早期关于长期使用来那度胺的试验报告了二次原发性恶性肿瘤（SPM）的发生率增加，包括急性髓系白血病和骨髓增生异常综合征。随后进行的荟萃分析表明这种联系可能是来那度胺与梅法仑联合使用的结果。Myeloma XI是一个大型的III期随机试验，其中在可移植和不可移植的新诊断患者中应用来那度胺进行诱导和维持治疗（NCT01554852）。在本文中，我们对4358名参与试验的患者进行了一项SPM发生率分析和SPM类型描述，以确定自体干细胞移植（ASCT）和来那度胺暴露对患者的影响。根据试验方案时间表，数据收集从2010年5月开始，到2019年5月结束。维持治疗随机化后的中位随访时间分别为TE患者54.5个月和TNE患者46.1个月。 在TE路径中，与接受观察的患者相比，接受来那度胺维持治疗的患者整体SPM发生率为7.7％，而接受观察的患者为3.2％（p = 0.006）。虽然TNE接受来那度胺维持治疗的患者SPM发生率最高（15.4％），但与接受观察的患者相比并没有统计学意义（10％，p = 0.10）。 在接受来那度胺诱导和维持治疗（双重暴露）的患者中，SPM发生率较接受某一时间点来那度胺治疗（单一暴露）的患者更高。在TNE患者中，这一差距最为显著，双重暴露患者的整体SPM发生率为16.9％，而单一暴露患者为11.7％，未接受来那度胺治疗的患者为11.2％（p = 0.04）。这很可能是治疗持续时间的影响，TNE双重暴露患者的中位治疗周期为27次，而单一暴露患者为6次。 血液系统的SPM很少见，有50名患者被诊断出来（发生率为1.1％）。其中，大多数病例是在接受来那度胺维持治疗的TE患者中诊断出来（n = 25，发生率为2.8％），这可能与梅法仑有关。非黑色素皮肤癌在接受来那度胺维持治疗的患者中发生率最高，特别是TNE患者，鳞状细胞癌和基底细胞癌的发生率分别为5.5％和2.6％。在大多数实体肿瘤类型中，接受来那度胺维持治疗的患者的发生率更高。 来那度胺维持治疗可减少因进行性骨髓瘤导致的死亡，TE患者中接受来那度胺维持治疗的死亡率为16.6％，而接受观察的患者为22.6％；TNE患者中接受来那度胺维持治疗的死亡率为32.7％，而接受观察的患者为41.5％。与SPM相关的死亡率较低，TE和TNE接受来那度胺维持治疗的患者分别为1.8％和6.1％，而接受观察的患者分别为0.4％和2.8％。 这表明长期使用来那度胺治疗在TE和TNE人群中是安全的，并与改善预后相关，但应将SPM的发展监测纳入临床审查流程中。 本研究主要得到了英国癌症研究基金会的财务支持[C1298 / A10410]。 ©2023年该文章的作者们。

Early trials of long-term lenalidomide use reported an increased incidence of second primary malignancy (SPM), including acute myeloid leukaemia and myelodysplastic syndrome. Later, meta-analysis suggested the link to be secondary to lenalidomide in combination with melphalan.Myeloma XI is a large, phase III randomised trial in-which lenalidomide was used at induction and maintenance, in transplant eligible (TE) and non-eligible (TNE) newly diagnosed patients (NCT01554852). Here we present an analysis of SPM incidence and profile the SPM type to determine the impact of autologous stem cell transplantation (ASCT) and lenalidomide exposure in 4358 patients treated on study. Data collection took place from the start of the trial in May 2010, to May 2019, as per the protocol timeline. The Median follow-up following maintenance randomisation was 54.5 and 46.1 months for TE and TNE patients, respectively.In the TE pathway, the overall SPM incidence was 7.7% in lenalidomide maintenance patients compared to 3.2% in those being observed (p = 0.006). Although the TNE lenalidomide maintenance patients had the greatest SPM incidence (15.4%), this was not statistically significant when compared to the observed patients (10%, p = 0.10).The SPM incidence was higher in patients who received lenalidomide at induction and maintenance (double exposure), when compared to those treated with lenalidomide at one time point (single exposure). Again, this was most marked in TNE patients where the overall SPM incidence was 16.9% in double exposed patients, compared to 11.7% in single exposed patients, and 11.2% in patients who did not receive lenalidomide (p = 0.04). This is likely an effect of treatment duration, with the median number of cycles being 27 in the TNE double exposed patients, vs 6 in the single exposure patients.Haematological SPMs were uncommon, diagnosed in 50 patients (incidence 1.1%). The majority of cases were diagnosed in TE patients treated with lenalidomide maintenance (n = 25, incidence 2.8%), suggesting a possible link with melphalan. Non-melanoma skin cancer incidence was highest in patients receiving lenalidomide maintenance, particularly in TNE patients, where squamous cell carcinoma and basal cell carcinoma were diagnosed in 5.5% and 2.6% of patients, respectively. The incidence of most solid tumour types was higher in lenalidomide maintenance patients.Mortality due to progressive myeloma was reduced in patients receiving lenalidomide maintenance, noted to be 16.6% compared 22.6% in those observed in TE patients and 32.7% compared to 41.5% in TNE patients. SPM related mortality was low, 1.8% and 6.1% in TE and TNE lenalidomide maintenance patients, respectively, compared to 0.4% and 2.8% in those being observed.This provides reassurance that long-term lenalidomide treatment is safe and associated with improved outcomes in TE and TNE populations, although monitoring for SPM development should be incorporated into clinic review processes.Primary financial support was from Cancer Research UK [C1298/A10410].© 2023 The Authors.