Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study
Meletios A Dimopoulos, Philippe Moreau, Antonio Palumbo, Douglas Joshua, Ludek Pour, Roman Hájek, Thierry Facon, Heinz Ludwig, Albert Oriol, Hartmut Goldschmidt, Laura Rosiñol, Jan Straub, Aleksandr Suvorov, Carla Araujo, Elena Rimashevskaya, Tomas Pika, Gianluca Gaidano, Katja Weisel, Vesselina Goranova-Marinova, Anthony Schwarer, Leonard Minuk, Tamás Masszi, Ievgenii Karamanesht, Massimo Offidani, Vania Hungria, Andrew Spencer, Robert Z Orlowski, Heidi H Gillenwater, Nehal Mohamed, Shibao Feng, Wee-Joo Chng, ENDEAVOR Investigators, Michael Leahy, Douglas Joshua, Anthony Schwarer, Ian Kerridge, Simon Durrant, Julian Cooney, Andrew Spencer, Noemi Horvath, Philip Rowlings, Uwe Hahn, Keith Fay, William Renwick, Hang Quach, Kerry Taylor, Shir-Jing Ho, Amanda Johnston, Heinz Ludwig, Hedwig Kasparu, Michel Delforge, Henri Schots, Marie-Christiane Vekemans, Fritz Offner, Ka Lung Wu, Chantal Doyen, Rosane Bittencourt, Gislaine Duarte, Vania Hungria, Angelo Maiolino, Mariza Schaan, Adriana Scheliga, Cyntia Zadra, Vesselina Goranova-Marinova, Liana Gercheva, Georgi Mihaylov, Zhanet Grudeva-Popova, Irwindeep Sandhu, Anthony Reiman, Sindu Kanjeekal, Greg Dueck, Richard LeBlanc, Leonard Minuk, Jason Tay, Darrell White, Vladimir Maisnar, Ludek Pour, Vlastimil Scudla, Evzen Gregora, Roman Hajek, Jan Straub, Thierry Facon, Philippe Moreau, Anne-Marie Stoppa, Lionel Karlin, Laurent Garderet, Carla Araujo, Jean-Paul Fermand, Pascal Lenain, Sophie Rigaudeau, Jean-Richard Eveillard, Martine Escoffre-Barbe, Stefan Knop, Hartmut Goldschmidt, Martin Kropff, Christoph Rollig, Markus Munder, Christian Langer, Katja Weisel, Lars-Olof Mugge, Mathias Hanel, Dietger Niederwieser, Meletios Dimopoulos, Miklos Egyed, Tamas Masszi, Arpad Szomor, Zita Borbenyi, Arpad Illes, Dina Ben Yehuda, Noam Benyamini, Arnon Nagler, Moshe Mittleman, Hardan Izhar, Antonio Palumbo, Michele Cavo, Paolo De Fabritiis, Gianluca Gaidano, Mario Petrini, Massimo Offidani, Roberto Foa, Marco Gobbi, Giuseppe Rossi, Tommasina Guglielmelli, Antonio Lazzaro, Pellegrino Musto, Alessandro Gozzetti, Naoki Takazako, Tohru Izumi, Takaaki Chou, Shuji Ozaki, Kiyohiko Hatake, Kenshi Suzuki, Naokuni Uike, Shoji Asakura, Hiroshi Kosugi, Hiroshi Handa, Morio Matsumoto, Kensei Tobinai, Shinsuke Iida, Masahiro Kizaki, Toshihiro Miyamoto, Hirohiko Shibayama, Kiyoshi Ando, Takayuki Ishikawa, Tadao Ishida, Isamu Sugiura, Koji Izutsu, Masafumi Taniwaki, Jae Hoon Lee, Kihyun Kim, Jin Seok Kim, Chang-Ki Min, Sung-Soo Yoon, Jeong-Ok Lee, Cheolwon Suh, David Simpson, Peter Ganly, Hilary Blacklock, Richard