Antonio Palumbo1, Sara Bringhen2, Shaji K Kumar3, Giulia Lupparelli2, Saad Usmani4, Anders Waage5, Alessandra Larocca2, Bronno van der Holt6, Pellegrino Musto7, Massimo Offidani8, Maria T Petrucci9, Andrea Evangelista10, Sonja Zweegman11, Ajay K Nooka12, Andrew Spencer13, Meletios A Dimopoulos14, Roman Hajek15, Michele Cavo16, Paul Richardson17, Sagar Lonial18, Giovannino Ciccone10, Mario Boccadoro2, Kenneth Anderson17, Bart Barlogie4, Pieter Sonneveld19, Philip L McCarthy20. 1. Myeloma Unit, Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy. Electronic address: appalumbo@yahoo.com. 2. Myeloma Unit, Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy. 3. Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN, USA. 4. Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA. 5. Department of Hematology, St Olavs Hospital/Norwegian University of Science and Technology (NTNU) and KG Jebsen Myeloma Research Center, Trondheim, Norway. 6. HOVON Data Center, Erasmus MC-Clinical Trial Center, Rotterdam, Netherlands. 7. Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy. 8. Clinica di Ematologia, Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona, Ancona, Italy. 9. Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy. 10. Unit of Clinical Epidemiology, University of Turin, Turin, Italy. 11. Department of Hematology, VU University Medical Center, Amsterdam, Netherlands. 12. Division of Bone Marrow Transplant, Winship Cancer Institute, Atlanta, GA, USA. 13. Department of Clinical Hematology and Bone Marrow Transplant, Alfred Health-Monash University, Melbourne, VIC, Australia. 14. Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra Hospital, Athens, Greece. 15. Faculty of Medicine, and Department of Haematooncology, University Hospital Ostrava, University of Ostrava, Ostrava, Czech Republic. 16. "Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Bologna, Italy. 17. Dana-Farber Cancer Institute, Boston, MA, USA. 18. Department of Hematology and Medical Oncology, Winship Cancer Institute, Atlanta, GA, USA. 19. HOVON Data Center, Erasmus MC-Clinical Trial Center, Rotterdam, Netherlands; Department of Hematology, Erasmus MC, Rotterdam, Netherlands. 20. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
Abstract
BACKGROUND: Lenalidomide has been linked to second primary malignancies in myeloma. We aimed to pool and analyse available data to compare the incidence of second primary malignancies in patients with and without lenalidomide exposure. METHODS: We identified relevant studies through a search of PubMed and abstracts from the American Society of Clinical Oncology, American Society of Hematology, and the International Myeloma Workshop. Randomised, controlled, phase 3 trials that recruited patients with newly diagnosed multiple myeloma between Jan 1, 2000, and Dec 15, 2012, and in which at least one group received lenalidomide were eligible for inclusion. We obtained individual patient data (age, sex, date of diagnosis, allocated treatment and received treatment, duration of treatment and cause of discontinuation, maintenance treatment, date of first relapse, date of second primary malignancy diagnosis, type of second primary malignancy, date of death or last contact, and cause of death) by direct collaboration with the principal investigators of eligible trials. Primary outcomes of interest were cumulative incidence of all second primary malignancies, solid second primary malignancies, and haematological second primary malignancies, and were analysed by a one-step meta-analysis. FINDINGS: We found nine eligible trials, of which seven had available data for 3254 patients. 3218 of these patients received treatment (2620 had received lenalidomide and 598 had not), and were included in our analyses. Cumulative incidences of all second primary malignancies at 5 years were 6·9% (95% CI 5·3-8·5) in patients who received lenalidomide and 4·8% (2·0-7·6) in those who did not (hazard ratio [HR] 1·55 [95% CI 1·03-2·34]; p=0·037). Cumulative 5-year incidences of solid second primary malignancies were 3·8% (95% CI 2·7-4·9) in patients who received lenalidomide and 3·4% (1·6-5·2) in those that did not (HR 1·1 [95% CI 0·62-2·00]; p=0·72), and of haematological second primary malignancies were 3·1% (95% CI 1·9-4·3) and 1·4% (0·0-3·6), respectively (HR 3·8 [95% CI 1·15-12·62]; p=0·029). Exposure to lenalidomide plus oral melphalan significantly increased haematological second primary malignancy risk versus melphalan alone (HR 4·86 [95% CI 2·79-8·46]; p<0·0001). Exposure to lenalidomide plus cyclophosphamide (HR 1·26 [95% CI 0·30-5·38]; p=0·75) or lenalidomide plus dexamethasone (HR 0·86 [95% CI 0·33-2·24]; p=0·76) did not increase haematological second primary malignancy risk versus melphalan alone. INTERPRETATION: Patients with newly diagnosed myeloma who received lenalidomide had an increased risk of developing haematological second primary malignancies, driven mainly by treatment strategies that included a combination of lenalidomide and oral melphalan. These results suggest that alternatives, such as cyclophosphamide or alkylating-free combinations, should be considered instead of oral melphalan in combination with lenalidomide for myeloma. FUNDING: Celgene Corporation.
