DETROIT – Agent Orange exposure by military personnel has been linked with multiple malignant and nonmalignant conditions, including monoclonal gammopathy of undetermined significance.

MGUS is an indolent, premalignant plasma cell disorder with the potential of transforming into symptomatic multiple myeloma. A single center study published in Clinical Lymphoma, Myeloma & Leukemia  noted that multiple risk factors contribute to transformation.1

Researchers from the Karmanos Cancer Institute conducted a retrospective chart review of patients treated at John D. Dingell Veterans Affairs Medical Center in Detroit between 2005 and 2015 with monoclonal gammopathy, smoldering multiple myeloma, and MM. Researchers collected data on baseline patient characteristics and AO exposure, as well as dates of diagnosis, dates of progression, and expiration dates and their links to time to progression and overall survival.

Of 211 patients identified with monoclonal gammopathy; 96% were male and 122 were African American, according to the study, and 11 of them had reported AO exposure.

Cumulative risk of progression in the overall population was 1.4% at one year. Researchers calculated that risk of transformation in the population exposed to AO was significantly higher with a hazard ratio (HR) of 11.19 (95% confidence interval [CI], 2.10-59.47; P = .005). At the same time, overall survival was numerically shorter in AO-exposed patients with a median OS of seven years compared with 11.1 years in those not exposed. AO exposure was not associated with overall survival in multivariable analysis (HR, 0.50; 95% CI, 0.07-3.83; P = .508), however.

“Monoclonal gammopathy is a premalignant condition with the risk of progressing to MM,” the authors concluded. “Exposure to AO has been implicated in multiple conditions including MM. Our study demonstrates an increased risk of progression in exposed patients.:

The latest in a series of congressionally mandated biennial reviews of the evidence of health issues that may be linked to exposure to Agent Orange and other herbicides used during the Vietnam War found sufficient evidence of an association for monoclonal gammopathy of undetermined significance (MGUS). The report, Veterans and Agent Orange: Update 11 (2018), focused on the scientific literature published between Sept. 30, 2014, and Dec. 31, 2017.

Background information in the review noted that, from 1962 to 1971, the U.S. military made wide use of herbicides. The reasons were to eliminate thick jungle canopy that could conceal opposition forces, destroy crops that benefited the enemy and to clear areas for U.S. bases and outlying encampments.

Agent Orange, which contained the most toxic form of dioxin, was the most commonly used chemical mixture. The committee focused on herbicides and their effects on an estimated 2.6 million to 4.3 million servicemembers who served in some fashion in the theater of operation.

Panel members also concluded that there also was sufficient evidence of an association between exposure to at least one of the chemicals of interest and MGUS, a newly considered condition. This finding is based on a 2015 JAMA Oncology report in which investigators found a statistically significant higher prevalence of MGUS in Vietnam veterans involved in herbicide spray operations than in comparison veterans.2

The prospective cohort study conducted in 2013 to 2014, tested for MGUS in serum specimens collected and stored in 2002 by the Air Force Health Study and included former U.S. Air Force personnel who participated in Operation Ranch Hand (and other U.S. 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.  

MGUS is considered to be a clinically silent condition that is a precursor to multiple myeloma, although only an estimated 1% of MGUS cases progress to multiple myeloma each year.

  1. Bumma N, Nagasaka M, Hemingway G, Miyashita H, Chowdhury T, Kim S, VankayalaHM, Ahmed S, Jasti P. Effect of Exposure to Agent Orange on the Risk ofMonoclonal Gammopathy and Subsequent Transformation to Multiple Myeloma: ASingle-Center Experience From the Veterans Affairs Hospital, Detroit. ClinLymphoma Myeloma Leuk. 2019 Dec 28. pii: S2152-2650(19)32163-9. doi:10.1016/j.clml.2019.11.014. [Epub ahead of print] PubMed PMID: 32144026. 
  2. Landgren O, Shim YK, Michalek J, Costello R, Burton D, Ketchum N, Calvo KR, Caporaso N, Raveche E, Middleton D, Marti G, Vogt RF Jr. Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance: An Operation Ranch Hand Veteran Cohort Study. JAMA Oncol. 2015 Nov;1(8):1061-8. doi: 10.1001/jamaoncol.2015.2938. PubMed PMID: 26335650; PubMed Central PMCID: PMC5701511.