多发性骨髓瘤研究进展和治疗选择

New Developments and Treatment Options for Multiple Myeloma,Robert Z. Orlowski, MD, PhDMary Elizabeth Thomas Associate Professor of Medicine, Division of Hematology/OncologyAssociate Professor, Department of Pharmacology,多发性骨髓瘤研究进展和治疗选择,Robert Z. Orlowski, MD, PhDMary Elizabeth Thomas Associate Professor of Medicine, Division of Hematology/OncologyAssociate Professor, Department of Pharmacology,Outline,Diagnosis, staging and risk identificationInitial therapy in newly diagnosed myeloma patientsNovel options for patients in the relapsed and/or refractory settingRepresentative 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 Criteria1. Plasmacytoma on tissue biopsy2. Bone marrow plasmacytosis 30%3. Monoclonal serum protein3.5 g/dL IgG2.0 g/dL IgA1.0 g/24 hrs k or l light chain in urine,Minor CriteriaA. Bone marrow plasmacytosis 10-30%B. Smaller monoclonal spike than in major criterion #2C. Lytic bony lesionsD. Depressed normal IgsIgM 500 mg/dLIgA 1 g/dLIgG 30%3. 过量血清M蛋白3.5 g/dL IgG2.0 g/dL IgA尿中k 或 l轻链 1.0 g/24小时,次要标准A. 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/dLIgA 1 g/dLIgG 6 g/dL,Arriving at the Diagnosis,Two major criteriaOne major + one minor criterion1+B, 1+C, 1+D 2+B, 2+C, 2+D3+A, 3+C, 3+DThree minor criteria that include A and BA+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,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+D3+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 This Method,Criteria are cumbersomeDifficult to use for patients and physiciansThe boundaries are arbitrary31% 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 meet criteria, but needs systemic therapy40% 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,MGUS,International Myeloma Working Group criteriaM-protein in serum 3.0 g/dLClonal bone marrow plasmacytosis of 10%, and a low level of plasma cell infiltration in a marrow biopsy, if this was doneNo other B-cell proliferative disorderNo end organ damage, including bone lesions,Kyle, RA et al. Br. 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 0.25 mmol/L above upper limit of normal)Renal insufficiency (creatinine 173 mmol/L)Other (hyperviscosity, amyloidosis, recurrent 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.,Durie-Salmon Staging System,Several factors are included in the staging1HemoglobinRenal functionSerum calciumM-protein productionBony lesions and/or presence of a plasmacytoma,DrawbacksMany factors make it cumbersome to applyDoes not use new, powerful prognostic toolsInternational Myeloma Working Group studied 11,171 patients2Multivariate 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. 23:3412, 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 methodStill does not incorporate cytogenetics,1,Greipp, PR et al. J. Clin. Oncol. 23:3412, 2005.,ISS与预后的关系,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 therapyOS 65.1 9.8 vs 26.7 4.1 months,Facon, T et al. Blood 97:1566, 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 dexamethasone11/74 (15%) on the bortezomib arm and 13/94 (14%) on the dex arm had metaphase del 13Del 13 was associated with poor survival on dex arm compared with controlsDel 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 ISSNew prognostic factors are emerging that may help refine this furtherCytogenetic and FISH studies can provide additional prognostic information, 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 identificationInitial therapy in newly diagnosed myeloma patientsPatients with transplant as an optionNovel options for patients in the relapsed and/or refractory settingRepresentative 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)1Median time to response for both was 1.1 mosProgression 3% vs. 5% Progression free survival 25.3 vs. 17.3 monthsStem 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.Rajkumar 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 involved.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 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 2Stringent CR associated with an improved 4-year OS and EFSHowever, no difference 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 Therapy 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, Thomas 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 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, Thomas 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,摘要 781,Study Design,Study of “Rev/dex” regimen in 34 previously untreated patientsPhase II, prospective trial designLenalidomide: 25 mg po days 1-21 q 28 Dexamethasone 40 mg po days 1-4, 9-12, and 17-20Aspirin (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.,Responses,Response rate was 91% (31/34), defined as patients with 50% serum M-protein