Pieter Sonneveld1, Meletios A Dimopoulos2, Meral Beksac3, Bronno van der Holt4, Sara Aquino5, Heinz Ludwig6, Sonja Zweegman7, Thilo Zander8, Elena Zamagni9, Ruth Wester1, Roman Hajek10, Lucia Pantani11, Luca Dozza12, Francesca Gay13, AnneMaria Cafro14, Luca De Rosa15, Annamaria Morelli16, Henrik Gregersen17, Nina Gulbrandsen18, Petra Cornelisse19, Rosella Troia13, Stefania Oliva13, Vincent van de Velden20, KaLung Wu21, Paula F Ypma22, Gerard Bos23, Mark-David Levin24, Luca Pour25, Christoph Driessen26, Annemiek Broijl1, Alexandra Croockewit27, Monique C Minnema28, Anders Waage29, Cecilie Hveding30, Niels W C J van de Donk7, Massimo Offidani31, Giuseppe A Palumbo32, Andrew Spencer33, Mario Boccadoro13, Michele Cavo34. 1. Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. 2. Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. 3. Department of Hematology, Ankara University School of Medicine, Ankara, Turkey. 4. Department of Hematology, HOVON Data Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. 5. IRCCS Azienda Ospedaliera Universitaria San Martino, IST Instituto Nazionale per la Ricerca sul Cancro, Genova, Italy. 6. Wilhelminen Cancer Research Institute, c/o Wilhelminenspital, Vienna, Austria. 7. Department of Hematology, Amsterdam UMC, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. 8. Medical Oncology, Luzerner Kantonshospital, Luzern, Switzerland. 9. IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia "Seràgnoli" and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Università di Bologna, Bologna, Italy. 10. University Hospital Ostrava, Ostrava, Czech Republic. 11. IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli," Bologna, Italy. 12. Department of Experimental, Diagnostic and Experimental Medicine, Seràgnoli Institute of Hematology, Bologna University School of Medicine, S. Orsola Malpighi Hospital, Bologna, Italy. 13. Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy. 14. ASST Grande Ospedale Metropolitano, Niguarda, Milan, Italy. 15. Ospedale San Camillo Forlanini, Rome, Italy. 16. Department of Hematology, Transfusion Medicine and Biotechnology Santo Spirito, Civic Hospital, Pescara, Italy. 17. Department of Haematology, Aalborg University Hospital, Aalborg, Denmark. 18. Department of Hematology, Oslo University Hospital, Oslo, Norway. 19. HOVON Data Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. 20. Department of Immunology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. 21. Department of Hematology, ZNA Stuivenberg, Antwerp, Belgium. 22. Department of Hematology, Haga Ziekenhuis, The Hague, the Netherlands. 23. Maastricht University Medical Center, Maastricht, the Netherlands. 24. Albert Schweitzer Ziekenhuis, Dordrecht, the Netherlands. 25. University Hospital Brno, Brno, Czech Republic. 26. Department of Oncology/Hematology, Kantonsspital, St Gallen, Switzerland. 27. Department of Hematology, Radboud University Medical Centre, Nijmegen, the Netherlands. 28. Department of Hematology, University Medical Centre Utrecht, the Netherlands. 29. Department of Hematology, St Olav Hospital, Trondheim, Norway. 30. Sahlgrenska University Hospital, Gothenburg, Sweden. 31. Clinica di Ematologia, AOU Ospedali Riuniti di Ancona, Ancona, Italy. 32. Department of Scienze Mediche Chirurgiche e Tecnologie Avanzate "G.F. Ingrassia," University of Catania, Catania, Italy. 33. Department of Haematology, Alfred Hospital-Monash University, Melbourne, Australia. 34. IRCCS S.Orsola-Malpighi, Istituto di Ematologia "Seràgnoli," Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università degli Studi di Bologna, Bologna, Italy.
Abstract
PURPOSE: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS: The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS: Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively (P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without (P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease-negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION: Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.
PURPOSE: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS: The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS: Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively (P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without (P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease-negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION: Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.