Chinese consensus recommendations for the clinical application of selinexor in multiple myeloma(2022)
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摘要: 塞利尼索是全球首个强效、口服的核输出蛋白抑制剂，具备独特的作用机制且影响多条信号通路，能协同增强其他药物的抗肿瘤活性。国内外多项临床研究证实以塞利尼索为基础的联合方案治疗复发难治性多发性骨髓瘤，可获得较高缓解率，更好改善患者预后。塞利尼索联合方案已被多个指南推荐用于复发难治性骨髓瘤患者。2019年美国食品药品监督管理局(FDA)批准塞利尼索用于复发难治性多发性骨髓瘤。在我国，塞利尼索于2021年12月获批上市。鉴于上市之初临床医生用药经验尚不丰富，中华医学会血液学分会浆细胞疾病学组牵头制定了塞利尼索在骨髓瘤临床应用的专家共识，旨在为中国临床医生提供用药参考。Abstract: Selinexor, as the world's first-in-class oral drug, is a highly selective inhibitor against exportin 1. It has a unique mechanism of action and affects multiple signal pathways, which can synergistically enhance the antitumor activity of other drugs. Many studies have confirmed that the combination regimens based on selinexor in the treatment of relapsed and refractory multiple myeloma have achieved a high response rate and improved a better prognosis. In addition, selinexor has been recommended by several leading clinical guidelines for the treatment of multiple myeloma. In 2019, selinexor was approved by FDA for the treatment of patients with relapsed and refractory multiple myeloma and has received conditional approval for marketing by the China's National Medical Products Administration(NMPA) in December 2021. In view of the lack of clinical experience at the beginning of the market in China, the Plasma Cell Disease Group of Chinese Medical Association of Hematology Society is leading to develop an expert consensus on the clinical application of selinexor in myeloma, aiming to provide a reference for Chinese physician.
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Key words:
- multiple myeloma /
- mechanism of action /
- selinexor /
- treatment recommendation
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表 1 含塞利尼索方案治疗MM的关键临床研究
方案 研究名称 试验分期 患者总数/例 纳入标准 既往中位治疗线数(范围) 剂量/RP2D Sd[9] STORM Ⅱ期、单臂 123 五药暴露、三药难治的RRMM患者 7(3~18) S 80 mg+dex 20 mg，BIW Sd[10] MARCH Ⅱ期、单臂 82 IMiDs和PIs以及末线难治的RRMM患者 5(1~16) S 80 mg+dex 20 mg，BIW SDd[11] STOMP Ⅰb/Ⅱ期、多臂 34 既往接受过PIs和IMiDs治疗的RRMM患者 3(2~10) RP2D：S 100 mg QW+Dara 16 mg/kg+dex 40 mg QW SPd[12] STOMP Ⅰb/Ⅱ期、多臂 60 既往接受过来那度胺和PIs治疗的RRMM患者 