1、2015New Developments and Treatment Options for Multiple MyelomaRobert Z. Orlowski, MD, PhDMary Elizabeth Thomas Associate Professor of Medicine, Division of Hematology/OncologyAssociate Professor, Department of Pharmacology2015多发性骨髓瘤研究进展和治疗选择Robert Z. Orlowski, MD, PhDMary Elizabeth Thomas Associate
2、 Professor of Medicine, Division of Hematology/OncologyAssociate Professor, Department of PharmacologyOutlineOutlinelDiagnosis, staging and risk identificationlInitial therapy in newly diagnosed myeloma patientslNovel options for patients in the relapsed and/or refractory settinglRepresentative case
3、 presentations of current myeloma treatment algorithms内容大纲l诊断，分期，及风险评估诊断，分期，及风险评估l初治骨髓瘤病人的初始治疗l复发和/或难治性病人的新选择l当前骨髓瘤治疗法则的代表性病例分析Diagnostic CriteriaDiagnostic CriterialMajor 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
4、 1.0 g/24 hrs k or l light chain in urinelMinor 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 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l次要标准 A. 骨髓浆细胞增多
5、 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/dLArriving at the DiagnosisArriving at the DiagnosislTwo major criterialOne major + one minor criterion 1+B, 1+C, 1+D 2+B, 2+C, 2+D 3+A, 3+C, 3+DlThree minor criteria that include A and B A+B+C, A+B+D1Cluster of plasma c
6、ells in the bone marrow. Bataille, R and Harousseau, JL. N. Engl. J. Med. 336:1657, 1997.1确诊条件l2个主要标准l1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+Dl包含A及B的三个次要标准 A+B+C, A+B+D1Cluster of plasma cells in the bone marrow. Bataille, R and Harousseau, JL. N. Engl. J. Med. 336:1657, 1997.1Problem
7、s with This MethodProblems with This MethodlCriteria are cumbersome Difficult to use for patients and physicianslThe boundaries are arbitrary 31% marrow plasmacytosis is a major criterion while 29% isnt, but are these really different?lSome patients may “fall through the cracks” A patient with multi
8、ple painful lytic lesions may not 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l判定标准烦琐 不方便病人及医生使用l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?l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
9、现为M蛋白 30 g/L, 并且 5% 表现为 10% 骨髓侵润MGUSMGUSlInternational Myeloma Working Group criterialM-protein in serum 3.0 g/dLlClonal bone marrow plasmacytosis of 10%, and a low level of plasma cell infiltration in a marrow biopsy, if this was donelNo other B-cell proliferative disorderlNo end organ damage, incl
10、uding bone lesionsKyle, RA et al. Br. J. Haematol. 121:749, 2003.MGUSMGUSl国际骨髓瘤工作组判定标准l血清M蛋白 3.0 g/dLl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l无其它B细胞增殖异常l无终末器官损伤（包括骨病变）Kyle, RA et al. Br. J. Haematol. 121:749, 2003.Asymptomatic Multiple MyelomaAsymptomatic Multiple MyelomalPreviously “smo(u)ldering myeloma
11、”lSerum M-protein 3.0 g/dL and/orlClonal marrow plasmacytosis 10%lNo related organ or tissue impairment (no end organ damage, including bone lesions) or symptomsKyle, RA et al. Br. J. Haematol. 121:749, 2003.无症状多发性骨髓瘤l以前的“冒烟型骨髓瘤”l血清M蛋白 3.0 g/dL 和/或l骨髓浆细胞增多 10%l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 e
12、t al. Br. J. Haematol. 121:749, 2003.Symptomatic Multiple MyelomaSymptomatic Multiple MyelomalPresence of a serum and/or urine M-proteinlClonal marrow plasmacytosis or plasmacytoma10% is generally acceptedlRelated organ or tissue impairmentAnemia (2.75 mmol/L, or 0.25 mmol/L above upper limit of nor
