Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
Cancer Res Commun. 2023 Dec 18;3(12):2560-2571. doi: 10.1158/2767-9764.CRC-23-0093.
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.
在接受免疫调节药物（IMiD）治疗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（OS）和无进展生存（PFS）降低有关。然而，CH 在新诊断的患者中的意义，包括不适合移植的患者，以及在新型药物时代多发性骨髓瘤治疗过程中对克隆进化的影响，尚未得到很好的研究。使用我们新的算法来区分肿瘤和种系突变与 CH 突变，我们在来自临床结果在 MM 到个人评估的遗传图谱（CoMMpass）队列的 986 例多发性骨髓瘤患者中检测到大约 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。多发性骨髓瘤诊断时的 CH 与 OS 或 PFS 无不良关联，无论是否接受 ASCT，所有患者均受益于基于 IMiD 的治疗，而与 CH 的存在无关。对 52 例患者的连续采样显示，在治疗中位数为 3 年的时间内出现了 CH，使其患病率增加到 25%，主要是由于 DNMT3A 突变。
使用我们的算法将肿瘤和种系突变与 CH 突变区分开来，我们在大约 10%的新诊断骨髓瘤患者中检测到 CH，包括适合移植和不适合移植的患者。接受 IMiD 治疗改善了预后，无论 CH 状态如何，但在整个骨髓瘤靶向治疗过程中，CH 的患病率显著上升。
