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

Administration, Oral Antineoplastic Agents / administration & dosage Boron Compounds / administration & dosage Disease Progression Double-Blind Method Female Glycine / administration & dosage Humans Male Middle Aged Multiple Myeloma / drug therapy Stem Cell Transplantation Time Factors Transplantation, Autologous Treatment Outcome

Journal

Lancet (London, England)

ISSN: 1474-547X

Titre abrégé: Lancet

Pays: England

ID NLM: 2985213R

Informations de publication

Date de publication:
19 01 2019

Historique:

received: 06 11 2018

revised: 19 11 2018

accepted: 20 11 2018

pubmed: 14 12 2018

medline: 8 2 2019

entrez: 15 12 2018

Statut: ppublish

Résumé

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/m 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.

Sections du résumé

BACKGROUND

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

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.

Identifiants

DOI: 10.1016/S0140-6736(18)33003-4 PMID: 30545780

pubmed: 30545780

pii: S0140-6736(18)33003-4

doi: 10.1016/S0140-6736(18)33003-4

pii:

doi:

Substances chimiques

Antineoplastic Agents 0

Boron Compounds 0

ixazomib 71050168A2

Glycine TE7660XO1C

Banques de données

ClinicalTrials.gov

['NCT02181413']

Types de publication

Clinical Trial, Phase III Journal Article Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

253-264

Investigateurs

Daniel Bar (D)

Alfredo Basso (A)

Dorotea Fantl (D)

Simon He (S)

Neomi Horvath (N)

Cindy Lee (C)

Phillip Rowlings (P)

Kerry Taylor (K)

Andrew Spencer (A)

Tara Cochrane (T)

Fiona Kwok (F)

Sundreswran Ramanathan (S)

Hermine Agis (H)

Niklas Zojer (N)

Alain Kentos (A)

Fritz Offner (F)

Jan Van Droogenbroeck (J)

Ka Lung Wu (KL)

Angelo Maiolino (A)

Gracia Martinez (G)

Karla Zanella (K)

Marcelo Capra (M)

Sérgio Araújo (S)

Evzen Gregora (E)

Roman Hajek (R)

Vladimir Maisnar (V)

Ludek Pour (L)

Vlastimil Scudla (V)

Ivan Spicka (I)

Niels Abildgaard (N)

Niels Andersen (N)

Bo Amdi Jensen (BA)

Carsten Helleberg (C)

Torben Plesner (T)

Morten Salomo (M)

Asta Svirskaite (A)

Richard Delarue (R)

Philippe Moreau (P)

Igor Blau (I)

Hartmut Goldschmidt (H)

Aneta Schieferdecker (A)

Veronica Teleanu (V)

Markus Munder (M)

Christoph Röllig (C)

Han-Juergen Salwender (HJ)

Stephan Fuhrmann (S)

Katja Weisel (K)

Jan Duerig (J)

Matthias Zeis (M)

Stefan Klein (S)

Peter Reimer (P)

Christian Schmidt (C)

Christof Scheid (C)

Karin Mayer (K)

Martin Hoffmann (M)

Markus Sosada (M)

Athanasios Dimopoulos (A)

Sosana Delimpasi (S)

Mary-Christine Kyrtsonis (MC)

Achilleas Anagnostopoulos (A)

Zsolt Nagy (Z)

Árpád Illés (Á)

Miklós Egyed (M)

Zita Borbényi (Z)

Gabor Mikala (G)

Najib Dally (N)

Netanel Horowitz (N)

Odit Gutwein (O)

Anatoly Nemets (A)

Iuliana Vaxman (I)

Olga Shvetz (O)

Svetlana Trestman (S)

Rosa Ruchlemer (R)

Arnon Nagler (A)

Tamar Tadmor (T)

Ory Rouvio (O)

Meir Preis (M)

Francesca Gay (F)

Michele Cavo (M)

Luca De Rosa (L)

Pellegrino Musto (P)

Anna Cafro (A)

Patrizia Tosi (P)

Massimo Offidani (M)

Alessandro Corso (A)

Giuseppe Rossi (G)

Anna Marina Liberati (AM)

Alberto Bosi (A)

Kenshi Suzuki (K)

Shinsuke Iida (S)

Chiaki Nakaseko (C)

Takayuki Ishikawa (T)

Morio Matsumoto (M)

Hirokazu Nagai (H)

Kazutaka Sunami (K)

Takaaki Chou (T)

Koichi Akashi (K)

Naoki Takezako (N)

Shotaro Hagiwara (S)

Hyeon Seok Eom (HS)

Deog-Yeon Jo (DY)

Jin Seok Kim (JS)

Jae Hoon Lee (JH)

Chang Ki Min (CK)

Sung Soo Yoon (SS)

Dok Hyun Yoon (DH)

Kihyun Kim (K)

Sonja Zweegman (S)

Mark-David Levin (MD)

Edo Vellenga (E)

Monique Minnema (M)

Fredrik Schjesvold (F)

Anders Waage (A)

Einar Haukås (E)

Sebastian Grosicki (S)

Andrzej Pluta (A)

Tadeusz Robak (T)

Herlander Marques (H)

Rui Bergantim (R)

Fernando Campilho (F)

Wee Joo Chng (WJ)

Yeow Tee Goh (YT)

Andrew McDonald (A)

Bernado Rapoport (B)

Miguel Angel Álvarez Rivas (MA)

Felipe De Arriba de La Fuente (F)

Yolanda González Montes (Y)

Jesus Martin Sanchez (J)

Maria Victoria Mateos (MV)

Albert Oriol Rocafiguera (A)

Laura Rosinol (L)

Jesús San Miguel (J)

Jaime Pérez de Oteyza (J)

Cristina Encinas (C)

Adrian Alegre-Amor (A)

Ana López-Guía (A)

Per Axelsson (P)

Kristina Carlson (K)

Olga Stromberg (O)

Markus Hansson (M)

Cecile Hveding Blimark (C)

Rouven Mueller (R)

Chih-Cheng Chen (CC)

Ta-Chih Liu (TC)

Shang-Yi Huang (SY)

Po-Nan Wang (PN)

Thanyaphong Na Nakorn (T)

Kannadit Prayongratana (K)

Meral Beksac (M)

Ali Unal (A)

Hakan Goker (H)

Mehmet Sonmez (M)

Sybiryna Korenkova (S)

Aristeidis Chaidos (A)

Heather Oakervee (H)

Hamdi Sati (H)

Reuben Benjamin (R)

Ashutosh Wechalekar (A)

Mamta Garg (M)

Martin Kaiser (M)

Karthik Ramasamy (K)

Gordon Cook (G)

Andrew Chantry (A)

Matthew Jenner (M)

Francis Buadi (F)

Robert Berryman (R)

Murali Janakiram (M)

Commentaires et corrections

Type : CommentIn