3(1~10) RP2D：S 60 mg QW+POM 4 mg QD，d1~21+dex 40 mg QW SKd[13] STOMP Ⅰb/Ⅱ期、多臂 32 既往接受过硼替佐米治疗的RRMM患者 4(1~8) RP2D：S 80 mg QW+K 56 mg/m2+dex 40 mg QW SRd[14] STOMP Ⅰb/Ⅱ期、多臂 8(新诊断)24(复发) NDMM和既往接受过≥1线的RRMM患者 初治：0复发：2(1~8) RP2D在NDMM和RRMM：S 60 mg QW+R 25 mg QD，d1~21+dex 40 mg QW SVd[15] BOSTON Ⅲ期、随机对照 402 (SVd 195、Vd 207) 既往接受过1~3线治疗的RRMM患者 2(1~3) S 100 mg QW+V 1.3 mg/m2+dex 40 mg QW 方案 研究名称 ORR 中位PFS/月 中位OS/月 常见≥3级不良反应发生率 Sd[9] STORM 总体：26%五药难治亚组：25.3% 3.7 8.6 血小板减少58%；中性粒细胞减少21%；疲乏25%；恶心10% Sd[10] MARCH 29.3% 3.7 13.2 血小板减少51%；中性粒细胞减少40%；疲乏9.8%；恶心7.3% SDd[11] STOMP 69% 12.5 NA 血小板减少47%；中性粒细胞减少26.5%；恶心8.8%；呕吐2.9%；疲乏17.6% SPd[12] STOMP 50%(RP2D：60%) 12.2(RP2D：未达到) NA 血小板减少31.7%；中性粒细胞减少54%；恶心1.6%；疲乏9.5% SKd[13] STOMP 78% 15 未达到(中位随访15.1个月) 血小板减少47%；中性粒细胞减少6.3%；恶心6%；疲乏9% SRd[14] STOMP NDMM：100%RRMM(来那度胺未暴露)患者：92% NDMM：NARRMM：NA NA 血小板减少63%；中性粒细胞减少63%；恶心4%；疲乏17% SVd[15] BOSTON 76.4% vs 62.3%(P=0.001 2) 13.9 vs 9.5(P=0.007 5) 未达到vs 25(中位随访17.3个月) 血小板减少40% vs 18%；中性粒细胞减少8.7% vs 3.4%；疲乏13.3% vs 1%；恶心7.7% vs 0；周围神经病变4.6% vs 8.8% 注：S：塞利尼索；d/dex：地塞米松；V：硼替佐米；D/Dara：达雷妥尤单抗；P/POM：泊马度胺；K：卡非佐米；R：来那度胺；NDMM：新诊断多发性骨髓瘤；NA：不可及；ORR：总缓解率；PFS：无进展生存期；OS：总生存期；BIW：每周2次；QW：每周1次；QD：每日1次。 
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表 2 含塞利尼索方案在MM亚组人群的研究数据
亚组人群 国家 方案 例数 ORR/% PFS/月 细胞遗传学高危[13, 20] 美国 SVd vs Vd 70 vs 71 78.6 vs 57.7(P=0.004) 12.9 vs 8.6(P=0.082) 美国 SKd 17 82.4 15 首次复发[13, 21-22] 美国 SVd vs Vd 90 vs 90 80.8 vs 65.7(P=0.008) 16.6 vs 10.6(P=0.015) 美国 SKd 9 88.9 NA 西班牙 SDVd 33 82 未达到 来那度胺难治[12, 23] 美国 SVd vs Vd 53 vs 53 68 vs 47(P=0.016) 10.2 vs 7.1(P=0.012) 加拿大 SPd 60 50 12.2 肾功能不全(Ccr 30~60 mL/min)[24] 美国 SVd vs Vd 53 vs 60 79.2 vs 56.7(P=0.011) 16.6 vs 7.3(P=0.017) 老年(≥65岁)[25] 美国 SVd vs Vd 109 vs 132 76 vs 64(P=0.024) 21.0 vs 9.5(P=0.002)
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表 3 塞利尼索在国内外MM诊治指南中的推荐
指南名称 推荐 2022 V5 NCCN指南[28] 前线复发(1~3线)治疗推荐：SVd、SDd、SPd、SKd多线复发(> 3线)治疗推荐：Sd 2021 ESMO[29] 首次复发治疗推荐：SVd(包括来那度胺敏感、难治和PIs敏感)多线复发治疗推荐：SVd(PIs敏感)ⅠA；Sd(三类药物难治)ⅡB 2021 IMWG[30] 首次复发治疗推荐：SVd(非复发难治) 2022 CSCO[31] RRMM(含首次复发)治疗推荐：SVdⅠ级推荐；SDd、SPd、SKdⅡ级推荐 2022中国多发性骨髓瘤诊治指南[32] RRMM(含首次复发)治疗推荐：SVd、SPd、SDd、SKd 注：NCCN：美国国立综合癌症网络；ESMO：欧洲肿瘤内科学会；IMWG：国际骨髓瘤工作组。
