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Figure.
Adjusted Odds Ratios (ORs) of Overall MGUS Among US Veterans Associated With TCDD Exposure and Operation Ranch Hand
Adjusted Odds Ratios (ORs) of Overall MGUS Among US Veterans Associated With TCDD Exposure and Operation Ranch Hand

Adjusted ORs were estimated for cohort status and for 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) in separate logistic regression models. Both models included the following covariates: age in 2002 in 5-year increments, race, body mass index (BMI) in 2002 in increments of 2 units, and change in BMI between 2002 and at the time of blood draw for the TCDD measurement. Lipid-adjusted TCDD concentrations were either measured in 1987 or, if not measured, reconstructed for the 1987 level using TCDD concentrations measured between 1992 and 2002.36 Dioxin results below the limit of detection were calculated as the limit of detection divided by the square root of 2.38 Two Operation Ranch Hand veterans who had missing BMI or lipid-adjusted TCDD measurements were excluded, leaving 956 veterans in the analysis. MGUS indicates monoclonal gammopathy of undetermined significance; ppt, parts per trillion.

Table 1.  
Characteristics of Operation Ranch Hand and Comparison Veterans Selected for the Study
Characteristics of Operation Ranch Hand and Comparison Veterans Selected for the Study
Table 2.  
Age-Specific Prevalence of Overall MGUS Among Operation Ranch Hand and Comparison Veterans
Age-Specific Prevalence of Overall MGUS Among Operation Ranch Hand and Comparison Veterans
Table 3. 
Characteristics of MGUS Among Operation Ranch Hand Veterans and Comparison Veterans
Characteristics of MGUS Among Operation Ranch Hand Veterans and Comparison Veterans
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    1 Comment for this article
    EXPAND ALL
    AGent Orange Exposure and MGUS
    Han K. Kang, Dr.P.H. | Institute for Clinical Research, Washington, D.C.
    To the Editor

    The study by Landgren et a (1) published in JAMA Oncology demonstrated that Ranch Hand veterans who were occupationally exposed to herbicide in Vietnam showed a significantly higher prevalence of MGUS compared to other Air Force veterans serving in Vietnam. MGUS being a precursor for multiple myeloma (2), this study may be the first study that provides a biological plausibility for an association between exposure to Agent Orange and multiple myeloma among U.S. Air Force Vietnam veterans. To date, the evidence for an association between Agent Orange/TCDD exposure and the risk of multiple myeloma is considered only suggestive
    (3, 4). The study took advantage of the current state of the art clinical laboratory procedures to determine the presence of MGUS and the availability of the archived serum samples from exposed cohort, historical serum TCDD data, and prior physical examination data. This type of study should be further encouraged to expand our knowledge of the human health effects of herbicide exposure.

    As much as the study presented strong evidence that Ranch Hand veterans have a significantly increased risk of MGUS, the evidence for a relationship between body burden of TCDD and the prevalence of MGUS could be strengthened by additional analysis of the data already collected.

    In the current MGUS paper, 187 of 958 veterans do not have a direct TCDD measurement made in1987 and these missing data were substituted with the levels measured 5,10, or 15 years later. The paper by one of the authors (5) shows that TCDD levels for control veterans continue to decrease over time until they reach a steady state level whether they were higher or lower than10 ppt in 1987. Because more control veterans were missing 1987 data (26% of controls) than Ranch Hands (9%), a systematic underestimation of TCDD body burden for control veterans could have been introduced in the study. Therefore, the statement of “the odds of having MGUS increased with increasing body burden of TCDD, although the trend was not statistically significant” may be premature and should be considered tentative.

    This critical limitation of the study could be addressed by additional analysis of MGUS prevalence among 417 Ranch Hand veterans and 354 control veterans with actual 1987 serum TCDD measurements. I believe the authors will make an additional contribution to our knowledge of the health effects of Agent Orange/dioxin by addressing the limitations of the study recognized by the authors themselves.


    Word count: 399




    Han K. Kang, Dr.P.H.




    Author Affiliation: Institute for Clinical Research, Veterans Affairs Medical Center, 50 Irving St, NW, Washington DC

    Corresponding Author: Han K. Kang, Dr.P.H.

    Conflict of Interest Disclosure: None reported


    References

    1. Landgren O, Shim YK, Michalek J, Costello R, Burton D, et al. Agent Orange exposure and monoclonal gammopathy of undetermined significance. An Operation Ranch Hand Veteran Cohort Study. JAMA Oncol Online September 3, 2015.

