Successful Personalization of Propylene Glycol Free Melphalan (PGF-MEL) for Multiple Myeloma (MM) and AL Amyloidosis (AL) Patients Undergoing Autologous Hematopoietic Stem Cell Transplant (AHCT) Using Pharmacokinetic (PK)-Directed Dosing

Abstract

Background Body surface area-based dosing of melphalan prior to AHCT for MM and AL patients causes inter-patient variability in exposure measured by area under the curve (AUC). Higher AUC is associated with increased toxicity, but prolonged survival (Shaw et al., BBMT 2012). Using Evomela (PGF-MEL, Acrotech Biopharma LLC), a more stable and possibly less toxic intravenous formulation of melphalan, we examined the feasibility of PK-directed dosing to individualize and optimize therapy. Methods Prospectively, patients received 100mg/m2 of PGF-MEL on day -2 prior to AHCT. Serum samples were collected at 5, 15, 30, 40, 75, and 150 min after the dose and AUC PK modeling (Phoenix WinNonlin v6.4) was used to determine the dose required to achieve a target AUC of 13.5mg/L*h (+/-1). On day -1, patients received the balance of the calculated dose with samples collected at the same timepoints to calculate the total AUC. After 5 patients were enrolled, the protocol was amended to increase the maximum allowable dose to the equivalent of 260mg/m2 from 220mg/m2. On day +1, 6, 11, 30, 60, and 90, patients reported symptom burden was collected using the MD Anderson Symptom Inventory – MM (MDASI-MM). Results Results of 15 patients are presented with 11 having MM and 4 AL, 60% male, median age 62yr (range 48-71), median body surface area 1.9 (range 1.5-2.2), and median creatinine on day of Mel 0.8mg/dL (range 0.7-1.6). Target doses were calculated and given in 100% of patients. Thirteen of 15 patients (87%) achieved the target AUC. The median AUCs on day -2 and day -1 were 6.3 mg/L*h (range 4.2-11.4) and 5.6 (range 3.1 – 8.4) respectively, with a median total AUC of 13.2 (range 9.6-15.2, Figure 1). Three patients received the capped dose of 220mg/m2 prior to the amendment and achieved their predicted AUC; 1 patient received the minimum 140mg/m2 and also achieved the predicted AUC which was higher than the target AUC, as expected. 9/15 patients had AUCs between 12.5-14.5 with 4/6 patients out of range for the above reasons. Neutropenic fevers occurred in 40% and grade 2 diarrhea for at least 1 day in 80% (median 2 days, range 0-7). Median time to neutrophil engraftment was 9 days (range 9-12). The median number of red cell and platelet transfusions required were 0 (range 0-3) and 1 (range 0-8), respectively. Engraftment syndrome was seen in 30% of patients. The hematologic response rate post AHCT was 100%, including complete remission in 20% and ≥ very good partial response 73%. With median follow-up of 6.4 months (range 2.8-13.1 months), one patient with MM whose AUC was below the target (10.1 units) has relapsed. No patient has died. Conclusion We show for the first time that personalization of therapy to a target AUC using PK-directed PGF-MEL was logistically feasible and prevented underdosing. Full trial results for 35 patients, as well as patient-reported outcomes and toxicities will be presented at the meeting.