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1、1蛋白酶体抑制剂硼酸盐二肽治疗难治性多发性骨髓瘤作者：黄文荣李荣靖域张翼鷟吴晓雄高春记薄剑 于力王全顺达万明【摘要 】 多发性骨髓瘤是中老年人群常见且不能治愈的一种恶性肿瘤，蛋白酶体抑制剂硼酸盐二肽主要通过作用于 NF-B 而影响黏附分子表达、抑制血管生成、促进瘤细胞凋亡、降低 IL-6 等细胞因子分泌达到选择性杀伤骨髓瘤细胞目的。本研究报道了硼酸盐二肽对 2 例复发难治性多发性骨髓瘤的临床治疗情况。病例 1 为多发性骨髓瘤，IgA 型， A 期的复发难治性病例，在自体外周血干细胞移植后 8 个月出现病情复发进展，先后给予多种药物组成的联合化疗方案治疗 4 个疗程，病情呈侵袭性进展，表现为骨髓
2、中骨髓瘤细胞增加，血浆异常单克隆免疫球蛋白增高和骨骼破坏加重，并出现肋骨浆细胞瘤。给予硼酸盐二肽联合柔红霉素、地塞米松、沙利度胺的 VADT 方案治疗 1 个疗程获得显著疗效，表现为血浆 IgA由 54 g/L 降至 6.6 g/L，骨髓异常浆细胞由治疗前 40%降至0.6%，患者右侧前上胸壁外侧 5 cm6 cm 骨骼包块在治疗后基本消散；但第 2 个疗程 VADT 方案治疗无效并再次出现病情进展。病例 2 为多发性骨髓瘤，轻链 kappa 型， B 期的原发难治性患者，2先后 2 个疗程 VAD 和 1 疗程 MOFP 方案化疗无效；在 VADT 方案治疗 1 个疗程后即获得显著疗效，尿
3、kappa 由 24-30 g/24 h 降至1.12 g/24 h， 血肌酐由 475.3 mol/L 降至 124.2 mol/L，2微球蛋白由 1.61 mg/dl 降至 0.64 mg/dl；第 3 疗程后尿 kappa定量降至 0.088 g/24 h，2-MG、LDH 和白蛋白水平均在正常范围，获完全缓解。病例 1 主要不良反应有明显疲乏无力，水样腹泻，四肢指趾端轻微发麻发木，均可耐受，并经对症处理及停用治疗后逐渐消失。病例 2 的主要并发症为第 1 疗程第 3 次用药时硼酸盐二肽剂量增加为 1.45 mg/m2 后出现严重的亚急性左侧肢体偏身运动障碍，发病第 2 天最为严重，左侧
4、上肢近端肌力 1 级，远端 0 级，左下肢 2 级，2 周以后肌力逐渐恢复至正常；本例患者无疲乏、血小板减少等并发症。结论：硼酸盐二肽是一个靶向性治疗多发性骨髓瘤的有效药物，但作为一种新药需注意加强不良反应的观察，及时处理可能出现的并发症。 【关键词】 多发性骨髓瘤硼酸盐二肽蛋白酶体抑制剂Salvage Therapy with Proteasome Inhibitor Bortezomib for Relapsed and Refractory Multiple MyelomaAbstractMultiple myeloma is a malignant disease with high
5、incidence in middle-aged and old-aged population. 3Bortezomib is a proteasome inhibitor which target mainly is NF-B. This observation is to study the clinical treatment effect of bortezomib in one relapsed multiple myeloma (MM) patient and one primary refractory MM patient. The first patient diagnos
6、ed as IgA A stage, whose state of disease became worse after 8 months of autologous peripheral blood stem cell transplantation. And the disease became further aggressive with 4 courses of chemical therapy regimen including methylprednisolone, Arsenic trioxide, dexamethasone, cyclophosphamide, mitoxa
7、ntrone, VM-26. Myeloma cells in bone marrow and abnormal monoclonal immunoglobulin in blood plasma both increased. Bone destruction became severe, and there was a plasmacytoma about 56 cm on the patients right upper chest wall. Therefore, the patient received therapy of bortezomib combined with doxr
8、ubicin, dexamethasone and thalidomide (VADT). After one course of therapy with this VADT regimen, IgA in blood plasma decreased from 54 g/L to 6.6 g/L, and abnormal plasma cells in bone marrow decreased from 40% to 0.6%, and plasmacytoma on the patients right upper chest wall almost obsorbed. But th
