Amitai Irina, Gurion Ronit, Raanani Pia, Vaxman Iuliana, Yeshurun Moshe, Magen Hila, Gafter-Gvili Anat, Shargian Liat
Department of Haematology, Chaim Sheba Medical Center, Ramat Gan, Israel.
Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Acta Haematol. 2024 Sep 16:1-9. doi: 10.1159/000540232.
High-dose therapy with melphalan followed by autologous stem cell transplant in the upfront setting (upfront ASCT) has significantly improved clinical outcomes of myeloma patients and become the standard of care for the past 30 years. However, with the advent of modern induction therapy, the role of upfront ASCT approach has been called into question. Several prospective studies have examined whether continuing with triplet therapy as consolidation with optional ASCT at relapse (triplet-alone) could result in comparable outcomes.
This was a systematic review and meta-analysis of randomized controlled trials comparing upfront ASCT versus triplet-alone approach among myeloma patients treated with triplet therapy, which included two novel agents and a corticosteroid, as induction. Cochrane Library, PubMed and conference proceedings were searched. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), safety, and second primary malignancies (SPM). Subgroup analysis was conducted for high-risk cytogenetics.
Our search yielded three trials, conducted between 2010-2018, including 1,737 patients. Two trials evaluated bortezomib plus lenalidomide (VRd) induction and the third study tested carfilzomib plus lenalidomide (KRd) induction. Maintenance was given in all trials to both arms. There was no difference in OS between the arms; the pooled OS in all patients and those with high-risk cytogenetics was hazard ratio (HR) 1.03 (95% CI, 0.85-1.26; I2 = 0%; 1,737 patients, 3 trials) and 0.85 (95% CI, 0.59-1.23; I2 = 0%; 222 patients, 2 trials), respectively. The pooled PFS for upfront ASCT versus triplet-alone was significantly improved in all the patients and in the high-risk cytogenetics subgroup, HR 0.67 (95% CI 0.59-0.76; I2 = 0%; 1,737 patients, 3 trials) and HR 0.59 (95% CI: 0.44-0.7; I2 = 0%; 306 patients, 3 trials), respectively. The risk of any grade 3-4 adverse events was higher in the upfront ASCT arm versus triplet-alone approach (relative risk = 1.17 [95% CI, 1.12-1.23; 1,737 patients]). The risk of secondary malignancies was reported in all three trials and was comparable between both arms. Two trials reported on secondary myeloid neoplasms, which were significantly higher among upfront ASCT arm versus triplet-alone approach, OR 9.7 (1.8-52.25, I2 = 0%, 1,422 patients).
Although upfront ASCT approach, in the era of triplet therapy, resulted in a significantly longer PFS among all patients, this did not translate into a survival benefit, regardless of cytogenetic risk. Upfront ASCT was associated with an increased rate of secondary myeloid neoplasms. In the current plethora of innovative therapies, the role of upfront ASCT is debatable.
在初始治疗阶段采用马法兰大剂量疗法后进行自体干细胞移植（初始自体干细胞移植）显著改善了骨髓瘤患者的临床结局，并在过去30年成为标准治疗方法。然而，随着现代诱导疗法的出现，初始自体干细胞移植方法的作用受到质疑。多项前瞻性研究探讨了在复发时继续采用三联疗法作为巩固治疗并选择性进行自体干细胞移植（仅三联疗法）是否能产生相似的结果。
这是一项对随机对照试验的系统评价和荟萃分析，比较了在接受包含两种新型药物和一种皮质类固醇的三联疗法诱导治疗的骨髓瘤患者中，初始自体干细胞移植与仅三联疗法的方法。检索了Cochrane图书馆、PubMed和会议论文集。主要结局是总生存期（OS）。次要结局包括无进展生存期（PFS）、安全性和第二原发性恶性肿瘤（SPM）。对高危细胞遗传学进行了亚组分析。
我们的检索产生了三项在2010年至2018年期间进行的试验，包括1737例患者。两项试验评估了硼替佐米联合来那度胺（VRd）诱导治疗，第三项研究测试了卡非佐米联合来那度胺（KRd）诱导治疗。所有试验的两组均给予维持治疗。两组之间的总生存期无差异；所有患者和高危细胞遗传学患者的汇总总生存期危险比（HR）分别为1.03（95%CI，0.85 - 1.26；I² = 0%；1737例患者，3项试验）和0.85（95%CI，0.59 - 1.23；I² = 0%；222例患者，2项试验）。在所有患者和高危细胞遗传学亚组中，初始自体干细胞移植与仅三联疗法相比，汇总无进展生存期均显著改善，HR分别为0.67（95%CI 0.59 - 0.76；I² = 0%；1737例患者，3项试验）和HR 0.59（95%CI：0.44 - 0.7；I² = 零；306例患者，3项试验）。与仅三联疗法相比，初始自体干细胞移植组3 - 4级不良事件的风险更高（相对风险 = 1.17 [95%CI，1.12 - 1.23；1737例患者]）。所有三项试验均报告了第二原发性恶性肿瘤的风险，两组之间相当。两项试验报告了继发性髓系肿瘤，初始自体干细胞移植组明显高于仅三联疗法组，OR为9.7（1.8 - 52.25，I² = 0%，1422例患者）。
尽管在三联疗法时代，初始自体干细胞移植方法在所有患者中导致显著更长的无进展生存期，但无论细胞遗传学风险如何，这并未转化为生存获益。初始自体干细胞移植与继发性髓系肿瘤发生率增加相关。在当前众多创新疗法的情况下，初始自体干细胞移植的作用存在争议。
