1、1,浆细胞病(Plasma cell dyscrasias)多发性骨髓瘤(Multiple Myeloma),医科院肿瘤医院 内科,2,What Is Multiple Myeloma?,Cancer of plasma cells.Healthy plasma cells produce antibodies or immunoglobulins.Part of our humoral immunity, they are released in response to foreign body invasion. Myeloma cells produce abnormal immunog
2、lobulin.Overproduce monoclonal protein or paraprotein.Ineffective immunoglobulins.Leads to decreased bone marrow function. Destruction of bone tissue.,3,浆细胞病（Plasma cell dyscrasias）,定义：浆细胞或产生免疫球蛋白的B淋巴细胞过度增殖所引起的一组疾病。本疾病可分为两型骨髓瘤（孤立性、多发性、髓外浆细胞病、浆细胞白血病）；原发性巨球蛋白血症；重链病；原发淀粉样变性。,4,隐性浆细胞病良性单克隆免疫球蛋白血症；继发性单克隆
3、免疫球蛋白血症。病因：尚未完全明了可能与遗传有关，有染色体异常病毒感染继发于其他疾病（慢性骨髓炎、结核、慢性肝炎）,5,M蛋白免疫球蛋白两条相似的重链和两条轻链组成，重链，轻链。免疫球蛋白IgG IgA IgM IgD IgE,6,血清中M蛋白的特点和测定可能完整的单克隆免疫球蛋白或为一条重链和一条轻链的免疫球蛋白采用血清蛋白电泳定量测量法（M蛋白至少2g/L或0.2g/dL，才出现单峰）确定免疫球蛋白的类型（定性）,7,尿中M蛋白特点和测定通常是一条游离的轻链在某些重链疾病中，由某些特定区域的游离重链片段组成免疫球蛋白电泳：定量测定24小时的轻链蛋白（ ）,8,本周氏蛋白多条轻链。分子量小，
4、通过肾小球，从尿排出。加温45-60凝固沸点重新溶解冷至60 以下出现沉淀 又称凝溶蛋白初期时间间歇出现，本周氏蛋白阴性不能排除本病。,9,多发性骨髓瘤（multiple myeloma）,定义：浆细胞异常增生的恶性肿瘤，异常浆细胞（骨髓瘤细胞）浸润骨骼和软组织，产生M蛋白，引起骨骼破坏，出现贫血、肾功能损害和免疫功能异常。发病率：4/100，000，多发性骨髓瘤占恶性肿瘤的1%，血液恶性疾病的10%，通常无法治愈，接受标准治疗病人中位生存时间为4年。发病高峰年龄：60-70岁，男女比2：1,10,Multiple Myeloma: Epidemiology,Second most commo
5、n hematological malignancy.Incidence and rates:1% of all cancersUS incidence: 19,900 new cases per yearUS prevalence: 100,000 patientsDeaths: estimated 10,790 per yearMore than 80% of affected patients age 60.Affects slightly more men than women (1.6:1).,Merck Manual Professional. 2005; George ED, e
6、t al. Am Fam Phys. 1999;59(7):1401-1405.,11,Clinical Manifestations of Multiple Myeloma,Overproliferation of plasma cells can cause:Risk of infectionOsteolytic bone lesionsHypercalcemiaBone marrow suppression (pancytopenia)Renal complication riskProduction of monoclonal M proteins causes:Decreased l
7、evels of normal immunoglobulinsHyperviscosity,http:/myeloma.org/pdfs/ph07-eng_f2.pdf,12,溶骨性损害病理性骨折高钙血症,贫血,骨髓浸润,骨破坏,单克隆免疫球蛋白,尿：肾功能衰竭血：高粘滞性 冷凝球蛋白 神经病变组织：淀粉样变性,正常免疫球蛋白减少,感染,多发性骨髓瘤,病史和体检血细胞计数，分类及血小板尿素氮/肌酐，电解质，血钙/白蛋白血免疫球蛋白定量血清蛋白电泳及免疫沉淀24小时尿蛋白电泳及免疫沉淀,骨骼扫描骨髓穿刺+活检2-微球蛋白C反应蛋白LDH细胞遗传学检查FISH,通常有用的检查（对一些患者的预后判断
8、有帮助）浆细胞标记指数PCLI 反映浆细胞恶性克隆增生能力骨髓流式细胞仪检测 表达浆细胞抗原（PCA-1),CD20、CD40、CD28、CD31、CD54、CD44,13,Major Symptoms at Diagnosis,骨痛（Bone pain） - 58%乏力（Fatigue） - 32%体重减轻（Weight loss） - 24%感觉异常（Paresthesias） - 5%无症状（Asymptomatic） - 11%,Kyle RA. Mayo Clin Proc 2003;78:21,14,浸润性表现1.骨痛 早期和主要症状，发生率75%，腰骶痛（70%），胸痛（20%）
