Author Manuscript Published OnlineFirst on December 23, 2014; DOI: 10.1158/1055-9965.EPI-14-1145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. A Pooled Analysis of Cigarette Smoking and Risk of Multiple Myeloma from the International Multiple Myeloma Consortium Gabriella Andreotti1, Brenda M. Birmann2, Wendy Cozen3, Anneclaire J De Roos4, Brian C.H. Chiu5, Laura Costas6, Silvia de Sanjosé6, Kirsten Moysich7, Nicola J. Camp8, John J. Spinelli9,9b, Punam Pahwa10,10b, James A. Dosman10, John R. McLaughlin11, Paolo Boffetta12, Anthony Staines13, Dennis Weisenburger14, Véronique Benhaim-Luzon15, Paul Brennan15, Adele Seniori Costantini16, Lucia Miligi16, Marcello Campagna17, Alexandra Nieters18, Nikolaus Becker19, Marc Maynadié20, Lenka Foretová21, Tongzhang Zheng22, Guido Tricot23, Kevin Milliken24, Joseph Krzystan25, Emily Steplowski25, Dalsu Baris1, Mark P. Purdue1 1Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD; 2Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; 3Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA; 4Department of Environmental and Occupational Health, Drexel University School of Public Health, Philadelphia, PA; 5Department of Health Studies, University of Chicago, Chicago, IL; 6Unit of Infections and Cancer, Catalan Institute of Oncology, IDIBELL, University of Barcelona. Barcelona, Spain; 7Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY; 8Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, UT; 9Cancer Control Research, BC Cancer Agency, Vancouver, BC; 9bSchool of Population and Public Health, University of British Columbia, Vancouver, BC; 10Canadian Centre for Health and Safety in Agriculture, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; 10bCommunity Health and Epidemiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; 11Public Health Ontario, Toronto, Ontario, Canada; 11bSamuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; 12The Tisch Cancer Institute and Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY; 13Department of Public Health, Public Health University College, Dublin, Ireland; 14City of Hope National Medical Center, Duarte, CA; 15International Agency for Research on Cancer, Lyon, France; 16Center for Study and Prevention of Cancer, Unit of Occupational and Environmental Epidemiology, Florence, Italy; 17Department of Public Health, Clinical and Molecular Medicine, Occupational Health Section, University of Cagliari, Monserrato, Italy; 18Division of Clinical Epidemiology, German Cancer Research Centre, Heidelberg, Germany; 19German Cancer Center, Division of Cancer Epidemiology, Heidelberg, Germany; 20Registry of Hematological malignancies of Côte d’Or, EA4184, University of Burgundy, Dijon, France; 21Dept. of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic; 22Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT; 23Department of Internal Medicine, University of Iowa, Iowa City, Iowa; 24Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 25Information Management Services, Inc., Silver Spring, MD; Downloaded from cebp.aacrjournals.org on September 23, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 23, 2014; DOI: 10.1158/1055-9965.EPI-14-1145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Financial Support: 1. Funding for the Utah study was in part from the Leukemia and Lymphoma Society 6067-09 (NJC) and the NCI CA152336 (NJC). Data collection for the Utah resource was made possible by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). Partial support for all datasets within the UPDB was provided by the University of Utah Huntsman Cancer Institute (HCI) and the HCI Cancer Center Support grant, P30 CA42014 from the NCI. The UCR is funded by contract HHSN261201000026C from the NCI SEER program with additional support from the Utah State Department of Health and the University of Utah. 2. The work was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). The work conducted by Brenda Birmann was supported in part by grants from the NCI (K07 CA115687, CA149445) and the American Cancer Society (RSG-11-020-01-CNE). 3. EPILYMPH was supported by : European Commission (QLK4-CT-2000-00422 and FOOD- CT-2006-023103), Spanish Ministry of Health (CIBERESP, PI11/01810, PI14/01219,RCESP C03/09, RTICESP C03/10, and RTIC RD06/0020/0095), Rio Hortega (CM13/00232), Agència de Gestió d’Ajuts Universitaris i de Recerca–Generalitat de Catalunya (Catalonian Government, 2014SGR756-F), National Institutes of Health (contract NO1-CO-12400), Italian Ministry of Education, University and Research (PRIN 2007 prot.2007WEJLZB, PRIN 2009 prot. 20092ZELR2), Italian Association for Cancer Research (IG grant 11855/2011); Federal Office for Radiation Protection (StSch4261 and StSch4420), José Carreras Leukemia Foundation (DJCLS-R04/08), German Federal Ministry for Education and Research (BMBF-01-EO-1303), Health Research Board, Ireland and Cancer Research Ireland [EpiLymph]. 4. This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute. Conflict of Interest: The authors of this paper have no conflicts of interest to disclose. Running Title: Smoking and Multiple Myeloma Word Count: Abstract=235, Text=803 2 Downloaded from cebp.aacrjournals.org on September 23, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 23, 2014; DOI: 10.1158/1055-9965.EPI-14-1145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Background: Past investigations of cigarette smoking and multiple myeloma have been underpowered to detect moderate associations, particularly within subgroups. To clarify this association we conducted a pooled analysis of nine case-control studies in the International Multiple Myeloma Consortium, with individual-level questionnaire data on cigarette smoking history and other covariates. Methods: Using a pooled population of 2,670 cases and 11,913 controls, we computed odds ratios (ORs) and 95% confidence intervals (CIs) relating smoking to multiple myeloma risk using unconditional logistic regression adjusting for gender, age group, race, education, body mass index, alcohol consumption, and study center. Results: Neither ever smokers (OR=0.95, 95% CI 0.87-1.05), current smokers (OR=0.82, 95% CI 0.73-0.93), nor former smokers (OR=1.03, 95% CI 0.92-1.14) had increased risks of multiple myeloma compared to never smokers. Analyses of smoking frequency, pack-years, and duration did not reveal significant or consistent patterns, and there was no significant effect modification by subgroups. Conclusion: Findings from this large pooled analysis do not support the hypothesis of cigarette smoking as a causal factor for multiple myeloma. Impact: Cigarette smoking is one of the most important risk factors for cancer, but the association with multiple myeloma was inconclusive. This study had excellent power to detect modest associations, and had individual-level data to evaluate confounding and effect modification by potentially important factors that were not evaluated in previous studies. Our findings confirm that smoking is not a risk factor for multiple myeloma. 3 Downloaded from cebp.aacrjournals.org on September 23, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 23, 2014; DOI: 10.1158/1055-9965.EPI-14-1145 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION Multiple myeloma is a B-cell malignancy characterized by abnormal monoclonal plasma cells in the bone marrow, monoclonal immunoglobulin in serum and/or urine, and lytic bone lesions. The etiology of this malignancy remains poorly understood. Past investigations of cigarette smoking and multiple myeloma have generally yielded null results (1, 2), although most studies have been underpowered to detect moderate associations, particularly within population subgroups. To clarify the relationship between cigarette smoking and multiple myeloma, we conducted a pooled analysis of case-control studies participating in the International Multiple Myeloma Consortium (IMMC). MATERIALS AND METHODS We pooled individual-level questionnaire data from nine case-control studies in the IMMC that collected data on cigarette smoking (2,670 cases, 11,913 controls). The methods of the participating studies and this pooled analysis have been previously described (3). Smoking status was based on participants’ usual behavior prior to the diagnosis of multiple myeloma or index date for controls; and former/current smoking status was based on direct questions or calculated from smoking duration. In sensitivity analyses, participants who reported quitting within the two years prior to study interview were re-grouped