Philippe Moreau1, Tamás Masszi1, Norbert Grzasko1, Nizar J Bahlis1, Markus Hansson1, Ludek Pour1, Irwindeep Sandhu1, Peter Ganly1, Bartrum W Baker1, Sharon R Jackson1, Anne-Marie Stoppa1, David R Simpson1, Peter Gimsing1, Antonio Palumbo1, Laurent Garderet1, Michele Cavo1, Shaji Kumar1, Cyrille Touzeau1, Francis K Buadi1, Jacob P Laubach1, Deborah T Berg1, Jianchang Lin1, Alessandra Di Bacco1, Ai-Min Hui1, Helgi van de Velde1, Paul G Richardson1. 1. From University Hospital Hôtel Dieu, Nantes (P.M., C.T.), the Department of Hematology, Institut Paoli-Calmettes, Marseille (A.-M.S.), and the Department of Hematology and Cell Therapy, Hospital Saint Antoine, Paris (L.G.) - all in France; the Department of Haematology and Stem Cell Transplantation, St. István and St. László Hospital, 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary (T.M.); the Department of Haemato-oncology and Bone Marrow Transplantation, Medical University of Lublin, and St. John's Cancer Center, Lublin, Poland (N.G.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary (N.J.B.), and the Division of Hematology, Department of Medicine, University of Alberta, Edmonton (I.S.) - both in Canada; the Department of Hematology, Skåne University Hospital, Lund University, Lund, Sweden (M.H.); Hematology and Oncology, University Hospital Brno, Brno, Czech Republic (L.P.); the Department of Haematology, Christchurch Hospital, Christchurch (P. Ganly), the Department of Haematology, Palmerston North Hospital, Palmerston North, Manawatu (B.W.B.), the Department of Haematology, Middlemore Hospital, Auckland (S.R.J.), and the Department of Haematology, North Shore Hospital, Auckland (D.R.S.) - all in New Zealand; the Department of Hematology, University Hospital Rigshospitalet, Copenhagen (P. Gimsing); Myeloma Unit, Division of Hematology, University of Turin, Turin (A.P.), and Seràgnoli Institute of Haematology, Bologna University School of Medicine, St. Orsola-Malpighi University Hospital, Bologna (M.C.) - both in Italy; the Division of Hematology, Mayo Clinic, Rochester, MN (S.K., F.K.B.); and Dana-Farber Cancer Institute, Boston (J.P.L., P.G.R.), and Millennium Pharmaceuticals, Cambridge (D.T.B., J.L., A.D.B., A.-M.H., H.V.) - both in Massachusetts.
Abstract
BACKGROUND:Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receiveixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebogroup). The primary end point was progression-free survival. RESULTS:Progression-free survival was significantly longer in the ixazomibgroup than in the placebogroup at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomibgroup, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomibgroup and 72% in the placebogroup, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomibgroup and 1.9 months in the placebogroup, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomibgroup and 49% in the placebogroup), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomibgroup (12% and 7% of the patients, respectively) than in the placebogroup (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomibgroup than in the placebogroup (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomibgroup and 22% in the placebogroup (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups. CONCLUSIONS: The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.).
RCT Entities:
BACKGROUND:Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival. RESULTS: Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups. CONCLUSIONS: The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.).
Authors: Hervé Avet-Loiseau; Rafael Fonseca; David Siegel; Meletios A Dimopoulos; Ivan Špička; Tamás Masszi; Roman Hájek; Laura Rosiñol; Vesselina Goranova-Marinova; Georgi Mihaylov; Vladimír Maisnar; Maria-Victoria Mateos; Michael Wang; Ruben Niesvizky; Albert Oriol; Andrzej Jakubowiak; Jiri Minarik; Antonio Palumbo; William Bensinger; Vishal Kukreti; Dina Ben-Yehuda; A Keith Stewart; Mihaela Obreja; Philippe Moreau Journal: Blood Date: 2016-07-20 Impact factor: 22.113
Authors: S Ailawadhi; J R Mikhael; B R LaPlant; K M Laumann; S Kumar; V Roy; D Dingli; P L Bergsagel; F K Buadi; S V Rajkumar; R Fonseca; M A Gertz; P Kapoor; T Sher; S R Hayman; A K Stewart; A Dispenzieri; R A Kyle; W I Gonsalves; C B Reeder; Y Lin; R S Go; N Leung; T Kourelis; J A Lust; S J Russell; A A Chanan-Khan; M Q Lacy Journal: Leukemia Date: 2017-09-01 Impact factor: 11.528