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

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From: The Lancet(Vol. 393, Issue 10168)
Publisher: Elsevier B.V.
Document Type: Article
Length: 1,264 words

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Byline: Prof Meletios A Dimopoulos, MD [mdimop@med.uoa.gr] (a,*), Francesca Gay, MD (b), Fredrik Schjesvold, MD (c,d), Prof Meral Beksac, MD (e), Prof Roman Hajek, MD (f), Katja Christina Weisel, MD (g), Prof Hartmut Goldschmidt, MD (h), Prof Vladimir Maisnar, MD (i), Prof Philippe Moreau, MD (j), Chang Ki Min, MD (k), Agnieszka Pluta, MD (l), Prof Wee-Joo Chng, MBChB (m), Martin Kaiser, MD (n,o), Prof Sonja Zweegman, MD (p), Prof Maria-Victoria Mateos, MD (q), Prof Andrew Spencer, MBBS (r), Prof Shinsuke Iida, MD (s), Gareth Morgan, MD (t), Kaveri Suryanarayan, MD (u), Zhaoyang Teng, PhD (u), Tomas Skacel, MD (u), Antonio Palumbo, MD (u,v,w), Ajeeta B Dash, PhD (u), Neeraj Gupta, PhD (u), Richard Labotka, MD (u), Prof S Vincent Rajkumar, MD (x), Daniel Bar, 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, Angelo Maiolino, Gracia Martinez, Karla Zanella, Marcelo Capra, Sergio Araujo, Evzen Gregora, Roman Hajek, Vladimir Maisnar, Ludek Pour, Vlastimil Scudla, Ivan Spicka, Niels Abildgaard, Niels Andersen, Bo Amdi Jensen, Carsten Helleberg, Torben Plesner, Morten Salomo, Asta Svirskaite, Richard Delarue, Philippe Moreau, Igor Blau, Hartmut Goldschmidt, Aneta Schieferdecker, Veronica Teleanu, Markus Munder, Christoph Rollig, 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, Athanasios Dimopoulos, Sosana Delimpasi, Mary-Christine Kyrtsonis, Achilleas Anagnostopoulos, Zsolt Nagy, Arpad Illes, Miklos Egyed, Zita Borbenyi, Gabor Mikala, Najib Dally, Netanel Horowitz, Odit Gutwein, Anatoly Nemets, Iuliana Vaxman, Olga Shvetz, Svetlana Trestman, Rosa Ruchlemer, Arnon Nagler, Tamar Tadmor, Ory Rouvio, Meir Preis, Francesca Gay, Michele Cavo, Luca De Rosa, Pellegrino Musto, Anna 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 Kim, Sonja Zweegman, Mark-David Levin, Edo Vellenga, Monique Minnema, Fredrik Schjesvold, Anders Waage, Einar Haukas, Sebastian Grosicki, Andrzej Pluta, Tadeusz Robak, Herlander Marques, Rui Bergantim, Fernando Campilho, Wee Joo Chng, Yeow Tee Goh, Andrew McDonald, Bernado Rapoport, Miguel Angel Alvarez Rivas, Felipe De Arriba de La Fuente, Yolanda Gonzalez Montes, Jesus Martin Sanchez, Maria Victoria Mateos, Albert Oriol Rocafiguera, Laura Rosinol, Jesus San Miguel, Jaime Perez de Oteyza, Cristina Encinas, Adrian Alegre-Amor, Ana Lopez-Guia, Per Axelsson, Kristina Carlson, Olga Stromberg, 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 Unal, Hakan Goker, Mehmet Sonmez, Sybiryna Korenkova, Aristeidis Chaidos, Heather Oakervee, Hamdi Sati, Reuben Benjamin, Ashutosh Wechalekar, Mamta Garg, Martin Kaiser, Karthik Ramasamy, Gordon Cook, Andrew Chantry, Matthew Jenner, Francis Buadi, Robert Berryman, Murali Janakiram Summary Background 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. Methods 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/m.sup.2) 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. Findings 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. Interpretation Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. Funding Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company. Author Affiliation: (a) Hematology & Medical Oncology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece (b) Department of Oncology and Hematology, Azienda Ospedaliero-Universitaria City of Health and Science of Turin, Turin, Italy (c) Oslo Myeloma Center, Oslo University Hospital, Oslo, Norway (d) KG Jebsen Center for B cell malignancies, University of Oslo, Oslo, Norway (e) Department of Hematology, Ankara University, Ankara, Turkey (f) Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic (g) Department of Internal Medicine II, University of Tuebingen, Tuebingen, Germany (h) Department of Internal Medicine V, University Medical Hospital and National Center of Tumor Diseases, University of Heidelberg, Heidelberg, Germany (i) Fourth Department of Medicine--Hematology, FN and LF UK Hradec Kralove, Hradec Kralove, Czech Republic (j) Department of Hematology, University Hospital Hotel Dieu, University of Nantes, Nantes, France (k) Department of Internal Medicine, Seoul St Mary's Hospital, Seoul, South Korea (l) Department of Haematology, Medical University of Lodz, Multidisciplinary Provincial Centre of Traumatology and Oncology Nicolas Copernicus in Lodz, Lodz, Poland (m) Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore and Cancer Science Institute of Singapore, National University of Singapore, Singapore (n) Department of Haematology, The Royal Marsden Hospital, London, UK (o) Division of Molecular Pathology, The Institute of Cancer Research ICR, London, UK (p) Department of Hematology, Amsterdam University Medical Center, VU University Amsterdam, Cancer Center Amsterdam, Netherlands (q) Department of Hematology, University Hospital of Salamanca, CIC, IBMCC, Salamanca, Spain (r) Malignant Haematology and Stem Cell Transplantation Service, Alfred Health-Monash University, Melbourne, VA, Australia (s) Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan (t) Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA (u) Millennium Pharmaceuticals, Cambridge, MA, USA (v) Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria S Giovanni Battista, Torino, Italy (w) Center for Hematology and Oncology, University Hospital Zurich, Zurich, Switzerland (x) Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA * Correspondence to: Prof Meletios A Dimopoulos, Hematology & Medical Oncology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, 80 Vasilisis Sophias, 11528, Athens, Greece (footnote)[Dagger] Collaborators are listed in the

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Gale Document Number: GALE|A570152797