1、New Developments and Treatment Options for Multiple Myeloma,Robert Z. Orlowski, MD, PhD Mary Elizabeth Thomas Associate Professor of Medicine, Division of Hematology/Oncology Associate Professor, Department of Pharmacology,多发性骨髓瘤 研究进展和治疗选择,Robert Z. Orlowski, MD, PhD Mary Elizabeth Thomas Associate
2、Professor of Medicine, Division of Hematology/Oncology Associate Professor, Department of Pharmacology,Outline,Diagnosis, staging and risk identification Initial therapy in newly diagnosed myeloma patients Novel options for patients in the relapsed and/or refractory setting Representative case prese
3、ntations of current myeloma treatment algorithms,内容大纲,诊断，分期，及风险评估 初治骨髓瘤病人的初始治疗 复发和/或难治性病人的新选择 当前骨髓瘤治疗法则的代表性病例分析,Diagnostic Criteria,Major Criteria 1. Plasmacytoma on tissue biopsy 2. Bone marrow plasmacytosis 30% 3. Monoclonal serum protein 3.5 g/dL IgG 2.0 g/dL IgA 1.0 g/24 hrs k or l light chain i
4、n urine,Minor Criteria A. Bone marrow plasmacytosis 10-30% B. Smaller monoclonal spike than in major criterion #2 C. Lytic bony lesions D. Depressed normal Igs IgM 500 mg/dL IgA 1 g/dL IgG 6 g/dL,诊断标准,主要标准 1. 组织活检证实有浆细胞瘤 2. 骨髓浆细胞增多 30% 3. 过量血清M蛋白 3.5 g/dL IgG 2.0 g/dL IgA 尿中k 或 l轻链 1.0 g/24小时,次要标准 A
5、. 骨髓浆细胞增多 10-30% B. M蛋白未达主要标准的第3项 C. 溶骨性病变 D. 正常 Igs 降低 IgM 500 mg/dL IgA 1 g/dL IgG 6 g/dL,Arriving at the Diagnosis,Two major criteria One major + one minor criterion 1+B, 1+C, 1+D 2+B, 2+C, 2+D 3+A, 3+C, 3+D Three minor criteria that include A and B A+B+C, A+B+D,1Cluster of plasma cells in the bo
6、ne marrow. Bataille, R and Harousseau, JL. N. Engl. J. Med. 336:1657, 1997.,1,确诊条件,2个主要标准 1个主要 + 1个次要标准 1+B, 1+C, 1+D 2+B, 2+C, 2+D 3+A, 3+C, 3+D 包含A及B的三个次要标准 A+B+C, A+B+D,1Cluster of plasma cells in the bone marrow. Bataille, R and Harousseau, JL. N. Engl. J. Med. 336:1657, 1997.,1,Problems with Th
7、is Method,Criteria are cumbersome Difficult to use for patients and physicians The boundaries are arbitrary 31% marrow plasmacytosis is a major criterion while 29% isnt, but are these really different? Some patients may “fall through the cracks” A patient with multiple painful lytic lesions may not
8、meet criteria, but needs systemic therapy 40% of symptomatic patients have an M-protein of 30 g/L, and 5% have 10% marrow involvement,这项标准存在的问题,判定标准烦琐 不方便病人及医生使用 界线设定独断 31% 骨髓浆细胞增多为主要标准而 29%则不是, 但两者是否存在差异? 部分病人可能处于“夹缝状态” 某些有多发性痛性溶骨病变的病人可能没有达到判定标准，但需要系统性治疗 40% 有症状的病人表现为M蛋白 30 g/L, 并且 5% 表现为 10% 骨髓侵润,
9、MGUS,International Myeloma Working Group criteria M-protein in serum 3.0 g/dL Clonal bone marrow plasmacytosis of 10%, and a low level of plasma cell infiltration in a marrow biopsy, if this was done No other B-cell proliferative disorder No end organ damage, including bone lesions,Kyle, RA et al. B
10、r. J. Haematol. 121:749, 2003.,MGUS,国际骨髓瘤工作组判定标准 血清M蛋白 3.0 g/dL 骨髓浆细胞增多 10%； 并且如进行骨髓活检，可见浆细胞侵润程度低 无其它B细胞增殖异常 无终末器官损伤（包括骨病变）,Kyle, RA et al. Br. J. Haematol. 121:749, 2003.,Asymptomatic Multiple Myeloma,Previously “smo(u)ldering myeloma” Serum M-protein 3.0 g/dL and/or Clonal marrow plasmacytosis 10%
