Piechotta Vanessa, Jakob Tina, Langer Peter, Monsef Ina, Scheid Christof, Estcourt Lise J, Ocheni Sunday, Theurich Sebastian, Kuhr Kathrin, Scheckel Benjamin, Adams Anne, Skoetz Nicole
Faculty of Medicine and University Hospital Cologne, University of Cologne, Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Kerpener Str. 62, Cologne, NRW, Germany, 50937.
Faculty of Medicine and University Hospital Cologne, University of Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Stem Cell Transplantation Program, Kerpener Str. 62, Cologne, NRW, Germany, 50937.
Cochrane Database Syst Rev. 2019 Nov 25;2019(11):CD013487. doi: 10.1002/14651858.CD013487.
Multiple myeloma is a bone marrow-based hematological malignancy accounting for approximately two per cent of cancers. First-line treatment for transplant-ineligible individuals consists of multiple drug combinations of bortezomib (V), lenalidomide (R), or thalidomide (T). However, access to these medicines is restricted in many countries worldwide.
To assess and compare the effectiveness and safety of multiple drug combinations of V, R, and T for adults with newly diagnosed transplant-ineligible multiple myeloma and to inform an application for the inclusion of these medicines into the World Health Organization's (WHO) list of essential medicines.
We searched CENTRAL and MEDLINE, conference proceedings and study registries on 14 February 2019 for randomised controlled trials (RCTs) comparing multiple drug combinations of V, R and T for adults with newly diagnosed transplant-ineligible multiple myeloma.
We included RCTs comparing combination therapies of V, R, and T, plus melphalan and prednisone (MP) or dexamethasone (D) for first-line treatment of adults with transplant-ineligible multiple myeloma. We excluded trials including adults with relapsed or refractory disease, trials comparing drug therapies to other types of therapy and trials including second-generation novel agents.
Two review authors independently extracted data and assessed risk of bias of included trials. As effect measures we used hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) for adverse events. An HR or RR < 1 indicates an advantage for the intervention compared to the main comparator MP. Where available, we extracted quality of life (QoL) data (scores of standardised questionnaires). Results quoted are from network meta-analysis (NMA) unless stated.
We included 25 studies (148 references) comprising 11,403 participants and 21 treatment regimens. Treatments were differentiated between restricted treatment duration (treatment with a pre-specified amount of cycles) and continuous therapy (treatment administered until disease progression, the person becomes intolerant to the drug, or treatment given for a prolonged period). Continuous therapies are indicated with a "c". Risk of bias was generally high across studies due to the open-label study design. Overall survival (OS) Evidence suggests that treatment with