Emotional functioning and NR3C1 and FKBP5 expression in multiple myeloma

Introduction: Emotional distress is common following a cancer diagnosis, and for some cancers it has also been associated with worse outcomes. However, the impact of emotional distress in patients with multiple myeloma (MM) remains relatively understudied. Methods: This study utilized data from CoMMpass (IA22), a longitudinal study of over 1000 patients who provided biospecimens, clinical data, patient reported outcomes (PROs). In this analysis, we aimed to determine if patient-reported and/or biomarker-based indicators of emotional distress at MM diagnosis were associated with patient outcomes. Patients completed the EORTC QLQ-C30 at diagnosis. The emotional functioning subscale was calculated, with scores ranging 0-100 and lower scores indicating higher distress. CoMMpass lacks data on common biomarkers for distress such as cortisol and cytokines. Therefore, we used mRNA expression (mRNA-seq on CD138-enriched MM cells) of two genes that play an important role in stress response and are dysregulated in people with emotional distress, NR3C1 and FKBP5. Analysis: Patient reported emotional functioning and NR3C1 and FKBP5 expression were classified into quartiles. Patients in the lowest quartile of emotional functioning were classified as having emotional distress. Associations between emotional functioning, stress biomarkers, and relevant clinical factors were assessed using ANOVA and x 2 . Associations with progression-free and overall survival were assessed using Cox Regression and adjusted for patient age, sex, race, and stage (International Staging System [ISS]). Results: 572 patients had baseline PROs and mRNA-seq data. The median age was 64 [IQR 57-71], 59% were male, 78% were White, 15% were Black, and 7% were another race. The median emotional functioning score was 75 [IQR 58.3-91.7]. There was an association between patient reported emotional functioning and higher FKBP5 expression (p = 0.043), but not NR3C1 (p = 0.932), despite a strong positive association between FKBP5 and NR3C1 (p < 0.001). Emotional functioning was also associated with age (p = 0.023), sex (p = 0.006), and race (p = 0.003), but not ISS stage (p = 0.980). In multivariable models, both emotional distress and FKBP5 expression were independently associated with prognosis. Patients with emotional distress had a 39% increase in hazard for progression (aHR 1.39; 95% CI 1.07-1.79; p = 0.012), but emotional distress was not associated with overall survival. Patients in the highest quartile of FKBP5 expression had a 53% increase in hazard for progression (aHR 1.53; 95% CI 1.16-2.03; p = 0.003) and 64% increase in hazard for death (aHR 1.64; 95% CI 1.14-2.36; p = 0.007). Conclusion: Emotional Functioning and FKBP5 expression are both independently associated with MM prognosis. In further analyses, we aim explore the mechanisms underlying these associations and to evaluate potential interventions to mitigate the adverse effects on MM outcomes.