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Oral Ixazomib, lenalidomide, and dexamethasone for multiple myeloma

Moreau, Philippe; Masszi, T.; Grzasko, N.; Bahlis, N. J.; Hansson, Markus LU ; Pour, L.; Sandhu, I.; Ganly, P.; Baker, B. W. and Jackson, S. R., et al. (2016) In New England Journal of Medicine 374(17). p.1621-1634
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... (More)

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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New England Journal of Medicine
volume
374
issue
17
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14 pages
publisher
Massachusetts Medical Society
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  • scopus:84964931441
  • wos:000374843400006
ISSN
0028-4793
DOI
10.1056/NEJMoa1516282
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English
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@article{5d27737e-aa02-4c42-bbdd-021bb927cf4f,
  abstract     = {<p>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.</p>},
  author       = {Moreau, Philippe and Masszi, T. and Grzasko, N. and Bahlis, N. J. and Hansson, Markus and Pour, L. and Sandhu, I. and Ganly, P. and Baker, B. W. and Jackson, S. R. and Stoppa, A. M. and Simpson, D. R. and Gimsing, P. and Palumbo, A. and Garderet, L. and Cavo, M. and Kumar, S. and Touzeau, C. and Buadi, F. K. and Laubach, J. P. and Berg, D. T. and Lin, J. and Di Bacco, A. and Hui, A. M. and Van De Velde, H. and Richardson, P. G. and Kupperman, Eric and Berger, Allison and Dick, Larry and Williamson, Mark and Chauhan, Dharminder and Anderson, Kenneth and Esseltine, Dixie Lee and Niculescu, Liviu and Taraskiewicz, Stacey and Stecklair, Jeff and Lonial, Sagar and Rajkumar, Vincent and Miquel, Jésus San and Einsele, Hermann and Orlowski, Robert},
  issn         = {0028-4793},
  language     = {eng},
  month        = {04},
  number       = {17},
  pages        = {1621--1634},
  publisher    = {Massachusetts Medical Society},
  series       = {New England Journal of Medicine},
  title        = {Oral Ixazomib, lenalidomide, and dexamethasone for multiple myeloma},
  url          = {http://dx.doi.org/10.1056/NEJMoa1516282},
  volume       = {374},
  year         = {2016},
}