High-dose busulfan-melphalan vs melphalan and reinforced VRD for newly diagnosed multiple myeloma: a phase 3 GEM trial
Abstract
Abstract In retrospective studies, autologous stem cell transplantation (ASCT) conditioning with intravenous busulfan and melphalan (BUMEL) led to longer progression-free survival (PFS) than melphalan alone (MEL200). We compared long-term outcomes of BUMEL vs MEL200 in the context of intensified bortezomib, lenalidomide, and dexamethasone (VRD) induction and consolidation therapies. GEM12 was a phase 3 trial for patients with newly diagnosed multiple myeloma (NDMM) eligible for ASCT including 6 reinforced VRD cycles followed by ASCT conditioned with BUMEL or MEL200 and 2 VRD consolidation cycles. The primary end point was PFS. Subgroup analyses were based on International Staging System (ISS) stages and high-risk genetic abnormalities. Patients were randomized with an open-label 2 × 2 factorial design and 1:1:1:1 allocation ratio to ensure the balance between the GEM12 and the subsequent phase 3 GEM14 trial. Between 2013 and 2015, 458 patients were randomized (BUMEL, n = 230; MEL200, n = 228). The 10⁻⁶ MRD-negative rate was 63%, 68% for BUMEL vs 58% for MEL200 (odds ratio, 1.51; P = .035). The median PFS was 89 months for BUMEL and 73.1 for MEL200 (hazard ratio, 0.89 [95% confidence interval, 0.70-1.14]; P = .3). BUMEL showed benefit for patients with ISS stages II or III, t(14;16), and del(1p). For subcohorts ISS stages II or III treated with BUMEL and ISS I treated with MEL200 the median PFS was 96.5 months (95% confidence interval, 76 to not estimable). No safety concerns were observed. After a median follow-up of 8.4 years, GEM2012 demonstrated one of the longest PFS values reported in patients with NDMM, with significant differences favoring BUMEL in advanced ISS stages. The trial was registered at www.ClinicalTrials.gov as #NCT01916252 and at European Union Drug Regulating Authorities Clinical Trials as EudraCT 2012-005683-10.
Article Details
Authors (33)
Juan José Lahuerta
1Hematology Department, Instituto de Investigación Hospital Universitario 12 de Octubre, Madrid, Spain
Jesus San-Miguel
Ana Jiménez-Ubieto
12Hospital Universitario 12 de Octubre, Hematology, Madrid, Spain
Rafael Alonso
1Hospital 12 de Octubre, Hematology and Hemotherapy, Madrid, Spain
Bruno Paiva
Noemi Puig
M. Teresa Cedena
5Hematology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Biomédica i+12, Madrid, Spain
Norma Carmen Gutierrez
6Hematology Department, Hospital Universitario de Salamanca, Institute of Biomedical Research of Salamanca, Cancer Research Center–Institute for Molecular and Cellular Biology of Cancer, University of Salamanca–Spanish National Research Council, Centre for Biomedical Research in the Cancer Network, Salamanca, Spain
María José Calasanz
7Genetics Department, CIMALAB Diagnostics, Clínica Universidad de Navarra, Pamplona, Spain
Manuela Fernández Guijarro
8Genetics Department, Hospital Universitario 12 de Octubre, Madrid, Spain
Rafael Rios Tamayo
14Hospital Universitario Virgen de las Nieves, ibs.Granada, Spain, Granada, Spain
Albert Oriol Rocafiguera
10Hematology Department, Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias I Pujol, Badalona, Spain
María Jesús Blanchard
11Hematology Department, Hospital Ramón y Cajal, Madrid, Spain
Estrella Carrillo Cruz
12Hematology Department, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla/Spanish National Research Council, Universidad de Sevilla, Sevilla, Spain
Rafael Martínez-Martínez
13Hematology Department, Hospital Clínico San Carlos, Madrid, Spain
Joan Bargay
Hospital Universitario Son LLatzer, Instituto de Investigación Sanitaria Illes Balears (IdISBa),, Palma de Mallorca, Spain
Ana Sureda Balari
15Hematology Department, Institut Català d'Oncologia, Hospital Duran i Reynals, Hospitalet de Llobregat, Spain
Javier de la Rubia
10Hospital La Fe, Valencia, Spain
Miguel Teodoro Hernández Garcia
6Department of Hematology, Hospital Universitario de Canarias, Tenerife, Spain
Valentin Cabañas
21Department of Hematology, IMIB Virgen de la Arrixaca University Hospital, University of Murcia, Murcia, Spain
Felipe Casado Montero
19Hematology Department, HM Hospitales Madrid, Madrid, Spain
Luis Palomera Bernal
20Hematology Department, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
Yolanda González Montes
21Hematology Department, Instituto Catalán Oncología Girona, Girona, Spain
Joaquín Martínez-López
Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Complutense University of Madrid, Centro Nacional de Investigaciones Oncológicas, Madrid Institute of Cancer, Madrid
Paula Rodriguez-Otero
Isabel Krisnik
24Hematology Department, Hospital Universitario Puerta de Hierro, Majadahonda, Spain
José M. Arguiñano
25Hematology Department, Hospital Universitario de Navarra, Pamplona, Spain
María Esther Gonzalez García
26Hematology Department, Hospital Universitario de Cabueñes, Gijon, Spain
Enrique M. Ocio
From Tel Aviv Sourasky Medical Center (Y.C.C., I.A.), and the Faculty of Medical and Health Sciences, Tel Aviv University (Y.C.C., H.M., I.A.), Tel Aviv, Chaim Sheba Medical Center, Ramat Gan (H.M.), and Hadassah Hebrew University Medical Center, Jerusalem (M.G.) — all in Israel; McGill University and McGill University Health Centre, Montreal (M.S.), and Alberta Health Services, Edmonton (M.P.C.) — all in Canada; Samsung Medical Center, Sungkyunkwan University School of Medicine (K.K.), Seoul St. Mary’s Hospital, Catholic University of Korea (C.-K.M.), and Seoul National University College of Medicine (S.-S.Y.) — all in Seoul, South Korea; Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla, Universidad de Cantabria, Santander (E.M.O.), Cancer Center Clínica Universidad de Navarra, Center for Applied Medical Research, Pamplona (P.R.-O.), Institut Català d’Oncologia, Josep Carreras Leukemia Research Institute, and the Hospital Germans Trias i Pujol, Barcelona (A.O.)...
Javier De la Cruz
4Instituto de Investigación 12 de Octubre, Madrid, Spain
Maria Victoria Mateos
Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca, Instituto de Biología Molecular y Celular del Cáncer (Universidad de Salamanca–Consejo Superior de Investigaciones Científicas), Centro de Investigación Biomédica en Red de Cáncer, Salamanca, Spain
Laura Rosiñol
Hospital Clínic de Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona
Joan Bladé
Hospital Clínic i Provincial, Institut de Investicacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain