Paul G Richardson1, Shaji K Kumar2, Tamás Masszi3, Norbert Grzasko4,5, Nizar J Bahlis6, Markus Hansson7,8, Luděk Pour9, Irwindeep Sandhu10, Peter Ganly11, Bartrum W Baker12, Sharon R Jackson13, Anne-Marie Stoppa14, Peter Gimsing15, Laurent Garderet16, Cyrille Touzeau17, Francis K Buadi2, Jacob P Laubach1, Michele Cavo18, Mohamed Darif19, Richard Labotka19, Deborah Berg19, Philippe Moreau17. 1. Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. 2. Division of Hematology, Mayo Clinic, Rochester, MN. 3. 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary. 4. Department of Experimental Haematooncology, Medical University of Lublin, Lublin, Poland. 5. Center of Oncology of the Lublin Region St Jana z Dukli, Lublin, Poland. 6. Arnie Charbonneau Cancer Research Institute, University of Calgary, Calgary, Canada. 7. Department of Hematology, Skåne University Hospital, Lund, Sweden. 8. Sahlgrenska Academy, Göteborg, Sweden. 9. Hematology and Oncology, University Hospital Brno, Brno, Czech Republic. 10. Cross Cancer Institute, University of Alberta, Edmonton, Canada. 11. Department of Haematology, Christchurch Hospital, Christchurch, New Zealand. 12. Department of Haematology, Palmerston North Hospital, Palmerston North, New Zealand. 13. Department of Haematology, Middlemore Hospital, Auckland, New Zealand. 14. Department of Hematology, Institut Paoli-Calmettes, Marseille, France. 15. Department of Hematology, University Hospital Rigshospitalet, Copenhagen, Denmark. 16. Hôpital Pitié-Salpêtrière, Paris, France. 17. University Hospital Hôtel Dieu, Nantes, France. 18. IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy. 19. Millennium Pharmaceuticals Inc, Cambridge, MA.
Abstract
PURPOSE: The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS). PATIENTS AND METHODS: Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 v 2 or 3), previous proteasome inhibitor (PI) exposure (yes v no), and International Staging System disease stage (I or II v III). OS (intent-to-treat population) was a key secondary end point. RESULTS: With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; P = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% v 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns. CONCLUSION: Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.
PURPOSE: The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS). PATIENTS AND METHODS: Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 v 2 or 3), previous proteasome inhibitor (PI) exposure (yes v no), and International Staging System disease stage (I or II v III). OS (intent-to-treat population) was a key secondary end point. RESULTS: With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; P = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% v 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns. CONCLUSION: Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.
Authors: Shaji Kumar; Lawrence Baizer; Natalie S Callander; Sergio A Giralt; Jens Hillengass; Boris Freidlin; Antje Hoering; Paul G Richardson; Elena I Schwartz; Anthony Reiman; Suzanne Lentzsch; Philip L McCarthy; Sundar Jagannath; Andrew J Yee; Richard F Little; Noopur S Raje Journal: Blood Cancer J Date: 2022-06-29 Impact factor: 9.812
Authors: Catherine S Y Lecat; Jessica B Taube; William Wilson; Jonathan Carmichael; Christopher Parrish; Gabriel Wallis; Charalampia Kyriakou; Lydia Lee; Shameem Mahmood; Xenofon Papanikolaou; Neil K Rabin; Jonathan Sive; Ashutosh D Wechalekar; Kwee Yong; Gordon Cook; Rakesh Popat Journal: Front Oncol Date: 2021-07-21 Impact factor: 6.244