ABSTRACT
Multiple myeloma is the second most common hematological cancer; it accounts for approximately 10% of all hematologic malignancies and 1%-2% of all cancer diagnoses. From 1990 to 2019, an ecological study was conducted to describe and evaluate trends in Brazil’s morbidity, mortality, and disease. The Global Burden of Disease data described age-standardized (+40 years) incidence, prevalence, mortality, disability-adjusted life years, and its components in Brazil and across its 27 federative units according to sex and Socio-demographic Index quintiles. Trends were estimated using linear regression and expressed as Average Annual Percentage Changes (AAPC) and 95% Confidence Intervals (CI). Ascending trends of the measures were found for both sexes in Brazil and its federative units. Mortality increased to a lesser extent than incidence (AAPC=1.3%; 95%CI=1.2-1.3 vs. AAPC=1.5%; 95%CI= 1.5-1.5 for men; AAPC=0.9%; 95%CI=0.9-0.9 vs. AAPC=1.1%; 95%CI=1.1-1.2 for women), resulting in higher rising trends in prevalence for both sexes. All the measures were significantly higher in high- and high-middle socio-demographic quintiles; however, higher ascending trends were found in lower socio-demographic quintiles. Aging, level of development, diagnosis, and treatment appear to explain Brazil’s ascending multiple myeloma rates and their differences among the federative units.
KEYWORDS
Multiple myeloma; Incidence; Mortality; disability-adjusted life years; Brazil
RESUMO
O mieloma múltiplo é o segundo câncer hematológico mais comum; representa aproximadamente 10% de todas os cânceres hematológicos e 1%-2% de todos as neoplasias. Foi conduzido um estudo ecológico para descrever a morbidade, a mortalidade e a carga da doença no Brasil e suas 27 unidades federativas e avaliar tendências entre 1990-2019. Dados do estudo da Carga Global de Doenças foram avaliados para descrever medidas ajustadas por idade: incidência, prevalência, mortalidade, anos de vida ajustados pela incapacidade e seus componentes de acordo com sexo e Índice Sociodemográfico. As tendências foram estimadas usando regressão linear e expressas como Variação Percentual Anual Média (AAPC) e Intervalos de Confiança (IC) 95%. Tendências ascendentes das medidas foram observadas. A mortalidade aumentou em menor extensão comparada à incidência (AAPC=1,3%;IC95%=1,2-1,3 vs. AAPC=1,5%;IC95%=1,5-1,5 homens; AAPC=0,9%; IC95%=0,9-0,9 vs. AAPC=1,1%; IC95%=1,1-1,2 mulheres), resultando em tendências crescentes da prevalência para ambos os sexos. Todas as medidas foram mais altas nos quintis do índice sociodemográfico alto e médio-alto; tendências ascendentes mais altas foram encontradas em quintis do índice sociodemográfico mais baixos. Envelhecimento, nível de desenvolvimento, acesso ao diagnóstico e tratamento parecem explicar as medidas ascendentes do mieloma múltiplo no Brasil e suas diferenças entre as unidades federativas.
PALAVRAS-CHAVES
Mieloma múltiplo; Incidência; Mortalidade; Anos de vida ajustados pela incapacidade; Brasil
Introduction
Multiple Myeloma (MM) is an incurable hematological malignancy that primarily affects older adults11 Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548-567. DOI: https://doi.org/10.1002/ajh.25791
https://doi.org/10.1002/ajh.25791... . It is characterized by the proliferation of clonal plasma cells in the bone marrow, resulting in damage to end organs (hypercalcemia, renal failure, anemia, or lytic bone lesions – CRAB features)11 Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548-567. DOI: https://doi.org/10.1002/ajh.25791
https://doi.org/10.1002/ajh.25791... , 22 Cowan AJ, Green DJ, Kwok M, et al. Diagnosis and management of multiple myeloma: A review. JAMA. 2022;327(5):464-477. DOI: https://doi.org/10.1001/jama.2022.0003
https://doi.org/10.1001/jama.2022.0003... . MM usually evolves from asymptomatic conditions of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering MM (SMM) to symptomatic MM at progression rates of approximately 1% and 10% per year, respectively11 Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548-567. DOI: https://doi.org/10.1002/ajh.25791
https://doi.org/10.1002/ajh.25791... . Known risk factors for MM are aging, male sex, black race, genetic factors11 Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548-567. DOI: https://doi.org/10.1002/ajh.25791
https://doi.org/10.1002/ajh.25791... , 22 Cowan AJ, Green DJ, Kwok M, et al. Diagnosis and management of multiple myeloma: A review. JAMA. 2022;327(5):464-477. DOI: https://doi.org/10.1001/jama.2022.0003
https://doi.org/10.1001/jama.2022.0003... , family history of MM33 Curado MP, Oliveira MM, Silva DRM, et al. Epidemiology of multiple myeloma in 17 Latin American countries: An update. Cancer Med. 2018;7(5):2101-2108. DOI: https://doi.org/10.1002/cam4.1347
https://doi.org/10.1002/cam4.1347... , high Body Mass Index (BMI)44 Zhou L, Yu Q, Wei G, et al. Measuring the global, regional, and national burden of multiple myeloma from 1990 to 2019. BMC Cancer. 2021;21(1):606. DOI: https://doi.org/10.1186/s12885-021-08280-y
https://doi.org/10.1186/s12885-021-08280... , and occupational exposures, such as pesticides55 Institute for Health Metrics and Evaluation. GBD Compare [Internet]. Seattle, WA: IHME, University of Washington; 2015 [cited 2022 Dec 10]. Available from: https://www.healthdata.org/.
https://www.healthdata.org/.... , 66 Correa C, Gonzalez-Ramella O, Baldomero H. Increasing access to hematopoietic cell transplantation in Latin America: Results of the 2018 LABMT activity survey and trends since 2012. Bone Marrow Transplant. 2022;57(6):881-888. DOI: https://doi.org/10.1038/s41409-022-01630-9
https://doi.org/10.1038/s41409-022-01630... .