RD (HR 0.63 (95% confidence interval (CI) 0.40 to 0.99), median OS 55.2 months (35.2 to 87.0)); TMP (HR 0.75 (95% CI 0.58 to 0.97), median OS: 46.4 months (35.9 to 60.0)); and VRDc (HR 0.49 (95% CI 0.26 to 0.92), median OS 71.0 months (37.8 to 133.8)) probably increases survival compared to median reported OS of 34.8 months with MP (moderate certainty). Treatment with VMP may result in a large increase in OS, compared to MP (HR 0.70 (95% CI 0.45 to 1.07), median OS 49.7 months (32.5 to 77.3)), low certainty). Progression-free survival (PFS) Treatment withRD (HR 0.65 (95% CI0.44 to 0.96), median PFS: 24.9 months (16.9 to 36.8)); TMP (HR 0.63 (95% CI 0.50 to 0.78), median PFS:25.7 months (20.8 to 32.4)); VMP (HR 0.56 (95% CI 0.35 to 0.90), median PFS: 28.9 months (18.0 to 46.3)); and VRDc (HR 0.34 (95% CI 0.20 to 0.58), median PFS: 47.6 months (27.9 to 81.0)) may result in a large increase in PFS (low certainty) compared to MP (median reported PFS: 16.2 months). Adverse events The risk of polyneuropathies may be lower with RD compared to treatment with MP (RR 0.57 (95% CI 0.16 to 1.99), risk for RD: 0.5% (0.1 to 1.8), mean reported risk for MP: 0.9% (10 of 1074 patients affected), low certainty). However, the CIs are also compatible with no difference or an increase in neuropathies. Treatment with TMP (RR 4.44 (95% CI1.77 to 11.11), risk: 4.0% (1.6 to 10.0)) and VMP (RR 88.22 (95% CI 5.36 to 1451.11), risk: 79.4% (4.8 to 1306.0)) probably results in a large increase in polyneuropathies compared to MP (moderate certainty). No study reported the amount of participants with grade ≥ 3 polyneuropathies for treatment with VRDc. VMP probably increases the proportion of participants with serious adverse events (SAEs) compared to MP (RR 1.28 (95% CI 1.06 to 1.54), risk for VMP: 46.2% (38.3 to 55.6), mean risk for MP: 36.1% (177 of 490 patients affected), moderate certainty). RD, TMP, and VRDc were not connected to MP in the network and the risk of SAEs could not be compared. Treatment with RD (RR 4.18 (95% CI 2.13 to 8.20), NMA-risk: 38.5% (19.6 to 75.4)); and TMP (RR 4.10 (95% CI 2.40 to 7.01), risk: 37.7% (22.1 to 64.5)) results in a large increase of withdrawals from the trial due to adverse events (high certainty) compared to MP (mean reported risk: 9.2% (77 of 837 patients withdrew)). The risk is probably slightly increased with VMP (RR 1.06 (95% CI 0.63 to 1.81), risk: 9.75% (5.8 to 16.7), moderate certainty), while it is much increased with VRDc (RR 8.92 (95% CI 3.82 to 20.84), risk: 82.1% (35.1 to 191.7), high certainty) compared to MP. Quality of life QoL was reported in four studies for seven different treatment regimens (MP, MPc, RD, RMP, RMPc, TMP, TMPc) and was measured with four different tools. Assessment and reporting differed between studies and could not be meta-analysed. However, all studies reported an improvement of QoL after initiation of anti-myeloma treatment for all assessed treatment regimens.
