P-242: Clonal Hematopoiesis of Indeterminate Potential (CHIP) is associated with shorter overall survival (OS) in patients with multiple myeloma

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is frequently observed in patients with multiple myeloma (MM). Previous studies demonstrated that CHIP is associated with shorter survival in MM patients undergoing autologous stem cell transplantation (ASCT), particularly those who do not receive maintenance therapy with an immunomodulatory agent. This study aims to evaluate the implications of CHIP on both clinical characteristics and survival outcomes in a large cohort of MM patients. We present our preliminary findings describing the impact of CHIP on OS.

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 bone marrow for CHIP-associated somatic mutations. The patient population included in this analysis consented to mutational testing and did not include all consecutive patients seen at our institution. The presence of 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. The Kaplan-Meier method was used to estimate OS, and univariate comparisons between groups were made with the log-rank test. Updated results will be presented at the meeting with multivariate analyses for OS after accounting for baseline clinical characteristics.

Results: A total of 317 patients underwent gene sequencing, of whom 167 (53%) had CHIP. Preliminary findings show that patients with CHIP had significantly shorter OS from the time of MM diagnosis compared to patients without CHIP (8.6 vs. 14.5 years; p=0.007). Five patients (1.6%) also had myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Among these patients, three patients developed MDS/AML after the diagnosis of MM, whereas two patients had MDS/AML prior to the diagnosis of MM. There was no statistical difference in the incidence of MDS/AML after the diagnosis of MM when accounting for death as a competing risk between patients with and without CHIP (Fine-Gray p=0.81). Four out of five of these patients harbored CHIP-associated mutations and two out of the five patients had an ASCT. Cytogenetic testing of two MDS patients also revealed a t (11;14) mutation.

Conclusions: The present study supports previous data that the presence of CHIP is associated with shorter OS in MM patients. The high incidence of CHIP in our patients may be biased given that mutational testing was not performed on all consecutive patients. Updated multivariate analyses for OS will be presented at the meeting with a detailed analysis on patients with MDS/AML.