Lancet oncol:帕比司他联合皮下给予硼替佐米治疗复发性/难治性多发性骨髓瘤的疗效和安全性

2020-12-11 MedSci原创 MedSci原创

复发性/难治性多发性骨髓瘤患者的治疗选择亟待改善。皮下注射硼替佐米的毒性作用更小,现已取代了静脉给药(硼替佐米)。PANORAMA 3试验旨在评估三种不同剂量方案口服帕比司他(panobinostat

复发性/难治性多发性骨髓瘤患者的治疗选择亟待改善。皮下注射硼替佐米的毒性作用更小,现已取代了静脉给药(硼替佐米)。PANORAMA 3试验旨在评估三种不同剂量方案口服帕比司他(panobinostat)联合硼替佐米(皮下)和地塞米松(口服)用于这类患者的活性和安全性。

该试验是一项中21个国家的71家医疗机构开展的开放标签、随机化的2期试验,招募年满18岁的复发性/难治性多发性骨髓瘤患者,要求受试患者既往已接受过1-4线治疗。将患者按1:1:1分至三组,帕比司他的剂量分别为20mg·3次/周(A组)、20mg·2次/周(B组)或10mg·3次/周(C组),硼替佐米和地塞米松的剂量相同。主要终点是8个疗程(21天/疗程)后的总体缓解率。

2016年4月27日-2019年1月17日,共248位患者被随机分组(A组 82位、B组 83位、C组 83位)。总体中位随访时间为14.7个月(IQR 7.8-24.1)。8个疗程后的总体缓解率分别是:A组 62.2%、B组 65.1%、C组 50.6%。

A、B、C三组的3-4级不良反应发生率分别为91%、83%和75%;最常见的3-4级不良反应有血小板减少症(42%、31%和24%)和中性粒细胞减少症(23%、16%和8%)。三组还分别发生了42例(54%)、40例(48%)和35例(44%)重度不良反应;最常见的重度不良反应为肺炎(12%、12%和11%)。研究期间共有14例死亡病例(A、B、C三组分别有5例、3例和6例),无死亡病例被判定与治疗相关。

帕比司他 20mg·3次/周与皮下注射硼替佐米联合应用的安全性优于既往该剂量与静脉给予硼替佐米的安全性更好,提示硼替佐米皮下给药还可提高帕比司他与其联合方案的耐受性。20mg·3次/周和20mg·2次/周时的总体缓解率最高,10mg·3次/周时的耐受性最好

原始出处:

Jacob P Laubach, et al. Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study. The Lancet Oncology. December 07, 2020.