MM is the second most common hematological cancer; it accounts for approximately 10% of all hematologic malignancies and 1%-2% of all cancer diagnoses. Globally, from 1990 to 2019, the age-standardized incidence rate of MM has increased from 1.73 cases per 100,000 to 1.92 cases per 100,000, with a significant age-standardized prevalence increase [4.21 (95% Uncertainty Interval – UI, 3.86-4.64) to 5.55 (95% UI, 4.89-6.18)] and the downward tendency of age-standardized mortality rates since the early 2000’s44 Zhou L, Yu Q, Wei G, et al. Measuring the global, regional, and national burden of multiple myeloma from 1990 to 2019. BMC Cancer. 2021;21(1):606. DOI: https://doi.org/10.1186/s12885-021-08280-y
https://doi.org/10.1186/s12885-021-08280... . These reflect the global disease burden estimated at 2.5 million Disability-Adjusted Life Years (DALYs) in 2019, corresponding to an age-standardized rate of30.26 DALYs per 100,00077 Cowan AJ, Baldomero H, Atsuta Y, et al. The Global State of Hematopoietic Cell Transplantation for Multiple Myeloma: An Analysis of the Worldwide Network of Blood and Marrow Transplantation Database and the Global Burden of Disease Study. Biol Blood Marrow Transplant. 2020;26(12):2372-2377. DOI: https://doi.org/10.1016/j.bbmt.2020.08.018
https://doi.org/10.1016/j.bbmt.2020.08.0... .
Although MM still has no cure, the disease is treatable. Increasing survival rates have been attributed to the availability of Autologous Stem Cell Transplantation (ASCT)88 Cowan AJ, Allen C, Barac A, et al. Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018;4(9):1221-1227. DOI: https://doi.org/10.1001/ja-maoncol.2018.2128
https://doi.org/10.1001/ja-maoncol.2018.... , 99 Pulte D, Jansen L, Castro FA, et al. Trends in survival of multiple myeloma patients in Germany and the United States in the first decade of the 21st century. Br J Haematol. 2015;171(2):189-196. DOI: https://doi.org/10.1111/bjh.13537
https://doi.org/10.1111/bjh.13537... and to the Introduction of Immunomodulatory Drugs – IMiDs (e.g., thalidomide and its analog lenalidomide) and Proteasome Inhibitor – PI drugs (e.g., bortezomib) in the MM treatment in the early 2000’s1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... , 1111 Piechotta V, Jakob T, Langer P, et al. Multiple drug combinations ofbortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev. 2019;(11):CD013487. DOI: https://doi.org/10.1002/14651858.cd013487
https://doi.org/10.1002/14651858.cd01348... . These drug classes are recommended to be used in the induction therapy followed by ASCT in transplant-eligible newly diagnosed MM patients and preferred first line therapy for patients unsuitable for transplantation in developed countries1212 Magalhães Filho RJP, Crusoe E, Riva E, et al. Analysis of Availability and Access of Anti-myeloma Drugs and Impact on the Management of Multiple Myeloma in Latin American Countries. Clin Lymphoma Myeloma Leuk. 2019;19(1):e43-e50. DOI: https://doi.org/10.1016/j.clml.2018.08.005
https://doi.org/10.1016/j.clml.2018.08.0... , 1313 Paumgartten FJR. The tale of lenalidomide clinical superiority over thalidomide and regulatory and cost-effectiveness issues. Ciênc saúde coletiva. 2019;24(10):3783-3792. DOI: https://doi.org/10.1590/1413-812320182410.28522017
https://doi.org/10.1590/1413-81232018241... .
Despite the advances in the MM treatment, there are marked inequalities concerning access to ASCT88 Cowan AJ, Allen C, Barac A, et al. Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018;4(9):1221-1227. DOI: https://doi.org/10.1001/ja-maoncol.2018.2128
https://doi.org/10.1001/ja-maoncol.2018.... , 99 Pulte D, Jansen L, Castro FA, et al. Trends in survival of multiple myeloma patients in Germany and the United States in the first decade of the 21st century. Br J Haematol. 2015;171(2):189-196. DOI: https://doi.org/10.1111/bjh.13537
https://doi.org/10.1111/bjh.13537... and drug availability worldwide1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... , 1414 Ministério da Saúde (BR). Diretrizes Diagnósticas e Terapêuticas do Mieloma Múltiplo [Internet]. Brasília, DF: Ministério da Saúde; 2022 [cited 2022 Dec 10]. Available from: https://www.gov.br/conitec/pt-br/midias/consultas/relatorios/2022/20220526_ddt_mieloma_multiplo_cp.pdf
https://www.gov.br/conitec/pt-br/midias/... . In Brazil, thalidomide (2002) and bortezomib (2020) have been made available free of charge through the national Unified Health System (Sistema Único de Saúde – SUS) for patients treated in public (High-Complexity Oncology Centers – CACONs and High-Complexity Oncology Units – UNACONs) and private specialized health centers. Lenalidomide was approved for MM treatment in Brazil in 20171515 Agência Nacional de Vigilância Sanitária (BR). Consultas. Portal Anvisa [Internet]. 2023 [cited 2023 Mar 10]. Available from: https://consultas.anvisa.gov.br/
https://consultas.anvisa.gov.br/... ; however, it was not incorporated into SUS and made accessible without costs for use1616 Associação Brasileira de Linfoma e Leucemia (BR). Tratamento – Mieloma múltiplo. Abrale [Internet]. 2023 [cited 2023 Mar 10]. Available from: https://www.abrale.org.br/doencas/mieloma-multiplo
https://www.abrale.org.br/doencas/mielom... .
