Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Health Sciences Library System, University of Pittsburgh, Pittsburgh, PA, USA.
Lancet Haematol. 2022 Dec;9(12):e906-e918. doi: 10.1016/S2352-3026(22)00289-7. Epub 2022 Oct 27.
Lenalidomide has been standard therapy for multiple myeloma and other haematological malignancies for more than a decade. Previous meta-analyses identified an association between lenalidomide and second primary malignancies (SPM) in patients with multiple myeloma. However, newer randomised controlled trials using lenalidomide for other indications have not reported an increased incidence of SPM. The aim of this study was to investigate the risk of developing SPM with lenalidomide use in all disease settings.
We did a systematic review of randomised controlled trials that reported SPM in patients treated with lenalidomide. PubMed, Embase, CENTRAL, Europe PubMed Central, and ClinicalTrials.gov were searched from Jan 1, 2004, to March 18, 2022. Randomised controlled trials with at least one lenalidomide group and one non-lenalidomide group were selected, regardless of the disease setting. Studies with a median follow-up of less than 12 months were excluded. Summary data were extracted by two reviewers (KS and KL) independently and verified by a third reviewer (JF). We then conducted a meta-analysis to assess the risk ratio (RR) of SPM with lenalidomide use across various disease subtypes using a random-effects model. We chose random effects for the primary analysis because of anticipated heterogeneity between different diseases, but we used fixed effects for stratified meta-analysis of multiple myeloma studies. Risk of bias was assessed with the PROTECT tool. The study was registered with PROSPERO, CRD42021257508.
Our search yielded 9078 studies, and 38 trials that included 14 058 patients were eligible for meta-analysis after screening, 18 of which were in multiple myeloma. The RR across all malignancies was 1·16 (95% CI 0·96-1·39). However, there was heterogeneity across indications (p=0·020). The RR when lenalidomide was used for multiple myeloma was 1·42 (1·09-1·84). There was no increase in SPM in lymphoma or chronic lymphocytic leukaemia (0·90 [0·76-1·08]) and myelodysplastic syndrome (0·96 [0·23-3·97]) trials. In the setting of multiple myeloma, lenalidomide increased both solid and haematological SPM, both in the no-transplantation and post-transplantation settings. From the 38 trials, 21 (55%) had low risk of bias, 12 (32%) had unclear risk of bias, and five (13%) had high risk of bias.
Based on the current data, lenalidomide-induced SPM seem to occur exclusively in patients with multiple myeloma. Thus, lenalidomide can be used for other indications without the major concern of a therapy-related neoplasm. In the multiple myeloma setting, lenalidomide is an effective drug, but patients should be monitored both for haematological and solid tumour SPM. This monitoring includes patients that have not received autologous haematopoietic stem-cell transplantation. Further investigations are needed to improve understanding on why lenalidomide only promotes SPM in patients with multiple myeloma.
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来那度胺作为多发性骨髓瘤和其他血液系统恶性肿瘤的标准治疗药物，已经有十余年的应用历史。先前的荟萃分析发现，来那度胺与多发性骨髓瘤患者的第二原发恶性肿瘤（SPM）之间存在关联。然而，使用来那度胺治疗其他适应证的最新随机对照试验并未报告 SPM 发生率增加。本研究旨在探讨在所有疾病情况下使用来那度胺治疗与 SPM 发病风险之间的关系。
我们对报道了来那度胺治疗患者 SPM 的随机对照试验进行了系统评价。从 2004 年 1 月 1 日至 2022 年 3 月 18 日，我们检索了 PubMed、Embase、CENTRAL、欧洲 PubMed 中心和 ClinicalTrials.gov。选择了至少有一个来那度胺组和一个非来那度胺组的随机对照试验，无论疾病背景如何。排除了中位随访时间少于 12 个月的研究。两名评审员（KS 和 KL）独立提取汇总数据，并由第三名评审员（JF）进行验证。然后，我们使用随机效应模型对不同疾病亚型中使用来那度胺的 SPM 风险比（RR）进行了荟萃分析。由于不同疾病之间存在预期的异质性，我们选择了随机效应作为主要分析，但我们对多发性骨髓瘤研究进行了分层荟萃分析，使用了固定效应。使用 PROTECT 工具评估了偏倚风险。本研究在 PROSPERO 注册，CRD42021257508。
我们的检索结果为 9078 项研究，经过筛选后，有 38 项试验（包括 14058 例患者）符合荟萃分析的条件，其中 18 项涉及多发性骨髓瘤。所有恶性肿瘤的 RR 为 1.16（95%CI 0.96-1.39）。然而，各适应证之间存在异质性（p=0.020）。当来那度胺用于多发性骨髓瘤时，RR 为 1.42（1.09-1.84）。在淋巴瘤或慢性淋巴细胞白血病（0.90 [0.76-1.08]）和骨髓增生异常综合征（0.96 [0.23-3.97]）试验中，并未增加 SPM。在多发性骨髓瘤的情况下，来那度胺既增加了实体瘤 SPM，也增加了血液学 SPM，无论是否进行了移植。在这 38 项试验中，21 项（55%）的偏倚风险较低，12 项（32%）的偏倚风险不明确，5 项（13%）的偏倚风险较高。
根据目前的数据，来那度胺诱导的 SPM 似乎仅发生在多发性骨髓瘤患者中。因此，来那度胺可用于其他适应证，而不必过分担心治疗相关的肿瘤。在多发性骨髓瘤的治疗中，来那度胺是一种有效的药物，但应监测患者的血液学和实体瘤 SPM。这种监测包括未接受自体造血干细胞移植的患者。需要进一步的研究来提高我们对为什么来那度胺仅在多发性骨髓瘤患者中促进 SPM 的认识。
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