11、 No related organ or tissue impairment (no end organ damage, including bone lesions) or symptoms,Kyle, RA et al. Br. J. Haematol. 121:749, 2003.,无症状多发性骨髓瘤,以前的“冒烟型骨髓瘤” 血清M蛋白 3.0 g/dL 和/或 骨髓浆细胞增多 10% 无相关器官或组织损伤（无终末器官损伤，包括骨病变) 或症状,Kyle, RA et al. Br. J. Haematol. 121:749, 2003.,Symptomatic Multiple Mye
12、loma,Presence of a serum and/or urine M-protein Clonal marrow plasmacytosis or plasmacytoma 10% is generally accepted Related organ or tissue impairment Anemia (2.75 mmol/L, or 0.25 mmol/L above upper limit of normal) Renal insufficiency (creatinine 173 mmol/L) Other (hyperviscosity, amyloidosis, re
13、current bacterial infections 2 episodes in 12 months),Kyle, RA et al. Br. J. Haematol. 121:749, 2003.,有症状多发性骨髓瘤,血清和/或尿中有M蛋白 骨髓浆细胞增多或浆细胞瘤 通常以10% 为标准 相关器官或组织损伤 贫血 (2.75 mmol/L, 或高于正常值上限 0.25 mmol/L) 肾功能不全 (肌酐 173 mmol/L) 其他 (高粘血症, 淀粉样变, 反复细菌感染 2 次/12个月),Kyle, RA et al. Br. J. Haematol. 121:749, 2003.,
14、Durie-Salmon Staging System,Several factors are included in the staging1 Hemoglobin Renal function Serum calcium M-protein production Bony lesions and/or presence of a plasmacytoma,Drawbacks Many factors make it cumbersome to apply Does not use new, powerful prognostic tools International Myeloma Wo
15、rking Group studied 11,171 patients2 Multivariate analysis found only b2-microglobulin and albumin as prognostic factors,1Durie, BGM and Salmon, SE. Cancer 36:842, 1975. 2Greipp, PR et al. Blood 102:190a, Abstract 664, 2003.,Durie-Salmon 分期系统,本分期系统中包括下列指标1 血红蛋白 肾功能 血清钙 M蛋白 骨病变 和/或 有浆细胞瘤,缺点 指标太多不方便使用
16、 没有包括新的、有力的预后工具 国际骨髓瘤工作组研究了 11,171例病人2 多变量分析发现，只有 b2微球蛋白及白蛋白是预后因子,1Durie, BGM and Salmon, SE. Cancer 36:842, 1975. 2Greipp, PR et al. Blood 102:190a, Abstract 664, 2003.,International Staging System,Greipp, PR et al. J. Clin. Oncol. 23:3412, 2005.,国际分期系统（ISS）,Greipp, PR et al. J. Clin. Oncol. 23:341
17、2, 2005.,1,Greipp, PR et al. J. Clin. Oncol. 23:3412, 2005.,ISS and Prognosis,Significant survival differences for three stages (P 0.0001) Better outcome predictor than the prior Durie-Salmon method Still does not incorporate cytogenetics,1,Greipp, PR et al. J. Clin. Oncol. 23:3412, 2005.,ISS与预后的关系,
18、三期间有显著的生存差异 (P 0.0001) 与Durie-Salmon分期相比，有更好的预测结果 但仍未包括细胞遗传学指标,Cytogenetic Factors : Del 13,Deletion of chromosome 13 was the single most powerful adverse prognostic factor for all times to events in patients referred for high-dose therapy OS 65.1 9.8 vs 26.7 4.1 months,Facon, T et al. Blood 97:1566
19、, 2001.,细胞遗传学指标 : 13号染色体缺失,在接受高剂量化疗的病人中，13 号染色体缺失是单一最有效的负面预后因子，影响所有的“至事件发生时间”指标 总生存 65.1 9.8 vs 26.7 4.1 个月,Facon, T et al. Blood 97:1566, 2001.,Bortezomib and Del 13,APEX randomized patients to bortezomib or dexamethasone 11/74 (15%) on the bortezomib arm and 13/94 (14%) on the dex arm had metaphas
20、e del 13 Del 13 was associated with poor survival on dex arm compared with controls Del 13 was not associated with an inferior survival on the bortezomib arm,Jagannath, S et al. ASCO Abstract 6501, 2005.,万珂 与 13号染色体缺失,APEX 将病人随机分入万珂组或地塞米松组 万珂组11/74 (15%) 、地塞米松组13/94 (14%) 有分裂中期13号染色体缺失 地塞米松组，13号染色体缺