Some studies have provided valuable knowledge on MM epidemiology and addressed the influence of factors such as population growth, aging, structure of health care system, and treatment availability on the burden of disease in high- to low-income countries33 Curado MP, Oliveira MM, Silva DRM, et al. Epidemiology of multiple myeloma in 17 Latin American countries: An update. Cancer Med. 2018;7(5):2101-2108. DOI: https://doi.org/10.1002/cam4.1347
https://doi.org/10.1002/cam4.1347... , 44 Zhou L, Yu Q, Wei G, et al. Measuring the global, regional, and national burden of multiple myeloma from 1990 to 2019. BMC Cancer. 2021;21(1):606. DOI: https://doi.org/10.1186/s12885-021-08280-y
https://doi.org/10.1186/s12885-021-08280... , 1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... , 1717 Hungria VTM, Chiattone C, Pavlovsky M, et al. Epidemiology of hematologic malignancies in real-world settings: Findings From the Hemato-Oncology Latin America Observational Registry Study. J Glob Oncol. 2019;5:1-19. DOI: https://doi.org/10.1200/jgo.19.00025
https://doi.org/10.1200/jgo.19.00025... , 1818 Zhao Y, Niu D, Ye E, et al. Secular trends in the burden of multiple myeloma from 1990 to 2019 and its projection until 2044 in China. Front Public Health. 2022;10:938770. DOI: https://doi.org/10.3389/fpubh.2022.938770
https://doi.org/10.3389/fpubh.2022.93877... . Age-standardized mortality rates have decreased in high Socio-demographic Index (SDI) countries yet have shown a rising trend in low- to high-middle SDI countries44 Zhou L, Yu Q, Wei G, et al. Measuring the global, regional, and national burden of multiple myeloma from 1990 to 2019. BMC Cancer. 2021;21(1):606. DOI: https://doi.org/10.1186/s12885-021-08280-y
https://doi.org/10.1186/s12885-021-08280... , 1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... as in many countries of Latin America33 Curado MP, Oliveira MM, Silva DRM, et al. Epidemiology of multiple myeloma in 17 Latin American countries: An update. Cancer Med. 2018;7(5):2101-2108. DOI: https://doi.org/10.1002/cam4.1347
https://doi.org/10.1002/cam4.1347... . Age-standardized incidence rates have increased globally. Particularly in low- to middle-SDI regions, the increase in incidence rates has been regarded as due to aging and population growth1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... . In addition, the authors pointed out that disparities in access to treatment (ASCT and novel therapies) and early diagnosis could explain the geographical heterogeneity of MM. The pattern of disease is also different between sexes, affecting mainly men. Although some risk factors for MM have been established (e.g., race, family history of MM, BMI, and occupational exposures), further investigation on etiologic factors is still needed44 Zhou L, Yu Q, Wei G, et al. Measuring the global, regional, and national burden of multiple myeloma from 1990 to 2019. BMC Cancer. 2021;21(1):606. DOI: https://doi.org/10.1186/s12885-021-08280-y
https://doi.org/10.1186/s12885-021-08280... , 55 Institute for Health Metrics and Evaluation. GBD Compare [Internet]. Seattle, WA: IHME, University of Washington; 2015 [cited 2022 Dec 10]. Available from: https://www.healthdata.org/.
https://www.healthdata.org/.... , 66 Correa C, Gonzalez-Ramella O, Baldomero H. Increasing access to hematopoietic cell transplantation in Latin America: Results of the 2018 LABMT activity survey and trends since 2012. Bone Marrow Transplant. 2022;57(6):881-888. DOI: https://doi.org/10.1038/s41409-022-01630-9
https://doi.org/10.1038/s41409-022-01630... , 1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... .
MM estimates are not released periodically in Brazil; thus, reporting epidemiological patterns of the disease is crucial to inform national health decision-making and planning and to guide research. Therefore, we performed a comprehensive analysis of the Global Burden of Disease (GBD) study 2019 to describe the epidemiological pattern of MM in Brazil. Our objective was to report age-standardized (+40 years) incidence, mortality, DALY, years of life lost (YLL) and years lived with disability (YLD) and assess trends in morbidity, mortality, and burden of MM from 1990 to 2019, by age and SDI group in Brazil, across its 27 federative units.
Material and methods
This is a time-series ecological study using data from the GBD study. Data on MM were obtained to calculate incidence, prevalence, mortality, DALY, and its components – YLL and YLD of MM in Brazil between 1990 and 2019. Data were extracted from the Global Health Data Exchange (GHDx) query tool77 Cowan AJ, Baldomero H, Atsuta Y, et al. The Global State of Hematopoietic Cell Transplantation for Multiple Myeloma: An Analysis of the Worldwide Network of Blood and Marrow Transplantation Database and the Global Burden of Disease Study. Biol Blood Marrow Transplant. 2020;26(12):2372-2377. DOI: https://doi.org/10.1016/j.bbmt.2020.08.018
https://doi.org/10.1016/j.bbmt.2020.08.0... , 1919 Institute for Health Metrics and Evaluation. Global Health Data Exchange – GHDx [Internet]. Seattle, WA: IHME, University of Washington; 2021 [cited 2022 Dec 10]. Available from: http://ghdx.healthdata.org/gbd-results-tool
http://ghdx.healthdata.org/gbd-results-t... . C88 and C90 codes of the International Disease Classification, tenth revision (ICD-10) were considered for MM definition.
