A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation

Abstract

Autologous stem cell transplantation (ASCT) after high-dose melphalan conditioning is considered a standard of care procedure for patients with multiple myeloma (MM). Current formulations of melphalan (eg, Alkeran for Injection [melphalan hydrochloride]; GlaxoSmithKline, Research Triangle Park, NC, USA) have marginal solubility and limited chemical stability upon reconstitution. Alkeran requires the use of propylene glycol as a co-solvent, which itself has been reported to cause such complications as metabolic/renal dysfunction and arrhythmias. EVOMELA (propylene glycol-free melphalan HCl; Spectrum Pharmaceuticals, Inc., Irvine, CA, USA) is a new i.v. melphalan formulation that incorporates Captisol (Ligand Pharmaceuticals, Inc., La Jolla, CA, USA), a specially modified cyclodextrin that improves the solubility and stability of melphalan and eliminates the need for propylene glycol. This new formulation has been shown to be bioequivalent to Alkeran. EVOMELA (200 mg/m(2)) was administered as 2 doses of 100 mg/m(2) each in a phase IIb, open-label, multicenter study to confirm its safety and efficacy as a high-dose conditioning regimen for patients with MM undergoing ASCT. At 5 centers, 61 patients (26 women) with a median age of 62 years (range, 32-73) were enrolled. All patients achieved myeloablation with a median time of 5 days post-ASCT, and all successfully achieved neutrophil and platelet engraftment with median times of 12 days post-ASCT and 13 days post-ASCT, respectively; treatment-related mortality on day 100 was 0%. Overall response rate (according to independent, blinded review) was high (100%), with an overall complete response rate of 21% (13% stringent complete response; 8% complete response) and overall partial response rate of 79% (61% very good partial response; 18% partial response). The incidence of grade 3 mucositis and stomatitis was low (10% and 5%, respectively) with no grade 4 mucositis or stomatitis reported (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events). Based on investigators' assessment of mucositis using the World Health Organization (WHO) oral toxicity scale, 75% of patients had a shift in mucositis score from WHO grade 0 at baseline to a higher grade on study, of which 13% of patients reported WHO grade 3 as the worst post-treatment mucositis over the course of the study; there were no reports of WHO grade 4 mucositis during the study. This study confirms the efficacy and acceptable safety profile of EVOMELA, a new propylene glycol-free melphalan formulation, as a high-dose conditioning regimen for ASCT in patients with MM.

Use of propylene glycol-free melphalan conditioning in light-chain amyloidosis patients undergoing autologous hematopoietic cell transplantation is well tolerated and effective

“…Likewise, the day 100 post-transplant response rate was 100% in both groups. Equivalent tolerability and responses observed in our cohort of AL patients receiving PG-free melphalan is parallel to the observation in the pivotal clinical trail of MM patients undergoing auto-HCT [7]. In that study, neutrophil and platelet engraftment was observed on 12 and 13 days post transplant, respectively.…”

“…A novel PG-free melphalan preparation, Evomela ® (PG-free melphalan), uses captisol as a solubilizing agent and thus may be less toxic than PG melphalan formulations. In a phase IIb study of multiple myeloma (MM) patients undergoing auto-HCT, PG-free melphalan showed an acceptable safety profile and comparable efficacy [7]. Consequently, PG-free melphalan was granted FDA approval for use as a conditioning regimen in patients undergoing auto-HCT.…”

“…Approximately 6 g of PG is used for every 50 mg of lyophilized melphalan, resulting in patient being exposed to up to 24 g of PG with high-dose melphalan conditioning at 200 mg/m 2 . PG-free melphalan demonstrated better safety profile and comparable efficacy in patients with MM and lymphoma requiring high-dose melphalan conditioning for auto-HCT [7,10], thus providing a safer and equally efficacious alternative. Lesser number of post-transplant PRBC transfusion requirement was observed in PG-free melphalan group compared to PG melphalan group.…”

Supportive (Maintenance) Therapy in Hematopoietic Stem Cell Transplantation: Main Principles and New Perspectives

“…Еще одной опцией, позволяющей уменьшить проявления мелфаланового мукозита и другой ток-сичности препарата, является попытка изменить его состав. Разработан препарат мелфалана гидрохлорид, не содержащий в качестве растворителя пропиленгли-коль [19]. В клиническом исследовании IIb фазы [19] у больных ММ (n = 61) после аутоТГСК оральный мукозит III степени по классификации ВОЗ был только у 13 % пациентов после введения мелфалана гидрохлорида.…”

“…Разработан препарат мелфалана гидрохлорид, не содержащий в качестве растворителя пропиленгли-коль [19]. В клиническом исследовании IIb фазы [19] у больных ММ (n = 61) после аутоТГСК оральный мукозит III степени по классификации ВОЗ был только у 13 % пациентов после введения мелфалана гидрохлорида. Мукозит IV степени в этом исследовании не наблюдался по сравнению с данными проспективного исследования, в котором мукозит III-IV степени после традиционного мелфалана выявлялся в 46 % случаев [20].…”