多发性骨髓瘤

自体干细胞移植术后接受异体移植物

自体干细胞移植术后接受非清髓性异体移植物是一种极具前景的治疗方案。这一治疗策略与两次自体移植相比改善了生存期，尽管需要长期随访，且并非所有患者都有合格的供者。[159]Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007 Mar 15;356(11):1110-20.http://www.nejm.org/doi/10.1056/NEJMoa065464http://www.ncbi.nlm.nih.gov/pubmed/17360989?tool=bestpractice.com 移植在新型疗法领域的进展尤为卓著。异体移植应仅在专科中心或临床试验的背景下实施。非清髓移植方案保留移植物抗骨髓瘤的异体移植免疫效应，可能有助于降低毒性反应。[82]Lokhorst H, Einsele H, Vesole D, et al. International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma. J Clin Oncol. 2010 Oct 10;28(29):4521-30.http://ascopubs.org/doi/full/10.1200/JCO.2010.29.7929http://www.ncbi.nlm.nih.gov/pubmed/20697091?tool=bestpractice.com[160]Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011 Dec;12(13):1195-203.http://www.ncbi.nlm.nih.gov/pubmed/21962393?tool=bestpractice.com

组蛋白脱乙酰基化酶 (HDAC) 抑制剂

组蛋白乙酰化作用通过调整染色质结构来调节蛋白转录。HDAC 抑制剂引起乙酰化核心核小体组蛋白积聚，诱导转化的细胞凋亡或分化。已在复发性/难治性 MM 患者中检验了这些药物与地塞米松或硼替佐米的联合用药，患者对疗法的应答率最高可达 70%。帕比司他已在一些国家获得批准，除此药之外，还有其他泛-HDAC 或选择性 HDAC 抑制剂正在进行临床试验。另一种 HDAC 抑制剂伏立诺他 (vorinostat) 与硼替佐米联合使用时具有毒性，多达 40% 的患者可出现严重不良事件。[161]Dimopoulos M, Siegel DS, Lonial S, et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013 Oct;14(11):1129-40.http://www.ncbi.nlm.nih.gov/pubmed/24055414?tool=bestpractice.com 正在进行的研究通过评估替代剂量和给药时间表，以及选择性 HDAC6 抑制剂，改善耐受性和提高活性。[162]Santo L, Hideshima T, Kung AL, et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood. 2012 Mar 15;119(11):2579-89.http://www.bloodjournal.org/content/119/11/2579.longhttp://www.ncbi.nlm.nih.gov/pubmed/22262760?tool=bestpractice.com[163]Raje N, Vogl DT, Hari PN, et al. ACY-1215, a selective histone deacetylase (HDAC) 6 inhibitor: interim results of combination therapy with bortezomib in patients with multiple myeloma (MM). ASH annual meeting 2013. Oral sessions; abstract 759. Blood. 2013;122(21):759.http://www.bloodjournal.org/content/122/21/759[164]Yee A, Vorhees P, Bensinger WI, et al. ACY-1215, a selective histone deacetylase (HDAC) 6 inhibitor, in combination with lenalidomide and dexamethasone (dex), is well tolerated without dose limiting toxicity (DLT) in patients (Pts) with multiple myeloma (MM) at doses demonstrating biologic activity: interim results of a phase 1b trial. ASH annual meeting 2013. Poster sessions; abstract 3190. Blood. 2013;122(21):3190.http://www.bloodjournal.org/content/122/21/3190

哺乳动物雷帕霉素靶蛋白 (mTOR) 抑制剂

细胞因子和微环境基质成分激活了 MM 细胞中的生长信号通路，例如 AKT 及其下游的哺乳动物雷帕霉素靶蛋白 (mTOR)。在临床前试验中，以 mTOR 为靶向可引起 MM 细胞凋亡。重要的是，其与地塞米松和来那度胺产生协同效应，为这一联合用药的临床评估提供了框架。[165]Raje N, Kumar S, Hideshima T, et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood. 2004 Dec 15;104(13):4188-93.http://www.bloodjournal.org/content/104/13/4188.fullhttp://www.ncbi.nlm.nih.gov/pubmed/15319277?tool=bestpractice.com

细胞周期蛋白 D1 抑制剂

细胞周期蛋白 D 过表达和调节异常被认为是 MM 的关键致病事件。细胞周期蛋白 D1 抑制剂单药治疗及与新型药物联合用药均导致 MM 细胞系和原代 MM 细胞的有效凋亡。针对难治性和复发性 MM 患者的临床试验仍在进行。[166]Cassaday RD, Goy A, Advani S, et al. A phase II, single-arm, open-label, multicenter study to evaluate the efficacy and safety of P276-00, a cyclin-dependent kinase inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2015 Jul;15(7):392-7.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484300/http://www.ncbi.nlm.nih.gov/pubmed/25816934?tool=bestpractice.com

下一代蛋白酶体抑制剂

为了克服耐药性及提高安全性，已开发了几种第二代蛋白酶体抑制剂，且正在接受临床研究。其中包括 marizomib（又名 NPI-0052）[167]Chauhan D, Catley L, Li G, et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from bortezomib. Cancer Cell. 2005 Nov;8(5):407-19.http://www.ncbi.nlm.nih.gov/pubmed/16286248?tool=bestpractice.com 和 oprozomib。[168]Kumar SK, Bensinger WI, Zimmerman TM, et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014 Aug 14;124(7):1047-55.http://www.bloodjournal.org/content/124/7/1047.longhttp://www.ncbi.nlm.nih.gov/pubmed/24904120?tool=bestpractice.com[169]Richardson PG, Baz R, Wang M, et al. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014 Aug 14;124(7):1038-46.http://www.bloodjournal.org/content/124/7/1038.longhttp://www.ncbi.nlm.nih.gov/pubmed/24920586?tool=bestpractice.com 在一项 I 期剂量递增临床试验中，硼替佐米难治性患者对 Marizomib 单药治疗有应答，副作用最小。尤其是无骨髓抑制和周围神经病变的报告。[170]Richardson PG, Spencer A, Cannell P, et al. Phase 1 clinical evaluation of twice-weekly marizomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma (MM). ASH annual meeting 2011. Oral sessions; abstract 302. Blood. 2011;118(21):302.http://www.bloodjournal.org/content/118/21/302 美国食品药品监督管理局和欧洲药品管理局已认定 marizomib 为治疗多发性骨髓瘤的孤儿药。