GBD uses standard approaches for data correction. In the case of mortality, the main adjustments include the redistribution of unspecific codes (garbage codes) or codes that cannot be considered the underlying cause of death. Mortality was adjusted for all-cause mortality separately estimated through a process called ‘CodCorrect’, as reported by other authors1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... , 2020 GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1204-1222. DOI: https://doi.org/10.1016/s0140-6736(20)30925-9
https://doi.org/10.1016/s0140-6736(20)30... , 2121 Foreman KJ, Lozano R, Lopez AD, et al. Modeling causes of death: an integrated approach using CODEm. Popul Health Metr. 2012;10(1):1. DOI: https://doi.org/10.1186/1478-7954-10-1
https://doi.org/10.1186/1478-7954-10-1... . Incidence data were derived from population-based cancer registries, as described elsewhere1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... .
GBD calculates DALYs for MM as the sum of the YLL. YLL is calculated by the difference between a standard life expectancy and the age at death, and YLD is obtained by multiplying the prevalence by disability weights for mutually exclusive sequelae of MM1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... .
We used age-standardized (40+ years) measures to calculate incidence, mortality rates DALYs, YLL, and YLD, and prevalence over the 30-year study period, according to sex and federative units and SDI group. SDI is a composite indicator based on the total fertility rate under the age of 25, mean education for those ages 15 and older, and lag-distributed income per capita. It varies from 0 (minimum level of development) to 1 (maximum level of development), allowing the comparison of the level of development relevant to health across Brazilian federative units2222 Estudo de Carga Global de Doença 2015: resumo dos métodos utilizados. Rev Bras Epidemiol. 2017;20:4-20. DOI: https://doi.org/10.1590/1980-54972017000500020
https://doi.org/10.1590/1980-54972017000... . We calculated SDI quintiles annually between 1990 and 2019 for Brazil and all its 27 federative units, which were categorized into five groups: low-, low-middle-, middle-, highmiddle-, and high-quantile.
A direct method was employed to standardize all health indicators, using the world population as a reference. All rates were expressed per 100,000. The Average Annual Percentage Change (AAPC), with a 95% Confidence Interval (CI), was calculated to identify trends for MM measures in Brazil and its federative units by sex and SDI quintiles. AAPC is the weighted average of the angular coefficients of the regression line, with weights equal to the length of each segment throughout the interval. An increase or decrease in trend is statistically significant when different from 0 (p < 0.05) and stable when equal to 0 (p > 0.05)2323 Kim HJ, Fay MP, Feuer EJ, et al. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med. 2000;19(3):335-351. DOI: https://doi.org/10.1002/(sici)1097-0258(20000215)19:3%-3C335::aid-sim336%3E3.0.co;2-z
https://doi.org/10.1002/(sici)1097-0258(... . Trend analysis was carried out by linear regression using the Joinpoint regression program, version 4.9.1.0 – April 11, 2022, from the Surveillance, Epidemiology and End Results program (SEER) of the National Cancer Institute2424 National Cancer Institute. Joinpoint regression program, Version 4.9.1.0 – April 11, 2022; statistical methodology and applications branch, surveillance research program [Internet]. [unknown location]. 2022 [cited 2022 Sep 15]. Available from: https://surveillance.cancer.gov/joinpoint/
https://surveillance.cancer.gov/joinpoin... .
This study complies with the Resolution nº 466/20122525 Ministério da Saúde (BR); Conselho Nacional de Saúde. Resolução nº 466, de 12 de dezembro de 2012. Aprova as diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos e revoga as Resoluções CNS nos. 196/96, 303/2000 e 404/2008. Diário Oficial da União [Internet], Brasília, DF. 2013 jun 13 [cited 2024 Aug 16]; Seção I:549. Available from: https://www.gov.br/conselho-nacional-de-saude/pt-br/acesso-a-informacao/legislacao/resolucoes/2012
https://www.gov.br/conselho-nacional-de-... , which regulates human subject research in Brazil. The Ethics Committee of the Universidade Federal de Minas Gerais approved the study (CAAE 62803316.7.0000.5149, Opinion Number 1.873.624).
Results
Incidence and prevalence
In Brazil, 1,240 and 4,843 new cases (+40 years, both sexes) of MM were registered in 1990 and 2019, respectively. There was a rising trend in the incidence of MM for both sexes over the period. Men had the largest incidence (from 4.40/100,000 in 1990 to 6.78/100,000 in 2019 – AAPC= 1.5; 95%CI=1.5-1.5) compared to women (3.97/100,000 in 1990 and 5.50/100,000 in 2019 – AAPC= 1.1; 95%CI=1.1;1.12) (table 1). In all federative units, there was an upward incidence trend from 1990 to 2019 for both sexes (table 1). The lowest rates among men were found in the state of Amapá (2.21/100,000 in 1990 vs. 3.96/100,000 in 2019) and the highest in the Distrito Federal (8.55/100,000 in 1990 vs. 10.35/100,000 in 2019). The most pronounced increasing trends in incidence were observed in Bahia and the least one in the Distrito Federal. In women, the lowest rates were in Maranhão in 1990 (2.08/100,000) and Pará in 2019 (2.92/100,000); the highest incidences were observed in the Distrito Federal in both periods (7.01 and 8.56/100,000 in 1990 and 2019, respectively). Incidence rose for all SDI groups; the most increasing trends were found in the low- and low-middle SDI quintiles for men (AAPC= 2.2; 95%CI=2.1-2.3 AAPC= 2.2; 95%CI=2.1-2.2, respectively) and in the low SDI quintile for women (AAPC= 1.9; 95%CI=1.9-2.2) (figure 1A, table 4).
