Curr Oncol. 2006 Oct;13(5):160-72. doi: 10.3747/co.v13i5.106.
In patients with multiple myeloma, Waldenström macroglobulinemia, or lymphoma, what is the efficacy of bortezomib alone or in combination as measured by survival, quality of life, disease control (for example, time to progression), response duration, or response rate?What is the toxicity associated with the use of bortezomib?Which patients are more or less likely to benefit from treatment with bortezomib?
Evidence was selected and reviewed by two members of the Hematology Disease Site Group and by methodologists from the Program in Evidence-based Care (pebc) at Cancer Care Ontario. The practice guideline report was reviewed and approved by the Hematology Disease Site Group, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to practitioners throughout Ontario to obtain their feedback.
Outcomes of interest were overall survival, quality of life, response rates and duration, and rates of adverse events.
A systematic search was conducted of the medline, embase, HealthStar, cinahl, and Cochrane Library databases for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. Those recommendations were appraised by a sample of practitioners in Ontario and modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body w theithin pebc.
The literature review found one randomized controlled trial (rct)-the only published rct of bortezomib in relapsed myeloma. A number of phase ii studies were also retrieved, including a randomized phase ii study. No randomized trials were retrieved for lymphoma. The rct found bortezomib to be superior to high-dose dexamethasone for median time to progression and 1-year survival in patients with relapsed myeloma, although grade 3 adverse events were more common in the bortezomib arm. Bortezomib is recommended as the preferred treatment option in patients with myeloma relapsing within 1 year of the conclusion of initial treatment; it may also be a reasonable option in patients relapsing at least 1 year after autologous stem-cell transplantation.
This evidence-based series applies to adult patients with myeloma, Waldenström macroglobulinemia, or lymphoma of any type, stage, histology, or performance status.
Based on the results of a large well-conducted rct, which represents the only published randomized study in relapsed myeloma, the Hematology Disease Site Group (dsg) offers the following recommendations: For patients with myeloma refractory to or relapsing within 1 year of the conclusion of initial or subsequent treatment or treatments, including autologous stem-cell transplantation, and who are candidates for further chemotherapy, bortezomib is recommended as the preferred treatment option.Bortezomib is also a reasonable option for patients relapsing at least 1 year after autologous stem-cell transplantation. The dsg is aware that thalidomide, alkylating agents, or repeat transplantation may also be options for these patients. However, evaluation of these other options is beyond the scope of this practice guideline.For patients with myeloma relapsing at least 1 year after the conclusion of alkylating agent-based chemotherapy who are candidates for further chemotherapy, further treatment with alkylating agent-based chemotherapy is recommended.Evidence is insufficient to support the use of bortezomib in patients with non-Hodgkin lymphoma or Waldenström macroglobulinemia outside of clinical trials.
Limited evidence supports the appropriateness of a specific time-to-relapse period as being indicative of treatment-insensitive disease. The 1-year threshold provided in the foregoing recommendations is based on the opinion of the Hematology dsg. For specific details related to the administration of bortezomib therapy, the dsg suggests that clinicians refer to the protocols used in major trials. Some of those details are provided here for informational purposes.
Bortezomib 1.3,g/m(2) is given as a rapid intravenous bolus over 3-5 seconds on days 1, 4, 8, and 11 of a 21-day cycle; a minimum of 72 hours between doses is required to allow for recovery of normal proteasome function. Vital signs should be checked before and after each dose. A complete blood count is recommended before each dose, with blood chemistries (including electrolyte and creatinine levels) monitored at a minimum on days 1 and 8 of each cycle. The dose of bortezomib should be reduced or held immediately upon development of painful neuropathy, as described in the product monograph; dose modification may also be required for peripheral sensory neuropathy without pain or for other toxicities. Most toxicities are reversible if dose modification guidelines are followed. RESPONSE TO TREATMENT: Responses are usually apparent by 6 weeks (2 cycles). For patients achieving complete remission (determined by negative electrophoresis and immunofixation), bortezomib should be given for 2 additional cycles beyond the date of confirmed complete remission. In patients with progressive disease after 2 cycles or stable disease after 4 cycles, dexamethasone added to the bortezomib regimen (20 mg by mouth the day of and the day after each bortezomib dose) may produce an objective response. Bortezomib (with or without dexamethasone) should be continued in patients showing benefit from therapy (excluding those in complete remission) unless disease progression or significant toxicity is observed. Therapy should be discontinued in patients who do not respond to bortezomib alone if disease progression is seen within 2 cycles of the addition of dexamethasone. The Hematology dsg recognizes that thalidomide is an active agent in multiple myeloma patients who have relapsed after autologous stem-cell transplantation or who are refractory to alkylating agent-based chemotherapy. To date, no reported rcts have evaluated thalidomide in this role, and specifically, no trials have compared thalidomide with bortezomib. Given these limitations, the members of the Hematology dsg regard thalidomide or bortezomib as therapy alternatives to dexamethasone.
