Antonio Palumbo1, Federica Cavallo, Francesca Gay, Francesco Di Raimondo, Dina Ben Yehuda, Maria Teresa Petrucci, Sara Pezzatti, Tommaso Caravita, Chiara Cerrato, Elena Ribakovsky, Mariella Genuardi, Anna Cafro, Magda Marcatti, Lucio Catalano, Massimo Offidani, Angelo Michele Carella, Elena Zamagni, Francesca Patriarca, Pellegrino Musto, Andrea Evangelista, Giovannino Ciccone, Paola Omedé, Claudia Crippa, Paolo Corradini, Arnon Nagler, Mario Boccadoro, Michele Cavo. 1. From the Myeloma Unit, Division of Hematology, University of Turin (A.P., F.C., F.G., C. Cerrato, M.G., P.O., M.B.), and Unit of Clinical Epidemiology and Centro di Referimento per l'Epidemiologia-Piemonte, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino (A.E., G.C.), Turin, Division of Hematology, Ospedale Ferrarotto, Azienda Policlinico-Ospedale Vittorio Emanuele, University of Catania, Catania (F.D.R.), Hematology, Sapienza University of Rome (M.T.P.), and Cattedra di Ematologia, Ospedale S. Eugenio-University Tor Vergata (T.C.), Rome, Divisione di Ematologia, Ospedale S. Gerardo, Monza (S.P.), La Struttura Complessa di Ematologia, Dipartimento di Ematologia ed Oncologia, Azienda Ospedaliera Niguarda Ca' Granda (A.C.), Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute (M.M.), and Division of Hematology and Bone Marrow Transplantation, IRCCS Istituto Nazionale dei Tumori-University of Milan (P.C.), Milan, Ematologia, Policlinico Federico II, Naples (L.C.), Clinica di Ematologia, Azienda Ospedaliera Universitaria Ospedali Riuniti di Ancona, Ancona (M.O.), Unità Operativa Complessa Ematologia 1, IRCCS Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa (A.M.C.), Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna (E.Z., M.C.), Clinica Ematologia, Dipartimento di Scienze Mediche Sperimentali e Cliniche, Azienda Ospedaliera-Universitaria di Udine, Udine (F.P.), Scientific Direction, IRCCS, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture (P.M.), and Struttura Complessa Ematologia e Dipartimento Oncologia Medica, Spedali Civili di Brescia, Brescia (C. Crippa) - all in Italy; and the Hematology Division, Hadassah University Hospital, Jerusalem (D.B.Y.), and the Hematology Institute, Chaim Sheba Medical Center, Tel Hashomer (E.R., A.N.) - both in Israel.
Abstract
BACKGROUND: This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. METHODS: We randomly assigned 273 patients 65 years of age or younger to high-dosemelphalan plus stem-cell transplantation or MPR consolidation therapyafter induction, and 251 patients tolenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. RESULTS: The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P<0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P=0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P=0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively). CONCLUSIONS:Consolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00551928.).
RCT Entities:
BACKGROUND: This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. METHODS: We randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. RESULTS: The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P<0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P=0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P=0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively). CONCLUSIONS: Consolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00551928.).
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