Doocey, Shingirai Chiruka, Andrzej Hellmann, Slawomir Gornik, Mieczyslaw Komarnicki, Malgorzata Calbecka, Sebastian Grosicki, Artur Jurczyszyn, Razvan Stoia, Emanuil Gheorghita, Catalin Doru Danaila, Kudrat Abdulkadyrov, Andrey Zaritskiy, Alexander Suvorov, Natalia Andreeva, Elena Rimashevskaya, Tatiana Balakireva, Elleonora Podoltseva, Viktor Rossiev, Alexander Pristupa, Wee-Joo Chng, Wen Son Hsieh, Sathish Kumar Gopalakrishnan, Martin Mistrik, Albert Oriol Rocafiguera, Victoria Mateos, Javier Rubia, Laura Rosinol Dachs, Jesus Martin Sanchez, Adrian Alegre, Joan Bargay, Jaime Perez de Oteyza, Joaquin Martinez, Tsai-Yun Chen, Tung-Liang Lin, Jin-Hwang Liu, Ming-Chung Wang, Su-Peng Yeh, Shang-Yi Huang, Yuriy Vinnyk, Iryna Kriachok, Halyna Pylypenko, Yarosiav Shparyk, Polina Kaplan, Levgenii Karamanesht, Grygoriy Rekhtman, Nataliya Romanyuk, Martin Kaiser, Atul Mehta, Cathy Williams, Supratik Basu, Neil Rabin, Karthik Ramasamy, Hannah Hunter, Eleni Tholouli, Daniel Lebovic, David Siegel, Michael Wang, Ruben Niesvizky, Tibor Kovacsovics, David Hurd, Nashat Gabrail, Jeffrey Matous, Kelly Pendergrass, Mannish Agrawal, Ralph Boccia, Sumeet Chandra, Adetola Kassim, Slobodan Stanisic, Morton Coleman, Todd Gersten, Ira Braunschweig, Saeeda Chowdhury, Entezam Sahovic, Meletios A Dimopoulos, Philippe Moreau, Antonio Palumbo, Douglas Joshua, Ludek Pour, Roman Hájek, Thierry Facon, Heinz Ludwig, Albert Oriol, Hartmut Goldschmidt, Laura Rosiñol, Jan Straub, Aleksandr Suvorov, Carla Araujo, Elena Rimashevskaya, Tomas Pika, Gianluca Gaidano, Katja Weisel, Vesselina Goranova-Marinova, Anthony Schwarer, Leonard Minuk, Tamás Masszi, Ievgenii Karamanesht, Massimo Offidani, Vania Hungria, Andrew Spencer, Robert Z Orlowski, Heidi H Gillenwater, Nehal Mohamed, Shibao Feng, Wee-Joo Chng, ENDEAVOR Investigators, Michael Leahy, Douglas Joshua, Anthony Schwarer, Ian Kerridge, Simon Durrant, Julian Cooney, Andrew Spencer, Noemi Horvath, Philip Rowlings, Uwe Hahn, Keith Fay, William Renwick, Hang Quach, Kerry Taylor, Shir-Jing Ho, Amanda Johnston, Heinz Ludwig, Hedwig Kasparu, Michel Delforge, Henri Schots, Marie-Christiane Vekemans, Fritz Offner, Ka Lung Wu, Chantal Doyen, Rosane Bittencourt, Gislaine Duarte, Vania Hungria, Angelo Maiolino, Mariza Schaan, Adriana Scheliga, Cyntia Zadra, Vesselina Goranova-Marinova, Liana Gercheva, Georgi Mihaylov, Zhanet Grudeva-Popova, Irwindeep Sandhu, Anthony Reiman, Sindu Kanjeekal, Greg Dueck, Richard LeBlanc, Leonard Minuk, Jason Tay, Darrell White, Vladimir Maisnar, Ludek Pour, Vlastimil Scudla, Evzen Gregora, Roman Hajek, Jan Straub, Thierry Facon, Philippe