Increased Risk of Monoclonal Gammopathy of Undetermined Significance in US Military Service Members: A Case-Control Study of 1,589 Service Members Deployed to Either Iraq, Germany, or Not-Deployed Ex-US with or without Reported Burn Pit and Toxic Smoke Exposure

Background: Soldiers and First Responders may be at higher risk of developing Monoclonal Gammopathy of Undetermined Significance (MGUS) as evidenced by a 2.4-fold increased risk for MGUS in Vietnam Veterans exposed to Agent Orange (Landgren et al, JAMA Oncol. 2015) and a 1.8-fold higher risk in World Trade Center (9/11)-exposed fire fighters compared to reference populations (Landgren, JAMA Onc 2018). US Service Members (SMs) deployed to Southwest Asia (e.g., Iraq and Afghanistan) may have been exposed to various airborne hazards including smoke and fumes from open burn pits, oil well fires, and aircraft fuel/exhaust. Potential long-term consequences from these exposures motivated us to determine whether SMs who deployed to Iraq, Germany, or did not deploy are at increased risk of developing MGUS.

Methods: Serum samples and clinical data (N=1,589) were attained from the Armed Forces Health Surveillance Division (AFHSD) epidemiologic health registry and biorepository after IRB exemptions. A total of 534 US SMs who deployed to Iraq between January 1, 2005 and June 30, 2007 and reported burn pit exposure, etc. on their post-deployment health assessment form (Dep-Iraq) were matched 1:1 to 534 SMs deployed to Germany (Dep-DEU; No Southwest Asia deployment or toxic exposure) and 521 SMs who never deployed Ex-US (Non-Dep). Dep cases were deployed ≥ 6 months, were ≥ 35 years old at time of deployment, remained in the military ≥ 10 years and had serum available in the AFHSD repository 10 years after deployment. Non-Dep cases were active SMs during the same period as Dep cases were deployed and had a specimens within +/- 2 years of Dep-Iraq cases. Match criteria included deployment year (+/- 10 years), age (+/- 3 years), sex, service branch, military rank, and occupation. The 10-year post-dep/non-dep samples underwent laboratory testing for monoclonal protein by immunofixation (IFE) using pentavalent antisera with positive samples confirmed and typed using IFE gels (Sebia) and for serum free light chains (sFLC; Sebia) performed on the DYNEX Agility platform. IFE-positive samples underwent serum protein electrophoresis (SPEP) quantification by capillary electrophoresis (Sebia).

Results: The median age of all SMs was 37 years (range: 31-55); 65.0%, 18.8%, 7.4%, and 89% were White, Black, Hispanic, and male, respectively. Military occupation included: repair/engineering (27.3%), communications/intelligence (22.3%), infantry/artillery/combat engineering (15.5%), healthcare (9.8%), pilot/aircrew (4.5%), and motor transport (4.2%); Rank: enlisted (62.6%) and officer (37.4%); service branch: Army (95.2%) and Air Force 76 (4.8%).

The prevalence of MGUS (IFE+ monoclonal protein) in all SMs (N=1,589) was 4.7% (95% CI: 3.7-5.9%) and free light-chain (LC) MGUS (abnormal sFLC ratio) was 1.1% (95% CI: 0.7-1.8%) for a combined (MGUS+LC MGUS) prevalence of 5.9% (95% CI: 4.7-7.1%). Deployed SMs (N=1,068) compared to non-Dep (N=521) had similar rates of MGUS (4.5% (95% CI: 3.3-5.9%) vs 5.2% (95% CI: 3.4-7.5%), respectively; p=0.31), however, deployed SMs had an increased risk of LC-MGUS (1.6% (95% CI: 0.9-2.5%) vs 0.2% (95% CI: 0-1.1%), respectively; p=0.007). Moreover, burnpit exposure (N=534) did not alter the risk of MGUS/LC-MGUS (6.7% (95% CI: 4.8-9.2%)) among deployed SMs (p=0.17).

Conclusion: In our cohort of 1,589 SMs, the prevalence of MGUS or LC-MGUS was 5.9%. When considering the median age at deployment (37 years) and that samples were attained ~10 years later (~47 years of age), the observed prevalence is 6-fold higher than that reported in the population-based National Health and Nutrition Examination Survey Study (0.88% in the 40-49 -year age group; Landgren, BCJ, 2017). Moreover, the increased risk in SMs does not appear to be due to international deployment nor burnpit exposure but from yet un-identified etiology. Importantly, deployment was associated with development of LC-MGUS suggesting that some inciting factor associated with deployment may be biologically driving the development of this particular type with different underlying genomic pathophysiology. Future studies are needed to further elucidate causes for the increased prevalence of MGUS in SMs and the association between LC-MGUS and deployment.

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