13、mal)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l血清和/或尿中有M蛋白l骨髓浆细胞增多或浆细胞瘤通常以10% 为标准l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
14、 (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 SystemDurie-Salmon Staging SystemlSeveral factors are included in the staging1 Hemoglobin Renal function Serum calcium M-protein production Bony lesions and/or presence of a plasmacytomalDrawbacks Many
15、factors make it cumbersome to apply Does not use new, powerful prognostic tools International Myeloma Working Group studied 11,171 patients2 Multivariate analysis found only b2-microglobulin and albumin as prognostic factors1Durie, BGM and Salmon, SE. Cancer 36:842, 1975. 2Greipp, PR et al. Blood 10
16、2:190a, Abstract 664, 2003.Durie-Salmon Durie-Salmon 分期系统l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l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 Sta
17、ging SystemInternational Staging SystemGreipp, PR et al. J. Clin. Oncol. 23:3412, 2005.Stageb2MAlbuminNOSI3.53.5240162 mos.II3.53.5 -5.53.5 OR327844III5.5277029国际分期系统（ISSISS）Greipp, PR et al. J. Clin. Oncol. 23:3412, 2005.分期b2M白蛋白N总生存期I3.53.5240162 mos.II3.53.5 -5.53.5 或327844III5.52770291Greipp, PR
18、 et al. J. Clin. Oncol. 23:3412, 2005.ISS and PrognosisISS and PrognosislSignificant survival differences for three stages (P 0.0001)lBetter outcome predictor than the prior Durie-Salmon methodlStill does not incorporate cytogenetics1Greipp, PR et al. J. Clin. Oncol. 23:3412, 2005.ISSISS与预后的关系l三期间有显
19、著的生存差异 (P , serum+ urine (%)CR (%)PR or , serum(%)DexThal/Dex1Best 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lThal/dex 优于dex (p =
20、 0.002)1l中位至缓解时间均为 1.1个月l进展 3% vs. 5% l无进展生存 25.3 vs. 17.3 个月l可成功采集干细胞41630 3507301020304050607080PR or ,serum + urine(%)CR (%)PR or ,serum (%)DexThal/Dex1Best 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 w
21、as involved.Rajkumar SV et al. J. Clin. Oncol. 24:431, 2006.DVd vs. VAd as Initial TherapyDVd vs. VAd as Initial TherapyResponseDVd (n=97)VAd (n=95)CR3 (3.1%)0Remission15 (15.5%)15 (15.8%)PR25 (25.8%)24 (25.3%)SD38 (39.2%)46 (48.4%)PD2 (2.1%)0DVd: D 40 mg/m2 d1, V 1.4 mg/m2 with max. of 2 mg d1, d 4
22、0 mg d1-4. Rifkin, RM et al. ASCO Abstract 6509, 2004.lDVd also had less neutropenia, alopecia, and changes in the LVEF, but at the cost of HFS/PPEDVd vs. VAd DVd vs. VAd 作为初始治疗疗效情况疗效情况DVd (n=97)VAd (n=95)CR3 (3.1%)0Remission15 (15.5%)15 (15.8%)PR25 (25.8%)24 (25.3%)SD38 (39.2%)46 (48.4%)PD2 (2.1%)0
23、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.lDVd 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 ?Should We Push Harder for a CR ?l668 pts undergoing Total Therapy 2lStringent CR associated with an improved 4-year OS
24、and EFSlHowever, no difference in outcome between PR and PR patients, who had virtually super imposable survival curvesTricot, G et al. ASH Abstract 936, 2004.我们是否应更努力去取得 CR ? CR ?l668 例病人接受Total Therapy 2 方案治疗l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l但是，PR与1 prior treatmentlLen/dex had a better overall RR &
25、CR rate欧洲结果欧洲结果24592034.73.4150.620 0101020203030404050506060RR (%)RR (%)PR (%)PR (%)CR (%)CR (%)uCR (%)uCR (%)DexDex +Lenl351 名患者随机入组 len/dex 176例 dex/安慰剂175 例l复发或难治、之前的治疗 1次lLen/dex 总 RR & CR率更高Time to ProgressionTime to ProgressionTime to Progression (months)Proportion of Patients2.557.51012.5151
