Clonal Hematopoiesis of Indeterminate Potential Does Not Impact Overall Survival in Multiple Myeloma

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is frequently observed in patients with multiple myeloma (MM). A previous study demonstrated that CHIP is associated with shorter progression-free survival in MM patients undergoing autologous stem cell transplantation (ASCT), particularly those who do not receive maintenance therapy with an immunomodulatory agent (Mouhieddine Nat Commun 2020). We sought to further characterize the impact of CHIP on overall survival (OS) in a large cohort of MM patients, as well as the risk of developing a myeloid neoplasm. Methods: Study participants include MM patients evaluated at the Massachusetts General Hospital between January 2019 and December 2022 who underwent targeted exome sequencing (i.e., Heme SNaPshot) on DNA extracted from unselected bone marrow for CHIP-associated somatic mutations. CHIP was defined by the presence of a leukemia-associated mutation with a variant allele fraction >2% in unselected bone marrow aspirate samples. Medical records were manually reviewed for all patients to extract data on baseline clinical characteristics and survival outcomes. Time-to-event outcomes were estimated using the Kaplan-Meier method, and comparisons were made with the log-rank test. Cox-proportional hazard regression analyses were performed to fit univariate and multivariate models for OS; the outcome measure was hazard ratio (HR) with 95% confidence interval (CI). OS was defined as the time from CHIP diagnosis to death or last follow-up. Cumulative incidence estimates for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) were made with the Fine-Gray method to account for death as a competing risk. Only patients who consented to mutational testing were included in this analysis and does not represent all consecutive MM patients seen at our institution. Results: A total of 317 patients with MM underwent gene sequencing, of whom 167 (53%) had CHIP. By univariate analysis, patients with CHIP had a significantly shorter median OS (4.2 years versus not reached; p<0.001). However, on multivariate analysis, CHIP was not associated with OS (HR 1.40, 95% CI 0.83-2.38; p=0.21) after adjusting for age, sex, time from MM diagnosis, tumor burden, extramedullary disease, high-risk cytogenetics, R-ISS, prior therapy, albumin, LDH, and beta-2 microglobulin level. Four patients (1.3%) developed MDS/AML in this cohort, of whom 3 out of 4 patients (75%) had CHIP. Between patients with and without CHIP, there was no statistical difference in the risk of developing MDS/AML after both the diagnosis of MM and time of mutational testing when accounting for death as a competing risk (Fine-Gray p=0.49 and p=0.33, respectively). Conclusion: The presence of CHIP is not associated with OS and does not appear to be associated with risk of myeloid neoplasms in MM patients.