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    2021-07-15 minlingfeng
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    2021-04-08 jml2009
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createdAvatar=, createdBy=b63894, createdName=minlingfeng, createdTime=Thu Jul 15 05:45:29 CST 2021, time=2021-07-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1890197, encodeId=87db189019e20, content=<a href='/topic/show?id=760c430895a' target=_blank style='color:#2F92EE;'>#多发性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=43089, encryptionId=760c430895a, topicName=多发性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=04d6114, createdName=jml2009, createdTime=Thu Apr 08 04:45:29 CST 2021, time=2021-04-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1720978, encodeId=84331e2097843, content=<a href='/topic/show?id=634ee040179' target=_blank style='color:#2F92EE;'>#疗效和安全性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, 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topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4b3d5290623, createdName=14861974m47(暂无昵称), createdTime=Mon Dec 14 17:29:32 CST 2020, time=2020-12-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=907721, encodeId=daf290e7210f, content=学习到了, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ced72552013, createdName=章鱼爸爸, createdTime=Mon Dec 14 00:41:11 CST 2020, time=2020-12-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1528717, encodeId=68321528e17fe, content=<a href='/topic/show?id=74b798601a1' target=_blank style='color:#2F92EE;'>#难治性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=18, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=98601, encryptionId=74b798601a1, topicName=难治性)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a1ef11916292, createdName=freve, createdTime=Sun Dec 13 05:45:29 CST 2020, time=2020-12-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1909856, encodeId=23dd19098561a, content=<a href='/topic/show?id=8f1f42518d8' target=_blank style='color:#2F92EE;'>#复发性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=19, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42518, encryptionId=8f1f42518d8, topicName=复发性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Tue Apr 06 14:45:29 CST 2021, time=2021-04-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=907217, encodeId=a82790e217ed, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=59, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTLF5mbPBJvibvadENtUg1SpPOpWoCsiamJricsKZQySYVJP8exP2RAzVXWzQgicfvmOzN52CvZ98ugR4g/132, createdBy=14a12354025, createdName=疯狂的熊大, createdTime=Sat Dec 12 01:16:24 CST 2020, time=2020-12-12, status=1, ipAttribution=)]
  5. [GetPortalCommentsPageByObjectIdResponse(id=1670491, encodeId=7b4216e049138, content=<a href='/topic/show?id=b6d642519a6' target=_blank style='color:#2F92EE;'>#复发性/难治性多发性骨髓瘤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42519, encryptionId=b6d642519a6, topicName=复发性/难治性多发性骨髓瘤)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=55e026702513, createdName=zhangj7117, createdTime=Sun Dec 13 22:45:29 CST 2020, time=2020-12-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1865951, encodeId=072f1865951c1, content=<a href='/topic/show?id=16ce133504e' target=_blank style='color:#2F92EE;'>#Oncol#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13350, encryptionId=16ce133504e, topicName=Oncol)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b63894, createdName=minlingfeng, createdTime=Thu Jul 15 05:45:29 CST 2021, time=2021-07-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1890197, encodeId=87db189019e20, content=<a href='/topic/show?id=760c430895a' target=_blank style='color:#2F92EE;'>#多发性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=43089, encryptionId=760c430895a, topicName=多发性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=04d6114, createdName=jml2009, createdTime=Thu Apr 08 04:45:29 CST 2021, time=2021-04-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1720978, encodeId=84331e2097843, content=<a href='/topic/show?id=634ee040179' target=_blank style='color:#2F92EE;'>#疗效和安全性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=70401, encryptionId=634ee040179, topicName=疗效和安全性)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=16ef32982072, createdName=经常头晕, createdTime=Sun Oct 31 08:45:29 CST 2021, time=2021-10-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1830936, encodeId=9fbf1830936a9, content=<a href='/topic/show?id=1b6210686b2' target=_blank style='color:#2F92EE;'>#Lancet#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=17, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=10686, encryptionId=1b6210686b2, topicName=Lancet)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Sat Jul 24 13:45:29 CST 2021, time=2021-07-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=907882, encodeId=1b3d90e882b5, content=赞👍, beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4b3d5290623, createdName=14861974m47(暂无昵称), createdTime=Mon Dec 14 17:29:32 CST 2020, time=2020-12-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=907721, encodeId=daf290e7210f, content=学习到了, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ced72552013, createdName=章鱼爸爸, createdTime=Mon Dec 14 00:41:11 CST 2020, time=2020-12-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1528717, encodeId=68321528e17fe, content=<a href='/topic/show?id=74b798601a1' target=_blank style='color:#2F92EE;'>#难治性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=18, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=98601, encryptionId=74b798601a1, topicName=难治性)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a1ef11916292, createdName=freve, createdTime=Sun Dec 13 05:45:29 CST 2020, time=2020-12-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1909856, encodeId=23dd19098561a, content=<a href='/topic/show?id=8f1f42518d8' target=_blank style='color:#2F92EE;'>#复发性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=19, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42518, encryptionId=8f1f42518d8, topicName=复发性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Tue Apr 06 14:45:29 CST 2021, time=2021-04-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=907217, encodeId=a82790e217ed, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=59, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTLF5mbPBJvibvadENtUg1SpPOpWoCsiamJricsKZQySYVJP8exP2RAzVXWzQgicfvmOzN52CvZ98ugR4g/132, createdBy=14a12354025, createdName=疯狂的熊大, createdTime=Sat Dec 12 01:16:24 CST 2020, time=2020-12-12, status=1, ipAttribution=)]
    2021-07-24 hb2008ye
  6. [GetPortalCommentsPageByObjectIdResponse(id=1670491, encodeId=7b4216e049138, content=<a href='/topic/show?id=b6d642519a6' target=_blank style='color:#2F92EE;'>#复发性/难治性多发性骨髓瘤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42519, encryptionId=b6d642519a6, topicName=复发性/难治性多发性骨髓瘤)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=55e026702513, createdName=zhangj7117, createdTime=Sun Dec 13 22:45:29 CST 2020, time=2020-12-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1865951, encodeId=072f1865951c1, content=<a href='/topic/show?id=16ce133504e' target=_blank style='color:#2F92EE;'>#Oncol#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13350, encryptionId=16ce133504e, topicName=Oncol)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b63894, createdName=minlingfeng, createdTime=Thu Jul 15 05:45:29 CST 2021, time=2021-07-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1890197, encodeId=87db189019e20, content=<a href='/topic/show?id=760c430895a' target=_blank style='color:#2F92EE;'>#多发性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=23, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=43089, encryptionId=760c430895a, topicName=多发性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=04d6114, createdName=jml2009, createdTime=Thu Apr 08 04:45:29 CST 2021, time=2021-04-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1720978, encodeId=84331e2097843, content=<a href='/topic/show?id=634ee040179' target=_blank style='color:#2F92EE;'>#疗效和安全性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=70401, encryptionId=634ee040179, topicName=疗效和安全性)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=16ef32982072, createdName=经常头晕, createdTime=Sun Oct 31 08:45:29 CST 2021, time=2021-10-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1830936, encodeId=9fbf1830936a9, content=<a href='/topic/show?id=1b6210686b2' target=_blank style='color:#2F92EE;'>#Lancet#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=17, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=10686, encryptionId=1b6210686b2, topicName=Lancet)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Sat Jul 24 13:45:29 CST 2021, time=2021-07-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=907882, encodeId=1b3d90e882b5, content=赞👍, beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4b3d5290623, createdName=14861974m47(暂无昵称), createdTime=Mon Dec 14 17:29:32 CST 2020, time=2020-12-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=907721, encodeId=daf290e7210f, content=学习到了, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ced72552013, createdName=章鱼爸爸, createdTime=Mon Dec 14 00:41:11 CST 2020, time=2020-12-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1528717, encodeId=68321528e17fe, content=<a href='/topic/show?id=74b798601a1' target=_blank style='color:#2F92EE;'>#难治性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=18, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=98601, encryptionId=74b798601a1, topicName=难治性)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a1ef11916292, createdName=freve, createdTime=Sun Dec 13 05:45:29 CST 2020, time=2020-12-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1909856, encodeId=23dd19098561a, content=<a href='/topic/show?id=8f1f42518d8' target=_blank style='color:#2F92EE;'>#复发性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=19, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42518, encryptionId=8f1f42518d8, topicName=复发性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Tue Apr 06 14:45:29 CST 2021, time=2021-04-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=907217, encodeId=a82790e217ed, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=59, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTLF5mbPBJvibvadENtUg1SpPOpWoCsiamJricsKZQySYVJP8exP2RAzVXWzQgicfvmOzN52CvZ98ugR4g/132, createdBy=14a12354025, createdName=疯狂的熊大, createdTime=Sat Dec 12 01:16:24 CST 2020, time=2020-12-12, status=1, ipAttribution=)]
    2020-12-14 14861974m47(暂无昵称)

