Calcineurin inhibitors reduce risk of MGUS progression to multiple myeloma in immunosuppressant users: A retrospective multi-institution cohort study

Abstract Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder with a risk of progression to multiple myeloma (MM). Immune dysregulation plays a complex and significant role in this transformation. Autoimmune diseases (AID) are associated with higher prevalence of MGUS but immunoparesis, caused by immunosuppressants (IST) use in AID may be a concern about progression to MM. Recent studies showed that increased expansion of GZMB(+) CD8(+) effector memory T cells is associated with a higher risk of MM progression and shorter overall survival. Therefore, in AID, the impact of suppressing T-cell activity on the risk of MGUS progression to MM warrants further investigation. Methods This retrospective cohort study was conducted using the TriNetX platform to analyze patients having autoimmune diseases diagnosed with MGUS, with or without exposure to calcineurin inhibitors (CNi). The primary outcome was progression to MM. To ensure maximal consistency across the studied population, both the exposure group and the control group had received at least one of the following IST—azathioprine, leflunomide, cyclophosphamide, methotrexate, sulfasalazine, or mycophenolate mofetil—within 1 year prior to, or any time after, the initial diagnosis of MGUS but before any diagnosis of MM. Patients in CNi group were defined by additional CNi exposure (excluding topical and ophthalmic route) within the same time window, whereas control had never received CNi. The two cohorts were matched 1:1 using propensity score matching (PSM) based on demographics, body mass index, renal function, free light chain ratio, and the presence of autoimmune diseases. The observation period extended from 6 months to 10 years following MGUS diagnosis. Secondary outcomes included all-cause mortality, progression to other hematologic malignancies, and renal toxicity. Subgroup analyses included sex, age, BMI, eGFR, free light chain ratio, use of steroids or mTOR inhibitors, prior CNi use within 1 year before MGUS diagnosis, and history of transplantation. Sensitivity analyses were performed based on different time windows of CNi initiation. Results After PSM, 1898 patients were included in both cohorts. The median follow-up time was 1109.5 days in CNi group and 891 days in control. The percentage of the white, the black or African American, and Asian in CNi group were 64.33%, 21.34%, and 2.69%, respectively, and those in control were 65.70%, 21.97%, and 2.90%, respectively. Compared to control, the cumulative incidence of MGUS progression to MM was lower in CNi group (hazard ratio (HR): 0.592, 95% CI: [0.435-0.806]). Incidence of progression to AL amyloidosis (HR: 0.303 [0.196-0.469]), and progression to other hematologic diseases (HR: 0.415 [0.348-0.494]) are lower as well. All-cause mortality did not show significant difference (HR: 1.127 [0.978-1.298]). Incidence of chronic kidney disease stage 3~5 was higher in CNi group (HR: 1.69 [1.531-1.866]). For subgroup analysis of MM progression, CNi usage in patients less than 65 years old presented a lower risk (HR: 0.448 [0.25-0.803]), while in those more than 65 years old, no significant difference was observed (HR: 0.729 [0.495-1.075]).The benefit of CNi was statistically significant in those with eGFR lower than 60 (HR: 0.448 [0.25-0.803]), those without previous CNi usage (HR: 0.546 [0.356-0.838]), and those underwent organ transplantation(HR: 0.143 [0.064-0.315]), but not in their counter group. For sensitivity analysis of progression to MM, the results of CNi usage within 1 year before (HR: 0.489 [0.273-0.874]), within 0-1 months after (HR: 0.39 [0.231-0.659]), within 1-3 months after (HR: 0.486 [0.301-0.785]), and within 3-6 months after (HR: 0.655 [0.435-0.987]) the diagnosis of MGUS were consistent. Conclusions Compared to IST use alone, additional CNi exposure was associated with a reduced risk of MGUS progression to MM, AL amyloidosis and other hematologic malignancies. These findings support the hypothesis that dampening immune activation may lower the risk of malignant transformation in MGUS. Clinically, this study alleviates concerns regarding the potential oncogenic risks of cytotoxic T cell suppression in patients with coexisting autoimmune disorders and MGUS. Furthermore, it raises the potential role of T cell inhibitors as one of the interventions to prevent MGUS progression in broader patient populations, warranting further studies.