Moreau, Anne-Marie Stoppa, Lionel Karlin, Laurent Garderet, Carla Araujo, Jean-Paul Fermand, Pascal Lenain, Sophie Rigaudeau, Jean-Richard Eveillard, Martine Escoffre-Barbe, Stefan Knop, Hartmut Goldschmidt, Martin Kropff, Christoph Rollig, Markus Munder, Christian Langer, Katja Weisel, Lars-Olof Mugge, Mathias Hanel, Dietger Niederwieser, Meletios Dimopoulos, Miklos Egyed, Tamas Masszi, Arpad Szomor, Zita Borbenyi, Arpad Illes, Dina Ben Yehuda, Noam Benyamini, Arnon Nagler, Moshe Mittleman, Hardan Izhar, Antonio Palumbo, Michele Cavo, Paolo De Fabritiis, Gianluca Gaidano, Mario Petrini, Massimo Offidani, Roberto Foa, Marco Gobbi, Giuseppe Rossi, Tommasina Guglielmelli, Antonio Lazzaro, Pellegrino Musto, Alessandro Gozzetti, Naoki Takazako, Tohru Izumi, Takaaki Chou, Shuji Ozaki, Kiyohiko Hatake, Kenshi Suzuki, Naokuni Uike, Shoji Asakura, Hiroshi Kosugi, Hiroshi Handa, Morio Matsumoto, Kensei Tobinai, Shinsuke Iida, Masahiro Kizaki, Toshihiro Miyamoto, Hirohiko Shibayama, Kiyoshi Ando, Takayuki Ishikawa, Tadao Ishida, Isamu Sugiura, Koji Izutsu, Masafumi Taniwaki, Jae Hoon Lee, Kihyun Kim, Jin Seok Kim, Chang-Ki Min, Sung-Soo Yoon, Jeong-Ok Lee, Cheolwon Suh, David Simpson, Peter Ganly, Hilary Blacklock, Richard Doocey, Shingirai Chiruka, Andrzej Hellmann, Slawomir Gornik, Mieczyslaw Komarnicki, Malgorzata Calbecka, Sebastian Grosicki, Artur Jurczyszyn, Razvan Stoia, Emanuil Gheorghita, Catalin Doru Danaila, Kudrat Abdulkadyrov, Andrey Zaritskiy, Alexander Suvorov, Natalia Andreeva, Elena Rimashevskaya, Tatiana Balakireva, Elleonora Podoltseva, Viktor Rossiev, Alexander Pristupa, Wee-Joo Chng, Wen Son Hsieh, Sathish Kumar Gopalakrishnan, Martin Mistrik, Albert Oriol Rocafiguera, Victoria Mateos, Javier Rubia, Laura Rosinol Dachs, Jesus Martin Sanchez, Adrian Alegre, Joan Bargay, Jaime Perez de Oteyza, Joaquin Martinez, Tsai-Yun Chen, Tung-Liang Lin, Jin-Hwang Liu, Ming-Chung Wang, Su-Peng Yeh, Shang-Yi Huang, Yuriy Vinnyk, Iryna Kriachok, Halyna Pylypenko, Yarosiav Shparyk, Polina Kaplan, Levgenii Karamanesht, Grygoriy Rekhtman, Nataliya Romanyuk, Martin Kaiser, Atul Mehta, Cathy Williams, Supratik Basu, Neil Rabin, Karthik Ramasamy, Hannah Hunter, Eleni Tholouli, Daniel Lebovic, David Siegel, Michael Wang, Ruben Niesvizky, Tibor Kovacsovics, David Hurd, Nashat Gabrail, Jeffrey Matous, Kelly Pendergrass, Mannish Agrawal, Ralph Boccia, Sumeet Chandra, Adetola Kassim, Slobodan Stanisic, Morton Coleman, Todd Gersten, Ira Braunschweig, Saeeda Chowdhury, Entezam Sahovic
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.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Source: PubMed