 is an open-label, randomized controlled trial (NCT04181827) comparing the CAR-T therapy ciltacabtagene autoleucel (cilta-cel) with physician’s choice of standard of care (SOC) in lenalidomide (len)-refractory patients (pts) with multiple myeloma (MM). Cilta-cel significantly improved median progression-free survival (PFS) vs SOC (hazard ratio, 0.26 [95% CI, 0.18–0.38]; P< 0.0001) in the intent-to-treat population at a median follow-up of 15.9 months. Here, we report pharmacokinetic (PK) and correlative analyses in the 176 pts who received cilta-cel as study treatment.

Methods: Eligible pts were len-refractory with 1–3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug and had an ECOG performance status score of ≤1. Pts randomized to cilta-cel underwent apheresis, received physician’s choice of pomalidomide-based bridging treatment, and then 1 cilta-cel infusion (target dose 0.75×10⁶ CAR+ viable T cells/kg) 5–7 d after lymphodepletion. The primary endpoint was PFS. PK was assessed by both CAR transgene levels and flow cytometry (CAR+ T cells per microliter in peripheral blood). Expression levels of BCMA on plasma cells in bone marrow aspirate (BMA) were assessed by flow cytometry. A ligand binding assay was used to quantify serum soluble BCMA (sBCMA).

Results: As of Aug 2022, among the 176 pts who received cilta-cel as study treatment, CD3+CAR+ cells in blood peaked at median 13 d post infusion (mean, 1451 cells/µL; SD, 6169 cells/µL) and remained detectable for median 57 d (range, 13–631). Mean AUC00-28d of CD3+CAR+ cells in blood was 11,710 cells/µL (SD, 56,994 cells/µL). In 13 pts with progressive disease (PD) and available data, we did not observe a reappearance or re-expansion of CD3+CAR+ cells in blood at PD; CAR+ T cells were below the lower limit of quantification (LLOQ; 2 cells/mL) in all pts. sBCMA decreased following cilta-cel infusion in all patients, becoming undetectable (LLOQ, 0.25000 µg/L) at median day 56. At PD, results for sBCMA and proportion of BCMA+ MM cells in BMA were available for 3 and 6 pts respectively. After an initial decline following cilta-cel infusion, sBCMA levels either returned to or exceeded baseline levels at PD. Similar findings were observed in the 6 pts with available data on the proportion of BCMA+ MM cells in bone marrow.

Conclusions: CAR transgene and cellular levels in CARTITUDE-4 were concordant with observations in CARTITUDE-1 and showed similar expansion and persistence profiles. Based on the samples available at data cut-off, sBCMA levels and proportion of BCMA+ MM cells return to levels at or above baseline at time of relapse, without reappearance or re-expansion of CD3+CAR+ cells in blood. Study follow-up is ongoing, and more samples may be available with additional follow-up. Understanding mechanisms of resistance is an area of interest which will ultimately assist with the sequencing of MM therapies.