AUTHORS' CONCLUSIONS: Based on our four pre-selected comparisons of interest, continuous treatment with VRD had the largest survival benefit compared with MP, while RD and TMP also probably considerably increase survival. However, treatment combinations of V, R, and T also substantially increase the incidence of AEs, and lead to a higher risk of treatment discontinuation. Their effectiveness and safety profiles may best be analysed in further randomised head-to-head trials. Further trials should focus on consistent reporting of safety outcomes and should use a standardised instrument to evaluate QoL to ensure comparability of treatment-combinations.
多发性骨髓瘤是一种起源于骨髓的血液系统恶性肿瘤，约占所有癌症的2%。对于不适合进行移植的患者，一线治疗方案包括硼替佐米（V）、来那度胺（R）或沙利度胺（T）的多种药物联合使用。然而，在世界上许多国家，这些药物的可及性受到限制。
评估和比较V、R、T三种药物联合使用对新诊断的不适合移植的成年多发性骨髓瘤患者的有效性和安全性，并为将这些药物纳入世界卫生组织基本药物清单提供依据。
2019年2月14日，我们检索了Cochrane系统评价数据库（CENTRAL）、医学期刊数据库（MEDLINE）、会议论文集和研究注册库，以查找比较V、R、T三种药物联合使用与其他治疗方案治疗新诊断的不适合移植的成年多发性骨髓瘤患者的随机对照试验（RCT）。
我们纳入了比较V、R、T联合马法兰和泼尼松（MP）或地塞米松（D）用于一线治疗不适合移植的成年多发性骨髓瘤患者的RCT。我们排除了纳入复发或难治性疾病患者的试验、比较药物治疗与其他类型治疗的试验以及纳入第二代新型药物的试验。
两位综述作者独立提取数据，并评估纳入试验的偏倚风险。作为效应指标，我们使用总生存期（OS）和无进展生存期（PFS）的风险比（HR）以及不良事件的风险比（RR）。HR或RR<1表示干预措施相对于主要对照MP具有优势。如有可用数据，我们提取了生活质量（QoL）数据（标准化问卷得分）。除非另有说明，结果引用自网络荟萃分析（NMA）。
我们纳入了25项研究（148篇参考文献），共11,403名参与者和21种治疗方案。治疗方案分为限制治疗时长（预先设定疗程数的治疗）和持续治疗（持续给药直至疾病进展、患者出现药物不耐受或长期治疗）。持续治疗方案用“c”表示。由于研究采用开放标签设计，各研究的偏倚风险普遍较高。总生存期（OS） 证据表明，与MP的中位OS 34.8个月相比，RD治疗（HR 0.63（95%置信区间（CI）0.40至0.99），中位OS 55.2个月（35.2至87.0））；TMP治疗（HR 0.75（95%CI 0.58至0.97），中位OS：46.4个月（35.9至60.0））；以及VRDc治疗（HR 0.49（95%CI 0.26至0.92），中位OS 71.0个月（37.8至133.））可能会提高生存率（中等确定性）。与MP相比，VMP治疗可能会使OS大幅提高（HR 0.70（95%CI 0.45至1.07），中位OS 49.7个月（32.5至77.3）），确定性较低）。无进展生存期（PFS） 与MP的中位PFS 16.2个月相比，RD治疗（HR 0.65（95%CI 0.44至0.96），中位PFS：24.9个月（16.9至36.8））；TMP治疗（HR 0.63（95%CI 0.50至0.78），中位PFS：25.7个月（20.8至32.4））；VMP治疗（HR 0.56（95%CI 0.35至0.90），中位PFS：28.9个月（18.0至46.3））；以及VRDc治疗（HR 0.34（95%CI 0.20至0.58），中位PFS：4个月（27.9至81.0））可能会使PFS大幅提高（低确定性）。不良事件 与MP治疗相比，RD治疗发生多发性神经病的风险可能较低（RR 0.57（95%CI 0.16至1.99），RD风险：0.5%（0.1至1.8），MP平均报告风险：0.9%（1074例患者中有10例受影响），低确定性）。然而，置信区间也与无差异或多发性神经病增加相符。与MP相比，TMP治疗（RR 4.44（95%CI 1.77至11.11），风险：4.0%（1.6至10.0））和VMP治疗（RR 88.22（95%CI 5.36至1451.11），风险：79.4%（4.8至1306.0））可能会使多发性神经病大幅增加（中等确定性）。没有研究报告VRDc治疗中≥3级多发性神经病的患者数量。与MP相比，VMP可能会增加严重不良事件（SAE）的参与者比例（RR 1.28（95%CI 1.06至1.54），VMP风险：46.2%（38.3至55.6），MP平均风险：36.1%（490例患者中有177例受影响），中等确定性）。RD、TMP和VRDc在网络中未与MP相连，无法比较SAE的风险。与MP相比，RD治疗（RR 4.18（95%CI 2.13至8.20），NMA风险：38.5%（19.6至75.4））；和TMP治疗（RR 4.10（95%CI 2.40至7.01），风险：37.7%（22.1至64.5））因不良事件导致试验退出的比例大幅增加（高确定性）。VMP治疗的风险可能略有增加（RR 1.06（95%CI 0.63至1.81），风险：9.75%（5.8至16.7），中等确定性），而与MP相比，VRDc治疗的风险大幅增加（RR 8.92（95%CI 3.82至20.84），风险：82.1%（35.1至191.7），高确定性）。生活质量 四项研究报告了七种不同治疗方案（MP、MPc、RD、RMP、RMPc、TMP、TMPc）中的生活质量，并用四种不同工具进行测量。各研究的评估和报告存在差异，无法进行荟萃分析。然而，所有研究均报告，对于所有评估的治疗方案，抗骨髓瘤治疗开始后生活质量均有所改善。
基于我们预先选择的四项比较，与MP相比，VRD持续治疗的生存获益最大，而RD和TMP也可能显著提高生存率。然而，V、R和T的联合治疗也会大幅增加不良事件的发生率，并导致更高的治疗中断风险。它们的有效性和安全性概况最好在进一步的随机头对头试验中进行分析。未来的试验应注重一致报告安全结果，并应使用标准化工具评估生活质量，以确保治疗方案的可比性。
