Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond.
Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond.
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DOI：
10.1038/leu.2017.329
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发表时间：
2018-03
期刊：
影响因子：
11.4
通讯作者：
Anderson KC
中科院分区：
文献类型：
--
作者：
Chim CS;Kumar SK;Orlowski RZ;Cook G;Richardson PG;Gertz MA;Giralt S;Mateos MV;Leleu X;Anderson KC
尽管取得了巨大进展，但多发性骨髓瘤（MM）的管理仍然具有挑战性。多种因素影响MM复发/进展时的治疗决定或使用何种方案。最近的主要随机对照试验（RCT）显示无进展生存期（PFS）差异很大，范围从中位4个月（MM-003）至23.6个月（ASPIRE）。基于这些RCT，下一代蛋白酶体抑制剂（卡非佐米和ixazomib）、下一代免疫调节剂（泊马度胺）和单克隆抗体（埃罗妥珠单抗和达雷妥尤单抗）获批用于治疗复发性和难治性MM。达雷妥尤单抗靶向CD 38，具有多种作用机制，包括调节免疫抑制性骨髓微环境。除了在难治性MM中具有显著的单药活性外，达雷妥尤单抗与来那度胺/地塞米松或硼替佐米/地塞米松联合治疗时，在MM中产生了深度缓解和上级PFS。其他抗CD 38抗体（如isatuximab和MOR 202）正在接受评估。靶向SLAMF 7的埃罗妥珠单抗与来那度胺/地塞米松联合使用时，产生了更优的上级缓解率和PFS。这些下一代新药剂和/或抗体的新组合正在进行临床试验。维奈托克是一种抑制BCL 2的口服BH 3模拟物，在t（11;14）MM中显示出单药活性，目前正在研究与硼替佐米/地塞米松联合使用。Selinexor是一种Exportin-1抑制剂，在四或五难治性MM（包括达雷妥尤单抗耐药患者）中产生了有希望的结果。Pembrolizumab是一种抗PD 1检查点抑制剂，正在与来那度胺/地塞米松或pomalidomide/地塞米松联合试验。靶向B细胞成熟抗原的嵌合抗原受体-T细胞在RRMM中产生了深度应答。最后，补救性自体干细胞移植（ASCT）仍然是首次ASCT后MM复发/进展的重要治疗方法。本文总结了这些药物的临床试验数据，强调了对RCT的谨慎解释，并提出了复发/难治性MM的挽救治疗算法。
Despite enormous advances, management of multiple myeloma (MM) remains challenging. Multiple factors impact the decision to treat or which regimen to use at MM relapse/progression. Recent major randomized controlled trials (RCTs) showed widely varying progression-free survivals (PFS), ranging from a median of 4 months (MM-003) to 23.6 months (ASPIRE). Based on these RCTs, next-generation proteasome inhibitors (carfilzomib and ixazomib), next-generation immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab) were approved for relapsed and refractory MM. Daratumumab, targeting CD38, has multiple mechanisms of action including modulation of the immunosuppressive bone marrow micro-environment. In addition to the remarkable single agent activity in refractory MM, daratumumab produced deep responses and superior PFS in MM when combined with lenalidomide/dexamethasone, or bortezomib/dexamethasone. Other anti-CD38 antibodies, such as isatuximab and MOR202, are undergoing assessment. Elotuzumab, targeting SLAMF7, yielded superior response rates and PFS when combined with lenalidomide/dexamethasone. New combinations of these next generation novel agents and/or antibodies are undergoing clinical trials. Venetoclax, an oral BH3 mimetic inhibiting BCL2, showed single agent activity in MM with t(11;14), and is being studied in combination with bortezomib/dexamethasone. Selinexor, an Exportin-1 inhibitor, yielded promising results in quad- or penta-refractory MM including patients resistant to daratumumab. Pembrolizumab, an anti-PD1 check-point inhibitor, is being tested in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone. Chimeric antigen receptor-T cells targeting B-cell maturation antigen have yielded deep responses in RRMM. Finally, salvage autologous stem cell transplantation (ASCT) remains an important treatment in MM relapsing/progressing after a first ASCT. Herein, the clinical trial data of these agents are summarized, cautious interpretation of RCTs highlighted, and algorithm for salvage treatment of relapse/refractory MM proposed.
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影响因子：
51.1
作者：
Cook, Gordon;Williams, Cathy;Morris, Treen C. M.
通讯作者：
Morris, Treen C. M.
影响因子：
20.3
作者：
Catley, Laurence;Weisberg, Ellen;Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
3.5
作者：
Chim, C. S.;Lie, A. K. W.;Kwong, Y. L.
通讯作者：
Kwong, Y. L.
影响因子：
4.8
作者：
de Lavallade, H.;El-Cheikh, J.;Mohty, M.
通讯作者：
Mohty, M.
影响因子：
6.8
作者：
Emilce Alejandre, Mariel;Bibiana Madalena, Leticia;Antonio Pizzolato, Marco
通讯作者：
Antonio Pizzolato, Marco