CLINICAL NEWS
Adding Ixazomib to Lenalidomide and Dexamethasone Results in Longer Progression-Free Survival in Patients with Relapsed / Refractory Myeloma
Treatment with ixazomib plus lenalidomide and dexamethasone increased progression-free survival ( PFS ) by approximately six months – and with limited additional toxic effects – compared with lenalidomide and dexamethasone alone in patients with relapsed , refractory , or relapsed / refractory multiple myeloma ( RRMM ), according to results of the phase III TOURMALINE-MM1 trial published in The New England Journal of Medicine .
The study authors , led by Philippe Moreau , MD , the head of the Hematology Department at the University Hospital Hôtel Dieu in Nantes , France , also reported that the benefit with ixazomib was seen across pre-specified subgroups of patients with typically poor prognoses , including older patients and those with high-risk cytogenetic abnormalities .
“ An increased focus on continuous therapy has heightened the need for regimens that have acceptable side-effect profiles , that allow quality of life to be maintained , and that are easy to administer ,” Dr . Moreau and colleagues wrote . “ In consideration of its adverse-event profile and efficacy , this all-oral regimen provides an additional therapeutic option for patients with RRMM .”
The randomized , doubleblind , placebo-controlled , phase III TOURMALINE-MM1 trial compared the safety and efficacy of lenalidomide and dexamethasone plus placebo or the proteasome inhibitor ( PI ) ixazomib in 722 patients ( median age = 66 years ; range = 30-91 years ) with RRMM .
Patients were excluded from the trial if they had grade > 1 peripheral neuropathy or were refractory to prior lenalidomide therapy or PI – based therapy .
Randomization was stratified based on the number of prior therapies ( 1 vs . 2-3 ), previous exposure to PIs ( not exposed vs . exposed ), and International Staging System ( ISS ) disease stage ( I or II vs . III ).
All patients received a 28-day cycle of lenalidomide 25 mg ( days
1-21 ) and dexamethasone 40 mg ( days 1 , 8 , 15 , and 22 ), with 360 patients receiving ixazomib 4 mg ( days 1 , 8 , and 15 ) and 362 patients receiving placebo .
At the data cut-off point on October 30 , 2014 , the median follow-up was 14.8 months in the ixazomib combination group and 14.6 months in the placebo group . Progression-free survival ( the study ’ s primary endpoint ) was significantly longer in the ixazomibtreated group : 20.6 months versus 14.7 months ( hazard ratio [ HR ] = 0.74 ; 95 % CI 0.59-0.94 ; p = 0.01 ).
The PFS benefit was consistent across pre-specified subgroups , including those :
• with ISS stage III disease : 18.4 months vs . 10.1 months
• older than 75 years : 18.5 months vs . 13.1 months
• who had received 2-3 prior therapies : 17.5 months vs . 14.1 months
Ixazomib also lengthened median PFS in patients with high-risk cytogenetic abnormalities ( 75 in the ixazomib group and 62 in the placebo group ): 21 months versus 9.7 months ( HR = 0.54 ; 95 % CI 0.32-0.92 ; p = 0.02 ).
“ Data on median PFS suggest that an ixazomib regimen may improve the prognosis for patients with high-risk cytogenetic features ( including del17p , t [ 4 ; 14 ], and t [ 14 ; 16 ]), which have traditionally been associated with a poor prognosis by lengthening the PFS to a point that is similar to that among patients with standard-risk cytogenetic features ,” the authors wrote .
The overall response rate ( a secondary endpoint ) was 78.3 percent in the ixazomib group versus 71.5 percent in the placebo group ( p = 0.04 ). “ The responses were durable and deepened with increasing duration of treatment ,” the authors noted .
Disease progression or death occurred less often in the ixazomib combination cohort ( n = 129 events ) compared with the placebo group ( n = 157 events ).
Based on the results of TOURMALINE-MM1 , the U . S . Food and Drug Administration approved ixazomib in combination with lenalidomide and dexamethasone for MM patients who have received at least one prior therapy . The safety profiles were similar between each treatment group , with comparable rates of serious adverse events ( AEs ), AE-related discontinuation of the
study regimen , and death during the study period .
By 23 months , 171 deaths had occurred : 81 in the ixazomib combination group and 90 in the placebo group . “ The only grade ≥3 AE for which there was at least a 5-percent difference between the ixazomib and placebo groups was thrombocytopenia , a known side effect of bortezomib and carfilzomib , for which there were no apparent clinical sequelae ,” they added .
The most common any-grade hematologic adverse events ( AEs ) occurring in both study cohorts included :
• neutropenia ( n = 118 ; 33 % vs . n = 111 ; 31 %)
• thrombocytopenia ( n = 112 ; 31 % vs . n = 57 ; 16 %)
• anemia ( n = 103 ; 29 % vs . n = 48 ; 13 %)
The most common any-grade nonhematologic AEs that occurred in both cohorts included : diarrhea ( n = 164 ; 45 % vs . n = 139 ; 39 %), rash ( n = 131 ; 36 % vs . n = 82 ; 23 %), and constipation ( n = 126 ; 35 % vs . n = 94 ; 26 %).
Dr . Moreau and colleagues also found that ixazomib was well tolerated , with patients in the ixazomib group receiving a median of 17 treatment cycles ( range = 1-34 cycles ) and patients in the
“ An increased focus on continuous therapy has heightened the need for regimens that have acceptable side-effect profiles , that allow quality of life to be maintained , and that are easy to administer .”
placebo group receiving a median of 15 cycles ( range = 1-34 cycles ). “ The duration of therapy with the ixazomib regimen was notable ; almost half the patients had received treatment for at least 18 cycles at the 23-month analysis ,” the authors wrote .
The authors reported that no AEs affecting quality of life were reported in the ixazomib combination cohort , although the tendency to overestimate the quality-of-life benefit in open-label trials was noted as a limitation of this study .
Overall survival was not reached in either treatment group , though follow-up is ongoing .
REFERENCE
Moreau P , Masszi T , Grzasko N , et al . Oral ixazomib , lenalidomide , and dexamethasone for multiple myeloma . N Engl J Med . 2016 ; 374:1621-34 .
— PHILIPPE MOREAU , MD
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