PI-070 - EXPOSURE-TARGETED MELPHALAN DOSING INDIVIDULIZATION IN PATIENTS WITH MULTIPLE MYELOMA UNDERGOING AUTOLOGOUS TRANSPLANT.

K. Kim¹, Y. Guo¹, K. Hill¹, N. Abbott¹, D. Irby¹, C. Hofmeister², P. Patel³, K. Sweiss³, M. Phelps¹; ¹The Ohio State University, Columbus, OH, USA, ²Emory University, Atlanta, GA, USA, ³University of Illinois Chicago, Chicago, IL, USA.

Background: High-dose melphalan (HDM) and autologous stem cell transplant is a standard of care in multiple myeloma. The standard HDM, melphalan dose of 200 mg/m2, yields a 5-fold variation in melphalan exposure which is associated with variability in drug responses or adverse drug reactions1. Therefore, HDM dose individualization is needed to improve clinical outcomes.

Methods: We evaluated methods to perform HDM individualization. Data were obtained from a multicenter phase I trial (NCT04483206), where HDM was separated into an initial dose of 100 mg/m2 on Day -3 and a personalized dose on Day -1 to target a prespecified exposure (AUC0-inf) of 13-14 mg*hr/L. Seven blood samples were collected after each dose and melphalan AUC0-inf was estimated using non-compartment analysis (NCA) and non-linear mixed effect modeling (NONMEM) approaches. Per protocol, the Day -1 dose determination and target attainment assessment was based on NCA. In NONMEM approach, an in-house melphalan pharmacokinetic model was used and the performance of NONMEM was evaluated in post-hoc analysis.

Results: Seven patients with a total of 95 blood samples were evaluated. Based on NCA, the total HDM dose was 140 (116-196) mg/m2, with 30.0% (2.04 - 42.2%) reduction from the standard dose of 200 mg/m2. The total AUC0-inf was 13.5 (12.8 - 13.9) mg*hr/L, with 6 patients achieving the target. In NONMEM, the total AUC0-inf was well-correlated with NCA (R2=0.98). Compared with NCA, NONMEM approach would have resulted in a -0.57% (-9.89% – 4.77%) variation in total HDM dose and the same target attainment.

Conclusion: NCA and NONMEM methods were both sufficient to perform exposure-targeted HDM individualization. However, the performance could differ with missing or sparse samples. The source of variability remains to be investigated to further optimize HDM dose.

1. Nath, C. E. et al. Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy. British Journal of Clinical Pharmacology 69, 484–497 (2010).