Shaji K Kumar1, Jesus G Berdeja2, Ruben Niesvizky3, Sagar Lonial4, Jacob P Laubach5, Mehdi Hamadani6, A Keith Stewart7, Parameswaran Hari8, Vivek Roy9, Robert Vescio10, Jonathan L Kaufman4, Deborah Berg11, Eileen Liao11, Alessandra Di Bacco11, Jose Estevam11, Neeraj Gupta11, Ai-Min Hui11, Vincent Rajkumar12, Paul G Richardson5. 1. Division of Hematology, Mayo Clinic, Rochester, MN, USA. Electronic address: kumar.shaji@mayo.edu. 2. Sarah Cannon Research Institute, Nashville, TN, USA. 3. Myeloma Center, Weill Cornell Medical College, New York Presbyterian Hospital, NY, USA. 4. Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA. 5. Dana-Farber Cancer Institute, Boston, MA, USA. 6. West Virginia University, Mary Babb Randolph Cancer Center, Morgantown, WV, USA. 7. Mayo Clinic College of Medicine, Scottsdale, AZ, USA. 8. Division of Hematology Oncology, Medical College of Wisconsin, Milwaukee, WI, USA. 9. Mayo Clinic, Jacksonville, FL, USA. 10. Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA. 11. Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company, Cambridge, MA, USA. 12. Division of Hematology, Mayo Clinic, Rochester, MN, USA.
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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company.
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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company.
Authors: Chang-Xin Shi; K Martin Kortüm; Yuan Xiao Zhu; Laura A Bruins; Patrick Jedlowski; Patrick G Votruba; Moulun Luo; Robert A Stewart; Jonathan Ahmann; Esteban Braggio; A Keith Stewart Journal: Mol Cancer Ther Date: 2017-09-27 Impact factor: 6.261
Authors: A Alloo; H Khosravi; S R Granter; S M Jadeja; P G Richardson; J J Castillo; N R LeBoeuf Journal: Support Care Cancer Date: 2018-02-01 Impact factor: 3.603