9、，肢体其他部位（10%）。2.骨骼变形和病理性骨折 骨骼变形：主要在胸骨和脊椎，胸骨柄及胸部凹陷，胸肋锁骨连接外呈串珠样结节。 病理性骨折：多发生在肋骨，多在第五肋以下可引起胸腔积液及胸部疼痛。,15,3.造血器官的损害：贫血，多为中度。4、髓外浸润：脾、肝、淋巴结，肾常见。神经系统病变以胸腰椎脊髓压迫症状为主（10.5%）,16,1.易感染性：与异常M蛋白大量产生，正常免疫球蛋白减少或-球蛋白分解增加有关。细菌感染尤以革兰氏阴性杆菌感染为主（72%）病毒感染有所增加感染常是本病致死的主要原因。,大量M蛋白的及其多肽链引起的临床表现,17,2.高粘滞血症IgA分子易形成多聚体，IgA型更易发生
10、此症。3.出血倾向M蛋白被血小板吸附，导致血小板聚集和血小板第3因子释放失常有关。4.肾功能损害40-60%蛋白尿慢性肾功能衰竭（尿中本周氏蛋白阳性发生率是无本周氏蛋白的2倍）,18,5.淀粉样变10-20%，IgD型常见，有淀粉样变者生存1年，多死于心脏病。舌、心、胃肠道、骨骼、平滑肌、神经、皮肤是发生淀粉样变常见部位,19,1.主要标准：组织活检为浆细胞瘤；骨髓浆细胞增多，30% M蛋白IgG 3.5/dL或IgA 2.0/dL，轻链每日排出1g2.次要标准骨髓浆细胞增多，10-30%；M蛋白IgG3.5 /dL或IgA 2.0/dL； 溶骨性改变；正常免疫球蛋白降低，IgM 50mg/d
11、L， IgA 100mg/dL， IgG 600mg/dL。,SWOG有关多发性骨髓瘤的诊断标准,20,对于一个有症状的病人，凡符合以下条件者可以诊断主要诊断标准或 +次要标准、或；主要诊断标准；次要诊断标准+或+,21,国内 诊断标准,*注释: 诊断IgM型,除符合1、2项外，须具备MM临床表现和多部位溶骨病变。只有1、3项属不分泌MM；对仅有1、2项者 ，尤其无原、幼浆者，除外意义未明的单克隆丙种球蛋白血症和反应性浆细胞增多症,22,Criteria for Diagnosis of Multiple Myeloma,Monoclonal plasma cells present in t
12、he bone marrow 10%, and/or presence of a documented plasmacytoma.+Presence of M component in serum and/or urine.* +One or more of the following (CRAB criteria):Calcium elevation (serum calcium 11.5 mg/dL)Renal insufficiency (serum creatinine 2 mg/dL)Anemia (hemoglobin 10 g/dL or 2 g/dL 3.5 g/dL, IgA
13、 2 g/dL, light chain 1 g/dL in 24-hour urine sample.,23,Diagnostic Evaluation of Multiple Myeloma,Alb = albumin; CBC = complete blood count; Creat = creatinine; Hgb = hemoglobin; MRI = magnetic resonance imaging; WBC = white blood cell.,Abella. Oncology News International. 2007;16:27; Barlogie et al
14、. In: Williams Hematology. 7th ed. 2006:1501; Durie et al. Hematol J. 2003;4:379; MMRF. Multiple Myeloma: Disease Overview. 2006. www.multiplemyeloma.org; Rajkumar et al. Blood. 2005;106(3):812.,24,Durie-Salmon Staging System for Multiple Myeloma,Durie and Salmon, Cancer 1975;36(9):842-854,Subclassi
15、fication criteria: A Normal renal function (serum creatinine level 2.0 mg/dL) B Abnormal renal function (serum creatinine level 2.0 mg/dL),25,临床分期,26,2M=serum 2 microglobulin in mg/dL; ALB=serum albumin in g/dL,International Staging System for Symptomatic Multiple Myeloma,Greipp PR, et al. Blood 200
16、5; 102: 190a,27,多发性骨髓瘤预后因素,新的多发性骨髓瘤国际分期系统 (ISS) 使用了两项实验室参数: 2-微球蛋白 (2M) 水平 和 血清白蛋白水平. I 期 : 2M水平 75%的疗效中位起效时间: 0.9 个月 VAD 方案可使50的患者达部分缓解（PR), 5-10%的患者达完全缓解 (CR) (蛋白电泳及免疫固定电泳无单克隆球蛋白且骨髓浆细胞5) 。,Barlogie B et al. N Engl J Med. 1984;310:1353International Myeloma Foundation. Basic myeloma statistics. Avai
17、lable at: http:/www.myeloma.org/main.jsp?type=article&id=738,51,VAD方案 优点在于在伴有高钙血症或肾功能损害的病人中，可获早期缓解。药物不经肾脏排泄，在肾功衰竭的病人中应用较安全。突出优点是对造血干细胞影响较小。,52,DVD方案,患者：33位新诊断的MM患者方案：DVD方案楷莱：40mg/m2,第1天长春新碱：2.0mg,第1天地塞米松40mg/d（口服或静脉），连用4天每4周一个周期连续应用6个或更多周期，和/或达最佳治疗反应后再继续应用2个周期,Hussein MA, et al. Cancer 2002;95:2160-
