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. In this analysis, CH at a low variant allele frequency (VAF) was associated with prolonged cytopenia at three months following B-cell maturation antigen chimeric antigen receptor (CAR) T-cell therapy. However, CH mutations did not affect CAR T-cell expansion, toxicities, or efficacy.
“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 said.
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 than 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, 27 who received CAR-T (idecabtagene vicleucel, n=21; ciltacabtagene autoleucel, n=6) were sequenced. Respective baseline characteristics between the 14 patients with and 13 without CH mutations with VAF greater than 0.3% appeared similar, including age, number of prior therapy lines, and pretreatment tumor burden assessed by circulating tumor DNA. When looking at CAR-T efficacy and toxicity for those with and without CH mutations, no significant difference occurred in the CAR-T peak expansion level, the rates of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, or progression-free survival.
To assess cytopenias prior to lymphodepletion chemotherapy and at three months post-CAR-T therapy, the researchers classified the 27 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). Patients with CHneg experienced fewer grade 3 or greater cytopenias of any cell lineages prior to lymphodepletion chemotherapy versus CH0.3-2 and CH2. At three months post-CAR-T therapy, no patients with CHneg experienced grade 3 or greater cytopenia, which persisted in CH0.3-2 (p=0.039) and CH2 (p=0.13).
“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.
