Fludarabine Lymphodepletion Exposure Is Associated with Idecabtagene Vicleucel Toxicity in Relapsed and Refractory Multiple Myeloma Patients: Real-World Experience from the US Myeloma Immunotherapy Consortium

Background. Idecabtagene vicleucel (ide-cel) is an anti-B-cell maturation antigen (BCMA) CAR-T associated with durable responses in relapsed/refractory multiple myeloma (RRMM) patients. Fludarabine (Flu), part of standard lymphodepleting chemotherapy (LDC), improves T-cell expansion and persistence, but BSA dosing results in significant pharmacokinetic (PK) variability. Flu exposure, defined by the area under the curve (AUC), has been shown to predict rates of relapse after anti-CD19 CAR-T in B-cell acute lymphoblastic leukemia (Fabrizio et al, Blood Advances 2022). We hypothesized Flu AUC may predict outcomes after ide-cel and, using a published population model (Langenhorst et al, Clin Pharmacokinet 2019 ) we assessed the impact of Flu AUC on standard-of-care (SOC) ide-cel outcomes. Methods. RRMM patients receiving SOC ide-cel from 11 of the US Myeloma Immunotherapy Consortium centers were retrospectively analyzed. FluCy was given on days -5 to -3 before CAR-T infusion. Patients were excluded if they did not receive FluCy LDC or ide-cel infusion, had ESRD on hemodialysis, or did not have creatinine values on LDC days. A population PK approach using cumulative Flu dose and PK covariates, eGFR and body weight (BW), was used to calculate C max and AUC 0-72h. PK parameters were first tested as continuous variables in univariable and multivariable (MV) analysis. ORs are expressed per 1 mg * hr/L in the model. Results. 285 patients were included with a median follow-up of 8.7 (4.3-14.2) months. eGFR distribution indicated large variability (mean=86.5 ml/min, CV 38.4%), with 151 (53%) having renal dysfunction (eGFR /= 2 cytokine release syndrome (CRS) (OR 1.083; 95% CI 1.013-1.160; p=0.020). While there was no difference in the occurrence of Grade 3/4 cytopenias, each 1 mg * h/L increment in Flu AUC was significantly associated with