Philippe Moreau1, Michel Attal2, Cyrille Hulin3, Bertrand Arnulf4, Karim Belhadj5, Lotfi Benboubker6, Marie C Béné7, Annemiek Broijl8, Hélène Caillon9, Denis Caillot10, Jill Corre11, Michel Delforge12, Thomas Dejoie9, Chantal Doyen13, Thierry Facon14, Cécile Sonntag15, Jean Fontan16, Laurent Garderet17, Kon-Siong Jie18, Lionel Karlin19, Frédérique Kuhnowski20, Jérôme Lambert21, Xavier Leleu22, Pascal Lenain23, Margaret Macro24, Claire Mathiot25, Frédérique Orsini-Piocelle26, Aurore Perrot27, Anne-Marie Stoppa28, Niels Wcj van de Donk29, Soraya Wuilleme7, Sonja Zweegman29, Brigitte Kolb30, Cyrille Touzeau31, Murielle Roussel2, Mourad Tiab32, Jean-Pierre Marolleau33, Nathalie Meuleman34, Marie-Christiane Vekemans35, Matthijs Westerman36, Saskia K Klein37, Mark-David Levin38, Jean Paul Fermand39, Martine Escoffre-Barbe40, Jean-Richard Eveillard41, Reda Garidi42, Tahamtan Ahmadi43, Sen Zhuang44, Christopher Chiu45, Lixia Pei44, Carla de Boer46, Elena Smith47, William Deraedt48, Tobias Kampfenkel46, Jordan Schecter44, Jessica Vermeulen46, Hervé Avet-Loiseau11, Pieter Sonneveld8. 1. Hematology, University Hospital Hôtel-Dieu, Nantes, France. Electronic address: philippe.moreau@chu-nantes.fr. 2. Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France. 3. Department of Hematology, Hopital Haut Leveque, University Hospital Bordeaux, Bordeaux, France. 4. Immuno-Hématologie, Hopital Saint Louis, Paris, France. 5. Hematology, Hopital Henri Mondor, Creteil, France. 6. Hôpital de Bretonneau, Centre Hospitalier Régional Universitaire de Tours, Tours, France. 7. Hematology Biology, University Hospital Hôtel Dieu, Nantes, France. 8. Erasmus University Medical Center Cancer Institute, Rotterdam, Netherlands. 9. Biochemistry Laboratory, Hospital of Nantes, Nantes, France. 10. Hôpital Du Bocage, Centre Hospitalier Universitaire Dijon, Dijon, France. 11. Unite de Genomique du Myelome, Institut universitaire du cancer de Toulouse Oncopole, Toulouse, France. 12. Universitaire Ziekenhuizen Leuven, Leuven, Belgium. 13. Centre Hospitalier Universitaire UCL Namur-site Godinne, Yvoir, Belgium. 14. Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France. 15. Hopital Hautepierre, Strasbourg, France. 16. Jean Minjoz Hôpital, Besancon, France. 17. Team Proliferation and Differentiation of Stem Cells, Centre de Recherche Saint-Antoine, Inserm, Sorbonne Université, Paris, France; Département d'Hématologie et de Thérapie Cellulaire, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France. 18. Zuyderland Medisch Centrum, Sittard, Netherlands. 19. Service d'Hématologie Clinique, Centre Hospitalier Lyon-Sud, Lyon, France. 20. Institut Curie Paris, Paris, France. 21. Biostatistical Department, Hôpital Saint Louis, Paris, France. 22. Hôpital la Milétrie, Centre Hospitalier Universitaire de Poitiers, Poitiers, France. 23. Centre de Lutte Contre le Cancer-Centre Henri Becquerel, Rouen, France. 24. Centre Hospitalier Universitaire de Caen, Caen, France. 25. Institut Français de la Mode, Paris, France. 26. Centre Hospitalier Annecy Genevois, Pringy, France. 27. Hematology Department, Vandoeuvre Les Nancy, University Hospitals Nancy, France. 28. Institut Paoli Calmettes, Marseille, France. 29. Department of Hematology, University Medical Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, Netherlands. 30. Hôpital Robert Debré, Centre Hospitalier Universitaire de Reims, Reims, France. 31. Centre Hospitalier Universitaire de Nantes, Nantes, France. 32. Centre Hospitalier Départemental Vendée, La Roche sur Yon, France. 33. Centre Hospitalier Universitaire Amiens Sud, Amiens, France. 34. Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. 35. Cliniques Universitaires Saint-Luc, Brussels, Belgium. 36. Northwest Clinics, Alkmaar, Netherlands. 37. Meander Medical Center, Amersfoort, Netherlands. 38. Albert Schweitzer Hospital, Dordrecht, Netherlands. 39. Service d'Immuno-Hématologie, Département d'Immunologie Clinique, Inserm and Intergroupe Francophone du Myélome, Hôpital Saint-Louis, Paris, France. 40. Hôpital de Pontchaillou, Centre Hospitalier Universitaire de Rennes, Rennes, France. 41. Hôpital A. Morvan, Centre Hospitalier Universitaire de Brest, Brest, France. 42. Hospital Center de Saint-Quentin, Saint Quentin, France. 43. Genmab US, Inc, Princeton, NJ, USA. 44. Janssen Research & Development, Raritan, NJ, USA. 45. Janssen Research & Development, Spring House, PA, USA. 46. Janssen Research & Development, LLC, Leiden, Netherlands. 47. Janssen Research & Development, LLC, High Wycombe, UK. 48. Janssen Research & Development, Beerse, Belgium.
Abstract
BACKGROUND:Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma. METHODS: In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383. FINDINGS: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21-2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10-5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33-0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23-0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%). INTERPRETATION: D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma. FUNDING: The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.
RCT Entities:
BACKGROUND:Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma. METHODS: In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383. FINDINGS: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21-2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10-5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33-0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23-0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%). INTERPRETATION:D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma. FUNDING: The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.
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