Fludarabine Lymphodepletion Exposure is Associated with Toxicities after Idecabtagene-Vicleucel in Relapsed/Refractory Multiple Myeloma: Real-World Experience from the US Myeloma Immunotherapy Consortium.

BACKGROUND

Idecabtagene vicleucel (ide-cel) is a BCMA-directed CAR-T associated with high response rates in relapsed/refractory multiple myeloma (RRMM), yet responses are not durable and most patients experience toxicities. Fludarabine (Flu) is a key component of lymphodepletion but exhibits significant pharmacokinetic (PK) variability.

OBJECTIVE

Given Flu exposure (AUC) predicts outcomes after CD19-directed CAR-T, we hypothesized it would predict outcomes after ide-cel. Our objective was to determine the association between fludarabine AUC and clinical outcomes after standard-of-care (SOC) ide-cel.

STUDY

DESIGN

RRMM patients receiving ide-cel from 10 US Multiple Myeloma Immunotherapy Consortium centers were retrospectively analyzed. A population PK approach using cumulative Flu dose and PK covariates, eGFR and body weight (BW), was used to predict Flu AUC and Cmax and these were tested in univariable and multivariable analysis.

RESULTS

285 patients were analyzed, and the median predicted Flu AUC was 19.01 (11.23-41.47) mg * h/L. We observed an association between Flu AUC and Day 90 ORR (OR 2.11; 95% CI 0.99-4.68; P = .057). Flu AUC was significantly associated with grade ≥1 CRS (P = .013), and grade ≥1 ICANS (P = .032), which was consistent with the observed increase in tocilizumab and corticosteroid use in these patients. Flu AUC was also associated with day 60 grade 3/4 thrombocytopenia (P = .03). A non-statistical but clinically significant increase in the odds of occurrence of day 90 grade 3/4 neutropenia (P = .058) and infection (P = .017) was also observed.

CONCLUSION

Predicted Flu exposure is an independent predictor of CAR-T toxicities in this real-world ide-cel-treated population. Validation of these findings with prospective therapeutic drug monitoring is needed to gain further insight into how personalized Flu dosing can mitigate these toxicities after ide-cel.