Age-standardized incidence rate and prevalence per 100,000 and Average Annual Percent Change (AAPC) by sex, according to Federative unit and Brazil, 1990-2019
Age-standardized measures per 100,000, by sex according to Socio-demographic Index (SDI) quintiles. Brazil, 1990-2019. (A) incidence, prevalence, and mortality; (B) Disability-Adjusted Life Years (DALYs), Years of Life Lost (YLLs), and Years Lived with Disability (YLDs)
Age-standardized of measures per 100,000 and Average Annual Percent Change (AAPC) by sex, according to Socio-Demographic Index (SDI) quintiles, 1990-2019
The number of prevalent cases (+40 years) of MM for both sexes was 2,649 in 1990 and 11,820 in 2019. Prevalence among men in Brazil was 8.45/100,000 in 1990 and 15.10/100.000 in 2019, corresponding to an ascending trend of 2.0% per year (95%CI=2.0-2.1). Among women, annual changes in prevalence increased by 1.7% (95%CI=1.7-1.8) (8.58/100,000 in 1990 and 14.12/100.000 in 2019) (table 1). The lowest rates in men were found in Amapá e and the highest in the Distrito Federal. In women, the lowest prevalence rates were in Maranhão (1990) and Pará (2019) and the largest in the Distrito Federal in both periods. Increasing trends in the prevalence rates were observed for all Brazilian States over the period, with the higher rising trends registered in Maranhão and the lowest ones in Rio de Janeiro, Goiás, and the Distrito Federal (table 1). There were increasing prevalence trends for all SDI groups, with the low-SDI quintile group having the highest changes for both sexes (figure 1A, table 4).
Mortality
Higher mortality rates of MM were observed in Brazil in 2019 for men and women; however, showing a slightly lower upward trend in comparison to incidence. Incidence increased in men from 3.93/100,000 in 1990 to 5.68/100,000 in 2019 (AAPC=1.3; 95%CI=1.2-1.3), whereas an annual increase of 0.9% (95%CI=0.9-0.9) from 1990 to 2019 was found for women (table 2). The number of deaths due to MM (+40 years, both sexes) was 1,059 in 1990 and 3,907 in 2019.
Age-standardized mortality rate and Disability-Adjusted Life Years (DALYs) per 100,000 and Average Annual Percent Change (AAPC) by sex, according to Federative unit and Brazil, 1990-2019
The lowest mortality rates for men were observed in Amapá (1.99/100,000 in 1990 and 3.40/100,000 in 2019) and the highest in the Distrito Federal (7.78/100,000 in 1990 and 8.50/100,000 in 2019). In women, the lowest rates were in Tocantins in 1990 (1.92/100,000) and in Pará in 2019 (2.38/100,000); the highest were found in the Distrito Federal in both periods (6.02/100,000 in 1990 and 6.58/100,000 in 2019). There was an upward trend of mortality in all federative units for men and women, varying from 0.3 (95%CI=0.2-0.4) in the Distrito Federal to 2.5 (95%CI=2.5-2.6) in Bahia and from 0.3 (95%CI=0.3-0.4) in the Distrito Federal to 1.8 (95%CI=1.8-1.9) in Amapá and Maranhão (AAPC=1.8; 95%CI=1.7-1.9) (table 2). Upward mortality trends were observed for all SDI quintiles, being the changes more pronounced in the low-SDI quintile for men and women (figure 1A, table 4).
YLD, YLL and DALY
DALY and its components – YLD and YLL had ascending trends in Brazil and its federative units from 1990 to 2019, except YLL in the Distrito Federal, which remained constant over the years among women (tables 2 and 3). YLD for men rose from 2.08/100.000 in 1990 to 3.37/100.000 in 2019 (AAPC= 1.7; 95%CI=1.7-1.8) in Brazil, whereas for women it varied from 1.99/100.000 in 1990 to 2.93/100.000 (AAPC= 1.3; 95%CI= 1.3-1.4). Compared to YLD, slighter upward trends were found for YLL in men (AAPC= 1.1; 95%CI=1.0-1.1) and women (AAPC= 0.6; 95%CI=0.6-0.6) (tables 2 and 3), corresponding to increased DALYs for men (96.18/100,000 vs. 131.18/100.000; AAPC= 1.1 95%CI=1.1-1.2) and for women (82.38/100,000 vs. 99.22/100.000; AAPC= 0.6; 95%CI=0.6-0.7) from 1990 to 2019 (tables 2 and 3). The number of DALYs (+40 years, both sexes) was 27,736 in 1990 and 92,224 in 2019, corresponding to 27,123 YLL and 613 YLD in 1990 and 89,714 YLL and 2,510 YLD in 2019.
Age-standardized Years Lived with Disability (YLDs) and Age-standardized Years of Life Lost (YLLs) per 100,000 and Average Annual Percent Change (AAPC) by sex, according to Federative unit and Brazil, 1990-2019
The lowest DALYs for men in both periods were found in Amapá, while the highest DALYs were found in the Distrito Federal. Among women, the lowest DALYs were observed in Tocantins in 1990 and Pará in 2019, and the highest in the Distrito Federal in both years (table 2). Ascending trends of DALYs, YLL, and YLD were found for both sexes in all SDI quintiles (figure 1B, table 4).
