title: Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Celgene Corporation.
authors: 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.
authors: Antonio
authors: A
authors: Palumbo
authors: Myeloma Unit, Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
authors: Sara
authors: S
authors: Bringhen
authors: Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: Shaji K
authors: SK
authors: Kumar
authors: Myeloma Unit, Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
authors: Giulia
authors: G
authors: Lupparelli
authors: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors: Saad
authors: S
authors: Usmani
authors: Department of Hematology, St Olavs Hospital/Norwegian University of Science and Technology (NTNU) and KG Jebsen Myeloma Research Center, Trondheim, Norway.
authors: Anders
authors: A
authors: Waage
authors: Myeloma Unit, Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
authors: Alessandra
authors: A
authors: Larocca
authors: HOVON Data Center, Erasmus MC-Clinical Trial Center, Rotterdam, Netherlands.
authors: Bronno
authors: B
authors: van der Holt
authors: Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy.
authors: Pellegrino
authors: P
authors: Musto
authors: Clinica di Ematologia, Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona, Ancona, Italy.
authors: Massimo
authors: M
authors: Offidani
authors: Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors: Maria T
authors: MT
authors: Petrucci
authors: Unit of Clinical Epidemiology, University of Turin, Turin, Italy.
authors: Andrea
authors: A
authors: Evangelista
authors: Department of Hematology, VU University Medical Center, Amsterdam, Netherlands.
authors: Sonja
authors: S
authors: Zweegman
authors: Division of Bone Marrow Transplant, Winship Cancer Institute, Atlanta, GA, USA.
authors: Ajay K
authors: AK
authors: Nooka
authors: Department of Clinical Hematology and Bone Marrow Transplant, Alfred Health-Monash University, Melbourne, VIC, Australia.
authors: Andrew
authors: A
authors: Spencer
authors: Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra Hospital, Athens, Greece.
authors: Meletios A
authors: MA
authors: Dimopoulos
authors: Faculty of Medicine, and Department of Haematooncology, University Hospital Ostrava, University of Ostrava, Ostrava, Czech Republic.
authors: Roman
authors: R
authors: Hajek
authors: "Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Bologna, Italy.
authors: Michele
authors: M
authors: Cavo
authors: Dana-Farber Cancer Institute, Boston, MA, USA.
authors: Paul
authors: P
authors: Richardson
authors: Department of Hematology and Medical Oncology, Winship Cancer Institute, Atlanta, GA, USA.
authors: Sagar
authors: S
authors: Lonial
authors: Unit of Clinical Epidemiology, University of Turin, Turin, Italy.
authors: Giovannino
authors: G
authors: Ciccone
authors: Myeloma Unit, Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
authors: Mario
authors: M
authors: Boccadoro
authors: Dana-Farber Cancer Institute, Boston, MA, USA.
authors: Kenneth
authors: K
authors: Anderson
authors: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors: Bart
authors: B
authors: Barlogie
authors: HOVON Data Center, Erasmus MC-Clinical Trial Center, Rotterdam, Netherlands; Department of Hematology, Erasmus MC, Rotterdam, Netherlands.
authors: Pieter
authors: P
authors: Sonneveld
authors: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Philip L
authors: PL
authors: McCarthy
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D006801:Humans; D000077269:Lenalidomide; D008558:Melphalan / Q000009:adverse effects; D009101:Multiple Myeloma / Q000188:drug therapy*; D016609:Neoplasms, Second Primary / Q000139:chemically induced*; D013792:Thalidomide / Q000009:adverse effects / Q000031:analogs & derivatives*
chemical_list: D020533:Angiogenesis Inhibitors; D013792:Thalidomide; D000077269:Lenalidomide; D008558:Melphalan