21、失与更差的生存期相关（与对照相比） 万珂组，13号染色体缺失与更差的生存期无关,Jagannath, S et al. ASCO Abstract 6501, 2005.,Conclusions,Staging and prognosis is most accurately determined using the ISS New prognostic factors are emerging that may help refine this further Cytogenetic and FISH studies can provide additional prognostic inf
22、ormation, and in the very near future may guide therapeutic decisions,结 论,用ISS能更好地确定分期及预后 新的预后因子正在显现，未来可对分期预后系统有进一步的改进 细胞遗传学及FISH研究能提供更多的预后信息，在不久的将来可能会为治疗方法的确定提供指导,Outline,Diagnosis, staging and risk identification Initial therapy in newly diagnosed myeloma patients Patients with transplant as an op
23、tion Novel options for patients in the relapsed and/or refractory setting Representative case presentations of current myeloma treatment algorithms,内容大纲,诊断，分期，及风险评估 初治骨髓瘤病人的初始治疗 能进行移植的病人 复发和/或难治性病人的新选择 当前骨髓瘤治疗法则的代表性病例分析,Thalidomide + Dexamethasone,Thal/dex superior to dex (p = 0.002)1 Median time to
24、 response for both was 1.1 mos Progression 3% vs. 5% Progression free survival 25.3 vs. 17.3 months Stem cell harvests were successful,1Best response was evaluated within 4 cycles. 200 mg po qd. PR was 50% serum & urine M-protein reduction, or 90% urine M-reduction if only urine was involved. Rajkum
25、ar SV et al. J. Clin. Oncol. 24:431, 2006.,沙立度胺 + 地塞米松,Thal/dex 优于dex (p = 0.002)1 中位至缓解时间均为 1.1个月 进展 3% vs. 5% 无进展生存 25.3 vs. 17.3 个月 可成功采集干细胞,1Best response was evaluated within 4 cycles. 200 mg po qd. PR was 50% serum & urine M-protein reduction, or 90% urine M-reduction if only urine was involve
26、d. Rajkumar SV et al. J. Clin. Oncol. 24:431, 2006.,DVd vs. VAd as Initial Therapy,DVd: D 40 mg/m2 d1, V 1.4 mg/m2 with max. of 2 mg d1, d 40 mg d1-4. Rifkin, RM et al. ASCO Abstract 6509, 2004.,DVd also had less neutropenia, alopecia, and changes in the LVEF, but at the cost of HFS/PPE,DVd vs. VAd
27、作为初始治疗,DVd: D 40 mg/m2 d1, V 1.4 mg/m2 with max. of 2 mg d1, d 40 mg d1-4. Rifkin, RM et al. ASCO Abstract 6509, 2004.,DVd 组中性粒细胞减少、脱发、LVEF改变发生少, 但HFS/PPE较多,Should We Push Harder for a CR ?,668 pts undergoing Total Therapy 2 Stringent CR associated with an improved 4-year OS and EFS However, no diff
28、erence in outcome between PR and PR patients, who had virtually super imposable survival curves,Tricot, G et al. ASH Abstract 936, 2004.,我们是否应更努力去取得 CR ?,668 例病人接受Total Therapy 2 方案治疗 以严格的CR判定标准，取得了更好的4年总生存率及无事件生存率 但是，PR与 PR间结果无差异，其生存曲线令人意外,Tricot, G et al. ASH Abstract 936, 2004.,Combination Therap
29、y with Lenalidomide Plus Dexamethasone (Rev/Dex) for Newly Diagnosed Myeloma,S. Vincent Rajkumar, Suzanne Hayman, Martha Q. Lacy, Angela Dispenzieri, Susan M. Geyer, Brian Kabat, Steven R. Zeldenrust, Shaji Kumar, Philip R. Greipp, Rafael Fonseca, John A. Lust, Stephen J. Russell, Robert A. Kyle, Th
