Lower PG-Free Mel (Evomela) Clearance and Higher Exposure Are Associated with Better Treatment Response in Newly Diagnosed Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation

Background Melphalan (Alkeran) is unstable after reconstitution, preventing prolonged infusions or pharmacokinetic (PK) analysis. Propylene glycol-free melphalan (PG-free Mel; Evomela) is stable at room temperature for ∼24 hours. We studied the PK analysis of Evomela and its relationship with the disease response in patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation. Methods The study enrolled newly diagnosed MM adults, age ≤ 70, randomized (1:1) to 2 infusion schedules [30-60 min (short) or 8-9 hr. (long)] using Evomela (2 mg/mL, either 200 mg/m2 or 225 mg/m2). Evomela plasma concentration at various time points was determined using liquid chromatography-mass spectrometry, and PK parameters were estimated using noncompartmental analysis. Disease response was measured using IMWG criteria. MRD was measured by flow cytometry at 10−5. We estimated the associations of Evomela exposure and clearance (CL) with the probabilities of achieving stringent complete response (sCR) or CR and achieving MRD negativity at the end of 1-year post-transplant, using a nonparametric loess regression smoother. Inferences were based on visual inspection of the smoothed plots. Results Sixty patients were enrolled of which 30/30 (100%) in short infusion (S-IV) and 27/30 in long infusion (L-IV) received maintenance therapy post-transplant. One subject each in the S-IV and L-IV schedule groups lacked enough samples for PK analysis. For the 2 infusion schedules (Table 1), Cmax and dose-normalized Cmax were higher in S-IV, while CL in the L-IV was higher and trended to have lower dose-normalized AUC0-∞, and lower exposure (AUC0-∞). The proportion of patients (14/30, 47%) with lower AUC (<16,000 hr.ng/ml) was higher in L-IV. There were no deaths, and no patient experienced grade > 3 adverse events (AE). Grade 2-3 AEs were seen in 53 (98%) patients (26 [96%] in the S-IV; 27 [100%] in the L-IV). The median follow-up was 14.5 (range: 6-40) months (13.8 months in the S-IV and 14.8 months in the L-IV). The median progression-free survival (PFS) was not reached in the overall trial population, 4 progressed in S-IV and 5 progressed in L-IV. sCR/CR was observed in 16 (53%) in S-IV and 17 (57%) in L-IV, while 18/23 (78%) in S-IV and 12/23 (52%) in L-IV were MRD-ve at the end of 1 year. The estimates (Figure 1) suggest that the probability of sCR/CR or being MRD-ve at the end of 1-year decreases with higher CL. Similarly, the probability of sCR/CR or being MRD-ve at the end of 1-year increases with higher AUC. Conclusions Our analyses of Evomela PK suggested higher Cmax, lower CL, and higher exposure in S-IV compared to L-IV schedules. Patients with lower CL and therefore higher exposure had greater probabilities of achieving sCR/CR and achieving MRD negativity. Further analyses in a larger sample population is needed to determine the target exposure range to achieve optimal treatment response.