Original Research

Agent Orange Exposure, Transformation From MGUS to Multiple Myeloma, and Outcomes in Veterans

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Background: Multiple myeloma (MM) accounts for 1% to 2% of all cancers. Exposure to the pesticide Agent Orange (AO) has been established as a potential risk factor for the development of monoclonal gammopathy of undetermined significance (MGUS) and, subsequently, MM in Vietnam War veterans.

Methods: This study explored variation in survival related to AO exposure, transformation from MGUS to MM, and covariates. Vietnam War veterans with MM or MGUS were identified in Veterans Health Administration (VHA) health records data. Cox proportional hazards models analyzed survival as a function of AO, race, ethnicity, body mass index, nicotine dependence, alcohol use disorder, Charlson Comorbidity Index, and treatment. Autologous hematopoietic cell transplantation for MM was defined by procedure codes.

Results: In the VHA 16,366 patients were identified: 11,112 patients diagnosed with MGUS and 7261 with MM during fiscal years 2010 to 2015 were identified; 12% (n = 2007) had both diagnoses. No statistically significant difference in the rate of transformation from MGUS to MM in the AO exposed and AO not exposed groups was found. In survival models, AO exposure was associated with slightly lower mortality. Alcohol use disorder, nicotine dependence, older age, and greater comorbidity burden increased mortality risk. Black race, female sex, obesity/overweight, and hematopoietic cell transplantation for patients with MM were protective factors. AO exposure was associated with decreased mortality for both MM/MGUS groups. Transformation increased mortality risk for patients with MGUS and decreased mortality risk for patients with MM.

Conclusions: Because AO exposure is a nonmodifiable risk factor, focus should be placed on modifiable risk factors (eg, nicotine dependence, alcohol and drug use disorders, underlying comorbid conditions) as these were associated with worse outcomes. Future studies should examine the correlation of AO exposure, cytogenetics, and clinical outcomes in these veterans to best identify their disease course and optimize their care in the latter part of their life.



Multiple myeloma (MM) accounts for 1% to 2% of all cancers and slightly more than 17% of hematologic malignancies in the United States.1 MM is characterized by the neoplastic proliferation of immunoglobulin (Ig)-producing plasma cells with ≥ 10% clonal plasma cells in the bone marrow or biopsy-proven bony or soft tissue plasmacytoma, plus presence of related organ or tissue impairment or presence of a biomarker associated with near-inevitable progression to end-organ damage.2


Up to 97% of patients with MM will have a monoclonal (M) protein produced and secreted by the malignant plasma cells, which can be detected by protein electrophoresis of the serum and an aliquot of urine from a 24-hour collection combined with immunofixation of the serum and urine. The M protein in MM usually consists of IgG 50% of the time and light chains 16% of the time. Patients who lack detectable M protein are considered to have nonsecretory myeloma. MM presents with end-organ damage, which includes hypercalcemia, renal dysfunction, anemia, or lytic bone lesions. Patients with MM frequently present with renal insufficiency due to cast nephropathy or light chain deposition disease.3

MM is thought to evolve from monoclonal gammopathy of uncertain significance (MGUS), an asymptomatic premalignant stage of clonal plasma cell proliferation with a risk of progression to active myeloma at 1% per year.4,5 Epidemiologic data suggest that people who develop MM have a genetic predisposition, but risk factors may develop or be acquired, such as age, immunosuppression, and environmental exposures. To better assess what causes transformation from MGUS to MM, it is important to identify agents that may cause this second hit.6

In November 1961, President John F. Kennedy authorized the start of Operation Ranch Hand, the US Air Force’s herbicide program during the Vietnam War. Twenty million gallons of various chemicals were sprayed in Vietnam, eastern Laos, and parts of Cambodia to defoliate rural land, depriving guerillas of their support base. Agent Orange (AO) was one of these chemicals; it is a mixed herbicide with traces of dioxin, a compound that has been associated with major health problems among exposed individuals.7 Several studies have evaluated exposure to AO and its potential harmful repercussions. Studies have assessed the link between AO and MGUS as well as AO to various leukemias, such as chronic lymphocytic leukemia.8,9 Other studies have shown the relationship between AO exposure and worse outcomes in persons with MM.10 To date, only a single abstract from a US Department of Veterans Affairs (VA) medical center has investigated the relationships between AO exposure and MGUS, MM, and the rate of transformation. The VA study of patients seen from 2005 to 2015 in Detroit, Michigan, found that AO exposure led to an increase in cumulative incidence rate of MGUS/MM, suggesting possible changes in disease biology and genetics.11

In this study, we aimed to determine the incidence of transformation of MGUS to MM in patients with and without exposure to AO. We then analyzed survival as a function of AO exposure, transformation, and clinical and sociodemographic variables. We also explored the impact of psychosocial variables and hematopoietic stem cell transplantation (HSCT), a standard of treatment for MM.


This retrospective cohort study assembled electronic health record (EHR) data from the Veterans Health Administration Corporate Data Warehouse (CDW). The VA Central Texas Veterans Healthcare System Institutional Review Board granted a waiver of consent for this record review. Eligible patients were Vietnam-era veterans who were in the military during the time that AO was used (1961-1971). Veterans were included if they were being cared for and received a diagnosis for MGUS or MM between October 1, 2009, and September 30, 2015 (all prevalent cases fiscal years 2010-2015). Cases were excluded if there was illogical death data or if age, race, ethnicity, body mass index (BMI), or prior-year diagnostic data were missing.


Patients were followed through April 2020. Presence of MGUS was defined by the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code 273.1. MM was identified by ICD-9 diagnosis codes 203.00, 203.01, and 203.02. The study index date was the earliest date of diagnosis of MGUS or MM in fiscal years 2010-2015. It was suspected that some patients with MM may have had a history of MGUS prior to this period. Therefore, for patients with MM, historical diagnosis of MGUS was extracted going back through the earliest data in the CDW (October 1999). Patients diagnosed with both MGUS and MM were considered transformation patients.

Other measures included age at index date, sex, race, ethnicity, VA priority status (a value 1 to 8 summarizing why the veteran qualified for VA care, such as military service-connected disability or very low income), and AO exposure authenticated per VA enrollment files and disability records. Service years were separated into 1961 to 1968 and 1969 to 1971 to match a change in the formulation of AO associated with decreased carcinogenic effect. Comorbidity data from the year prior to first MGUS/MM diagnosis in the observation period were extracted. Lifestyle factors associated with development of MGUS/MM were determined using the following codes: obesity per BMI calculation or diagnosis (ICD-9, 278.0), tobacco use per diagnosis (ICD-9, 305.1, V15.82), and survival from MGUS/MM diagnosis index date to date of death from any cause. Comorbidity was assessed using ICD-9 diagnosis codes to calculate the Charlson Comorbidity Index (CCI), which includes cardiovascular diseases, diabetes mellitus, liver and kidney diseases, cancers, and metastatic solid tumors. Cancers were omitted from our adapted CCI to avoid collinearity in the multivariable models. The theoretical maximum CCI score in this study was 25.12,13 Additional conditions known to be associated with variation in outcomes among veterans using the VA were indicated, including major depressive disorder, posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), substance use disorder (SUD), and common chronic disease (hypertension, lipid disorders).14

Treatment with autologous HSCT was defined by Current Procedural Terminology and ICD-9 Clinical Modification procedure codes for bone marrow and autologous HSCT occurring at any time in the CDW (eAppendix). Days elapsed from MM diagnosis to HSCT were calculated.


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