BACKGROUND:Lenalidomide has been linked to second primary malignancies in myeloma. We aimed to pool and analyse available data to compare the incidence of second primary malignancies in patients with and without lenalidomide exposure. METHODS: We identified relevant studies through a search of PubMed and abstracts from the American Society of Clinical Oncology, American Society of Hematology, and the International Myeloma Workshop. Randomised, controlled, phase 3 trials that recruited patients with newly diagnosed multiple myeloma between Jan 1, 2000, and Dec 15, 2012, and in which at least one group received lenalidomide were eligible for inclusion. We obtained individual patient data (age, sex, date of diagnosis, allocated treatment and received treatment, duration of treatment and cause of discontinuation, maintenance treatment, date of first relapse, date of second primary malignancy diagnosis, type of second primary malignancy, date of death or last contact, and cause of death) by direct collaboration with the principal investigators of eligible trials. Primary outcomes of interest were cumulative incidence of all second primary malignancies, solid second primary malignancies, and haematological second primary malignancies, and were analysed by a one-step meta-analysis. FINDINGS: We found nine eligible trials, of which seven had available data for 3254 patients. 3218 of these patients received treatment (2620 had received lenalidomide and 598 had not), and were included in our analyses. Cumulative incidences of all second primary malignancies at 5 years were 6·9% (95% CI 5·3-8·5) in patients who received lenalidomide and 4·8% (2·0-7·6) in those who did not (hazard ratio [HR] 1·55 [95% CI 1·03-2·34]; p=0·037). Cumulative 5-year incidences of solid second primary malignancies were 3·8% (95% CI 2·7-4·9) in patients who received lenalidomide and 3·4% (1·6-5·2) in those that did not (HR 1·1 [95% CI 0·62-2·00]; p=0·72), and of haematological second primary malignancies were 3·1% (95% CI 1·9-4·3) and 1·4% (0·0-3·6), respectively (HR 3·8 [95% CI 1·15-12·62]; p=0·029). Exposure to lenalidomide plus oral melphalan significantly increased haematological second primary malignancy risk versus melphalan alone (HR 4·86 [95% CI 2·79-8·46]; p<0·0001). Exposure to lenalidomide plus cyclophosphamide (HR 1·26 [95% CI 0·30-5·38]; p=0·75) or lenalidomide plus dexamethasone (HR 0·86 [95% CI 0·33-2·24]; p=0·76) did not increase haematological second primary malignancy risk versus melphalan alone. INTERPRETATION:Patients with newly diagnosed myeloma who received lenalidomide had an increased risk of developing haematological second primary malignancies, driven mainly by treatment strategies that included a combination of lenalidomide and oral melphalan. These results suggest that alternatives, such as cyclophosphamide or alkylating-free combinations, should be considered instead of oral melphalan in combination with lenalidomide for myeloma. FUNDING: Celgene Corporation.
Authors: Lindsay M Morton; Wael Saber; K Scott Baker; A John Barrett; Smita Bhatia; Eric A Engels; Shahinaz M Gadalla; David E Kleiner; Steven Pavletic; Linda J Burns Journal: Biol Blood Marrow Transplant Date: 2016-09-12 Impact factor: 5.742
Authors: Kylee Maclachlan; Benjamin Diamond; Francesco Maura; Jens Hillengass; Ingemar Turesson; C Ola Landgren; Dickran Kazandjian Journal: Best Pract Res Clin Haematol Date: 2020-01-11 Impact factor: 3.020