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.
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.
Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address: phari@mcw.edu.
Parameswaran
P
Hari
Blood and Marrow Transplant Program, Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
Omar S
OS
Aljitawi
Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.
Carlos
C
Arce-Lara
Division of Hematology/Oncology, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts.
Rajneesh
R
Nath
Bone Marrow Transplant Clinic, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Natalie
N
Callander
Departments of Biostatistics, Data Management, and Medical Writing, Spectrum Pharmaceuticals, Irvine, California.
Gajanan
G
Bhat
Departments of Biostatistics, Data Management, and Medical Writing, Spectrum Pharmaceuticals, Irvine, California.
Lee F
LF
Allen
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Keith
K
Stockerl-Goldstein
D000328:Adult; D000368:Aged; D003505:Cyclodextrins / Q000737:chemistry; D004334:Drug Administration Schedule; D005260:Female; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008558:Melphalan / Q000737:chemistry / Q000627:therapeutic use*; D008875:Middle Aged; D052016:Mucositis / Q000209:etiology / Q000473:pathology; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019653:Myeloablative Agonists / Q000737:chemistry / Q000627:therapeutic use*; D019946:Propylene Glycol; D012720:Severity of Illness Index; D012995:Solubility; D013280:Stomatitis / Q000209:etiology / Q000473:pathology; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D014182:Transplantation, Autologous; D016896:Treatment Outcome
D003505:Cyclodextrins; D019653:Myeloablative Agonists; D019946:Propylene Glycol; D008558:Melphalan
Captisol-enabled melphalan formulation; Melphalan; Multiple myeloma; Preparative regimen; Propylene glycol-free melphalan; Stem cell transplantation; Transplantation conditioning