title: Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study.
abstract: BACKGROUND
  The combination of bortezomib, lenalidomide, and dexamethasone is a highly effective therapy for newly diagnosed multiple myeloma. Ixazomib is an investigational, oral, proteasome inhibitor with promising anti-myeloma effects and low rates of peripheral neuropathy. In a phase 1/2 trial we aimed to assess the safety, tolerability, and activity of ixazomib in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma.
  
  
  METHODS
  We enrolled patients newly diagnosed with multiple myeloma aged 18 years or older with measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and no grade 2 or higher peripheral neuropathy, and treated them with oral ixazomib (days 1, 8, 15) plus lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to 12 28-day cycles, followed by maintenance therapy with ixazomib alone. In phase 1, we gave patients escalating doses of ixazomib (1·68-3·95 mg/m(2)) to establish the recommended dose for phase 2. The primary endpoints were maximum tolerated dose for phase 1, and the rate of very good partial response or better for phase 2. Safety analyses were done in all patients who received at least one dose of study drug; efficacy analyses were done in all patients who received at least one dose of study drug at the phase 2 dose, had measurable disease at baseline, and had at least one post-baseline response assessment. This study is registered at ClinicalTrials.gov, number NCT01217957.
  
  
  RESULTS
  Between Nov 22, 2010, and Feb 28, 2012, we enrolled 65 patients (15 to phase 1 and 50 to phase 2). Four dose-limiting toxic events were noted in phase 1: one at a dose of ixazomib of 2·97 mg/m(2) and three at 3·95 mg/m(2). The maximum tolerated dose of ixazomib was established as 2·97 mg/m(2) and the recommended phase 2 dose was 2·23 mg/m(2), which was converted to a 4·0 mg fixed dose based on population pharmacokinetic results. Grade 3 or higher adverse events related to any drug were reported in 41 (63%) patients, including skin and subcutaneous tissue disorders (11 patients, 17%), neutropenia (eight patients, 12%), and thrombocytopenia (five patients, 8%); drug-related peripheral neuropathy of grade 3 or higher occurred in four (6%) patients. Five patients discontinued because of adverse events. In 64 response-evaluable patients, 37 (58%, 95% CI 45-70) had a very good partial response or better.
  
  
  CONCLUSIONS
  The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone was generally well tolerated and appeared active in newly diagnosed multiple myeloma. These results support the phase 3 trial development of this combination for multiple myeloma.
  
  
  BACKGROUND
  Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company.
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN, USA. Electronic address: kumar.shaji@mayo.edu.
authors.forename: Shaji K
authors.initials: SK
authors.lastname: Kumar
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Jesus G
authors.initials: JG
authors.lastname: Berdeja
authors.affiliation: Myeloma Center, Weill Cornell Medical College, New York Presbyterian Hospital, NY, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Niesvizky
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Laubach
authors.affiliation: West Virginia University, Mary Babb Randolph Cancer Center, Morgantown, WV, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Hamadani
authors.affiliation: Mayo Clinic College of Medicine, Scottsdale, AZ, USA.
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.affiliation: Division of Hematology Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Hari
authors.affiliation: Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Roy
authors.affiliation: Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Vescio
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Kaufman
authors.affiliation: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company, Cambridge, MA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Berg
authors.affiliation: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company, Cambridge, MA, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Liao
authors.affiliation: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company, Cambridge, MA, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Bacco
authors.affiliation: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company, Cambridge, MA, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Estevam
authors.affiliation: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company, Cambridge, MA, USA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company, Cambridge, MA, USA.
authors.forename: Ai-Min
authors.initials: AM
authors.lastname: Hui
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Rajkumar
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001896:Boron Compounds / Q000627:therapeutic use*; D003907:Dexamethasone / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D061988:Proteasome Inhibitors / Q000008:administration & dosage*; D012449:Safety; D015996:Survival Rate; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D001896:Boron Compounds; D061988:Proteasome Inhibitors; D013792:Thalidomide; C548400:ixazomib; D003907:Dexamethasone; D000077269:Lenalidomide; D005998:Glycine