title: Safety and efficacy of targeted-dose busulfan and bortezomib as a conditioning regimen for patients with relapsed multiple myeloma undergoing a second autologous blood progenitor cell transplantation.
abstract: Patients with multiple myeloma (MM) who relapse after autologous transplantation have limited therapeutic options. We conducted a prospective, multicenter, phase IIa study to investigate the safety and efficacy of i.v. busulfan (Bu) in combination with bortezomib as a conditioning regimen for a second autotransplantation. Because a safe Bu exposure was unknown in patients receiving this combination, Bu was initially targeted to a total area under the concentration-time curve (AUC) of 20,000 μM × minute. As no concentration-limiting toxicity was observed in 6 patients, this Bu exposure was utilized in the following treatment cohort (n = 24). Individualized Bu dose, based on test dose .8 mg/kg pharmacokinetics (PK), was administered daily for 4 consecutive days starting 5 days before transplantation, followed by a single dose of bortezomib (1.3 mg/m(2)) 1 day before transplantation. The total mean dose of i.v. Bu (including the test dose and 4-day administration) was 14.2 mg/kg (standard deviation = 2.48; range, 8.7 to 19.2). Confirmatory PK demonstrated that only 2 of 30 patients who underwent transplantation were dosed outside the Bu AUC target and dose adjustments were made for the last 2 doses of i.v. Bu. The median age was 59 years (range, 48 to 73). Median time from first to second transplantation was 28.0 months (range, 12 to 119). Of 26 evaluable patients, 10 patients attained a partial response (PR) or better at 3 months after transplantation, with 2 patients attaining a complete response. At 6 months after transplantation, 5 of 12 evaluable patients had maintained or improved their disease status. Median progression-free survival was 191 days, whereas median overall survival was not reached during the study period. The most common grade 3 and 4 toxicities were febrile neutropenia (50.0%) and stomatitis (43.3%). One transplantation-related death was observed. A combination of dose-targeted i.v. Bu and bortezomib induced PR or better in one third of patients with MM who underwent a second autotransplantation, with acceptable toxicity.
authors.affiliation: South Texas Veterans Health Care System, University of Texas Health Science Center at San Antonio, San Antonio, Texas. Electronic address: cesar.freytes@va.gov.
authors.forename: César O
authors.initials: CO
authors.lastname: Freytes
authors.affiliation: South Texas Veterans Health Care System, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Toro
authors.affiliation: Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Rosa F
authors.initials: RF
authors.lastname: Yeh
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Stadtmauer
authors.affiliation: Bone Marrow Transplantation, Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Voravit
authors.initials: V
authors.lastname: Ratanatharathorn
authors.affiliation: Department of Medical Oncology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland.
authors.forename: Görgün
authors.initials: G
authors.lastname: Akpek
authors.affiliation: Hematology/Oncology, Western Pennsylvania Hospital, Pittsburgh, Pennsylvania.
authors.forename: Entezam
authors.initials: E
authors.lastname: Sahovic
authors.affiliation: Division of Hematology/BMT and Myeloma Program, Department of Internal Medicine - Hematology, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Tricot
authors.affiliation: Texas Transplant Institute, San Antonio, Texas.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Shaughnessy
authors.affiliation: Division of Hematology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: White
authors.affiliation: Cardinal Bernardin Cancer Center, Loyola University Chicago Medical Center, Maywood, Illinois.
authors.forename: Tulio E
authors.initials: TE
authors.lastname: Rodriguez
authors.affiliation: The Blood and Marrow Transplant Program, Northside Hospital, Atlanta, Georgia.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Solomon
authors.affiliation: Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Louie H
authors.initials: LH
authors.lastname: Yu
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey.
authors.forename: Cathy
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey.
authors.forename: Shiva
authors.initials: S
authors.lastname: Patil
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Armstrong
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey.
authors.forename: Angela
authors.initials: A
authors.lastname: Smith
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey.
authors.forename: Agnes
authors.initials: A
authors.lastname: Elekes
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey.
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Kato
authors.affiliation: Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: Donna E
authors.initials: DE
authors.lastname: Reece
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D064592:Autografts; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000069286:Bortezomib; D002066:Busulfan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000401:mortality / Q000628:therapy; D019653:Myeloablative Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011446:Prospective Studies; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D015996:Survival Rate; D019172:Transplantation Conditioning
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D019653:Myeloablative Agonists; D011719:Pyrazines; D000069286:Bortezomib; D002066:Busulfan
keywords: Autologous transplantation; Bortezomib; Busulfan; Multiple myeloma