30、omas E. Witzig, Morie A. Gertz Division of Hematology, Mayo Clinic, Rochester, MN, USA; Division of Biostatistics, Mayo Clinic, Rochester, MN, USA; Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA,Abstract 781,Lenalidomide 联合地塞米松 (Rev/Dex) 治疗新诊断的骨髓瘤,S. Vincent Rajkumar, Suzanne Haym
31、an, Martha Q. Lacy, Angela Dispenzieri, Susan M. Geyer, Brian Kabat, Steven R. Zeldenrust, Shaji Kumar, Philip R. Greipp, Rafael Fonseca, John A. Lust, Stephen J. Russell, Robert A. Kyle, Thomas E. Witzig, Morie A. Gertz Division of Hematology, Mayo Clinic, Rochester, MN, USA; Division of Biostatist
32、ics, Mayo Clinic, Rochester, MN, USA; Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA,摘要 781,Study Design,Study of “Rev/dex” regimen in 34 previously untreated patients Phase II, prospective trial design Lenalidomide: 25 mg po days 1-21 q 28 Dexamethasone 40 mg po days 1-4, 9-12, a
33、nd 17-20 Aspirin (80 or 325 mg) daily for DVT prophylaxis,Rajkumar, SV et al. Blood 106:4050, 2005.,研究设计,34例初治患者接受“Rev/dex” 方案治疗 临床II期、前瞻性研究设计 Lenalidomide: 25 mg po days 1-21 q 28 地塞米松40 mg po days 1-4, 9-12, 17-20 阿司匹林 (每日80 or 325 mg)，预防深部静脉血栓形成(DVT),Rajkumar, SV et al. Blood 106:4050, 2005.,Resp
34、onses,Response rate was 91% (31/34), defined as patients with 50% serum M-protein reduction and 90% urine M-protein CR rate was 6% (2/34) Another 32% (11/34) achieved vgPR/nCR 53% (18/34) had a PR Among patients who did not achieve a response, 2 had MR and 1 had SD Stem cells could be collected succ
35、essfully,疗效,缓解率 91% (31/34)，定义为患者血浆M-蛋白减少50% ，及尿M-蛋白减少90% 完全缓解率- CR 6% (2/34) 另外 32% (11/34) 获得vgPR/nCR 53% (18/34) 部分缓解 未缓解者中，2例MR ，1 例 SD 可成功采集干细胞,Toxicities,毒性反应,PAD Regimen,Day,Bortezomib 1.3 mg/m2,1,4,8,15,18,Cycle 1,11,21,Dex 40 mg,Dox 0, 4.5, or 9 mg/m2,Bortezomib 1.3 mg/m2,1,4,8,15,18,Cycles
36、 24,11,21,Dex 40 mg,Dox 0, 4.5, or 9 mg/m2,Newly diagnosed pts before stem cell transplant Evaluate response rates, toxicity, and stem cell harvest and subsequent transplantation,Oakervee, HE et al. Br. J. Haematol. 129:755, 2005.,PAD方案,天,万珂 1.3 mg/m2,1,4,8,15,18,第1周期,11,21,地塞米松 40 mg,阿霉素 0, 4.5, or
37、 9 mg/m2,万珂 1.3 mg/m2,1,4,8,15,18,第24周期,11,21,地塞米松40 mg,阿霉素 0, 4.5, or 9 mg/m2,干细胞移植前的初治患者 评价疗效、毒性反应，干细胞采集、及后续移植治疗,Oakervee, HE et al. Br. J. Haematol. 129:755, 2005.,Outcomes Data,95% CR+PR rate after PAD induction therapy alone (20/21) CR+near-CR rate 24% 20/21 patients were mobilized successfully
38、 18/20 transplanted CR + near-CR rose to 57%,Myeloma Protein (g/L),0,10,20,30,40,50,60,70,80,90,Pre-Rx,#1,#2,#3,#4,Treatment Cycle,Oakervee, HE et al. Br. J. Haematol. 129:755, 2005.,疗效结果,单用PAD诱导治疗后, CR+PR 95% (20/21) CR+nCR 24% 20/21例干细胞动员成功 18/20进行了移植 CR + nCR 提高到 57%,M 蛋白 (g/L),0,10,20,30,40,50,6
39、0,70,80,90,Pre-Rx,#1,#2,#3,#4,治疗周期,Oakervee, HE et al. Br. J. Haematol. 129:755, 2005.,Toxicities,Discontinuations occurred due to postural hypotension and neuropathy Drug-related SAEs included postural hypotension, shingles, nausea/vomiting, and peripheral neuropathy Sensory neuropathy in 48% (5% g