26、7.52022.500.20.40.60.81.0Len/Dex13.3 mos.Dex alone5.1 mos.P 0.000001009009010010进展时间进展时间疾病进展时间疾病进展时间 (月月)患者百分数患者百分数2.557.51012.51517.52022.500.20.40.60.81.0Len/Dex13.3 月月Dex单药单药5.1 月月P 200 100-20070-10050-7020-50 75 X 103/mL to 50 10 50 X 103/mL - Grade 4: 200 100-20070-10050-7020-50 75 X 103/mL 至 5
27、0 10 50 X 103/mL - Grade 4: 200k, only 13% developed grade 3/4 thrombocytopenia 200-100k: 56% (1% grade 4) 100-70k: 90% (all grade 3) All pts developed a predictable 60% reduction Recovery occurs during the rest period VELCADE doesnt kill megakaryocytesLonial, S et al. Blood 106:3777-3784, 2006.血小板减
28、少概况l血小板减少 如果基线 200k, 只有13% 出现3/4级血小板减少 200-100k: 56% (1% 4级) 100-70k: 90% (均为3级) 所有病人出现可预测的60% 的降低 在休息期恢复 万珂 不杀伤巨核细胞Lonial, S et al. Blood 106:3777-3784, 2006.Kinetics of ThrombocytopeniaKinetics of ThrombocytopeniaPlatelet nadir is 40% of baselineMean Platelet Count (109/L)TimeLonial, S et al. Bloo
29、d 106:3777-3784, 2006.血小板减少的变化血小板最低值血小板最低值 为为 基线的基线的40%Mean Platelet Count (109/L)TimeLonial, S et al. Blood 106:3777-3784, 2006.Incidence of Platelet SupportIncidence of Platelet SupportlMedian baseline platelets for patients not requiring a transfusion = 182 x 103/mL lMedian baseline platelets for
30、 patients requiring a transfusion= 65.5 x 103/mLlRare instances of gastrointestinal and intracerebral hemorrhages86%14%Patients requiring platelet transfusionsPatients not requiring platelet transfusionsLonial, S et al. Blood 106:3777-3784, 2006.血小板减少的发生率l中位基线血小板（不需输注者） = 182 x 103/mL l中位基线血小板（需要输注者
31、） = 65.5 x 103/mLl消化道及颅内出血罕见86%14%需要输血小板需要输血小板不需输血小板不需输血小板Lonial, S et al. Blood 106:3777-3784, 2006.Thrombocytopenia and ResponseThrombocytopenia and Response41%56%0%10%20%30%40%50%60%70%80%90%100%RespondersNonresponders(CR + PR)P = .054lIn Phase II, there was a trend for patients with responsive d
32、isease to have a lower incidence of thrombocytopeniaLonial, S et al. Blood 106:3777-3784, 2006.血小板减少与疗效41%56%0%10%20%30%40%50%60%70%80%90%100%RespondersNonresponders(CR + PR)P = .054l在II期临床中, 观察到缓解的病人有血小板减少发生率低的趋势Lonial, S et al. Blood 106:3777-3784, 2006.Recommendation for Part IIRecommendation for
33、 Part IIlSince thrombocytopenia may suggest a lower likelihood of response, the patients disease status needs to be re-evaluatedlIf this shows a continuing response to therapy, or stable disease, and because the patient has grade 3 thrombocytopenia .THENlI would recommend continuing on schedule, and
34、 adding platelet support if needed对第 II II 部分建议l由于血小板减少可能提示缓解不佳，需重新评价病人的疾病状况l如果显示对治疗有持续的缓解或稳定，而病人有3级血小板减少.所以l我推荐按计划治疗，如果需要给予血小板输注支持Research PersonnelResearch PersonnellClinical E. Claire Dees Peter M. Voorhees Thomas E. Stinchcombe Reynaldo A. Garcia Melissa D. Hall Mary Jo Lehman Susan Natoli Steph
35、anie StahllLaboratory George W. Small Deborah J. Kuhn Peter M. Voorhees Yue Y. Shi Sivagurunathan Somasundaram参与研究人员l临床 E. Claire Dees Peter M. Voorhees Thomas E. Stinchcombe Reynaldo A. Garcia Melissa D. Hall Mary Jo Lehman Susan Natoli Stephanie Stahll实验室 George W. Small Deborah J. Kuhn Peter M. Voorhees Yue Y. Shi Sivagurunathan SomasundaramlBasic research supportAcknowledgementsAcknowledgementslClinical research supportl基础研究支持致 谢l临床研究支持
