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 <90 ml/min/1.73). BW ranged from 42 to 147.2 kg. Wide PK variability was observed with a median Flu AUC of 19.01 (11.23-41.47) mg * h/L (Fig 1). When adjusted for high-risk features including high risk cytogenetics, extramedullary disease, exposure to BCMA agents, and receipt of bridging therapy in a MV model, Flu AUC was not found to be associated with efficacy, including overall response and progression free survival. However, when adjusted for bridging therapy response and prior lines of therapy as an indicator of disease status/burden pre-CAR-T, each 1 mg * h/L increment in Flu AUC was found to be associated with maximum grade >/= 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 use of stem cell boost (OR 1.130; 95% CI 1.038-1.235; p=0.005).

Discussion. In this real-world dataset of ide-cel treated RRMM patients, Flu exposure was found to have a significant association with severe CRS and need for stem cell boost. This is consistent with prior studies (Hirayama et al, Blood, 2019) where a greater increase in cytokine levels and risk for CRS is seen with high intensity LDC. These data highlight how standard BSA-based Flu dosing results in significant PK variability and overestimates Flu AUC, increasing the risk of CAR-T toxicities. Prospective validation of our model-based findings through measurement of Flu blood levels, CAR-T PK, and clinical outcomes is warranted.