reduction and 90% urine M-proteinCR rate was 6% (2/34)Another 32% (11/34) achieved vgPR/nCR53% (18/34) had a PRAmong patients who did not achieve a response, 2 had MR and 1 had SDStem cells could be collected successfully,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/nCR53% (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 24,11,21,Dex 40 mg,Dox 0, 4.5, or 9 mg/m2,Newly diagnosed pts before stem cell transplantEvaluate 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 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 successfully18/20 transplantedCR + 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),0,10,20,30,40,50,60,70,80,90,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 neuropathySensory neuropathy in 48% (5% grade 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. 129:755, 2005.,Reduced Dose PAD Combination Therapy (PS-341/ Bortezomib, Adriamycin and Dexamethasone) for Previously Untreated Patients with Multiple MyelomaRakesh Popat, Heather E. Oakervee, Nicola 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, 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, Nicola 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, MA, USA,Abstract 2554,Toxicities,9% sensory and 9% painful neuropathy; all grade 1-21 discon-tinuationMRSA,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 rateStem cells mobilization not impacted by PADImproved toxicity profile compared with higher dose PAD,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 CRsPatients are able to have stem cells collected and move on to transplantation safelyAdditional studies will be needed to identify 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 identificationInitial therapy in newly diagnosed myeloma patientsPatients without transplant as an optionNovel options for patients in the relapsed and/or refractory settingRepresentative 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 Myeloma (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,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,Study Design,Phase I/II studyPatients with myeloma 65 years of ageFour cycles of 6 weeks eachMP days 1-4Bortezomib days 1, 4, 8, 11, 22, 25, 29, 32Five cycles of 5 weeks eachMP days 1-4Bortezomib days 1, 8, 15, 22,研究设计,临床 I/II期研究 65岁骨髓瘤病人 每周期6周，共4个周期MP 第 1-4天万珂第 1, 4, 8, 11, 22, 25, 29, 32天每周期5周，共5个周期MP 第1-4天万珂第 1, 8, 15, 22天,Toxicities,Events comparable to other myeloma regimensEvent-free survival 85%6 deathsBortezomib dose reductions in 35%Neuropathy,毒性反应,与其他骨髓瘤方案相似无事件生存率 85%6 例死亡35%的患者降低了万珂的剂量神经病变,Responses,86% of patients responded High proportion of CR/IFX-Response not influenced by del13 or IgHPhase III trial planned,疗效,缓解率86%CR/IFX-比例高疗效不受 del13 或IgH的影响计划进行临床 III 期研究,Major Superiority of Melphalan Prednisone (MP) + Thalidomide (THAL) over MP and Autologous Stem Cell Transplantation in the Treatment of Newly Diagnosed Elderly Patients with Multiple Myeloma,Thierry Facon, J.Y. Mary, C. Hulin, L. Benboubker, M. Attal, M. Renaud, J.L. Harousseau, B. Pegourie, G. Guillerm, C. Chaleteix, M. Dib, L. Voillat, H. Maisonneuve, J. Troncy, V. Dorvaux, M. Monconduit, C. Martin, P. Casassus, J. Jaubert, H. Jardel, B. Kolb, F. BautersCHU, LILLE, On Behalf of the Intergroupe Francophone du Myelome, France,Abstract 780,美法兰-强的松 (MP) +沙利度胺 (THAL) 治疗初治的高年多发性骨髓瘤患者优于美法兰-强的松 (MP) 和自体干细胞移植,Thierry Facon, J.Y. Mary, C. Hulin, L. Benboubker, M. Attal, M. Renaud, J.L. Harousseau, B. Pegourie, G. Guillerm, C. Chaleteix, M. Dib, L. Voillat, H. Maisonneuve, J. Troncy, V. Dorvaux, M. Monconduit, C. Martin, P. Casassus, J. Jaubert, H. Jardel, B. Kolb, F. BautersCHU, LILLE, On Behalf of the Intergroupe Francophone du Myelome, France,Abstract 780,Study Design,1Clodronate was given to all patients.,Standard MP1 12 courses at 6-week intervalsn = 191,MP + T1MP as above + Thal up to 400 mg qdn = 124,Mel 100 mg/m2 x 21VAD x 2; Cy 3 g/ m2 + G-CSF n = 121,Untreated, stage I-III patients age 65-75(N = 436),研究设计,1Clodronate was given to all patients.,标准的 MP1 12 疗程，6周间隔n = 191,MP + T1MP 同上 + 沙利度胺，至 400 mg qdn = 124,Mel 100 mg/m2 x 21VAD x 2; Cy 3 g/ m2 + G-CSF n = 121,初治, 临床I-III期研究、年龄 65-75岁(N = 436),A Response Edge for MPT,DVT 13% in MPT (vs. 5 and 6.5%)36% on MPT had PN,1Only 63% of patients underwent the second transplant.,MPT的疗效,MPT组 DVT发生率 13% (5、6.5%)36% MPT 出现 PN,1仅 63% 的患者接受第2次移植,Major Benefits in OS and PFS,Longer median overall survival with MPTMPT vs. MP : NR 56 vs. 30.3 mos. 5.8P = 0.0008MPT vs. Mel100 : NR 56 vs 38.6 3.0P = 0.014Longer median progression free survivalMPT vs. MP : 29.5 3.6 vs. 17.2 mos. 1.5MPT vs. Mel100 : 29.5 3.6 vs. 19.0 mos. 1.3,OS 、 PFS的临床获益,MPT总体生存时间更长 MPT vs. MP : NR 56 vs. 30.3 月 5.8P = 0.0008MPT vs. Mel100 : NR 56 vs 38.6 3.0P = 0.014无进展生存时间