Clinical Outcomes and Evolution of Clonal Hematopoiesis in Patients with Newly Diagnosed Multiple Myeloma.
Clinical Outcomes and Evolution of Clonal Hematopoiesis in Patients with Newly Diagnosed Multiple Myeloma.
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DOI：
10.1158/2767-9764.crc-23-0093
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发表时间：
2023-12-18
期刊：
影响因子：
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通讯作者：
Getz, Gad
中科院分区：
文献类型：
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作者：
Mouhieddine, Tarek H.;Nzerem, Chidimma;Redd, Robert;Dunford, Andrew;Leventhal, Matthew;Sklavenitis-Pistofidis, Romanos;Tahri, Sabrin;El-Khoury, Habib;Steensma, David P.;Ebert, Benjamin L.;Soiffer, Robert J.;Keats, Jonathan J.;Mehr, Shaadi;Auclair, Daniel;Ghobrial, Irene M.;Sperling, Adam S.;Stewart, Chip;Getz, Gad
在未接受免疫调节药物（IMiD）的多发性骨髓瘤患者中，自体干细胞移植（ASCT）时的克隆性造血（CH）与总生存期（OS）和无进展生存期（PFS）降低相关。然而，CH在新诊断患者（包括不适合移植的患者）中的意义及其在新型药物时代多发性骨髓瘤治疗期间对克隆演变的影响尚未得到充分研究。使用我们的新算法来区分肿瘤和生殖系突变与CH，我们在来自MM临床结局至遗传特征个人评估（CoMMpass）队列的986例多发性骨髓瘤患者中检测到约10%的CH（40/529例移植患者和59/457例非移植患者）。CH与年龄增加、复发性细菌感染和心血管疾病的风险有关。无论是否接受ASCT，多发性骨髓瘤诊断时的CH均与较差的OS或PFS无关，并且所有患者均受益于基于IMiD的治疗，无论是否存在CH。52例患者的连续采样显示，在中位治疗3年内出现CH，其患病率增加至25%，主要为DNMT 3A突变。使用我们的算法区分肿瘤和生殖系突变与CH突变，我们在约10%的新诊断骨髓瘤患者中检测到CH，包括符合移植条件和不符合移植条件的患者。接受IMiD治疗可改善预后，与CH状态无关，但在骨髓瘤定向治疗期间CH的患病率显著升高。
Clonal hematopoiesis (CH) at time of autologous stem cell transplant (ASCT) has been shown to be associated with decreased overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma not receiving immunomodulatory drugs (IMiD). However, the significance of CH in newly diagnosed patients, including transplant ineligible patients, and its effect on clonal evolution during multiple myeloma therapy in the era of novel agents, has not been well studied. Using our new algorithm to differentiate tumor and germline mutations from CH, we detected CH in approximately 10% of 986 patients with multiple myeloma from the Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) cohort (40/529 transplanted and 59/457 non-transplanted patients). CH was associated with increased age, risk of recurrent bacterial infections and cardiovascular disease. CH at time of multiple myeloma diagnosis was not associated with inferior OS or PFS regardless of undergoing ASCT, and all patients benefited from IMiD-based therapies, irrespective of the presence of CH. Serial sampling of 52 patients revealed the emergence of CH over a median of 3 years of treatment, increasing its prevalence to 25%, mostly with DNMT3A mutations. Using our algorithm to differentiate tumor and germline mutations from CH mutations, we detected CH in approximately 10% of patients with newly diagnosed myeloma, including both transplant eligible and ineligible patients. Receiving IMiDs improved outcomes irrespective of CH status, but the prevalence of CH significantly rose throughout myeloma-directed therapy.