Safety and Efficacy of Propylene Glycol-Free Melphalan (Evomela) in Patients with AL Amyloidosis Undergoing Autologous Stem Cell Transplantation: Preliminary Results of a Phase II Study
Authors: Sarosiek Shayna , Sloan John Mark , Quillen Karen , Brauneis Dina , Cruz Ramon , Schulman Amanda , Fennessey Salli , Shelton Anthony , Sanchorawala Vaishali 
Published: November 2019

INTRODUCTION: High dose melphalan and autologous stem cell transplantation (HDM/SCT) is effective for treatment of selected patients with light-chain (AL) amyloidosis with adequate functional status and preserved organ function. Despite rigorous patient selection, approximately 21% of AL amyloidosis patients receiving treatment with HDM/SCT develop acute renal injury and up to 22% develop cardiac arrhythmias in the peri-transplant period. Patients with AL amyloidosis are at greater risk of organ dysfunction in the peri-transplant period due to pre-existing amyloid deposition. This toxicity is potentially exacerbated by the co-solvent propylene glycol found in melphalan hydrochloride. Propylene glycol is reported to lead to metabolic acidosis, sepsis-like syndrome, renal dysfunction, and cardiac arrhythmias. Therefore a clinical trial investigating the use of propylene glycol-free melphalan during HDM/SCT was developed to evaluate the effect on organ toxicity in AL amyloidosis patients (NCT02994784).
PROTOCOL: This Phase II clinical trial began enrollment in April 2018. Eligibility criteria included the following: histologic diagnosis of systemic AL amyloidosis, involvement of ≥1 vital organ, eGFR of ≥30 mL/min, DLCO ≥50%, LVEF ≥40%, ECOG <3, NYHA status <3, and no prior HDM/SCT. Subjects underwent autologous stem cell transplantation per institutional guidelines, receiving the conditioning regimen of 140 or 200 mg/m2 propylene glycol-free melphalan via IV infusion on Days -3 and -2. Stem cell infusion occurred on Day 0. Primary objectives included evaluation for renal dysfunction (defined as a ≥1 mg/dL increase in creatinine or a doubling of creatinine to ≥1.5 mg/dL for ≥2 days), cardiac dysfunction (defined as development of new arrhythmia), and autonomic dysfunction (defined as a drop in SBP ≥20 mmHg on orthostatic measurements). Secondary objectives included evaluation of time to engraftment, treatment related mortality, overall hematologic response at 6 months after SCT, organ response at 12 months after SCT, and number of hospitalizations.
RESULTS : At the time of data cut-off (July 1, 2019) 17 patients had been enrolled. Median age was 59 years (range, 44-76) with 11 (65%) males. Median number of prior therapies was 0 (range, 0-2). Median number of organ systems involved was 1 (range, 0-3). 13 (76%) and 7 (41%) patients had renal and cardiac involvement, respectively. Median NT-proBNP level was 396 pg/mL (range, 63-6220), urine protein excretion was 3.14 g/24 h (range, 0-22.9), serum creatinine was 0.93 mg/L (range, 0.72-2.07), and median dFLC was 51 mg/L (range, 2-700). In the 7 patients with relapsed/refractory disease, median time from last therapy was 2 months. Subjects received either 140 mg/m2 (n = 2) or 200 mg/m2 (n = 15) of propylene glycol-free melphalan. There have been 0 deaths during the peri-transplant period or follow-up. Per the protocol defined criteria, 2 patients (11%) developed acute renal dysfunction, 3 subjects (18%) developed orthostatic hypotension, and 3 patients (18%) experienced a new cardiac arrhythmia (atrial fibrillation or ventricular tachycardia) while on study. Median time to neutrophil engraftment was 10 days. Median time to platelet engraftment was 17.5 days. Peri-transplant hospitalization occurred in 14 subjects (82%) and median hospitalization was 5 days. The most common non-hematologic adverse events included nausea/vomiting (82%), fatigue (82%), and diarrhea (88%). Of the 8 subjects who have completed their 6 month follow-up the hematologic response rates are as follows: 4 CRs (50%), 2 VGPRs (25%), 1 PR (13%) and 1 stable disease (13%).
CONCLUSION: In this ongoing trial investigating the safety of propylene glycol-free melphalan in patients with AL amyloidosis the cardiac toxicities appear comparable to historical data with 18% of patients developing a cardiac arrhythmia and with potentially improved renal toxicity (11%), although additional data are required to confirm this finding. Time to engraftment is similar to published data for HDM/SCT and no peri-transplant mortality has been seen. Hematologic responses are also comparable to historical controls (50% CR and 25% VGPR). Additional data will be obtained with ongoing patient enrollment to determine if there are significant differences in the safety of propylene glycol-free melphalan in this population of patients with high risk of organ dysfunction during HDM/SCT.

Disclosures
Sarosiek: Acrotech: Research Funding. Sloan:Merck: Other: endpoint review commitee; Stemline: Consultancy; Abbvie: Other: Endpoint Review Committee. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding.

OffLabel Disclosure:
propylene glycol-free melphalan is FDA approved for multiple myeloma, but not for AL amyloidosis (which has not FDA approved therapies)