Statistical Analysis
Sample characteristics were represented by frequencies and percentages for categorical variables and means and SDs (or medians and ranges where appropriate) for continuous variables. A χ2 test (or Fisher exact test when cell counts were low) assessed associations in bivariate comparisons. A 2-sample t test (or Wilcoxon rank sum test as appropriate) assessed differences in continuous variables between 2 groups. Kaplan-Meier curves depicted the unadjusted relationship of AO exposure to survival. Cox proportional hazards survival models examined an unadjusted model containing only the AO exposure indicator as a predictor and adjusted models were used for demographic and clinical factors for MGUS and patients with MM separately.
Predictors were age in decades, sex, Hispanic ethnicity, race, nicotine dependence, obesity, overweight, AUD, SUD, major depressive disorder, PTSD, and the adapted CCI. When modeling patients with MM, MGUS was added to the model to identify the transformation group. The interaction of AO with transformation was also analyzed for patients with MM. Results were reported as hazard ratios (HR) with their 95% CI.
Results
We identified 18,215 veterans diagnosed with either MGUS or MM during fiscal years 2010-2015 with 16,366 meeting inclusion criteria. Patients were excluded for missing data on exposure (n = 334), age (n = 12), race (n = 1058), ethnicity (n = 164), diagnosis (n = 47), treatment (n = 56), and BMI (n = 178). All were Vietnam War era veterans; 14 also served in other eras.
The cohort was 98.5% male (Table 1). Twenty-nine percent were Black veterans, 65% were White veterans, and 4% of individuals reported Hispanic ethnicity. Patients had a mean (SD) age of 66.7 (5.9) years (range, 52-96). Most patients were married (58%) or divorced/separated (27%). All were VA priority 1 to 5 (no 6, 7, or 8); 50% were priority 1 with 50% to 100% service-connected disability. Another 29% were eligible for VA care by reason of low income, 17% had 10% to 40% service-connected disability, and 4% were otherwise disabled.
During fiscal years 2010 to 2015, 68% of our cohort had a diagnosis of MGUS (n = 11,112; 9105 had MGUS only), 44% had MM (n = 7261; 5254 had MM only), and 12% of these were transformation patients (n = 2007). AO exposure characterized 3102 MGUS-only patients (34%), 1886 MM-only patients (36%), and 695 transformation patients (35%) (χ2 = 4.92, P = .09). Among 5683 AO-exposed patients, 695 (12.2%) underwent MGUS-to-MM transformation. Among 10,683 nonexposed veterans, 1312 (12.3%) experienced transformation.
Comorbidity in the year leading up to the index MGUS/MM date determined using CCI was a mean (SD) of 1.9 (2.1) (range, 0-14). Among disorders not included in the CCI, 71% were diagnosed with hypertension, 57% with lipid disorders, 22% with nicotine dependence, 14% with major depressive disorder, 13% with PTSD, and 9% with AUD. Overweight (BMI 25 to < 30) and obesity (BMI ≥ 30) were common (35% and 41%, respectively). For 98% of patients, weight was measured within 90 days of their index MGUS/MM date. Most of the cohort (70%) were in Vietnam in 1961 to 1968.
HSCT was provided to 632 patients with MM (8.7%), including 441 patients who were treated after their index date and 219 patients treated before their index date. From fiscal years 2010 to 2015, the median (IQR) number of days from MM index date to HSCT receipt was 349 (243-650) days. Historical HSCT occurred a median (IQR) of 857 (353-1592) days before the index date, per data available back to October 1999; this median suggests long histories of MM in this cohort.
The unadjusted survival model found a very small inverse association of mortality with AO exposure in the total sample, meaning patients with documented AO exposure lived longer (HR, 0.85; 95% CI, 0.81-0.89; Table 2; Figure). Among 11,112 MGUS patients, AO was similarly associated with mortality (HR, 0.79; 95% CI, 0.74-0.84). The effect was also seen among 7269 patients with MM (HR, 0.86; 95% CI, 0.81-0.91).
In the adjusted model of the total sample, the mortality hazard was greater for veterans who were older, with AUD and nicotine dependence, greater comorbidity per the CCI, diagnosis of MM, and transformation from MGUS to MM. Protective effects were noted for AO exposure, female sex, Black race, obesity, overweight, PTSD, and HSCT.
After adjusting for covariates, AO exposure was still associated with lower mortality among 11,112 patients with MGUS (HR, 0.85; 95% CI, 0.80-0.91). Risk factors were older age, nicotine dependence, AUD, the adapted CCI score (HR, 1.23 per point increase in the index; 95% CI, 1.22-1.25), and transformation to MM (HR, 1.76; 95% CI, 1.65-1.88). Additional protective factors were female sex, Black race, obesity, overweight, and PTSD.
After adjusting for covariates and limiting the analytic cohort to MM patients, the effect of AO exposure persisted (HR, 0.89; 95% CI, 0.84-0.95). Mortality risk factors were older age, nicotine dependence, AUD, and higher CCI score. Also protective were female sex, Black race, obesity, overweight, diagnosis of MGUS (transformation), and HSCT.
In the final model on patients with MM, the interaction term of AO exposure with transformation was significant. The combination of AO exposure with MGUS transformation had a greater protective effect than either AO exposure alone or MGUS without prior AO exposure. Additional protective factors were female sex, Black race, obesity, overweight, and HSCT. Older age, AUD, nicotine dependence, and greater comorbidity increased mortality risk.