18、2168.,53,Hussein MA, et al. Cancer 2002;95:2160-2168.,总有效率达88,54,3年的总生存率为67,Hussein MA, et al. Cancer 2002;95:2160-2168.,55,DVDT,多中心II期临床39例初治多发性骨髓瘤患者治疗方案 楷莱 40mg/m2 IV d1 VCR 2mg IV d1DXM 40mg d14，第1个化疗周期d1518Thalidomide（沙利度胺） 200mg，睡前口服每28天重复1次，共4疗程,Ann Oncol. 2004 Jan; 15(1):134-138,56,疗效总有效率74，C
19、R 4人（10）；PR 25人（64）微小反应3人（8） 级毒副反应中性粒细胞减少：15血小板减少15深静脉血栓10%便秘10，皮疹5，外周神经病5,Ann Oncol. 2004 Jan; 15(1):134-138,57,N,O,N,H,O,O,O,反应停 (Thalomid),口服免疫调节剂谷氨酸衍生物具有抗血管生成和诱导凋亡的作用,58,IL-6TNFIL-1,IGFVEGFbFGF,浆细胞,间质细胞,ICAM, VCAM,X,X,X,X,X,反应停的抑制作用,反应停的作用机制,X,血管,NF-B, CIAP-2, FLIP,Caspace-8, TRAIL,IL-2-IFN,PBMC
20、CD8NK cells,59,Thalidomide 25mg 300mg/d 中位有效剂量 200mg/d低剂量 Thalidomide的作用机制抗炎免疫调节作用抑制巨噬细胞分化分泌INF-和IL-2,60,Thalidomide,61,2,4,6,8,5,10,20,50,100,200,治疗时间（月）,肿瘤负荷,DXM对反应停的增效作用,HCVAD,反应停,200,400,600,600+Dexa,62,反应停联合DXM在初治患者的疗效,病例数,PR/CR %,深静脉血栓,Mayo,50,64,MDACC,69,130,24,ECOG*,69,51,103,107,18,3,TD联合,D
21、单药,*Rajkumar et al, ASH 2004, Abst #205,华法令1.0 mg抗凝n,5,无抗凝治疗n,p.05,63,N,N,H,反应停 (Thalomid),口服免疫调节剂, 谷氨酸衍生物具有抗血管生成和诱导凋亡的作用,Lenalidomide (CC-5013; Revlimid),64,Randomized multicenter Phase III ECOG E4A03 studyRD arm (223 patients)Lenalidomide 25 mg (days 1-21)Dexamethasone 40 mg (days 1-4,9-12,17-20)R
22、d arm (222 patients)Lenalidomide 25 mg (days 1-21)Dexamethasone 40 mg (days 1,8,15,22)Primary endpoint: response rate at 4 months,Lenalidomide/Dexamethasone (RD) vs Lenalidomide/Low-Dose Dexamethasone (Rd) in Transplant-Ineligible Patients,Rajkumar et al, Blood 2007 110: Abstract 74,65,Results From
23、Lenalidomide/Dexamethasone (RD) vs Lenalidomide/Low-Dose Dexamethasone (Rd),Rajkumar et al, Blood 2007 110: Abstract 74; Jacobus et al., Blood 2008 112: Abstract 1740,66,Velcade (bortezomib): prescribing information, 2004,Bortezomib (PS 341; Velcade),作用机制可逆性抑制26S蛋白酶体的糜蛋白酶样活性通过抑制蛋白酶体阻止泛素化蛋白的裂解破坏细胞的自稳
24、状态,引起凋亡,67,硼替佐米,68,Bortezomib (PS-341, Velcade),疗效,%,n,100,193,Total,6,12,CR IF +,4,7,CR,17,33,PR,Bortezomib 1.3 mg/m2 IV d 1, 4, 8, 11 x 最多8周期,或达到 CR的再给2周期,27%,Richardson, et al. NEJM 2003; 348:2609-2617,69,Bortezomib vs 大剂量DXM治疗复发的MM,*DXM治疗进展的患者给予bortezomib治疗,APEX研究, III期临床,DXM 40 mg PO*Days 14, 9
25、12, 17205周一疗程 4 周期(n=336),Bortezomib 13 mg/m2, IVDays 1, 4, 8, 113周为一疗程8 周期(n=333),DXM 40 mg PODays 14 28天一周期5 周期,Bortezomib 13 mg/m2, IVDays 1, 8, 15, 225周为一疗程3 周期,接受过13个疗程治疗的复发MM患者, 对DXM治疗无抗拒的(n=569),诱导化疗,维持治疗,治疗280天,治疗278天,Richardson P et al. Oral Presentation. 46th Annual Meeting of the American
