Feasibility and Toxicity of Pharmacokinetic (PK)-Directed Dosing of Evomela® (propylene glycol free melphalan, PGF-MEL) for Multiple Myeloma (MM) and AL Amyloidosis (AL) Patients Undergoing Autologous Hematopoietic Stem Cell Transplant (AHCT) (2018)

Background: For MM and AL patients undergoing AHCT, high-dose melphalan is given at a fixed dose based on body surface area with five-fold inter-patient variability in exposure by area under the curve (AUC). Pts with higher than the median AUC have prolonged survival, but increased toxicity (Shaw et al., BBMT 2012). Pharmacokinetic (PK)-directed dosing can determine the optimal concentration for each pt. We prospectively evaluated the feasibility of PK-directed dosing of PGF-MEL, a more stable and possibly less toxic intravenous formulation of melphalan, to personalize therapy for maximum efficacy and tolerability. Methods: MM and AL pts age 18-75 received a 10 mg/m2 test dose of PGF-MEL within 14 days of AHCT. AUC PK modeling was used to determine a target dose to achieve an AUC of 13.5 mg/L*h (+/-1), given on day -2 prior to AHCT. Pt-reported symptom burden was collected prospectively using the MD Anderson Symptom Inventory—MM (MDASI-MM). DNA was isolated from cell fractions using a QIAGEN kit and was analyzed by MALDI-TOF/TOF-MS for the adenine-melphalan chloride DNA adduct. Toxicities were compared using either a T-test or Fisher's exact test between patients above and below AUC 14.5 mg/L*h. Results: Ten pts (7 MM, 3 AL) with 50% male, median age 67 yr (range 53-74), and median body surface area 1.95 (range 1.56-2.35) had a median of 4.5 days (range 1-24) between the test and target doses of PGF-MEL. Target doses were calculated for 90% of patients and 70% received the calculated dose. The median target dose AUCs was 15.65 mg/L*h (range 10.1-17.2). No pts receiving the calculated target dose had an AUC within the goal range. MEL saliva levels peaked at 75 min after the dose (Figure 1). MDASI-MM AUCs were calculated for fatigue, pain, sleep, appetite, drowsiness, and the average of these 5 symptoms. Overall, higher scores were seen in pts with MEL AUCs above 14.5 mg/L*h compared with below (Figure 2). More pts with higher AUCs had fevers (83 vs 50%), ≥500 ml of diarrhea per day (83 vs 75%), grade ≥3 mucositis (50 vs 25%), and need for patient-controlled analgesia (33 vs 25%, P>.05). Pts with AUCs above 14.5 mg/L*h required more pRBC and platelet transfusions. DNA damage (adduct formation) and repair varied between pts, but could not be correlated with serum AUC (Figure 3). With a median follow-up of 217 days (range 179-250) in surviving patients, no pts progressed, and one AL pt died of failure to thrive at 134 days post AHCT.Figure 2MD Anderson Symptom Inventory—MM Scores.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3DNA Adduct Formation and Repair.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusion: Collection of PK levels and calculation of a target dose was feasible. However, using a 10 mg/m2 test dose we did not achieve the target AUC, which may be because the test dose was insufficient to saturate the two-compartment model, rendering the PK analysis inaccurate. There may be an ideal concentration to minimize toxicity and maximize efficacy. Further study is needed to determine the optimum test dose and schedule, and modifications to the schema are ongoing.