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表 4 塞利尼索剂量推荐
塞利尼索联合方案 RP2D 共识推荐塞利尼索起始剂量 SVd S 100 mg QW+V 1.3 mg/m2+dex 40 mg QW 80~100 mg QW SDd S 100 mg QW+Dara 16 mg/kg+dex 40 mg QW 80~100 mg QW SPd S 60 mg QW+POM 4 mg QD，d1~21+dex 40 mg QW 60 mg QW SKd S 80 mg QW+K 56 mg/m2+dex 40 mg QW 80 mg QW SRd S 60 mg QW+R 25 mg QD，d1~21+dex 40 mg QW 60 mg QW 以S为基础的四药联合方案[33] 在开展中的临床研究设计推荐40~60 mg QW 40~60 mg QW
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表 5 塞利尼索不良事件的管理
症状 不良事件分级 剂量调整 支持治疗 塞利尼索相关血液学不良事件* 血小板减少症 1~2级 无需调整 出现≥3级的血小板减少(即PLT < 50×109/L)时，应及时给予升血小板治疗
·促血小板生成素受体激动剂(TPO-R)，如艾曲泊帕、阿伐曲泊帕、海曲泊帕等
·输注血小板3级(PLT 25×109/L~50×109/L)不伴有出血 剂量减低20 mg(如100降至80 mg)，持续治疗 4级(PLT < 25×109/L)不伴有出血或3级有出血 暂停用药，监测PLT直至恢复至≥50×109/L，塞利尼索剂量降低20 mg(如100降至80 mg)，重新开始治疗 中性粒细胞减少症 1~2级 无需调整 使用G-CSF等升白细胞药物 3级(ANC 0.5×109/L~1.0×109/L)不伴随发热 剂量减低20 mg(如100降至80 mg)，持续治疗 4级(ANC < 0.5×109/L)或发热性中性粒细胞减少 暂停用药，使用G-CSF直至ANC恢复至 > 1.0×109/L，塞利尼索剂量降低20 mg(如100降至80 mg)，重新开始治疗 贫血 3级(Hb < 80 g/L)或有症状 无需调整 Hb < 60 g/L时，可考虑输血 塞利尼索相关非血液学不良事件* 恶心/ 呕吐 1~2级 无需调整 建议塞利尼索给药前给予两联止吐药物(以5-HT3受体拮抗剂为基础)，必要时考虑三联止吐
·5-HT3受体拮抗剂(如昂丹司琼、阿扎司琼、多拉司琼等)，建议在塞利尼索给药前1~2 h使用，若患者对5-HT3受体拮抗剂不耐受或效果不佳，可考虑其他止吐剂
·奥氮平，建议在给药前一天临睡前服用，2.5~5.0 mg/d，在用药前1~2个月内持续服用，给药频率和剂量可随耐受性改善而减低
·NK-1受体拮抗剂(如阿瑞匹坦、福沙匹坦等)，可根据恶心呕吐症状严重程度酌情应用
·足量补液，及时纠正电解质失衡3级 暂停用药，给予额外的抗恶心药物，直至缓解至≤2级或基线水平，塞利尼索剂量降低20 mg(如100降至80 mg)，重新开始治疗 厌食/ 体重下降 1~2级 无需调整 膳食咨询和营养补充 体重减轻≥2级或厌食≥3级 剂量减低20 mg(如100降至80 mg) 最常用的药物为醋酸甲地孕酮200~600 mg/d或奥氮平2.5~5.0 mg/d[35]，或根据相关指南添加支持性治疗药物[36] 疲乏 1级或2级持续时间 < 7 d 无需调整 首先排查并纠正可能会导致疲乏的潜在影响因素(抑郁、脱水、贫血、甲状腺功能减退症、肾上腺功能不全等)，Hb < 60 g/L时考虑进行输血 2级持续时间 > 7 d，或≥3级 暂停用药，直至改善至1级或基线水平；塞利尼索剂量降低20 mg(如100降至80 mg)，重新开始治疗 必要时考虑加用中枢兴奋剂哌甲酯5 mg口服，每日2次[33]，终末期患者可用皮质醇类激素非药物干预，包括体力活动、按摩治疗、心理社会干预、营养支持和睡眠认知行为治疗[37-38]
·积极治疗肿瘤并发症，同时可以开始和维持轻度运动，如耐力(步行、游泳)和抗阻力(力量)的训练
·终末期患者需保留体力给有价值的活动
·心理教育疗法和表达支持疗法
·明亮白光疗法低钠血症 1级和2级 无需调整 考虑膳食中加入盐片，咸食 3级无症状：≤130 mmol/L 暂停用药，直至改善至1级或基线水平；塞利尼索剂量降低20 mg(如100降至80 mg)，重新开始治疗 临床医师根据患者情况补液等 注：*在判断为塞利尼索不良事件前，首先需检查并排除其他潜在因素。PLT：血小板计数；ANC：中性粒细胞绝对值；TPO-R：促血小板生成素受体；G-CSF：粒细胞集落刺激因子；5-HT3：5-羟色胺3；NK-1：神经激肽-1。
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