    2. Kyle RA, Therneau TM, Rajkumar V, Offord JR, Larson JR, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002;346:564-569.

    3. Institute of Medicine. Veterans and Agent Orange: Update 2012. Washington, DC: National Academy Press;2013.

    4. Chang ET, Boffetta P, Adami HO, Mandel JS. A critical review of the epidemiology of Agent Orange or 2,3,7,8-tetrachlorodibenzo-p-dioxin and lymphoid malignancies. Ann Epidemiol 2015;25:275-292.

    5. Jackson W, Michaleck J. Temporal changes in TCDD levels in 1419 Air Force Vietnam- era veterans not occupationally exposed to herbicides. J Exposure Analysis and Environmental Epidemiology 2001;11:50-55
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    November 2015

    Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance: An Operation Ranch Hand Veteran Cohort Study

    Author Affiliations
    • 1National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    • 2Memorial Sloan Kettering Cancer Center, New York, New York
    • 3Agency for Toxic Substances and Disease Registry, Atlanta, Georgia
    • 4Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio
    • 5Clinical Center, National Institutes of Health, Bethesda, Maryland
    • 6Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark
    • 7Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, Maryland
    • 8National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia
    JAMA Oncol. 2015;1(8):1061-1068. doi:10.1001/jamaoncol.2015.2938
    Abstract

    Importance  Multiple myeloma has been classified as exhibiting “limited or suggestive evidence” of an association with exposure to herbicides in Vietnam War veterans. Occupational studies have shown that other pesticides (ie, insecticides, herbicides, fungicides) are associated with excess risk of multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance (MGUS); however, to our knowledge, no studies have uncovered such an association in Vietnam War veterans.

    Objective  To examine the relationship between MGUS and exposure to Agent Orange, including its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in Vietnam War veterans.

    Design, Setting, and Participants  This was a prospective cohort study conducted in 2013 to 2014, testing for MGUS in serum specimens collected and stored in 2002 by the Air Force Health Study (AFHS). The relevant exposure data collected by the AFHS was also used. We tested all specimens in 2013 without knowledge of the exposure status. The AFHS included former US Air Force personnel who participated in Operation Ranch Hand (Ranch Hand veterans) and other US Air Force personnel who had similar duties in Southeast Asia during the same time period (1962 to 1971) but were not involved in herbicide spray missions (comparison veterans). Agent Orange was used by the US Air Force personnel who conducted aerial spray missions of herbicides (Operation Ranch Hand) in Vietnam from 1962 to 1971. We included 479 Ranch Hand veterans and 479 comparison veterans who participated in the 2002 follow-up examination of AFHS.

    Exposures  Agent Orange and TCDD. Serum TCDD levels were measured in 1987, 1992, 1997, and 2002.

    Main Outcomes and Measures  Risk of MGUS measured by prevalence, odds ratios (ORs), and 95% CIs.

    Results  The 479 Ranch Hand veterans and 479 comparison veterans had similar demographic and lifestyle characteristics and medical histories. The crude prevalence of overall MGUS was 7.1% (34 of 479) in Ranch Hand veterans and 3.1% (15 of 479) in comparison veterans. This translated into a 2.4-fold increased risk for MGUS in Ranch Hand veterans than comparison veterans after adjusting for age, race, BMI in 2002, and the change in BMI between 2002 and the time of blood draw for TCDD measurement (adjusted OR, 2.37; 95% CI, 1.27-4.44; P = .007).

    Conclusions and Relevance  Operation Ranch Hand veterans have a significantly increased risk of MGUS, supporting an association between Agent Orange exposure and multiple myeloma.

