The Association of Agent Orange Exposure Duration with Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma Progression: A Population-Based Study

Background: Monoclonal Gammopathy of Undetermined Significance (MGUS) is an asymptomatic, premalignant plasma cell dyscrasia that has a low risk (1% per year) of transforming to multiple myeloma (MM). However, certain features (i.e., M-protein ≥ 1.5 g/dL, non-IgG subtype, and abnormal serum free light chains) can increase the risk of progression 3-fold. Currently, limited evidence reports agent orange (AO) exposure as a risk factor for progression to MM. Thus, we aimed to determine the association between AO exposure and progression to MM in a nation-wide study of U.S. Veterans with MGUS.

Methods: This was a retrospective, cohort study using data from the US Veterans Health Administration (VHA) system to identify all patients with a diagnosis of MGUS with or without AO exposure from October 1, 1999 to December 31, 2021. A natural language processing (NLP) algorithm was used to confirm MGUS diagnosis and progression status. Compared to our prior study presented at ASCO, we used a different source to obtain AO exposure data and also analyzed duration of AO exposure as a surrogate for AO "dose." AO exposure status was obtained from VHA's Corporate Data Warehouse; duration of exposure was quantified by exposure status, service location and duration and AO exposure status was verified by the branch of service. In the cohort without AO exposure, we excluded patients whose birth years fell out of the range of those of the AO exposed group to prevent inclusion of younger patients without exposure who were more likely to be censored than those with AO exposure. The association between AO and progression to MM was analyzed using multivariable Fine-Gray subdistribution hazard model with death as a competing event while adjusting for known progression risk factors.

Results: We included 20,206 patients with MGUS diagnoses of whom 3,290 had AO exposure. In multivariable analysis, AO exposure was associated with an increased risk of progression from MGUS to MM (hazard ratio [HR] 1.21, 95% Confidence Interval [CI] 1.06-1.38). When dose-response was analyzed, each month of AO exposure duration was associated with a 0.4% increased risk of progression (aHR 1.004, 95% CI 1.002-1.006).

Conclusions: In patients with MGUS, AO exposure is associated with an increased risk of progression to MM. AO exposure should be considered in MGUS risk assessment along with M-spike, serum free light chains, and heavy chain type.

Schroeder:Cellect Inc: Research Funding; Fortis: Research Funding; Incyte: Research Funding; Genentech Inc: Research Funding; Seagen Inc.: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Sanfilippo:ACS-IRG: Research Funding; Covington & Burling LLP: Other: Expert Case Review; Health Services Advisory Group: Consultancy; K01 NHLBI: Research Funding; NHLBI NIH: Other: Loan Repayment program; Quinn Johnston: Other: Expert Case Review.