Background

Clinical depression is associated with immune dysregulation and reduced activity of natural killer cells and lymphocytes, which play critical roles in immune surveillance against infection and malignancy. Depression is common among cancer patients and has been linked to poor treatment adherence, impaired immune function, and increased mortality. Multiple myeloma (MM) is associated with chronic immunosuppression, high symptom burden and frequent hospitalizations, all of which may amplify the impact of comorbid depression. The timing of antidepressant initiation relative to cancer diagnosis may reflect differences in disease trajectory, psychosocial burden, or underlying biology, but its impact on clinical outcomes in patients with multiple myeloma remains poorly understood.

Methods

We utilized the 2025 TriNetX database to conduct a multicenter retrospective cohort study. Adult patients with multiple myeloma since 2010 and prescribed antidepressants (sertraline, escitalopram, citalopram, paroxetine, fluoxetine, fluvoxamine, venlafaxine, duloxetine, trazodone, mirtazapine, or bupropion) were identified using ICD-10 diagnostic and RxNorm codes. Patients were stratified into two cohorts: cohort 1 included those who initiated antidepressants within 6 months prior to multiple myeloma diagnosis, and cohort 2 included those who started antidepressants anytime after diagnosis. Propensity score matching was performed, and outcomes were assessed using Kaplan-Meier analysis and log-rank testing. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated, with a p-value < 0.05 considered statistically significant. The primary outcome was all-cause mortality. Secondary outcomes included hospitalizations, relapse, pathologic fracture, and end-stage renal disease (ESRD).

Results

Each cohort consisted of 23,478 patients after propensity score matching, with similar baseline characteristics. Average age at the time of index was 66 years in both groups. In cohort 1, 52% of patients were male and the ethnicity distribution was 71% White, 5% Hispanic, and 17% African-American. In cohort 2, 55% of patients were male and the ethnicity distribution was 64% White, 5% Hispanic, and 19% African-American. Upon analysis, our study found that, within the last 15 years, patients who were started on antidepressants prior to their multiple myeloma diagnosis had a higher risk of mortality (HR 1.20, 95% CI: 1.16-1.24, p < 0.0001). The same patients also had a higher risk of hospitalizations (HR 1.26, 95% CI: 1.23-1.29, p < 0.0001), relapse (HR 2.83, 95% CI: 2.68-2.98, p < 0.0001), pathologic fracture (HR 1.67, 95% CI: 1.58-1.78, p < 0.0001), and end-stage renal disease (HR 1.17, 95% CI: 1.09-1.25, p < 0.0001).

Conclusion

Our study found that patients who initiated antidepressants prior to their multiple myeloma diagnosis had a higher risk of mortality, relapse, hospitalizations, pathologic fractures, and end-stage renal disease. While some associations were modest in magnitude, the consistent pattern of increased risk suggests that pre-existing depression and its treatment may identify a more vulnerable subgroup of multiple myeloma patients. Further prospective studies are needed to clarify underlying mechanisms and to evaluate the potential impact of early psychiatric intervention.

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2025
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