    Introduction

    More than 22 000 Americans are diagnosed annually as having multiple myeloma.1 The estimated US prevalence count was 51 930 in 20032 and 83 367 in 20111; this rising trend is likely to continue owing to improved diagnostics and therapeutics.3 The median age at diagnosis is 69 years,1 but it can occur in individuals as young as 30 years. Evidence from a large, prospective population-based cancer screening trial shows that multiple myeloma is consistently preceded by a precursor state, monoclonal gammopathy of undetermined significance (MGUS).4

    Although the cause of MGUS and multiple myeloma remains largely unclear, previous cohort5-12 and case control studies13-26 have reported an elevated risk of multiple myeloma among farmers and other agricultural workers. More specifically, pesticides (ie, insecticides, herbicides, fungicides) have been hypothesized as the basis for these associations.27-30 In the first prospective cohort study estimating MGUS risk in relation to pesticide exposure in a sample of 678 male pesticide applicators, a 2-fold significantly increased prevalence of MGUS was observed among pesticide applicators, adding support to the hypothesis that pesticides are linked to myelomagenesis.31

    To expand our knowledge on the association between herbicides and MGUS, a precursor state of multiple myeloma, we assayed 958 serum samples obtained from US Air Force (USAF) personnel who conducted aerial herbicide spray missions of Agent Orange in the Vietnam War from 1962 to 1971 (Operation Ranch Hand) and controls.32 The aims of our study were to determine the prevalence of MGUS among Operation Ranch Hand veterans (hereinafter, Ranch Hand veterans) vs controls and to assess the risk of MGUS in relation to the body burden of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an Agent Orange contaminant that has been classified as a human carcinogen.33

    Methods
    Study Population

    The study base population comprised 1951 USAF personnel who participated in the 2002 follow-up examination of the Air Force Health Study (AFHS)32: 777 who conducted aerial herbicide spray missions of Agent Orange in the Vietnam War from 1962 to 1971 (Ranch Hand veterans) and 1174 who had similar duties in Southeast Asia during the same time period but were not involved in herbicide spray missions (comparison veterans). The original Ranch Hand and comparison veterans were identified from historical data sources, including morning reports, military personnel records, and historical computer tapes at the National Personnel Records Center and the USAF Human Resources Laboratory at Brooks Air Force Base.34 The AFHS conducted 6 follow-ups from 1982 to 2002. At each follow-up, serum specimens were collected and stored at −70°C.

    The veterans eligible for this study were at least 50 years of age at the 2002 follow-up, had a saved serum specimen collected at the 2002 follow-up, and consented to the use of their data and specimen for future research studies. A total of 1349 veterans met the eligibility criteria, including 560 Ranch Hand veterans and 789 comparison veterans. Because the prevalence of MGUS increases rapidly with age, we systematically selected the oldest 480 of the 560 eligible Ranch Hand veterans for our study. Subsequently, we selected 480 of the 789 comparison veterans based on a stratified random sampling scheme determined by the age distribution (categories: 50-59, 60-69, 70-79, and ≥80 years in 2002) of the selected Ranch Hand veterans. Following the diagnostic criteria for MGUS,35 we excluded individuals with a history of multiple myeloma (International Classification of Diseases, Ninth Revision [ICD-9] code 203.0), Waldenström macroglobulinemia (ICD-9 code 273.3), solitary plasmacytoma (ICD-9 code 238.6), or amyloidosis (ICD-9 codes 277.30, 277.39). After applying the MGUS criteria, we excluded 1 Ranch Hand veteran and 1 comparison veteran with multiple myeloma, resulting in a final sample size of 958 veterans (479 Ranch Hand and 479 comparison veterans).

    The study protocol was approved by an institutional review board (IRB) of the US Centers for Disease Control and Prevention. Access to the AFHS data and stored serum specimens for this study was approved by the Institute of Medicine, which serves as a custodian for AFHS resources. As for the protein assays conducted at the National Institutes of Health (NIH), an exemption from IRB review was obtained from the NIH Office of Human Subjects Research.

    Clinical, Laboratory, and Exposure Data

    Following the study protocol, we obtained the AFHS questionnaire, physical examination, and laboratory data for the selected veterans. All data were obtained with coded ID numbers that were different from the original ID numbers of the AFHS participants. No personal identifying information was obtained. In brief, we obtained information regarding race, birth year, military occupation (enlisted ground, enlisted flyer, officer), body mass index (BMI) (weight in kilograms divided by height in meters squared), smoking history (pack-years), drinking history (drink-years), lipid-adjusted TCDD levels, serum creatinine levels, history of radiation therapy or chemotherapy for cancer treatments (yes, no), and coded diagnoses (ICD-9). One pack-year of smoking was defined as 365 packs of cigarettes smoked during a single year. One drink-year was the equivalent of drinking 1.5 ounces of an 80-proof alcoholic beverage, one 12-ounce beer, or one 5-ounce glass of wine per day for 1 year.36 We also obtained multiple causes of death for deceased veterans. Lipid-adjusted serum TCDD concentrations were measured by using high-resolution gas chromatographic/high-resolution mass spectrometric analysis, as previously described.37 The TCDD concentrations were either measured in 1987 or reconstructed.36 The 1987 reference point was chosen because most participants had a TCDD measurement in 1987.36 When a participant did not have a TCDD measurement in 1987, the measurement existing in the nearest subsequent follow-up was chosen (1992, 1997, 2002 follow-ups); for the Ranch Hand veterans whose chosen measurement exceeded 10 parts per trillion (ppt), their 1987 level was reconstructed by extrapolating the measurement using a first-order elimination model with a half-life of 7.6 years.36 Dioxin results below the limit of detection were estimated as the limit of detection divided by the square root of 2.38

