Meletios A Dimopoulos1, Francesca Gay2, Fredrik Schjesvold3, Meral Beksac4, Roman Hajek5, Katja Christina Weisel6, Hartmut Goldschmidt7, Vladimir Maisnar8, Philippe Moreau9, Chang Ki Min10, Agnieszka Pluta11, Wee-Joo Chng12, Martin Kaiser13, Sonja Zweegman14, Maria-Victoria Mateos15, Andrew Spencer16, Shinsuke Iida17, Gareth Morgan18, Kaveri Suryanarayan19, Zhaoyang Teng19, Tomas Skacel19, Antonio Palumbo20, Ajeeta B Dash19, Neeraj Gupta19, Richard Labotka19, S Vincent Rajkumar21. 1. Hematology & Medical Oncology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece. Electronic address: mdimop@med.uoa.gr. 2. Department of Oncology and Hematology, Azienda Ospedaliero-Universitaria City of Health and Science of Turin, Turin, Italy. 3. Oslo Myeloma Center, Oslo University Hospital, Oslo, Norway; KG Jebsen Center for B cell malignancies, University of Oslo, Oslo, Norway. 4. Department of Hematology, Ankara University, Ankara, Turkey. 5. Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic. 6. Department of Internal Medicine II, University of Tuebingen, Tuebingen, Germany. 7. Department of Internal Medicine V, University Medical Hospital and National Center of Tumor Diseases, University of Heidelberg, Heidelberg, Germany. 8. Fourth Department of Medicine-Hematology, FN and LF UK Hradec Králové, Hradec Králové, Czech Republic. 9. Department of Hematology, University Hospital Hôtel Dieu, University of Nantes, Nantes, France. 10. Department of Internal Medicine, Seoul St Mary's Hospital, Seoul, South Korea. 11. Department of Haematology, Medical University of Lodz, Multidisciplinary Provincial Centre of Traumatology and Oncology Nicolas Copernicus in Lodz, Lodz, Poland. 12. Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore and Cancer Science Institute of Singapore, National University of Singapore, Singapore. 13. Department of Haematology, The Royal Marsden Hospital, London, UK; Division of Molecular Pathology, The Institute of Cancer Research ICR, London, UK. 14. Department of Hematology, Amsterdam University Medical Center, VU University Amsterdam, Cancer Center Amsterdam, Netherlands. 15. Department of Hematology, University Hospital of Salamanca, CIC, IBMCC, Salamanca, Spain. 16. Malignant Haematology and Stem Cell Transplantation Service, Alfred Health-Monash University, Melbourne, VA, Australia. 17. Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 18. Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA. 19. Millennium Pharmaceuticals, Cambridge, MA, USA. 20. Millennium Pharmaceuticals, Cambridge, MA, USA; Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria S Giovanni Battista, Torino, Italy; Center for Hematology and Oncology, University Hospital Zürich, Zürich, Switzerland. 21. Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
Abstract
BACKGROUND: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. METHODS: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1-4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. FINDINGS:Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3-35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7-33·8] vs 21·3 months [18·0-24·7]; hazard ratio 0·72, 95% CI 0·58-0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. INTERPRETATION:Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.
RCT Entities:
BACKGROUND: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. METHODS: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1-4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. FINDINGS: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3-35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7-33·8] vs 21·3 months [18·0-24·7]; hazard ratio 0·72, 95% CI 0·58-0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. INTERPRETATION:Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.