Oral Ixazomib, lenalidomide, and dexamethasone for multiple myeloma

TOURMALINE-MM1 Study Group

Research output: Article

403 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1621-1634
Number of pages14
JournalNew England Journal of Medicine
Volume374
Issue number17
DOIs
Publication statusPublished - ápr. 28 2016

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Multiple Myeloma
Dexamethasone
Placebos
Disease-Free Survival
lenalidomide
ixazomib
Proteasome Inhibitors
Poisons
Peripheral Nervous System Diseases
Exanthema
Chromosome Aberrations
Disease Progression
Quality of Life

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Oral Ixazomib, lenalidomide, and dexamethasone for multiple myeloma. / TOURMALINE-MM1 Study Group.

In: New England Journal of Medicine, Vol. 374, No. 17, 28.04.2016, p. 1621-1634.

Research output: Article

TOURMALINE-MM1 Study Group. / Oral Ixazomib, lenalidomide, and dexamethasone for multiple myeloma. In: New England Journal of Medicine. 2016 ; Vol. 374, No. 17. pp. 1621-1634.
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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 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.",
author = "{TOURMALINE-MM1 Study Group} and P. Moreau and T. Masszi and N. Grzasko and Bahlis, {N. J.} and M. Hansson and L. Pour and I. Sandhu and P. Ganly and Baker, {B. W.} and Jackson, {S. R.} and Stoppa, {A. M.} and Simpson, {D. R.} and P. Gimsing and A. Palumbo and L. Garderet and M. Cavo and S. Kumar and C. Touzeau and Buadi, {F. K.} and Laubach, {J. P.} and Berg, {D. T.} and J. Lin and {Di Bacco}, A. and Hui, {A. M.} and {Van De Velde}, H. and Richardson, {P. G.} and Eric Kupperman and Allison Berger and Larry Dick and Mark Williamson and Dharminder Chauhan and Kenneth Anderson and Esseltine, {Dixie Lee} and Liviu Niculescu and Stacey Taraskiewicz and Jeff Stecklair and Sagar Lonial and Vincent Rajkumar and Miquel, {J{\'e}sus San} and Hermann Einsele and Robert Orlowski",
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TY - JOUR

T1 - Oral Ixazomib, lenalidomide, and dexamethasone for multiple myeloma

AU - TOURMALINE-MM1 Study Group

AU - Moreau, P.

AU - Masszi, T.

AU - Grzasko, N.

AU - Bahlis, N. J.

AU - Hansson, M.

AU - Pour, L.

AU - Sandhu, I.

AU - Ganly, P.

AU - Baker, B. W.

AU - Jackson, S. R.

AU - Stoppa, A. M.

AU - Simpson, D. R.

AU - Gimsing, P.

AU - Palumbo, A.

AU - Garderet, L.

AU - Cavo, M.

AU - Kumar, S.

AU - Touzeau, C.

AU - Buadi, F. K.

AU - Laubach, J. P.

AU - Berg, D. T.

AU - Lin, J.

AU - Di Bacco, A.

AU - Hui, A. M.

AU - Van De Velde, H.

AU - Richardson, P. G.

AU - Kupperman, Eric

AU - Berger, Allison

AU - Dick, Larry

AU - Williamson, Mark

AU - Chauhan, Dharminder

AU - Anderson, Kenneth

AU - Esseltine, Dixie Lee

AU - Niculescu, Liviu

AU - Taraskiewicz, Stacey

AU - Stecklair, Jeff

AU - Lonial, Sagar

AU - Rajkumar, Vincent

AU - Miquel, Jésus San

AU - Einsele, Hermann

AU - Orlowski, Robert

PY - 2016/4/28

Y1 - 2016/4/28

N2 - 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.

AB - 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.

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