    Serum Specimen and Laboratory Methods

    A 1-mL aliquot from the serum collected by the AFHS during the 2002 examination was obtained for each veteran selected for this study. Each aliquot tube was labeled only with the participant’s coded ID number and the specimen collection year. All specimens were shipped on dry ice to the Multiple Myeloma Research Laboratory at the National Cancer Institute, where protein assays were performed. The samples from the 2 cohorts (Ranch Hand and comparison) were tested concurrently in a blinded fashion by 3 of us (O.L., R.C., and D.B.). In brief, serum specimens were first analyzed using conventional agarose-gel electrophoresis to determine the occurrence and pattern of M-protein bands, as described previously.31 Samples observed with an M-protein band, equivocal band pattern, or abnormal free light-chain (FLC) ratio were further analyzed by immunofixation to characterize the heavy- and light-chain isotypes of the M protein. Serum protein electrophoresis and immunofixation were performed using the SPIFE 3000 (Helena Laboratories). The FLC levels in all serum specimens were determined using a turbidimetric assay (Freelite; The Binding Site) performed on a SPAPLUS Automated Analyzer for Specialist Protein Analysis.39 The Freelite assay comprises 2 separate measurements: one to detect free-κ light chains (normal range, 3.3-19.4 mg/L), and the other to detect free-λ light chains (normal range, 5.7-26.3 mg/L).40 We assessed monoclonality based on the κ/λ FLC ratios.39 In accordance with the literature,40 a normal FLC ratio was defined as 0.26 to 1.65 and 0.37 to 3.1 for individuals with estimated glomerular filtration rates (eGFR) of at least 60 mL/min/1.73 m2 and less than 60 mL/min/1.73m2, respectively. Using the Modification of Diet in Renal Disease Study equation (http://nkdep.nih.gov/lab-evaluation/gfr/estimating.shtml), we calculated eGFR from serum creatinine level. Based on current diagnostic criteria, MGUS was defined as either the presence of an M-protein band detected by immunofixation or an abnormal FLC ratio with an increased total concentration of the involved light chain.41 Light-chain MGUS (LC-MGUS) was defined as the presence of an FLC band without heavy-chain expression in immunofixation or presence of an abnormal FLC ratio with an increased level of the involved light chain.41

    Statistical Analysis

    We examined the differences in the demographic, exposure, and clinical characteristics between Ranch Hand and comparison veterans by using Fisher exact test for categorical variables and Kruskal-Wallis test for continuous variables. The relationship between MGUS status (present vs absent) and cohort status (Ranch Hand veteran vs comparison veteran) was assessed without adjustment by using Fisher exact test. Our study would achieve a power of 80% to detect a doubling of the MGUS prevalence in the Ranch Hand cohort relative to the comparison cohort, assuming an MGUS prevalence of 5% in the comparison cohort, with 474 veterans per cohort using 2-sided testing with a significance level of 5%. Our study included 479 veterans in each cohort. An adjusted contrast was carried out with a logistic regression model of MGUS status in terms of the cohort status and covariates. The relationship between MGUS status and TCDD body burden was assessed using a logistic regression model of MGUS in terms of TCDD. We used the lipid-adjusted TCDD concentrations of all veterans in our study categorized into 4 levels (cut points: 25th, 50th, 75th percentiles). We carried out logistic regression analyses for cohort status and TCDD body burden separately because they were highly correlated. Adjusted odds ratios (ORs) and 95% CIs were calculated by including the following covariates in all models: age, race, BMI at the 2002 examination, and changes in the BMI between 2002 and the time of blood draw for the TCDD measurement. These covariates were chosen because age and race are established risk factors for MGUS,42 whereas BMI is a known determinant of TCDD half-life43 and also a suggested risk factor for multiple myeloma.44 We also examined the following variables, individually or collectively, as potential additional covariates judged by the Wald test (P ≤ .30) and changes in ORs (>15%): military occupation, smoking history, drinking history, and history of radiation therapy or chemotherapy for cancer treatments. We did not assess interaction effects between the covariates. We used SAS statistical software (version 9.3 for Windows; SAS Institute Inc) for all analyses. Statistical significance was assessed using a 2-sided P = .05.