9、ere was no obvious clinical effect after the second course of therapy of VADT,and the 4disease status became progressive again.The second patient was MM patlent with a light chain kappa type, III B stage. There was no any effect after two courses of VAD therapy and one course of MOFP therapy. The pa
10、tient acquired near complete remission after one course of treatment with VADT. Quantity of kappa protein in urine reduced from 24-30 g/24 hours to 1.12 g/24 hours. Blood creatinine reduced from 475.3 mol/L to 124.2 mol/L. 2-MG reduced from 161g/L to 64 g/L. And this patient got complete remission a
11、fter three consecutive VADT therapy. The mainly side effects of the bortezomib regimen in the first patient include markedly lassitude, diarrhea, numbness of the end of extremities, marked increase of LDH. All the side effects could be tolerated and became disappeared after contraposing treatment an
12、d stopping the bortezomib regimen therapy. The second patient complicated with severe subacute left hemiplegia after the bortezomib dose had been increased to 1.45 mg/m2 at the third time of the first VADT course and the complication became worst at the following day. The upper limb muscle strength
13、was only 1 grade and the lower limb muscle strength was 2 grade. Then the condition improved 5with the support therapy and gradually recovered after two weeks. Therefore, bortezomib is an effective target drug for therapy in refractory multiple myeloma, and more attentions to the side effects should
14、 be paid in order to deal with those side effects in time .Key wordsmultiple myeloma; bortezomib; proteasome inhibitor多发性骨髓瘤（multiple myeloma, MM）是 1850 年由英国医生 Willianm 首先报道的发生在浆细胞的恶性克隆性疾病，其特征主要表现为大量克隆性浆细胞的增生和积聚，并分泌单克隆免疫球蛋白或其片段，同时伴有广泛的溶骨病变和骨质疏松1 。目前骨髓瘤的治疗手段和疗效仍很有限，其平均生存期为 3-5 年。硼酸盐二肽（bortezomib） ，商品
15、名万珂（velcade）是新开发的作用于泛素-蛋白酶体信号通路的一种生物制剂。基础和临床研究结果表明硼酸盐二肽能够相对选择性地作用于骨髓瘤细胞诱导瘤细胞凋亡，2003 年被美国 FDA 批准用于治疗初治和复发难治性 MM2 。在该药于 2005 年 9 月 24 日在我国上市前后，我们使用硼酸盐二肽对数例多发性骨髓瘤患者进行了治疗，现将其中可评价的 2 例难治性多发性骨髓瘤的临床资料报告如下。6材料和方法病例 1患者，男，42 岁。2003 年 5 月因为肋骨痛，血浆 IgA 73.6 g/L，骨髓异常浆细胞 34%，在当地医院诊断为多发性骨髓瘤，IgA型，A 期。在当地先后给予 VAD、M2
16、 和 VAD 方案化疗共 3 个疗程，血浆 IgA 由 73.6 g/L 降至 22 g/L，骨髓异常浆细胞由 34%降至 11%。2003 年 10 月来我院给予 VAD、EPAD、CDVD 化疗3 个疗程及采集自体外周血造血干细胞；2004 年 3 月经 TBI 8 Gy+马法兰 140 mg/m2 进行预处理后回输自体外周血干细胞，造血重建后复查血浆 IgA 为 7.48 g/L，骨髓浆细胞为 4%。随后给予沙利度胺 100-300 mg/d 进行维持治疗。2004 年 11 月患者病情出现进展，血浆 IgA 升至 15 g/L，随即给予沙利度胺加 3 疗程 MAC，病情继续进展。2005 年 5 月出现颅骨、肋骨痛，放射检查示颅骨多发性穿凿样改变，右侧前上胸壁外侧 5 cm6 cm 骨骼包块，血浆IgA 为 53.7 g/L，骨髓浆细胞为 40%。给予 DCME 方案化疗 1 疗程及胸壁局部放疗 45 Gy，血浆 IgA 及右胸壁包块变化不明显。2005