在多发性骨髓瘤、华氏巨球蛋白血症或淋巴瘤患者中，硼替佐米单独或联合使用的疗效如何，表现在生存、生活质量、疾病控制（例如，进展时间）、缓解持续时间或缓解率方面？硼替佐米的使用相关毒性有哪些？哪些患者更有可能或不太可能受益于硼替佐米治疗？
证据由两个血液学疾病站点组的成员以及安大略省癌症护理项目（pebc）的方法学家选择和审查。该实践指南报告由血液学疾病站点组审查和批准，该组由血液学家、医学和放射肿瘤学家以及一名患者代表组成。作为外部审查过程的一部分，报告分发给安大略省的医生，以获取他们的反馈。
感兴趣的结果是总生存、生活质量、缓解率和缓解持续时间以及不良事件的发生率。
对 medline、embase、HealthStar、cinahl 和 Cochrane 图书馆数据库进行了系统检索，以查找原始文章和实践指南。这些证据为制定临床实践建议提供了信息。在安大略省的医生样本中评估了这些建议，并根据收到的反馈进行了修改。系统评价和修改后的建议由 pebc 内部的审查机构批准。
文献综述发现了一项随机对照试验（RCT）-唯一发表的硼替佐米治疗复发性骨髓瘤的 RCT。还检索到了一些 II 期研究，包括一项随机 II 期研究。淋巴瘤没有检索到随机试验。该 RCT 发现硼替佐米在复发性骨髓瘤患者中比高剂量地塞米松更能延长进展时间和 1 年生存率，尽管硼替佐米组 3 级不良事件更常见。硼替佐米被推荐为初始治疗结束后 1 年内复发的骨髓瘤患者的首选治疗方案；对于至少在自体干细胞移植后 1 年复发的患者，也可能是合理的选择。
本循证系列适用于多发性骨髓瘤、华氏巨球蛋白血症或任何类型、分期、组织学或表现状态的淋巴瘤的成年患者。
基于一项大型、精心设计的 RCT 结果，该 RCT 代表了复发性骨髓瘤唯一发表的随机研究，血液学疾病站点组（DGS）提供了以下建议：对于对初始或后续治疗或治疗（包括自体干细胞移植）耐药或复发的骨髓瘤患者，且有进一步化疗适应证的患者，建议使用硼替佐米作为首选治疗方案。硼替佐米也是至少在自体干细胞移植后 1 年复发的患者的合理选择。DGS 知道沙利度胺、烷化剂或重复移植也可能是这些患者的选择。然而，评估这些其他选择超出了本实践指南的范围。对于在烷化剂为基础的化疗结束后至少 1 年复发的对进一步化疗有适应证的骨髓瘤患者，建议进一步使用烷化剂为基础的化疗。没有足够的证据支持硼替佐米在非霍奇金淋巴瘤或华氏巨球蛋白血症患者中的使用，除非在临床试验之外。
有限的证据支持特定的复发时间间隔作为治疗不敏感疾病的指标。本建议中规定的 1 年时间阈值是基于血液学 DGS 的意见。对于硼替佐米治疗管理的具体细节，DGS 建议临床医生参考主要试验中使用的方案。此处提供了一些信息供参考。
硼替佐米 1.3，g/m(2) 作为 3-5 秒快速静脉推注，在 21 天周期的第 1、4、8 和 11 天给予；为允许正常蛋白酶体功能恢复，两次剂量之间至少需要 72 小时。在每次剂量前应检查生命体征。建议在每个周期的第 1 和第 8 天之前进行全血细胞计数，并在最低限度上监测血液化学（包括电解质和肌酐水平）。如果发生疼痛性周围神经病，应立即减少或停止使用硼替佐米，如产品说明书所述；如果发生周围感觉神经病而无疼痛或发生其他毒性，也可能需要进行剂量修改。如果遵循剂量修改指南，大多数毒性是可逆的。
通常在 6 周（2 个周期）内出现反应。对于达到完全缓解（通过阴性电泳和免疫固定化确定）的患者，在确认完全缓解后，硼替佐米应再给予 2 个周期。对于 2 个周期后疾病进展或 4 个周期后稳定疾病的患者，在硼替佐米方案中添加地塞米松（硼替佐米剂量的 20 mg，每天和硼替佐米剂量的后一天口服）可能会产生客观反应。在观察到治疗受益（不包括完全缓解的患者）的患者中，应继续使用硼替佐米（加或不加地塞米松），除非出现疾病进展或严重毒性。如果在添加地塞米松后 2 个周期内观察到疾病进展，则在未对硼替佐米单独反应的患者中停止硼替佐米治疗。血液学 DGS 认识到，沙利度胺是在自体干细胞移植后复发或对烷化剂为基础的化疗耐药的多发性骨髓瘤患者的有效药物。迄今为止，尚未有报道的 RCT 评估了沙利度胺在该作用中的作用，并且特别没有试验将沙利度胺与硼替佐米进行比较。鉴于这些限制，血液学 DGS 的成员认为沙利度胺或硼替佐米是地塞米松的替代治疗选择。