    Results

    As shown in Table 1, the 479 Ranch Hand veterans and 479 comparison veterans had similar demographic characteristics, lifestyle characteristics, and medical histories. All veterans were men. The median age in 2002 was 65 years for both Ranch Hand veterans (range, 55-89 years) and comparison veterans (range, 55-84 years); less than 5% of the veterans were black in both cohorts (Table 1). The cohort status was significantly (P < .001) associated with the TCDD levels (≤3.65, 3.66-5.80, 5.81-10.92, and >10.92 ppt) from the 1987 reference year. This is illustrated most obviously by the increased percentage of men with TCDD levels greater than 10.92 ppt in the Ranch Hand veterans (47.5%) relative to those in the comparison veterans (2.5%) (Table 1). For most of the Ranch Hand veterans (417 [87%]) and comparison veterans (354 [74%]), the 1987 reference year level was determined by taking the direct measurement made in 1987. For the remaining veterans without a TCDD measurement made in 1987, the reference year value was determined as described in the Methods section; a total of 19 Ranch Hand veterans had been assigned a reconstructed 1987 value by extrapolation.

    Agent Orange and MGUS Prevalence

    The crude prevalence of overall MGUS was 7.1% (34 of 479) in Ranch Hand veterans and 3.1% (15 of 479) in comparison veterans (Table 2). This translated into a 2.4-fold increased risk for MGUS in Ranch Hand veterans than comparison veterans after adjusting for age, race, BMI in 2002, and the change in BMI between 2002 and the time of blood draw for TCDD measurement (adjusted OR, 2.37; 95% CI, 1.27-4.44; P = .007) (Figure). The risk of MGUS was significantly increased in veterans younger than 70 years (OR, 3.4; 95% CI, 1.46-8.13; P = .004), whereas no significant increase in the risk was seen in those 70 years or older (OR, 1.4; 95% CI, 0.55-3.63; P = .63). Although a logistic model of MGUS in terms of cohort (Ranch Hand or comparison), age (<70 or ≥70 years), and the cohort by age interaction term revealed a nonsignificant interaction term (P = .17), small cell counts may have contributed to the lack of significance. When compared with the veterans in the lowest TCDD level (≤3.65 ppt), the crude ORs for having MGUS were 2.09 (95% CI, 0.77-5.66; P = .15), 2.62 (95% CI, 1.00-6.88; P = .05), and 2.81 (95% CI, 1.08-7.31; P = .03) for veterans with TCDD levels of 3.66 to 5.80 ppt, 5.81 to 10.92 ppt, and more than 10.92 ppt, respectively (Figure). After adjusting for covariates, the TCDD effect observed at the greater than 10.92-ppt level was not statistically significant (adjusted OR, 2.43; 95% CI, 0.92-6.44; P = .07).

    MGUS Characteristics

    The most common heavy-chain isotypes among MGUS cases were IgG and IgM, followed by IgA in both Ranch Hand veterans and comparison veterans (Table 3). The Ranch Hand veterans had a slightly higher (P = .19) M-protein concentration (median, 0.48 g/dL; interquartile range [IQR], 0.32-0.76) than comparison veterans (median, 0.35 g/dL; IQR, 0.20-0.47). The prevalence of heavy-chain MGUS and LC-MGUS was 4.8% and 2.3% (7.1% overall MGUS) in Ranch Hand veterans, and 2.3% and 0.8% (3.1% overall MGUS) in the comparison veterans (Table 3). In a subgroup analysis, the risk for heavy-chain MGUS remained significant in the Ranch Hand cohort compared with the comparison cohort (adjusted OR, 2.2; 95% CI, 1.06-4.55; P = .04) (data not shown). In both Ranch Hand veterans and comparison veterans, the prevalence of MGUS increased with age (Table 2).

