Pharmacokinetics and Efficacy of Generic Melphalan Is Comparable to Innovator Formulation in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation

Abstract

High-dose Melphalan (MEL) is the standard conditioning regimen for Autologous Haematopoietic Stem Cell Transplantation (ASCT) in Multiple Myeloma (MM). Generic MEL is in routine use in our centre and others due to the reduced cost and ease of availability. However, the pharmacokinetics (PK) and the clinical efficacy of generic MEL in comparison with innovator MEL has not been tested before. We aimed to compare the PK of generic Melphalan (Megval, Emcure & Alphalan, Natco) with that of the innovator formulation (Alkeran, Aspen) in MM patients undergoing ASCT. Fifty-five patients diagnosed with MM at Christian Medial College (CMC), Vellore receiving high dose MEL (200mg/m2 or renal adjusted to 140 mg/m2) [generic (Megval, Emcure & Alphalan, Natco n=32], and innovator [Alkeran, Aspen, n=23] between March 2016 and August 2018 were included in this study. Peripheral blood samples were collected at different time points during and after MEL infusion, plasma was separated immediately and stored at -800 until analysis. MEL levels were analysed using LC-MS/MS as per previously published protocol (Guitton et al, 2009). The AUC and clearance of MEL was determined using trapezoidal rule assuming linear PK. The PK estimates as well as available clinical outcomes were compared between generic and innovator MEL. The Inter-individual variability (IIV) in Mel AUC and clearance were 4.39 and 5.88 fold for generic and 4.34 & 6.85 fold for innovator formulation respectively. The median MEL AUC and clearance were comparable between the two formulations [AUC: 12.71 (6.56-35.36) vs. 12.89 (4.16-22.22) mg*L/h and clearance 24.53 (8.69-57.9) vs. 25.06 (11.91-93.61) L/hr/m2 respectively for the generic and innovator formulations]. These parameters were also comparable to previous reports on Mel PK in patients with MM (Kuhne et al, 2008, Nath et al, 2010, Phelps et al, 2017). There were no significant differences in terms of onset and severity of mucositis, day to neutrophil and platelet engraftment, as well as response status on day 100 post ASCT between patients receiving generic or innovator formulations of MEL. Also, neither MEL AUC nor clearance was significantly associated with response, relapse or toxicity. Our study suggests that the PK and efficacy of the generic MEL is comparable to the innovator formulation.