Discussion
Morbidity, mortality, and the burden of MM have been rising in Brazil between 1990 and 2019. In accordance with the epidemiology of MM, the highest measures were registered for male sex. Mortality increased, nevertheless, at a slower pace than incidence, corresponding to a higher rising trend of prevalence for both sexes. YLL continues to be the main component of DALY yet shows a smaller upward trend than YLD. Overall, age-standardized incidence, prevalence mortality, DALY, YLL, and YLD were greater in federative units with higher SDI, especially in those from high- and high-middle quintiles, while the poorest places showed the highest ascending trends for all the measures from 1990 to 2019.
While we found a similar pattern of MM epidemiology across the Brazilian States, we also observed differences in the magnitude of the measures of MM, which is probably related to uneven access to healthcare services facilitating diagnosis and treatment, aging, population growth, and quality of data, as indicated by other investigations33 Curado MP, Oliveira MM, Silva DRM, et al. Epidemiology of multiple myeloma in 17 Latin American countries: An update. Cancer Med. 2018;7(5):2101-2108. DOI: https://doi.org/10.1002/cam4.1347
https://doi.org/10.1002/cam4.1347... , 44 Zhou L, Yu Q, Wei G, et al. Measuring the global, regional, and national burden of multiple myeloma from 1990 to 2019. BMC Cancer. 2021;21(1):606. DOI: https://doi.org/10.1186/s12885-021-08280-y
https://doi.org/10.1186/s12885-021-08280... , 55 Institute for Health Metrics and Evaluation. GBD Compare [Internet]. Seattle, WA: IHME, University of Washington; 2015 [cited 2022 Dec 10]. Available from: https://www.healthdata.org/.
https://www.healthdata.org/.... , 66 Correa C, Gonzalez-Ramella O, Baldomero H. Increasing access to hematopoietic cell transplantation in Latin America: Results of the 2018 LABMT activity survey and trends since 2012. Bone Marrow Transplant. 2022;57(6):881-888. DOI: https://doi.org/10.1038/s41409-022-01630-9
https://doi.org/10.1038/s41409-022-01630... , 77 Cowan AJ, Baldomero H, Atsuta Y, et al. The Global State of Hematopoietic Cell Transplantation for Multiple Myeloma: An Analysis of the Worldwide Network of Blood and Marrow Transplantation Database and the Global Burden of Disease Study. Biol Blood Marrow Transplant. 2020;26(12):2372-2377. DOI: https://doi.org/10.1016/j.bbmt.2020.08.018
https://doi.org/10.1016/j.bbmt.2020.08.0... , 88 Cowan AJ, Allen C, Barac A, et al. Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018;4(9):1221-1227. DOI: https://doi.org/10.1001/ja-maoncol.2018.2128
https://doi.org/10.1001/ja-maoncol.2018.... , 99 Pulte D, Jansen L, Castro FA, et al. Trends in survival of multiple myeloma patients in Germany and the United States in the first decade of the 21st century. Br J Haematol. 2015;171(2):189-196. DOI: https://doi.org/10.1111/bjh.13537
https://doi.org/10.1111/bjh.13537... , 1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... . Federative units with incidences above that found for Brazil – Distrito
Federal, São Paulo, Rio de Janeiro, Minas Gerais, Santa Catarina, Rio Grande do Sul (for men), and Goiás (for women), coincided with those having the highest proportions of persons aged 65 years or older in 2010 and 201 92626 Instituto Brasileiro de Geografia e Estatística (BR). Projeção da população do Brasil e das Unidades da Federação [Internet]. [Rio de Janeiro]: IBGE; 2022 [cited 2022 Dec 10]. Available from: https://www.ibge.gov.br/apps/populacao/projecao/index.html?utm_source=portal&utm_medium=popclock
https://www.ibge.gov.br/apps/populacao/p... , 2727 Azeredo Passos VM, Champs APS, Teixeira R, et al. The burden of disease among Brazilian older adults and the challenge for health policies: results of the Global Burden of Disease Study 2017. Popul Health Metr. 2020;18(Suppl1):14. DOI: https://doi.org/10.1186/s12963-020-00206-3
https://doi.org/10.1186/s12963-020-00206... and, in most cases, with the highest level of development. Therefore, the underreporting of MM data due to poor access to early diagnosis and treatment in low-income areas in Brazil must be taken into account when interpreting these results.
Increasing incidence trends can also be explained by improvements in MM diagnosis made over the period, despite the recognized inequalities between public and private health services concerning (timely) access to diagnosis and treatment2828 Maiolino A, Neto J, Leite L, et al. Unmet needs in multiple myeloma in Brazil from physicians’ perspective – barriers in quality of life and disease management. J Bras Econ Saúde. 2018;10(2):165-171. DOI: https://doi.org/10.21115/JBES.v10.n2.p165-171
https://doi.org/10.21115/JBES.v10.n2.p16... . Socio-economic disparities should have influenced MM detection among federative units, considering that the diagnosis of MM is quite complex and costly, resulting in underestimation of the disease especially in regions lacking infrastructure or having other health needs33 Curado MP, Oliveira MM, Silva DRM, et al. Epidemiology of multiple myeloma in 17 Latin American countries: An update. Cancer Med. 2018;7(5):2101-2108. DOI: https://doi.org/10.1002/cam4.1347
https://doi.org/10.1002/cam4.1347... , 44 Zhou L, Yu Q, Wei G, et al. Measuring the global, regional, and national burden of multiple myeloma from 1990 to 2019. BMC Cancer. 2021;21(1):606. DOI: https://doi.org/10.1186/s12885-021-08280-y
https://doi.org/10.1186/s12885-021-08280... , 55 Institute for Health Metrics and Evaluation. GBD Compare [Internet]. Seattle, WA: IHME, University of Washington; 2015 [cited 2022 Dec 10]. Available from: https://www.healthdata.org/.
