Meletios A Dimopoulos1, Sebastian Grosicki2, Wiesław W Jędrzejczak3, Hareth Nahi4, Astrid Gruber5, Markus Hansson6, Neeraj Gupta7, Catriona Byrne8, Richard Labotka9, Zhaoyang Teng10, Huyuan Yang11, Norbert Grzasko12, Shaji Kumar13. 1. Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece. Electronic address: mdimop@med.uoa.gr. 2. Department of Cancer Prevention, Silesian Medical University, Katowice, Poland. Electronic address: sgrosicki@wp.pl. 3. Department of Haematology and Oncology, Medical University of Warsaw, Warsaw, Poland. Electronic address: wieslaw.jedrzejczak@wum.edu.pl. 4. Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden. Electronic address: hareth.nahi@sll.se. 5. Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden. Electronic address: astridgruber7@gmail.com. 6. Hematology Clinic, Skåne University Hospital, Lund, Sweden; Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden. Electronic address: markus.hansson@med.lu.se. 7. Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. Electronic address: neeraj.gupta@takeda.com. 8. Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. Electronic address: Catriona.Byrne@takeda.com. 9. Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. Electronic address: Richard.labotka@takeda.com. 10. Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. Electronic address: zhaoyang.teng2@takeda.com. 11. Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. Electronic address: Huyuan.Yang@takeda.com. 12. Department of Haematology, St. John's Cancer Centre, Lublin, Poland; Department of Experimental Haemato-oncology, Medical University of Lublin, Lublin, Poland(1). Electronic address: norbertgrzasko@gmail.com. 13. Division of Hematology, Mayo Clinic, Rochester, MN, USA. Electronic address: kumar.shaji@mayo.edu.
Abstract
BACKGROUND: Novel efficacious treatments with long-term tolerability are needed for transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. This phase 2 study evaluated the safety and efficacy of all-oral ixazomib-cyclophosphamide-dexamethasone (ICd) followed by single-agent ixazomib maintenance. PATIENTS AND METHODS: Patients were randomised (1:1) to receive 4.0 mg of ixazomib, 300 (Arm A) or 400 (Arm B) mg/m2 of cyclophosphamide (days 1, 8, and 15), and 40 mg of dexamethasone (days 1, 8, 15, and 22) as induction (up to 13 × 28-day cycles), followed by single-agent ixazomib maintenance (28-day cycles) until progressive disease, death, or unacceptable toxicity. Primary end-point was complete response (CR) + very good partial response (VGPR) rate for ICd induction. RESULTS:Seventy patients were enrolled (n = 36 Arm A; n = 34 Arm B); median age was 73 years (range, 61-87). At data cut-off, 66% of patients had completed 13 induction cycles followed by ixazomib maintenance. Median overall treatment duration was 19 cycles (range, 1-29); 21% of patients discontinued treatment during induction and 3% during maintenance due to adverse events (AEs). During induction, among 67 response-evaluable patients, CR+VGPR rate was 25%, and overall response rate (ORR) was 73%. Including the maintenance phase, CR+VGPR rate was 33%, and ORR was 76%. Median progression-free survival was 23.5 months (median follow-up: 26.1 months). The most common all-grade AE was neutropenia (31%). Grade ≥3 AEs were reported by 73% of patients. Five on-study deaths occurred (not treatment-related). CONCLUSIONS: ICd treatment followed by ixazomib maintenance is tolerable and active in elderly, transplant-ineligible NDMM patients. TRIAL REGISTRATION NUMBER: NCT02046070.
RCT Entities:
BACKGROUND: Novel efficacious treatments with long-term tolerability are needed for transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. This phase 2 study evaluated the safety and efficacy of all-oral ixazomib-cyclophosphamide-dexamethasone (ICd) followed by single-agent ixazomib maintenance. PATIENTS AND METHODS: Patients were randomised (1:1) to receive 4.0 mg of ixazomib, 300 (Arm A) or 400 (Arm B) mg/m2 of cyclophosphamide (days 1, 8, and 15), and 40 mg of dexamethasone (days 1, 8, 15, and 22) as induction (up to 13 × 28-day cycles), followed by single-agent ixazomib maintenance (28-day cycles) until progressive disease, death, or unacceptable toxicity. Primary end-point was complete response (CR) + very good partial response (VGPR) rate for ICd induction. RESULTS: Seventy patients were enrolled (n = 36 Arm A; n = 34 Arm B); median age was 73 years (range, 61-87). At data cut-off, 66% of patients had completed 13 induction cycles followed by ixazomib maintenance. Median overall treatment duration was 19 cycles (range, 1-29); 21% of patients discontinued treatment during induction and 3% during maintenance due to adverse events (AEs). During induction, among 67 response-evaluable patients, CR+VGPR rate was 25%, and overall response rate (ORR) was 73%. Including the maintenance phase, CR+VGPR rate was 33%, and ORR was 76%. Median progression-free survival was 23.5 months (median follow-up: 26.1 months). The most common all-grade AE was neutropenia (31%). Grade ≥3 AEs were reported by 73% of patients. Five on-study deaths occurred (not treatment-related). CONCLUSIONS: ICd treatment followed by ixazomib maintenance is tolerable and active in elderly, transplant-ineligible NDMM patients. TRIAL REGISTRATION NUMBER: NCT02046070.
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