    Discussion

    Agent Orange was used by the USAF personnel who conducted aerial spray missions of herbicides (Operation Ranch Hand) in the Vietnam War from 1962 to 1971.32 The main ingredients of Agent Orange were 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), but the human carcinogen TCDD33 was also present in variable amounts as a contaminant.45 The measurement of serum TCDD levels in the Ranch Hand personnel confirmed TCDD exposure, raising concerns regarding long-term health effects from Agent Orange and TCDD.32 The AFHS that began in 1982 included multiple myeloma and other relatively rare cancers as end points, but it lacked statistical power to assess the excess risk associated with Agent Orange/TCDD exposure in the Ranch Hand cohort. A series of reports from the Institute of Medicine (IOM) from 1994 to 2013 addressed these concerns by reviewing available literature and drawing conclusions from the overall evidence.45 The IOM reports identified 7 specific types of cancer for which the evidence of a positive association with Agent Orange/TCDD exposure was considered sufficient or at least limited or suggestive. Four of these were B-cell lymphoid malignant neoplasms; the evidence was sufficient for chronic lymphocytic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma, whereas the evidence was only limited or suggestive for multiple myeloma.45 All 7 types of cancer were recognized by the US Department of Veterans Affairs and federal law as presumptive conditions for the purposes of health care and disability compensation. To our knowledge, our findings provide the first direct scientific evidence for an association between the multiple myeloma precursor, MGUS, and Agent Orange/TCDD exposure among the Ranch Hand veterans.

    Using 958 stored serum samples obtained from Ranch Hand veterans and comparison veterans, we found the prevalence of MGUS in Ranch Hand veterans to be twice that of comparison veterans. Our observations are important in that they add support to a previous finding that certain pesticides play a role in the development of MGUS.31 In our study, the odds of having MGUS increased with increasing body burden of TCDD, although the trend was not statistically significant.

    In a prior investigation based on 77 469 healthy adults enrolled in a US nationwide population-based prospective cancer screening trial, 71 persons developed multiple myeloma during the course of the study.4 In that study, with the use of serially collected prediagnostic serum samples obtained up to almost 10 years before multiple myeloma diagnosis, all multiple myeloma cases were found to be preceded by the premalignant plasma cell disorder MGUS.4 These findings establish a key role for MGUS in the pathway to multiple myeloma. The current findings are also in accordance with those of a prospective cohort study showing a 2-fold higher prevalence of MGUS among 678 private and commercial applicators licensed to apply restricted-use pesticides in Iowa or North Carolina.31 A large (n = 12 482) population-based MGUS screening study representative of the US population recently found striking geographical variations; the prevalence of MGUS was 3.1% and 2.1% (P = .05) for the North/Midwest vs South/West regions of the country, respectively.42 Future studies are needed to determine whether these geographic differences are attributable to environmental exposures associated with pesticide use.

    In our study, the prevalence of LC-MGUS was 2.3% among Ranch Hand veterans and 0.8% among comparison veterans. The prevalence in comparison veterans is similar to the age-standardized prevalence for men reported in a population screening study46 in the United States (prevalence = 1.0%; 95% CI, 0.8%-1.2%). The underlying mechanisms for the higher prevalence of LC-MGUS in the Ranch Hand veterans remain to be better understood. Prospective data show that approximately 20% of all patients with multiple myeloma have light-chain myeloma and that light-chain myeloma is preceded by LC-MGUS.47 Although the association is less well defined, it should be mentioned that both heavy-chain MGUS and LC-MGUS can precede the development of chronic lymphocytic leukemia, non-Hodgkin lymphoma, and other B-cell malignant neoplasms.48,49 We also observed an apparent excess of IgM MGUS in our study population. Based on prior studies, there is an excess risk of Waldenström macroglobulinemia and other B-cell lymphomas among individuals with IgM MGUS.49 In our study population, no veterans were diagnosed as having these conditions by 2002.