26、 Society of Hematology; December 47, 2004; San Diego, California abstract 336.5,70,Richardson P et al. Oral Presentation. 46th Annual Meeting of the American Society of Hematology; December 47, 2004; San Diego, California abstract 336.5,Bortezomib vs 大剂量DXM治疗复发的MM疗效总结,71,VTD vs. TD in Patients Who A
27、re Transplant Eligible,Study objectiveVTD vs TD in preparation for autologous stem cell transplantation (ASCT)Study designRandomized trialThree cycles of induction therapyMethodsPts. randomized to either VDT (n=199) or TD (n=200).Stem cells were collected.Consolidation therapy with same treatment to
28、 pts. Results drawn from a final analysis of 399 patients.,Phase III Bortezomib-Thalidomide-Dexamethasone (VTD) vs Thalidomide-Dexamethasone (TD) Prior to Stem Cell Transplantation (SCT),Cavo et al. Blood 2008 112: Abstract 158,72,ProphylaxisAcyclovir prophylaxis against reactivation of VZV.TEE prop
29、hylaxis with low molecular weight heparin, aspirin, or warfarin; fixed low-dose warfarin is effective.Conclusions:In comparison with TD, 3 21-d cycles of VTD as primary therapy significantly increased CR+nCR rates.These response rates translated into significantly higher CR+nCR after first ASCT in t
30、he VTD arm.Combinations of novel induction agents, such as VTD, can have a remarkable impact on both pre- and post-ASCT clinical outcome.,Conclusions From VTD vs. TD,Cavo et al. Blood 2008 112: Abstract 158,73,Bortezomib and Dexamethasone Prior to ASCT in Transplant-Eligible Patients,Phase III, acti
31、ve control, multicenter, open label, randomizedObjective: compare the CR rate with vincristine/adriamycin/dexamethasone (VAD) and bortezomib/dexamethasone combinations as induction therapy.Number of severe AE was similar between the arms:,Harousseau et al, Blood 2007 110: Abstract 450.,74,Post-induc
32、tion complete remission (CR) was increased by VD compared to VAD.One-year PFS and OS rates were 93% and 97% with VD and 90% and 95% with VAD, respectively.,Conclusions From Bortezomib and Dexamethasone Prior to ASCT,Harousseau et al, Blood 2007 110: Abstract 450.,75,VISTA Trial: VMP vs MP in Transpl
33、ant-Ineligible Patients,Study objective:Define the differences in efficacy and outcome between VMP vs MPStudy design and method:VMP arm (IV Bortezomib in combination with oral prednisone and oral melphalan) vs MP arm (oral melphalan and prednisone)Primary endpoint:Time to progression (TTP) Secondary endpoints:Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), time to progression (TTP) and duration of response (DOR), and safety,A Phase 3 Study Comparing Bortezomib/Melphalan/Prednisone (VMP) With Melphalan/Prednisone (MP),
