Seipel Katja, Veglio Nuria Z, Nilius Henning, Jeker Barbara, Bacher Ulrike, Pabst Thomas
Department for Biomedical Research, University of Bern, 3008 Bern, Switzerland.
Department of Medical Oncology, University Hospital Bern, 3010 Bern, Switzerland.
Curr Issues Mol Biol. 2024 Jul 29;46(8):8197-8208. doi: 10.3390/cimb46080484.
Multiple myeloma (MM) first-line treatment algorithms include immuno-chemotherapy (ICT) induction, high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) consolidation, followed by lenalidomide maintenance. After these initial therapies, most patients suffer a disease relapse and require subsequent treatment lines including ICT, additional HDCT and ASCT, or novel immunotherapies. The presence of somatic mutations in peripheral blood cells has been associated with adverse outcomes in a variety of hematological malignancies. Nonsense and frameshift mutations in the gene, a frequent driver alteration in clonal hematopoiesis (CH), lead to the gain-of-function of Wip1 phosphatase, which may impair the p53-dependent G1 checkpoint and promote cell proliferation. Here, we determined the presence of gene mutations in peripheral blood cells of 75 subsequent myeloma patients in remission after first or second HDCT/ASCT. The prevalence of truncating gene mutations emerged at 1.3% after first HDCT/ASCT, and 7.3% after second HDCT/ASCT, with variant allele frequencies (VAF) of 0.01 to 0.05. Clinical outcomes were inferior in the -mutated (mut) subset with median progression-free survival (PFS) of 15 vs. 37 months ( = 0.0002) and median overall survival (OS) of 36 vs. 156 months ( = 0.001) for the mut and wt population, respectively. Our data suggest that the occurrence of gene mutations in peripheral blood cells correlates with inferior outcomes after ASCT in patients with multiple myeloma.
多发性骨髓瘤（MM）的一线治疗方案包括免疫化疗（ICT）诱导、大剂量化疗（HDCT）及自体干细胞移植（ASCT）巩固，随后进行来那度胺维持治疗。经过这些初始治疗后，大多数患者会出现疾病复发，需要后续的治疗方案，包括ICT、额外的HDCT和ASCT，或新型免疫疗法。外周血细胞中体细胞突变的存在与多种血液系统恶性肿瘤的不良预后相关。该基因中的无义突变和移码突变是克隆性造血（CH）中常见的驱动改变，会导致Wip1磷酸酶功能获得，这可能会损害p53依赖的G1检查点并促进细胞增殖。在此，我们确定了75例首次或第二次HDCT/ASCT后处于缓解期的后续骨髓瘤患者外周血细胞中该基因突变的情况。首次HDCT/ASCT后截短型该基因突变的发生率为1.3%，第二次HDCT/ASCT后为7.3%，变异等位基因频率（VAF）为0.01至0.05。在该基因突变（mut）亚组中，临床结局较差，突变组和野生型（wt）组的无进展生存期（PFS）中位数分别为15个月和37个月（P = 0.0002），总生存期（OS）中位数分别为36个月和156个月（P = 0.001）。我们的数据表明，外周血细胞中该基因突变的发生与多发性骨髓瘤患者ASCT后的不良结局相关。
