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Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial

2018; Elsevier BV; Volume: 393; Issue: 10168 Linguagem: Inglês

10.1016/s0140-6736(18)33003-4

1474-547X

Meletios Α. Dimopoulos, Francesca Gay, Fredrik Schjesvold, Meral Beksaç, Roman Hájek, Katja Weisel, Hartmut Goldschmidt, Vladimír Maisnar, Philippe Moreau, Chang Ki Min, Agnieszka Pluta, Wee Joo Chng, Martin Kaiser, Sonja Zweegman, María‐Victoria Mateos, Andrew Spencer, Shinsuke Iida, Gareth J. Morgan, Kaveri Suryanarayan, Zhaoyang Teng, Tomáš Skácel, Antonio Palumbo, Ajeeta B. Dash, Neeraj Gupta, Richard Labotka, S. Vincent Rajkumar, Daniel Bär, Alfredo Basso, Dorotea Fantl, Simon He, Neomi Horvath, Cindy Lee, Phillip Rowlings, Kerry Taylor, Andrew Spencer, Tara Cochrane, Fiona Kwok, Sundreswran Ramanathan, Hermine Agis, Niklas Zojer, Alain Kentos, Fritz Offner, Jan Van Droogenbroeck, Ka Lung Wu, Ângelo Maiolino, Gracia Martínez, Karla Richter Zanella, Marcelo Capra, Sérgio Araújo, E Gregora, Roman Hájek, Vladimír Maisnar, Luděk Pour, Vlastimil Ščudla, Ivan Špıčka, Niels Abildgaard, N.H. Andersen, Bo Amdi Jensen, Carsten Helleberg, Torben Plesner, Morten Salomo, Asta Svirskaite, Richard Delarue, Philippe Moreau, Igor Wolfgang Blau, Hartmut Goldschmidt, Aneta Schieferdecker, Veronica Teleanu, Markus Munder, Christoph Röllig, Han-Juergen Salwender, Stephan Fuhrmann, Katja Weisel, Jan Duerig, Matthias Zeis, Stefan Klein, Peter Reimer, Christian Schmidt, Christof Scheid, Karin Mayer, Martin Hoffmann, Markus Sosada, Meletios Α. Dimopoulos, Sosana Delimpasi, Mary-Christine Kyrtsonis, Αchilles Anagnostopoulos, Zsolt Nagy, Árpád Illés, Miklós Egyed, Zita Borbényi, Gábor Mikala, Najib Dally, Netanel A. Horowitz, Odit Gutwein, Anatoly Nemets, Iuliana Vaxman, Olga Shvetz, Svetlana Trestman, Rosa Ruchlemer, Arnon Nagler, Tamar Tadmor, Ory Rouvio, Meir Preis, Francesca Gay, Michèle Cavo, Luca De Rosa, Pellegrino Musto, Anna Maria Cafro, Patrizia Tosi, Massimo Offidani, Alessandro Corso, Giuseppe Rossi, Anna Marina Liberati, Alberto Bosi, Kenshi Suzuki, Shinsuke Iida, Chiaki Nakaseko, Takayuki Ishikawa, Morio Matsumoto, Hirokazu Nagai, Kazutaka Sunami, Takaaki Chou, Koichi Akashi, Naoki Takezako, Shotaro Hagiwara, Hyeon Seok Eom, Deog‐Yeon Jo, Jin Seok Kim, Jae Hoon Lee, Chang Ki Min, Sung Soo Yoon, Dok Hyun Yoon, Kihyun Kım, Sonja Zweegman, Mark‐David Levin, Edo Vellenga, Monique C. Minnema, Fredrik Schjesvold, Anders Waage, Einar Haukås, Sebastian Grosicki, Andrzej Pluta, Tadeusz Robak, Herlander Marques, Rui Bergantim, Fernando Campilho, Wee Joo Chng, Yeow Tee Goh, Andrew McDonald, Bernado Rapoport, Miguel Ángel Álvarez Rivas, Felipe de Arriba, Yolanda González Montes, Jesús Martín, María‐Victoria Mateos, Albert Oriol Rocafiguera, Laura Rosiñol, Jesús F. San Miguel, Jaime Pérez de Oteyza, Cristina Encinas, Adrian Alegre-Amor, Ana López-Guía, Per Axelsson, Kristina Carlson, Olga Strömberg, Markus Hansson, Cecile Hveding Blimark, Rouven Mueller, Chih‐Cheng Chen, Ta‐Chih Liu, Shang‐Yi Huang, Po‐Nan Wang, Thanyaphong Na Nakorn, Kannadit Prayongratana, Meral Beksac, Ali Ünal, Hakan Göker, Mehmet Sönmez, Sybiryna Korenkova, Aristeidis Chaidos, Heather Oakervee, Hamdi Sati, Reuben Benjamin, Ashutosh D. Wechalekar, Mamta Garg, Martin Kaiser, Karthik Ramasamy, Gordon Cook, Andrew Chantry, Matthew Jenner, Francis K. Buadi, R.B. Berryman, Murali Janakiram,

Cancer Treatment and Pharmacology

Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT.The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1-4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing.Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3-35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7-33·8] vs 21·3 months [18·0-24·7]; hazard ratio 0·72, 95% CI 0·58-0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group.Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma.Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.