    Our study, using the serum specimens and data collected by the AFHS, has several important strengths. It includes both Ranch Hand veterans and other AFHS participants who had similar duties in Southeast Asia during the same period but were not involved in herbicide spray missions. We used the objective measurements of serum TCDD levels as a marker of exposure for both cohorts. Other strengths include 25 years of follow-up time over which the cohort has been monitored for a wide range of health effects and availability of multiple causes of death information. Furthermore, we used established and standardized protein assays that allowed comparison with other population-based studies.42,50

    Our study also has limitations. We had no objective measurements of exposure to phenoxy herbicides (2,4-D and 2,4,5-T), so cohort status was used as a surrogate for phenoxy herbicide exposure. The first TCDD measurements were made in 1987, up to 25 years after the veterans’ Agent Orange exposure in Vietnam, and we could not account for individual variations in whole-body elimination of TCDD. Furthermore, a higher proportion of Ranch Hand veterans (86.6%) had a TCDD level measured in 1987 than did comparison veterans (74.1%), which could have introduced a bias in our results. Other limitations include a limited demographic spectrum that excludes women and the potential confounding by unknown and uncontrolled confounders (eg, family medical history and civilian occupation). Despite the fact that we had access to a large cohort with stored serum samples and risk factor data, we were unable to assess the independent effects of TCDD and cohort status in relation to MGUS risk owing to multicollinearity (ie, TCDD levels and cohort status were correlated). Because of these weaknesses, we cannot discriminate among the phenoxy herbicides, the TCDD contaminant, or other cohort factors as the underlying causes of the increased prevalence of MGUS in Ranch Hand veterans.

    Conclusions

    Using stored serum samples obtained from USAF personnel who conducted aerial herbicide spray missions of Agent Orange in the Vietnam War from 1962 to 1971 (Operation Ranch Hand) and controls, we screened 958 veterans for MGUS and found the prevalence to be 2-fold higher among Ranch Hand veterans. The cohort status was significantly (P < .001) associated with TCDD levels (≤3.65, 3.66-5.80, 5.81-10.92, and >10.92 ppt), illustrated most obviously by the increased percentage of men with TCDD levels greater than 10.92 ppt in the Ranch Hand veterans (47.5%) relative to those in the comparison veterans (2.5%). The MGUS prevalence was 2.43-fold higher (95% CI, 0.92-6.44; P = .07) among veterans with TCDD levels greater than 10.92 ppt compared with veterans with TCDD levels of 3.65 ppt or lower. Our findings of increased MGUS risk among Ranch Hand veterans supports an association between Agent Orange exposure and multiple myeloma.

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    Article Information

    Corresponding Author: Ola Landgren, MD, PhD, Myeloma Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (landgrec@mskcc.org).

    Accepted for Publication: June 27, 2015.

    Published Online: September 3, 2015. doi:10.1001/jamaoncol.2015.2938.

    Author Contributions: Dr Landgren had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Study concept and design: Landgren, Shim, Michalek, Calvo, Raveche, Marti, Vogt.

    Acquisition, analysis, or interpretation of data: Landgren, Shim, Costello, Burton, Ketchum, Calvo, Caporaso, Middleton, Vogt.

    Drafting of the manuscript: Landgren, Shim, Michalek, Costello, Ketchum, Caporaso, Vogt.

    Critical revision of the manuscript for important intellectual content: Landgren, Shim, Michalek, Burton, Ketchum, Calvo, Caporaso, Raveche, Middleton, Marti, Vogt.

    Statistical analysis: Landgren, Shim, Michalek, Ketchum.

    Obtained funding: Landgren, Shim, Middleton, Vogt.

    Administrative, technical, or material support: Landgren, Shim, Costello, Calvo, Caporaso, Vogt.

    Study supervision: Landgren, Shim.

    Conflict of Interest Disclosures: Dr Landgren has given scientific presentations at meeting funded by Onyx Pharmaceuticals/AMGEN, Celgene, BMS and Jansen; has served on the Independent Data Monitoring Committee for clinical trials by Millennium Pharmaceuticals/Takeda; and has served on the advisory committee for Medscape Educations, Myeloma program.

    Funding/Support: This study was supported by the Intramural Program at the Agency for Toxic Substances and Disease Registry, the Intramural Program at the National Cancer Institute, and the Air Force Health Study (AFHS) Assets Research Program at the Institute of Medicine through an award to the Centers for Disease Control and Prevention (CDC) Foundation.

    Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Agency for Toxic Substances and Disease Registry, CDC, National Institutes of Health, or the US Food and Drug Administration.

    Additional Contributions: We acknowledge the contribution of the Medical Follow-Up Agency of the Institute of Medicine, which prepared the AFHS data used throughout this article. The publisher acknowledges the right of the US government to retain a nonexclusive royalty-free license in and to any copyright covering the article.

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