CLINICAL NEWS
Adding Carfilzomib to Lenalidomide and Dexamethasone Extends Overall Survival in Multiple Myeloma
Compared with standard therapy of lenalidomide and dexamethasone , the addition of carfilzomib improved survival , without increasing the risk of adverse events ( AEs ) in patients with relapsed or refractory multiple myeloma ( MM ), according to final results from the phase III ASPIRE trial . 1
“ At interim analysis … the addition of carfilzomib significantly improved progression-free survival ( PFS ) compared with [ lenalidomide and dexamethasone ],” the study investigators , led by David S . Siegel , MD , PhD , of John Theurer Cancer Center at Hackensack University Medical Center in New Jersey , wrote in the Journal of Clinical Oncology . 2 “ Despite prolonged treatment exposure in the [ carfilzomib ] group , rates of discontinuation because of AEs were lower … and the frequency of AE-related deaths was identical in the two groups ,” they noted .
In the final overall survival ( OS ) analysis , researchers evaluated long-term survival and safety data from 792 patients enrolled in the trial . All participants had MM and had previously received one to three lines of therapy . Patients were randomized 1:1 to receive lenalidomide and dexamethasone with or without the proteasome inhibitor carfilzomib in the following 28-day cycles :
• lenalidomide 25 mg on days 1-21 of each cycle
• dexamethasone 40 mg on days 1 , 8 , 15 , and 22 of each cycle
• carfilzomib administered as a 10-minute infusion at a starting dose of 20 mg / m 2 on days 1 and 2 of cycle 1 ; a target dose of 27 mg / m 2 on days 8 , 9 , 15 , and 16 of cycle 1 and days 1 , 2 , 8 , 9 , 15 , and 16 during cycles 2-12 ; and 27 mg / m 2 on days 1 , 2 , 15 , and 16 during cycles 13-18
Treatment continued until disease progression , study withdrawal , or unacceptable toxicity . After 18 cycles , patients in the carfilzomib group received lenalidomide and dexamethasone alone , due to limited long-term safety data with carfilzomib when the trial was initiated .
After a median follow-up of 48 months ( range not provided ), patients treated with carfilzomib had longer median PFS ( primary endpoint ) than those receiving standard-of-care alone : 26.1 months ( range = 23.2-30.3 months ) vs . 16.6 months ( range = 14.5-19.4 months ). This translated to a hazard ratio ( HR ) of death or disease progression of 0.66 ( 95 % CI 0.55-0.78 ; p < 0.001 ). OS , a secondary endpoint , was extended in the carfilzomib group , after a median followup of 67 months ( range not reported ): 48.3 months ( range = 42.4- 52.8 months ) versus 40.4 months ( range = 33.6-44.4 months ), for a 21-percent reduction in the risk of death ( HR = 0.79 ; 95 % CI 0.67- 0.95 ; p = 0.004 ). “ Notably , the OS benefit was not a result of poor outcomes in the lenalidomidedexamethasone group ,” the authors wrote . “ The reported median OS of 40.4 months in the lenalidomidedexamethasone group is similar to that observed in other phase III studies of relapsed / refractory MM .”
Investigators also conducted separate analyses to identify factors associated with longer median OS among carfilzomibtreated patients , finding that fewer prior lines of therapy and less-severe cytogenetic risk predicted extended survival ( p values not reported ):
• 1 prior line of therapy : 47.3 months vs . 35.9 months ( HR = 0.81 ; 95 % CI 0.62-1.06 )
• ≥2 previous therapies : 48.8 months vs . 42.3 months ( HR = 0.79 ; 95 % CI 0.62-0.99 )
• standard cytogenetic risk : 49.0 months vs . 41.4 months ( HR = 0.74 ; 95 % CI 0.56-0.97 )
However , in patients with high-risk cytogenetics , the median OS was similar in both groups ( 36 months vs . 36 months ; HR = 1.08 ; 95 % CI 0.67-1.74 ).
Additionally , there was an observed improvement in the median OS by 18.6 months among patients with prior transplantation at first relapse in the carfilzomib group versus the lenalidomide and dexamethasone group ( 57.2 months vs . 38.6 months , respectively ; HR = 0.71 ; 95 % CI 0.48-1.05 ).
Discontinuation of treatment was high in both groups ( 85.9 % for carfilzomib and 90.4 % for standard-of-care ), mostly due to disease progression ( 47.5 %
“[ This triplet combination ] is a highly effective therapy for patients at first relapse , which should be reflected in future treatment algorithms .”
and 56.6 %, respectively ). However , “ despite prolonged treatment exposure in the carfilzomib versus lenalidomidedexamethasone group , rates of treatment discontinuation because of AEs were similar in the two groups ( 19.9 % and 21.5 %, respectively ),” the investigators noted .
Safety profiles also were similar in both treatment arms and consistent with previous reports from these agents . The most common AEs of any grade in both groups included anemia , neutropenia , diarrhea , fatigue , cough , and respiratory tract infections . Rates of serious AEs were not significantly different between the carfilzomib and standard-of-care groups , as well ( 65.3 % vs . 56.8 %; p value not reported ).
“ Early treatment with an effective regimen is important to maximize OS , because shorter response durations and increased treatment resistance are associated with each subsequent line of therapy ,” the investigators concluded . “ Carfilzomib plus lenalidomide and
— DAVID S . SIEGEL , MD , PhD
dexamethasone is a highly effective therapy for patients at first relapse , which should be reflected in future treatment algorithms .”
The study is limited by its open-label design , which may have introduced bias .
The authors report financial relationships with Celgene and Amgen , which sponsored the trial .
REFERENCES
1 . Siegel DS , Dimopoulos MA , Ludwig H , et al . Improvement in overall survival with carfilzomib , lenalidomide , and dexamethasone in patients with relapsed or refractory multiple myeloma . J Clin Oncol . 2018 ; 36:728-34 .
2 . Dimopoulos MA , Stewart AK , Masszi T , et al . Carfilzomib , lenalidomide , and dexamethasone in patients with relapsed multiple myeloma categorised by age : secondary analysis from the phase 3 ASPIRE study . Br J Haematol . 2017 ; 177:404-13 .
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