蛋白酶体抑制剂硼酸盐二肽治疗难治性多发性骨髓瘤

Salvage Therapy with Proteasome Inhibitor Bortezomib for Relapsed and Refractory Multiple Myeloma

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-κB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,ⅢA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54g/L降至6.6g/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5cm×6cm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,ⅢB期的原发难治性患者,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kappa由24-30g/24h降至1.12g/24h,血肌酐由475.3μmol/L降至124.2μmol/L,β2微球蛋白由1.61mg/dl降至0.64mg/dl;第3疗程后尿kappa定量降至0.088g/24h,β2-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1.45mg/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。

Multiple myeloma is a malignant disease with high incidence in middle-aged and old-aged population. Bortezomib is a proteasome inhibitor which target mainly is NF-κB. 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 diagnosed as IgA Ⅲ 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, mitoxantrone, 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 5 × 6 cm on the patient＇s right upper chest wall. Therefore, the patient received therapy of bortezomib combined with doxrubicin, 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 patient＇s right upper chest wall almost obsorbed. But there was no obvious clinical effect after the second course of therapy of VADT, and the disease status became progressive again. The second patient was MM patient 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 patient 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 μmol/L to 124.2 μmol/L. β2-MG reduced from 161g/L to 64 g/L. And this patient got complete remission after 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 and 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/m^2 at the third time of the first VADT course and the complication became worst at the following day. The upper limb muscle strength was only 1 grade and the lower limb muscle strength was 2 grade. Then the condition improved with 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 be paid in order to deal with those side effects in time.