title: Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy.
abstract: In this open-label, intra-patient phase I/II trial, bortezomib was replaced with carfilzomib (escalated from 20 to 45 mg/m(2) on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle) for multiple myeloma (MM) patients who progressed while on or within 12 weeks of receiving a bortezomib-containing combination regimen. Study objectives included determination of the maximum tolerated dose (MTD), overall response rate (ORR), clinical benefit rate (CBR), time to progression, time to response, duration of response, progression-free survival and overall survival (OS). Of 38 registered patients, 37 were treated and evaluable for efficacy and safety. Thirty-one carfilzomib-based regimens using 14 different drug combinations were tested. One regimen (carfilzomib (45 mg/m(2)), ascorbic acid (1000 mg) and cyclophosphamide (2.2 mg/kg)) reached MTD. ORR and CBR were 43.2 and 62.2%, respectively. Median progression-free survival, time to progression and OS were 8.3, 9.9 and 15.8 months, respectively. Hematologic adverse events (AEs; ⩾grade 3) included lymphopenia (35.1%), thrombocytopenia (24.3%), anemia (10.8%) and neutropenia (10.8%). Nonhematologic AEs (⩾grade 3) included fever (5.4%) and hypokalemia (5.4%). These results demonstrate that replacing bortezomib with carfilzomib is safe and can be effective for MM patients failing bortezomib-containing combination regimens. This trial was registered at http://www.clinicaltrials.gov (#NCT01365559).
authors.affiliation: 1] Department of Hematology/Oncology, Institute for Myeloma and Bone Cancer Research, West Hollywood, CA, USA [2] Oncotherapeutics, West Hollywood, CA, USA [3] James R Berenson, MD, Inc., West Hollywood, CA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Berenson
authors.affiliation: Oncotherapeutics, West Hollywood, CA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Hilger
authors.affiliation: Oncotherapeutics, West Hollywood, CA, USA.
authors.forename: O
authors.initials: O
authors.lastname: Yellin
authors.affiliation: Department of Medical Oncology and Hematology, Central Coast Medical Oncology, Santa Maria, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dichmann
authors.affiliation: Department of Hematology, Fairfax Northern Virginia Hematology Oncology, Fairfax, VA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Patel-Donnelly
authors.affiliation: Center for Cancer and Blood Disorders, Bethesda, MD, USA.
authors.forename: R V
authors.initials: RV
authors.lastname: Boccia
authors.affiliation: Department of Medical Oncology and Hematology, California Cancer Associates for Research and Excellence, Encinitas, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bessudo
authors.affiliation: Pacific Cancer Care, Department of Medical Oncology & Hematology, Monterey, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Stampleman
authors.affiliation: Oncology Family Cancer Center Foundation, Memphis, TN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Gravenor
authors.affiliation: Department of Internal Medicine, Hematology, and Oncology, Cedars-Sinai Medical Center, Los Angeles, USA.
authors.forename: S
authors.initials: S
authors.lastname: Eshaghian
authors.affiliation: Cancer Care Institute, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Nassir
authors.affiliation: James R Berenson, MD, Inc., West Hollywood, CA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Swift
authors.affiliation: Department of Internal Medicine, Hematology, and Oncology, Cedars-Sinai Medical Center, Los Angeles, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Vescio
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001897:Boronic Acids / Q000008:administration & dosage / Q000627:therapeutic use; D000069286:Bortezomib; D057915:Drug Substitution; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000187:drug effects*; D011719:Pyrazines / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D009842:Oligopeptides; D011719:Pyrazines; D000069286:Bortezomib; C524865:carfilzomib