For patients with multiple myeloma (MM), clonal hematopoiesis (CH) mutations were common at both initial diagnosis and relapse, according to a study presented at the 2025 Tandem Meetings of the American Society for Transplantation and Cellular Therapy and the Center for International Blood and Marrow Transplant Research. The study also found that CH mutations did not affect B-cell maturation agent-directed chimeric antigen receptor (CAR) T-cell expansion, toxicity, or efficacy. However, CH at a low variant allele frequency (VAF) appeared connected to prolonged cytopenia at three months following CAR T-cell therapy.
“One of the major side effects of CAR-T therapy is cytopenia that lasts beyond the first month. This significantly affects the quality of life of our patients as well as infection risks,” said first author Hitomi Hosoya, MD, PhD, of Stanford University in California. “However, the genomic determinants of cytopenia are largely unknown.”
“In this study, we sought to characterize underlying CH in patients treated with CAR-T and associated with prolonged cytopenia. We found that patients who have CH-associated gene mutations, including those with lower allele frequencies than conventional definition of CH of indeterminate significance, resulted in higher rates of severe cytopenia at three months following CAR-T therapy,” Dr. Hosoya explained.
The researchers characterized mutations in canonical CH genes in 17 patients with newly diagnosed (ND) MM and 55 patients with relapsed or refractory (R/R) MM, using targeted DNA sequencing of the germline in peripheral blood mononuclear cells. CH mutations in 17 canonical genes were detected at VAF greater or equal to 2% in 5.9% of the patients with NDMM and 20% of those with R/R MM (p=0.27). When the VAF threshold was lowered to greater than 0.3%, the CH prevalences for NDMM and R/R MM increased to 65% and 56%, respectively (p=0.56).
The researchers next focused on patients receiving CAR T cells and associated cytopenias. Of the patients with R/R MM, 37 received CAR-T (idecabtagene vicleucel [ide-cel], n=29; ciltacabtagene autoleucel, n=8). Due to the larger sample size, the researchers further analyzed the ide-cel cohort. Respective baseline characteristics between the 16 patients with and 13 without CH mutations with VAF greater than 0.3% appeared similar, including age (median of 67 vs. 65; p=0.47), number of prior therapy lines (6 vs. 6; p=0.58), and pretreatment tumor burden assessed by circulating tumor DNA (2.2 vs. 1.4 log hGE/mL; p=0.27). For CAR-T efficacy and toxicity, no significant difference occurred in the CAR-T peak expansion level (1.4 vs. 1.2 log/uL; p=0.79), the rates of cytokine release syndrome (92% vs. 82%; p=0.56) and immune effector cell-associated neurotoxicity syndrome (14% vs. 18%; p=1.00), or progression-free survival (median 8.8 vs. 6.3 months; p=0.92).
To assess cytopenias prior to lymphodepletion chemotherapy and at three months post CAR-T therapy, the researchers classified patients according to whether they had no detectable CH mutations (CHneg), CH mutations with VAF between 0.3% and 2% (CH0.3-2), or VAF greater than 2% (CH2). Among patients with CHneg, 7.7% experienced grade 3 or greater cytopenias of any cell lineages prior to lymphodepletion chemotherapy compared with 38% for CH0.3-2 (p=0.16) and 33% for CH2 (p=0.35). At three months post-CAR-T therapy, no patients with CHneg experienced grade 3 or greater cytopenia compared with 42% for CH0.3-2 (p=0.039) and 33% for CH2 (p=0.23).
“CH-associated gene mutations are prevalent in patients with R/R MM, particularly when including those with low allele frequencies. Patients with CH mutations have a higher rate of developing severe prolonged cytopenia,” Dr. Hosoya concluded. “Further study is needed to validate our findings in a larger cohort.”
Conflicts of interest from the authors were not published in the original abstract.
Reference
Hosoya H, Carleton M, Tanaka K, et al. Clonal Hematopoiesis Underlies Prolonged Cytopenias after Anti-BCMA CAR-T Therapy. Abstract 435. Presented at the 2025 Tandem Meetings of ASTCT and CIBMTR; February 13, 2025; Honolulu, Hawaii.
