Scott Kathleen, Hayden Patrick J, Will Andrea, Wheatley Keith, Coyne Imelda
School of Nursing & Midwifery, Trinity College Dublin, 24 D'Olier St, Dublin, Ireland.
Cochrane Database Syst Rev. 2016 Apr 20;4(4):CD010816. doi: 10.1002/14651858.CD010816.pub2.
Multiple myeloma is a malignancy of plasma cells accounting for approximately 1% of cancers and 12% of haematological malignancies. The first-in-class proteasome inhibitor, bortezomib, is commonly used to treat newly diagnosed as well as relapsed/refractory myeloma, either as single agent or combined with other therapies.
We conducted a systematic review and meta-analysis to assess the effects of bortezomib on overall survival (OS), progression-free survival (PFS), response rate (RR), health-related quality of life (HRQoL), adverse events (AEs) and treatment-related death (TRD).
We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE (till 27 January 2016) as well as conference proceedings and clinical trial registries for randomised controlled trials (RCTs).
We included randomised controlled trials (RCTs) that compared i) bortezomib versus no bortezomib with the same background therapy in each arm; ii) bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s) and iii) bortezomib dose comparisons and comparisons of different treatment administrations and schedules.
Two review authors independently extracted outcomes data and assessed risk of bias. We extracted hazard ratios (HR) and their confidence intervals for OS and PFS and odds ratios (OR) for response rates, AEs and TRD. We contacted trial authors to provide summary statistics if missing. We estimated Logrank statistics which were not available. We extracted HRQoL data, where available.
We screened a total of 3667 records, identifying 16 relevant RCTs involving 5626 patients and included 12 trials in the meta-analyses. All trials were randomised and open-label studies. Two trials were published in abstract form and therefore we were unable to assess potential risk of bias in full.There is moderate-quality evidence that bortezomib prolongs OS (four studies, 1586 patients; Peto OR 0.77, 95% CI 0.65 to 0.92) and PFS (five studies, 1855 patients; Peto OR 0.65, 95% CI 0.57 to 0.74) from analysing trials of bortezomib versus no bortezomib with the same background therapy in each arm.There is high-quality evidence that bortezomib prolongs OS (five studies, 2532 patients; Peto OR 0.76, 95% CI 0.67 to 0.88) but low-quality evidence for PFS (four studies, 2489 patients; Peto OR 0.67, 95% CI 0.61 to 0.75) from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s).Four trials (N = 716) examined different doses, methods of administrations and treatment schedules and were reviewed qualitatively only.We identified four trials in the meta-analysis that measured time to progression (TTP) and were able to extract and analyse PFS data for three of the studies, while in the case of one study, we included TTP data as PFS data were not available. We therefore did not analyse TTP separately in this review.Patients treated with bortezomib have increased risk of thrombocytopenia, neutropenia, gastro-intestinal toxicities, peripheral neuropathy, infection and fatigue with the quality of evidence highly variable. There is high-quality evidence for increased risk of cardiac disorders from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or versus other agents. The risk of TRD in either comparison group analysed is uncertain due to the low quality of the evidence.Only four trials analysed HRQoL and the data could not be meta-analysed.Subgroup analyses by disease setting revealed improvements in all outcomes, whereas for therapy setting, an improved benefit for bortezomib was observed in all outcomes and subgroups except for OS following consolidation therapy.
AUTHORS' CONCLUSIONS: This meta-analysis found that myeloma patients receiving bortezomib benefited in terms of OS, PFS and response rate compared to those who did not receive bortezomib. This benefit was observed in trials of bortezomib versus no bortezomib with the same background therapy and in trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s). Further evaluation of newer proteasome inhibitors is required to ascertain whether these agents offer an improved risk-benefit profile, while more studies of HRQoL are also required.
多发性骨髓瘤是一种浆细胞恶性肿瘤，约占所有癌症的1%，血液系统恶性肿瘤的12%。首个蛋白酶体抑制剂硼替佐米，通常用于治疗新诊断以及复发/难治性骨髓瘤，可单独使用或与其他疗法联合使用。
我们进行了一项系统评价和荟萃分析，以评估硼替佐米对总生存期（OS）、无进展生存期（PFS）、缓解率（RR）、健康相关生活质量（HRQoL）、不良事件（AE）和治疗相关死亡（TRD）的影响。
我们检索了MEDLINE、Cochrane对照试验中央注册库和EMBASE（截至2016年1月27日）以及会议论文集和临床试验注册库，以查找随机对照试验（RCT）。
我们纳入了以下随机对照试验（RCT）：i）每组中硼替佐米与无硼替佐米且背景治疗相同的比较；ii）每组中硼替佐米与无硼替佐米且背景治疗不同或与其他药物比较的试验；iii）硼替佐米剂量比较以及不同治疗给药方式和方案的比较。
两位综述作者独立提取结局数据并评估偏倚风险。我们提取了OS和PFS的风险比（HR）及其置信区间，以及缓解率、AE和TRD的比值比（OR）。若数据缺失，我们联系试验作者以获取汇总统计数据。我们估计了无法获取的Logrank统计量。如有可用数据，我们提取了HRQoL数据。
我们共筛选了3667条记录，确定了16项相关RCT，涉及5626例患者，并将12项试验纳入荟萃分析。所有试验均为随机开放标签研究。两项试验以摘要形式发表，因此我们无法全面评估潜在的偏倚风险。有中等质量证据表明，在每组背景治疗相同的硼替佐米与无硼替佐米的试验分析中，硼替佐米可延长OS（四项研究，1586例患者；Peto OR 0.77，95% CI 0.65至0.92）和PFS（五项研究，1855例患者；Peto OR 0.65，95% CI 0.57至0.74）。有高质量证据表明，在每组背景治疗不同的硼替佐米与无硼替佐米或与其他药物比较的试验分析中，硼替佐米可延长OS（五项研究，2532例患者；Peto OR 0.76，95% CI 0.67至0.88），但PFS的证据质量较低（四项研究，2489例患者；Peto OR 0.67，95% CI 0.61至0.75）。四项试验（N = 716）研究了不同剂量、给药方法和治疗方案，仅进行了定性综述。我们在荟萃分析中确定了四项测量疾病进展时间（TTP）的试验，其中三项研究能够提取并分析PFS数据，而在一项研究中，由于无法获取PFS数据，我们将TTP数据纳入PFS数据。因此，我们在本综述中未单独分析TTP。接受硼替佐米治疗的患者血小板减少、中性粒细胞减少、胃肠道毒性、周围神经病变、感染和疲劳的风险增加，证据质量差异很大。在每组背景治疗不同的硼替佐米与无硼替佐米或与其他药物比较的试验分析中，有高质量证据表明心脏疾病风险增加。由于证据质量较低，两个比较组中TRD的风险均不确定。仅四项试验分析了HRQoL，且数据无法进行荟萃分析。按疾病情况进行的亚组分析显示所有结局均有改善，而按治疗情况分析，除巩固治疗后的OS外，硼替佐米在所有结局和亚组中均观察到改善。
本荟萃分析发现，与未接受硼替佐米治疗的患者相比，接受硼替佐米治疗的骨髓瘤患者在OS、PFS和缓解率方面均有获益。在每组背景治疗相同的硼替佐米与无硼替佐米的试验以及每组背景治疗不同或与其他药物比较的硼替佐米与无硼替佐米的试验中均观察到了这一获益。需要对新型蛋白酶体抑制剂进行进一步评估，以确定这些药物是否具有更好的风险效益比，同时也需要更多关于HRQoL的研究。
