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Lancet Oncol. 2016 Jan;17(1):27-38. doi: 10.1016/S1470-2045(15)00464-7. Epub 2015 Dec 5.

Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study.

Collaborators (200)

Leahy M, Joshua D, Schwarer A, Kerridge I, Durrant S, Cooney J, Spencer A, Horvath N, Rowlings P, Hahn U, Fay K, Renwick W, Quach H, Taylor K, Ho SJ, Johnston A, Ludwig H, Kasparu H, Delforge M, Schots H, Vekemans MC, Offner F, Wu KL, Doyen C, Bittencourt R, Duarte G, Hungria V, Maiolino A, Schaan M, Scheliga A, Zadra C, Goranova-Marinova V, Gercheva L, Mihaylov G, Grudeva-Popova Z, Sandhu I, Reiman A, Kanjeekal S, Dueck G, LeBlanc R, Minuk L, Tay J, White D, Maisnar V, Pour L, Scudla V, Gregora E, Hajek R, Straub J, Facon T, Moreau P, Stoppa AM, Karlin L, Garderet L, Araujo C, Fermand JP, Lenain P, Rigaudeau S, Eveillard JR, Escoffre-Barbe M, Knop S, Goldschmidt H, Kropff M, Rollig C, Munder M, Langer C, Weisel K, Mugge LO, Hanel M, Niederwieser D, Dimopoulos M, Egyed M, Masszi T, Szomor A, Borbenyi Z, Illes A, Yehuda DB, Benyamini N, Nagler A, Mittleman M, Izhar H, Palumbo A, Cavo M, De Fabritiis P, Gaidano G, Petrini M, Offidani M, Foa R, Gobbi M, Rossi G, Guglielmelli T, Lazzaro A, Musto P, Gozzetti A, Takazako N, Izumi T, Chou T, Ozaki S, Hatake K, Suzuki K, Uike N, Asakura S, Kosugi H, Handa H, Matsumoto M, Tobinai K, Iida S, Kizaki M, Miyamoto T, Shibayama H, Ando K, Ishikawa T, Ishida T, Sugiura I, Izutsu K, Taniwaki M, Lee JH, Kim K, Kim JS, Min CK, Yoon SS, Lee JO, Suh C, Simpson D, Ganly P, Blacklock H, Doocey R, Chiruka S, Hellmann A, Gornik S, Komarnicki M, Malgorzata Calbecka, Grosicki S, Jurczyszyn A, Stoia R, Gheorghita E, Danaila CD, Abdulkadyrov K, Zaritskiy A, Suvorov A, Andreeva N, Rimashevskaya E, Balakireva T, Podoltseva E, Rossiev V, Pristupa A, Chng WJ, Hsieh WS, Gopalakrishnan SK, Mistrik M, Rocafiguera AO, Mateos V, Rubia J, Dachs LR, Sanchez JM, Alegre A, Bargay J, de Oteyza JP, Martinez J, Chen TY, Lin TL, Liu JH, Wang MC, Yeh SP, Huang SY, Vinnyk Y, Kriachok I, Pylypenko H, Shparyk Y, Kaplan P, Karamanesht L, Rekhtman G, Romanyuk N, Kaiser M, Mehta A, Williams C, Basu S, Rabin N, Ramasamy K, Hunter H, Tholouli E, Lebovic D, Siegel D, Wang M, Niesvizky R, Kovacsovics T, Hurd D, Gabrail N, Matous J, Pendergrass K, Agrawal M, Boccia R, Chandra S, Kassim A, Stanisic S, Coleman M, Gersten T, Braunschweig I, Chowdhury S, Sahovic E.

Author information

1
School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: mdimop@med.uoa.gr.
2
University of Nantes, Nantes, France.
3
University of Turin, Turin, Italy.
4
Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
5
University Hospital Brno, Brno, Czech Republic.
6
University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
7
CHRU Lille Hôpital Claude Huriez, Lille, France.
8
Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria.
9
Institut Català d'Oncologia, Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain.
10
Heidelberg Medical University, Heidelberg, Germany.
11
Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain.
12
Vseobecna fakultni nemocnice v Praze, Prague, Czech Republic.
13
Hematological Department, First Republican Clinical Hospital of Udmurtia, Izhevsk, Russia.
14
Centre Hospitalier de la Cote Basque, Bayonne, France.
15
Semashko Central Clinical Hospital, Moscow, Russia.
16
Department of Hematooncology, University Hospital Olomouc, Olomouc, Czech Republic.
17
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
18
Universitatsklinikum Tubingen, Tubingen, Germany.
19
University Multiprofile Hospital for Active Treatment Sveti Georgi and Hematology Clinic, Plovdiv, Bulgaria.
20
Box Hill Hospital, Box Hill, Victoria, Australia.
21
London Health Sciences Centre, Western University, London, Ontario, Canada.
22
Department of Haematology and Stem-cell Transplant, St Istvan and St Laszlo Hospital of Budapest, Budapest, Hungary.
23
Kyiv Center for Bone Marrow Transplantation, Kyiv, Ukraine.
24
Clinica di Ematologia, Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I-G.M. Lancisi-G. Salesi di Ancona, Ancona, Italy.
25
Irmandade da Santa Casa de Misericórdia de Sao Paulo, Sao Paulo, Brazil.
26
Alfred Health-Monash University, Melbourne, Victoria, Australia.
27
The University of Texas MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.
28
Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA.
29
National University Cancer Institute, National University Health System, Singapore and Cancer Science Institute of Singapore, National University of Singapore, Singapore.

Abstract

BACKGROUND:

Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma.

METHODS:

In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m(2) on days 1 and 2 of cycle 1; 56 mg/m(2) thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m(2); intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866.

FINDINGS:

Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3-16·1) in the carfilzomib group and 11·1 months (8·2-14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6-not estimable) in the carfilzomib group versus 9·4 months (8·4-10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44-0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]).

INTERPRETATION:

For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option.

FUNDING:

Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

PMID:
26671818
DOI:
10.1016/S1470-2045(15)00464-7
[Indexed for MEDLINE]
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