https://www.healthdata.org/.... , 66 Correa C, Gonzalez-Ramella O, Baldomero H. Increasing access to hematopoietic cell transplantation in Latin America: Results of the 2018 LABMT activity survey and trends since 2012. Bone Marrow Transplant. 2022;57(6):881-888. DOI: https://doi.org/10.1038/s41409-022-01630-9
https://doi.org/10.1038/s41409-022-01630... , 77 Cowan AJ, Baldomero H, Atsuta Y, et al. The Global State of Hematopoietic Cell Transplantation for Multiple Myeloma: An Analysis of the Worldwide Network of Blood and Marrow Transplantation Database and the Global Burden of Disease Study. Biol Blood Marrow Transplant. 2020;26(12):2372-2377. DOI: https://doi.org/10.1016/j.bbmt.2020.08.018
https://doi.org/10.1016/j.bbmt.2020.08.0... , 88 Cowan AJ, Allen C, Barac A, et al. Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018;4(9):1221-1227. DOI: https://doi.org/10.1001/ja-maoncol.2018.2128
https://doi.org/10.1001/ja-maoncol.2018.... , 99 Pulte D, Jansen L, Castro FA, et al. Trends in survival of multiple myeloma patients in Germany and the United States in the first decade of the 21st century. Br J Haematol. 2015;171(2):189-196. DOI: https://doi.org/10.1111/bjh.13537
https://doi.org/10.1111/bjh.13537... , 1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... , 1111 Piechotta V, Jakob T, Langer P, et al. Multiple drug combinations ofbortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev. 2019;(11):CD013487. DOI: https://doi.org/10.1002/14651858.cd013487
https://doi.org/10.1002/14651858.cd01348... , 1212 Magalhães Filho RJP, Crusoe E, Riva E, et al. Analysis of Availability and Access of Anti-myeloma Drugs and Impact on the Management of Multiple Myeloma in Latin American Countries. Clin Lymphoma Myeloma Leuk. 2019;19(1):e43-e50. DOI: https://doi.org/10.1016/j.clml.2018.08.005
https://doi.org/10.1016/j.clml.2018.08.0... , 1313 Paumgartten FJR. The tale of lenalidomide clinical superiority over thalidomide and regulatory and cost-effectiveness issues. Ciênc saúde coletiva. 2019;24(10):3783-3792. DOI: https://doi.org/10.1590/1413-812320182410.28522017
https://doi.org/10.1590/1413-81232018241... , 1414 Ministério da Saúde (BR). Diretrizes Diagnósticas e Terapêuticas do Mieloma Múltiplo [Internet]. Brasília, DF: Ministério da Saúde; 2022 [cited 2022 Dec 10]. Available from: https://www.gov.br/conitec/pt-br/midias/consultas/relatorios/2022/20220526_ddt_mieloma_multiplo_cp.pdf
https://www.gov.br/conitec/pt-br/midias/... , 1515 Agência Nacional de Vigilância Sanitária (BR). Consultas. Portal Anvisa [Internet]. 2023 [cited 2023 Mar 10]. Available from: https://consultas.anvisa.gov.br/
https://consultas.anvisa.gov.br/... , 1616 Associação Brasileira de Linfoma e Leucemia (BR). Tratamento – Mieloma múltiplo. Abrale [Internet]. 2023 [cited 2023 Mar 10]. Available from: https://www.abrale.org.br/doencas/mieloma-multiplo
https://www.abrale.org.br/doencas/mielom... , 1717 Hungria VTM, Chiattone C, Pavlovsky M, et al. Epidemiology of hematologic malignancies in real-world settings: Findings From the Hemato-Oncology Latin America Observational Registry Study. J Glob Oncol. 2019;5:1-19. DOI: https://doi.org/10.1200/jgo.19.00025
https://doi.org/10.1200/jgo.19.00025... . The detection of MGUS and SMM, which usually precede MM, and a complete diagnostic investigation of MM would rarely been performed in federative units with low SDI. Thus, the increase in the incidence of MM observed in Brazil might not reflect a real rise in the disease, but rather an improved access to diagnosis and awareness of the disease. Another study1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... evaluated rising age-specific incidence rates, an aging population, and population growth as the main contributors to the increase in MM incidence worldwide. Similarly, all these factors should have influenced the ascending incidence of MM in Brazil, and the contribution of individual factors to new cases of myeloma should be demonstrated in future investigations.
The advances achieved in the treatment of MM in Brazil in the late 1980s brought with the ASCT and the use of thalidomide combined with the drug regimens combinations from the early 2000s, improved survival (decelerating mortality rate and YLL) and contributed to the rising trends in prevalence rates and YLD. Thalidomide has been made available nationwide without cost in public and private health care; however, the access to novel drug therapies have been unequal compared to developed countries1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... , 1414 Ministério da Saúde (BR). Diretrizes Diagnósticas e Terapêuticas do Mieloma Múltiplo [Internet]. Brasília, DF: Ministério da Saúde; 2022 [cited 2022 Dec 10]. Available from: https://www.gov.br/conitec/pt-br/midias/consultas/relatorios/2022/20220526_ddt_mieloma_multiplo_cp.pdf
https://www.gov.br/conitec/pt-br/midias/... . Other drugs such as bortezomib, lenalidomide and monoclonal antibodies, more recently approved in Brazil, have been made accessible for only a small part of patients, who are covered by private health insurance, acquire medicine via judicialization or participate in clinical trials2929 Gómez-Almaguer D, Moraes Hungria VT. Multiple myeloma in Latin America. Hematology. 2022;27(1):928-931. DOI: https://doi.org/10.1080/16078454.2022.2112643
https://doi.org/10.1080/16078454.2022.21... .