    赞👍

    0

  7. [GetPortalCommentsPageByObjectIdResponse(id=1670491, encodeId=7b4216e049138, content=<a href='/topic/show?id=b6d642519a6' target=_blank style='color:#2F92EE;'>#复发性/难治性多发性骨髓瘤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42519, encryptionId=b6d642519a6, topicName=复发性/难治性多发性骨髓瘤)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=55e026702513, createdName=zhangj7117, createdTime=Sun Dec 13 22:45:29 CST 2020, time=2020-12-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1865951, encodeId=072f1865951c1, content=<a href='/topic/show?id=16ce133504e' target=_blank style='color:#2F92EE;'>#Oncol#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13350, encryptionId=16ce133504e, topicName=Oncol)], attachment=null, authenticateStatus=null, 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topicList=[TopicDto(id=70401, encryptionId=634ee040179, topicName=疗效和安全性)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=16ef32982072, createdName=经常头晕, createdTime=Sun Oct 31 08:45:29 CST 2021, time=2021-10-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1830936, encodeId=9fbf1830936a9, content=<a href='/topic/show?id=1b6210686b2' target=_blank style='color:#2F92EE;'>#Lancet#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=17, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=10686, encryptionId=1b6210686b2, topicName=Lancet)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Sat Jul 24 13:45:29 CST 2021, time=2021-07-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=907882, encodeId=1b3d90e882b5, content=赞👍, beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4b3d5290623, createdName=14861974m47(暂无昵称), createdTime=Mon Dec 14 17:29:32 CST 2020, time=2020-12-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=907721, encodeId=daf290e7210f, content=学习到了, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ced72552013, createdName=章鱼爸爸, createdTime=Mon Dec 14 00:41:11 CST 2020, time=2020-12-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1528717, encodeId=68321528e17fe, content=<a href='/topic/show?id=74b798601a1' target=_blank style='color:#2F92EE;'>#难治性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=18, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=98601, encryptionId=74b798601a1, topicName=难治性)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a1ef11916292, createdName=freve, createdTime=Sun Dec 13 05:45:29 CST 2020, time=2020-12-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1909856, encodeId=23dd19098561a, content=<a href='/topic/show?id=8f1f42518d8' target=_blank style='color:#2F92EE;'>#复发性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=19, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42518, encryptionId=8f1f42518d8, topicName=复发性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Tue Apr 06 14:45:29 CST 2021, time=2021-04-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=907217, encodeId=a82790e217ed, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=59, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTLF5mbPBJvibvadENtUg1SpPOpWoCsiamJricsKZQySYVJP8exP2RAzVXWzQgicfvmOzN52CvZ98ugR4g/132, createdBy=14a12354025, createdName=疯狂的熊大, createdTime=Sat Dec 12 01:16:24 CST 2020, time=2020-12-12, status=1, ipAttribution=)]
    2020-12-14 章鱼爸爸

    学习到了

    0

  8. 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    2020-12-13 freve
  9. 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    2020-12-12 疯狂的熊大

    0

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