Efstathios Kastritis1, Xavier Leleu2, Bertrand Arnulf3, Elena Zamagni4, María Teresa Cibeira5, Fiona Kwok6, Peter Mollee7, Roman Hájek8, Philippe Moreau9, Arnaud Jaccard10, Stefan O Schönland11, Robin Filshie12, Emmanuelle Nicolas-Virelizier13, Bradley Augustson14, María-Victoria Mateos15, Ashutosh Wechalekar16, Eric Hachulla2, Paolo Milani17, Meletios A Dimopoulos1, Jean-Paul Fermand3, Andrea Foli17, Maria Gavriatopoulou1, Catherine Klersy18, Antonio Palumbo19, Pieter Sonneveld20, Hans Erik Johnsen21, Giampaolo Merlini17,22, Giovanni Palladini17,22. 1. Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece. 2. Hopital Huriez Centre Hospitalier Régional Universitaire, Lille, France. 3. Immunohematology Unit, Hospital Saint-Louis, Assistance Publique - Hôpitaux de Paris, Paris, France. 4. Bologna University School of Medicine, Bologna, Italy. 5. Amyloidosis and Myeloma Unit, Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain. 6. Westmead Hospital, Sydney, New South Wales, Australia. 7. Princess Alexandra Hospital and University of Queensland, Brisbane, Queensland, Australia. 8. Department of Hemato-oncology, University Hospital, Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic. 9. Centre Hospitalier Universitaire Hotel Dieu, Nantes, France. 10. Centre Hospitalier Universitaire, Limoges, France. 11. Medical Department V, Amyloidosis Centre, University Hospital, Heidelberg, Germany. 12. St Vincent's Hospital, Melbourne, Victoria, Australia. 13. Centre Leon Berard, Lyon, France. 14. Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. 15. University Hospital of Salamanca, Instituto de Investigación Biosanitaria de Salamanc, Institute of Cancer Molecular and Cellular Biology, Salamanca, Spain. 16. University College London Medical School, Royal Free Hospital Campus, London, United Kingdom. 17. Amyloidosis Research and Treatment Center "Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo," Pavia, Italy. 18. Clinical Epidemiology and Biometry Service, "Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo," Pavia, Italy. 19. University of Torino, Torino, Italy. 20. Erasmus MC Cancer Institute, Rotterdam, the Netherlands. 21. Aalborg University Hospital, Aalborg, Denmark. 22. Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Abstract
PURPOSE:Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS: This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016. RESULTS:A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION:BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.
RCT Entities:
PURPOSE: Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS: This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016. RESULTS: A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION:BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.
Authors: Marcus V Simões; Fabio Fernandes; Fabiana G Marcondes-Braga; Philip Scheinberg; Edileide de Barros Correia; Luis Eduardo P Rohde; Fernando Bacal; Silvia Marinho Martins Alves; Sandrigo Mangini; Andréia Biolo; Luis Beck-da-Silva; Roberta Shcolnik Szor; Wilson Marques Junior; Acary Souza Bulle Oliveira; Márcia Waddington Cruz; Bruno Vaz Kerges Bueno; Ludhmila Abrahão Hajjar; Aurora Felice Castro Issa; Felix José Alvarez Ramires; Otavio Rizzi Coelho Filho; André Schmidt; Ibraim Masciarelli Francisco Pinto; Carlos Eduardo Rochitte; Marcelo Luiz Campos Vieira; Cláudio Tinoco Mesquita; Celso Dario Ramos; José Soares-Junior; Minna Moreira Dias Romano; Wilson Mathias Junior; Marcelo Iório Garcia Junior; Marcelo Westerlund Montera; Marcelo Dantas Tavares de Melo; Sandra Marques E Silva; Pedro Manoel Marques Garibaldi; Aristóteles Comte de Alencar Neto; Renato Delascio Lopes; Diane Xavier de Ávila; Denizar Viana; José Francisco Kerr Saraiva; Manoel Fernandes Canesin; Glaucia Maria Moraes de Oliveira; Evandro Tinoco Mesquita Journal: Arq Bras Cardiol Date: 2021-09 Impact factor: 2.000