ctDNA improves prognostic prediction in relapsed/refractory MM receiving ixazomib, lenalidomide, and dexamethasone

来那度胺 克拉斯 医学 神经母细胞瘤RAS病毒癌基因同源物 肿瘤科 内科学 多发性骨髓瘤 癌症研究 癌症 结直肠癌
作者
Yasunori Kogure,Hiroshi Handa,Yuta Ito,Masaki Ri,Yuichi Horigome,Masaki Iino,Yoriko Harazaki,Takahiro Kobayashi,Masahiro Abe,Tadao Ishida,Shigeki Ito,Hiromi Iwasaki,Junya Kuroda,Yuzuru Kanakura,Kazutaka Sunami,Hiroyuki Takamatsu,Hideto Tamura,Toshiaki Hayashi,Kiwamu Akagi,Tomohiro Shinozaki,Takahiro Yoshida,Ikuo Mori,Shinsuke Iida,Takahiro Maeda,Keisuke Kataoka
出处
期刊:Blood [Elsevier BV]
被引量:4
标识
DOI:10.1182/blood.2023022540
摘要

It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here we performed targeted-capture sequencing using bone marrow plasma cells (BMPC) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis-associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, while KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the six relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥ 2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index (ctRRMM-PI), classifying patients into three categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM.
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