Moreover, despite the increase of ASCT rates for MM in Brazil (2009-2012)88 Cowan AJ, Allen C, Barac A, et al. Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018;4(9):1221-1227. DOI: https://doi.org/10.1001/ja-maoncol.2018.2128
https://doi.org/10.1001/ja-maoncol.2018.... , only about 30% of patients met eligibility for the procedure88 Cowan AJ, Allen C, Barac A, et al. Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018;4(9):1221-1227. DOI: https://doi.org/10.1001/ja-maoncol.2018.2128
https://doi.org/10.1001/ja-maoncol.2018.... , 3030 Malta JS, Drummond PLM. Effect of therapeutic regimens and polypharmacy on health-related quality of life of people with multiple myeloma: a cross-sectional study in Belo Horizonte, Brazil. Curr Med Res Opin. 2022;38(8):1275-1283. DOI: https://doi.org/10.1080/03007995.2022.2034387
https://doi.org/10.1080/03007995.2022.20... . Since ASCT criteria require healthier patients younger than 75 years1010 Hungria VTM, Martínez-Baños DM, Penafiel CR, et al. Multiple myeloma treatment patterns and clinical outcomes in the Latin America Haemato-Oncology (HOLA) Observational Study, 2008-2016. Br J Haematol. 2020;188(3):383-393. DOI: https://doi.org/10.1111/bjh.16124
https://doi.org/10.1111/bjh.16124... , patients from poorer regions with limited or no access to timely diagnosis and treatment, are unlikely to be candidates.
Downward trends in mortality have been observed for countries with higher SDI44 Zhou L, Yu Q, Wei G, et al. Measuring the global, regional, and national burden of multiple myeloma from 1990 to 2019. BMC Cancer. 2021;21(1):606. DOI: https://doi.org/10.1186/s12885-021-08280-y
https://doi.org/10.1186/s12885-021-08280... . Mortality rates increased by 1.3% and 0.9% per year for men and women, respectively, whereas incidence increased by 1.5% for men and 1.1% for women, suggesting some improvement in MM treatment in Brazil between 1990 and 2019. This same pattern can be found by comparing mortality and incidence according to SDI quintiles. Another study carried out in Brazil reported an ascending annual percent change of 2.5% in age-adjusted (20+ years) MM mortality for both sexes, from 1996 to 20153030 Malta JS, Drummond PLM. Effect of therapeutic regimens and polypharmacy on health-related quality of life of people with multiple myeloma: a cross-sectional study in Belo Horizonte, Brazil. Curr Med Res Opin. 2022;38(8):1275-1283. DOI: https://doi.org/10.1080/03007995.2022.2034387
https://doi.org/10.1080/03007995.2022.20... . In line with our findings, the authors also observed higher ascending trends of age-standardized mortality (> 20 years) in the North, Northeast, and Midwest regions compared to the Southwest and South regions of Brazil3131 Callera FAC. Mortality of adult patients with multiple myeloma from the Brazilian national health system over the past 20 years. GJRA. 2018;7(2):149-151..
We recognize the limitations of our study that was based on secondary data, which may compromise the accuracy of MM measures. Furthermore, considering the nature of the study design, the assessment of known risk factors that could have affected MM distribution (e.g. black race, high BMI and genetic factors11 Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5):548-567. DOI: https://doi.org/10.1002/ajh.25791
https://doi.org/10.1002/ajh.25791... ,22 Cowan AJ, Green DJ, Kwok M, et al. Diagnosis and management of multiple myeloma: A review. JAMA. 2022;327(5):464-477. DOI: https://doi.org/10.1001/jama.2022.0003
https://doi.org/10.1001/jama.2022.0003... ,44 Zhou L, Yu Q, Wei G, et al. Measuring the global, regional, and national burden of multiple myeloma from 1990 to 2019. BMC Cancer. 2021;21(1):606. DOI: https://doi.org/10.1186/s12885-021-08280-y
https://doi.org/10.1186/s12885-021-08280... ), was beyond the scope of this work. Nevertheless, our study provided an overview of the disease pattern at the population level in Brazil and its federative units. Future research should be performed to further assess the MM epidemiology in Brazil in the face of the demographic transition, the introduction of bortezomib, incorporated into SUS just after the study period, and emerging therapies, as well as the effect of the COVID-19 pandemic.
Conclusions
This study provided the first description of MM in Brazil and its 27 federative units from 1990 to 2019. Age-standardized (40+ years) incidence, prevalence, mortality, DALY, YLL, and YLD of MM showed increasing trends in Brazil over the period. Ascending trends of mortality were less pronounced than incidence (as well as YLL compared to YLD), approaching the scenario of high-income countries. In addition, federative units with higher levels of development showed the highest measures; however, poorer places had higher rising trends. Morbidity, mortality, and disease burden of MM were significantly higher in men compared to women.
- Financial support: the research was funded by the Health Surveillance Secretariat, Ministry of Health, via Decentralized Execution Term (Termo de Execução Descentralizada – TED) 67-2023.
Referências
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Publication Dates
- Publication in this collection
21 Oct 2024 - Date of issue
Jul-Sep 2024
History
- Received
28 Sept 2023 - Accepted
07 June 2024