Paul G Richardson1, Albert Oriol2, Meral Beksac3, Anna Marina Liberati4, Monica Galli5, Fredrik Schjesvold6, Jindriska Lindsay7, Katja Weisel8, Darrell White9, Thierry Facon10, Jesus San Miguel11, Kazutaka Sunami12, Peter O'Gorman13, Pieter Sonneveld14, Pawel Robak15, Sergey Semochkin16, Steve Schey17, Xin Yu18, Thomas Doerr18, Amine Bensmaine19, Tsvetan Biyukov19, Teresa Peluso19, Mohamed Zaki18, Kenneth Anderson20, Meletios Dimopoulos21. 1. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address: paul_richardson@dfci.harvard.edu. 2. Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain. 3. Ankara University, Ankara, Turkey. 4. Università degli studi di Perugia, Perugia, Italy. 5. Azienda Ospedaliera Papa Giovanni XXIII, Unità Operativa di Ematologia, Bergamo, Italy. 6. Oslo Myeloma Center, Oslo University Hospital, Oslo, Norway; K G Jebsen Center for B Cell Malignancies, University of Oslo, Oslo, Norway. 7. East Kent Hospitals University NHS Foundation Trust, Kent and Canterbury Hospital, Canterbury, UK. 8. Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 9. Dalhousie University and Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada. 10. University of Lille, Centre Hospitalier Universitaire Lille, Service des Maladies du Sang, Lille, France. 11. Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain. 12. National Hospital Organization Okayama Medical Center, Okayama, Japan. 13. Department of Haematology, Mater Misericordiae University Hospital, Dublin, Ireland; Cancer Trials Ireland, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland. 14. Erasmus MC Cancer Institute, Rotterdam, Netherlands. 15. Medical University of Lodz, Lodz, Poland. 16. Pirogov Russian National Research Medical University, Moscow, Russia. 17. Department of Hematology, King's College London, London, UK. 18. Celgene Corporation, Summit, NJ, USA. 19. Celgene International, Boudry, Switzerland. 20. Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. 21. National and Kapodistrian University of Athens, Athens, Greece.
Abstract
BACKGROUND: As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously receivedlenalidomide. METHODS: We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of β2 microglobulin at screening. Bortezomib (1·3 mg/m2) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. FINDINGS:Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assignedpomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9-21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66-13·73] vs 7·10 months [5·88-8·48]; hazard ratio 0·61, 95% CI 0·49-0·77; p<0·0001). 278 patients received at least one dose ofpomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%] of 270 patients; nine [3%] vs no patients had febrile neutropenia), infections (86 [31%] vs 48 [18%]), and thrombocytopenia (76 [27%] vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1]) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]). INTERPRETATION:Patients with relapsed or refractory multiple myeloma who previously receivedlenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously receivedlenalidomide. FUNDING: Celgene.
RCT Entities:
BACKGROUND: As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. METHODS: We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of β2 microglobulin at screening. Bortezomib (1·3 mg/m2) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. FINDINGS: Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9-21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66-13·73] vs 7·10 months [5·88-8·48]; hazard ratio 0·61, 95% CI 0·49-0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%] of 270 patients; nine [3%] vs no patients had febrile neutropenia), infections (86 [31%] vs 48 [18%]), and thrombocytopenia (76 [27%] vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1]) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]). INTERPRETATION:Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. FUNDING: Celgene.
Authors: Ajai Chari; Joaquín Martinez-Lopez; María-Victoria Mateos; Joan Bladé; Lotfi Benboubker; Albert Oriol; Bertrand Arnulf; Paula Rodriguez-Otero; Luis Pineiro; Andrzej Jakubowiak; Carla de Boer; Jianping Wang; Pamela L Clemens; Jon Ukropec; Jordan Schecter; Sagar Lonial; Philippe Moreau Journal: Blood Date: 2019-05-21 Impact factor: 22.113
Authors: G R Tundo; D Sbardella; A M Santoro; A Coletta; F Oddone; G Grasso; D Milardi; P M Lacal; S Marini; R Purrello; G Graziani; M Coletta Journal: Pharmacol Ther Date: 2020-05-19 Impact factor: 12.310