40、rade 3) Painful neuropathy in 48% (grade 3 in 5%) All improved after the completion of therapy,Oakervee, HE et al. Br. J. Haematol. 129:755, 2005.,毒性反应,因体位性低血压及神经毒性出现停药 药物相关的SAEs包括体位性低血压，带状疱疹，恶心/呕吐，及周围神经病变 感觉神经病变 48% (5%为3级) 神经病变伴疼痛 48% (3级为5%) 所以病例在治疗结束后有改善,Oakervee, HE et al. Br. J. Haematol. 129:
41、755, 2005.,Reduced Dose PAD Combination Therapy (PS-341/ Bortezomib, Adriamycin and Dexamethasone) for Previously Untreated Patients with Multiple Myeloma Rakesh Popat, Heather E. Oakervee, Nicola Curry, Nicola Foot, Curly Morris, Mary Drake, Samir Agrawal, Patricia Smith, David Schenkein, Dixie-Lee
42、 Esseltine, Jamie D. Cavenagh Haematology, St. Bartholomews Hospital, London, United Kingdom; Haematology, Belfast City Hospital, Belfast, United Kingdom; Millennium Pharmaceuticals, Cambridge, MA, USA,Abstract 2554,减量PAD联合方案（PS-341/硼替佐米, 阿霉素和地塞米松）治疗初治的多发性骨髓瘤 Rakesh Popat, Heather E. Oakervee, Nicol
43、a Curry, Nicola Foot, Curly Morris, Mary Drake, Samir Agrawal, Patricia Smith, David Schenkein, Dixie-Lee Esseltine, Jamie D. Cavenagh Haematology, St. Bartholomews Hospital, London, United Kingdom; Haematology, Belfast City Hospital, Belfast, United Kingdom; Millennium Pharmaceuticals, Cambridge, M
44、A, USA,Abstract 2554,Toxicities,9% sensory and 9% painful neuropathy; all grade 1-2 1 discon-tinuation MRSA,毒性反应,9% 感觉性、 9% 痛性周围神经病变; 所有均为1-2级 1退出治疗 MRSA（甲氧西林耐药金黄色葡萄球菌）,Responses,Excellent response rate Stem cells mobilization not impacted by PAD Improved toxicity profile compared with higher dose P
45、AD,疗效,出色的缓解率 PAD不影响干细胞动员 与高剂量PAD方案相比，毒性反应降低,Conclusions,New induction regimens are emerging that have the ability to induce overall response rates of 90% or more, with more CRs Patients are able to have stem cells collected and move on to transplantation safely Additional studies will be needed to i
46、dentify the optimal regimen(s),结论,新的诱导方案正在出现，能达到90以上的总缓解率，其中有更多的CRs 能进行干细胞采集，并安全地进行移植 需要进行更多的研究以发现最佳方案,Outline,Diagnosis, staging and risk identification Initial therapy in newly diagnosed myeloma patients Patients without transplant as an option Novel options for patients in the relapsed and/or ref
47、ractory setting Representative case presentations of current myeloma treatment algorithms,内容大纲,诊断，分期，及风险评估 初治骨髓瘤病人的初始治疗 不能进行移植的病人 复发和/或难治性病人的新选择 当前骨髓瘤治疗法则的代表性病例分析,A Phase I/II National, Multi-Center, Open-Label Study of Bortezomib Plus Melphalan and Prednisone (V-MP) in Elderly Untreated Multiple My
48、eloma (MM) Patients,M.V. Mateos, M. Hernndez, J. Daz Mediavilla, L. Palomera, M.J. Moro, J. Hernndez, J.J. Lahuerta, J. De la Rubia, M.J. Terol, A. Sureda, J. Bargay, F. Arriba, A. Alegre, P. Rivas, J. Garca-Laraa, J.M. Ribera, D. Carrera, J. Blad, F. Prsper, D.L. Esseltine, H. van de Velde, D. Schenkein, J.F. San Miguel Grupo Espaol de MM, GEM/PETHEMA, Spain; Milennium Pharmaceuticals,INC, Cambridge, MA, USA; Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium,Abstract 786,万珂联合美法兰、强的松 (V-MP) 用于老年初治的多发性骨髓瘤患者 (MM) 的I/II期全国、多中心、开放性的研究,
