多发性骨髓瘤的治疗课件

1、多发性骨髓瘤WHO浆细胞肿瘤分类 浆细胞骨髓瘤 Plasma cell myelomaVariants：非分泌型骨髓瘤 Non-secretory myeloma 惰性骨髓瘤 Indolent myeloma 冒烟型骨髓瘤 Smoldering myeloma 浆细胞性白血病 Plasma cell leukaemia浆细胞瘤Plasmacytoma 骨孤立性浆细胞瘤 Solitary Plasmacytoma of bone 髓外浆细胞瘤 Extramedullary plasmacytoma概 述0.8%恶性肿瘤、10%血液肿瘤新发病例约86 000例/每年中位年龄约71岁（40岁较少见）

2、发病率约0.4-5/10万，发病率男女性比，约1.4：1男性约1.7/10万、女性为1.2/10万全球：发病率和死亡率呈缓慢上升趋势 2009 US新发病20 580例、死亡病例10 580例EtiologyRadiationTherapeutic radiationOccupational exposureAgricultural occupations.Cosmetologists and hair dyes.Benzene and petroleum products.Engine exhaust.Other industrial exposures（Wood dust）Tobacco

3、exposureObesity, diet, and alcoholOther factors（years,Socioeconomic factors and race）Chronic immune stimulationFamilial multiple myelomaUS：SEER浆细胞骨髓瘤1873 The term multiple myeloma (MM) was coined 1927 Bone marrow aspiration1937 electrophoresis诊断标准一项主要标准加一项次要标准可以确诊如只有三项次要标准，必需同时包括第1、2条主要标准 骨髓中浆细胞30 组

4、织活检证实的浆细胞瘤 M-蛋白：血清电泳中出现单克隆免疫球蛋白峰， IgG35g/L或IgA20g/L或IgM15g/L IgD2.0g/L或IgE2.0g/L或 尿中Bence-Jones蛋白1g/24h。次要标准 10骨髓中浆细胞30 存在M-蛋白但低于上述标准 影像学证实存在骨髓瘤相关的溶骨性病变 正常免疫球蛋白成分定量低于正常（50%） IgG6g/L或IgA1g/L或IgM2mg/dLCa 11mg/dLWt loss (9 kg)% patients79Hb12g/dL73Bonepain6632131912Kyle RA. Mayo Clin Proc 2003;78:21-33

5、Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004NormalMonoclonal Protein免疫电泳免疫电泳或免疫固定：分型IgG 70%IgA 20%IgM 1%轻链M蛋白 5-10%轻度M蛋白峰+背景Ig抑制:IgD/IgE 1%非分泌型1%Biclonal or triclonal extremely rareidiotype switch rareFrom ASH 2008 education book ;299国际分期系统 分期标准比例中位生存期Durie-Salmon stage II

6、I比例I血清2-MG3.5mg/L同时ALB3.5g/dL29%62个月38%II非I期或III期38%44个月54%III血清2-MG3.5g/dL34%29个月70%国际分期系统 治疗原则国际工作组（International Working Group）推荐 无症状者 不需治疗症状性骨髓瘤 干细胞移植支持下高剂量Melphalan化疗 常规剂量化疗 国际工作组：骨髓瘤相关器官或组织损害标准CRAB Criteria项目诊断参数Hyper Calcemia高钙血症比正常上限高0.25 mmol/L或2.75 mmol/LRenal insufficiency 肾功不全Cr173 umol/

7、LAnemia贫血Hb低于正常下限20g/L以上或Hb100g/LBone lesions骨骼病变溶骨性病变或骨质疏松伴压缩型骨折（需MRI或CT评价）其它相关表现症状性高粘滞血症淀粉性病变复发性细菌性感染（2次/12个月）The broad arms of treatmentto control disease to maximise quality of life to prolong survival Current Treatment of MM1960s Conventional chemotherapy1980s Stem cell transplantation support

8、HDCT1990s supportive therapy1999 Targeted therapy常规化疗Melphalan since 1958MP regimen since 1962VAD regimen since 1980sHigh Dose-DXM since 1986Melphalan and Prednisone (MP)Conventional chemotherapy in use for over 40 yearsPR rate 50-60%CR rate 5% Median remission duration 18 mMedian Overall Survival 2

9、.53 yearsMyeloma Trialists Collaborative Group. J Clin Oncol. 1998;16:3832Myeloma Trialists Collaborative Group：MP standard of care27 RCT6633 ptsMP verse MP plus CTMPCCTPRR53.2%60% .000015YS24.4%23.0%0.66YS19.4%18%From J Clin Oncol 1998;16:3832Strategies to Improve Conventional ChemotherapyMelphalan

10、/Prednisone+LenalidomideBortezomibThalidomideororThalidomide：From Tragedy to Promise 1953 1956 1961 1965 1991 199419982000TodayThalidomide is synthesizedIntroduced in Germany as sedativeThalidomide withdrawnReport showingeffectivenessin patients with leprosyShown to inhibit TNF expressionAnti-angiog

11、enic properties shownFDA approves for ENLReports of effectiveness inMultiple myelomaStudyRegimen nCR+PR (%)CR%CR +VGPR(%)GIMEMA1MPT (T maintenance)MP12912676 4816416 4IFM 992MPT (72-wk Tx)MP (72-wk Tx)MEL10019112412176 35 6513218477IFM 013MPT (72-wk Tx)MP (72-wk Tx)113116623171238NMSG4MPT* (T mainte

12、nance)MP363 total422863237HOVON5MPT (T maintenance)MP152149634711299MP vs MPT: Response rates1. Palumbo et al. Blood 2008; Epub 2. Facon et al. Lancet 2007;370:12091218 3. Hulin et al. ASH 2007 (Abstract 75) 4. Gulbrandsen et al. EHA 2008 (Abstract 209)5.Wijermans EHA 2008 (Abstract 440)GIMEMABlood

13、08IFM 99-06Lancet 07IFM 01-01ASH 07NMSGEHA 08HOVONEHA 08PFS (med,mo.) MP MPT POS (med,mo.) MP MPT P14.522.00044745NS1827.5.00013351.5.00061924.00127.745.3.031416TTP Sig.3329NS913.0013037NSMP vs MPT: PFS and OSMPT vs MP:结论5/5项研究： MPT占优：RR、PFS and/or TTP2/5项研究：MPT生存期优于 MP 3/5项研究包括维持治疗未显示生存的获益MP vs MPT

14、 in NDMM：meta analysisMeta-analysis of 5 prospective RCTs(N = 1571)addition of thalidomide to MP improved response rates, PFS, and OSOR for PR with MP vs MPT: 0.307 (P .001), indicating MP worse than MPTHR for PFS: 1.59 (P .001) in favor of MPTHR for OS: 1.34 (P = .006) in favor of MPTKapoor P, et a

15、l. ASH 2009. Abstract 615.VISTAVMPCycles 14Bortezomib 1.3 mg/m2 IV d 1,4,8,11,22,25,29,32Melphalan 9 mg/m2 d1-4prednisone 60 mg/m2 d1-4Cycles 59Bortezomib 1.3 mg/m2 IV: d 1,8,22,29Melphalan 9 mg/m2 d1-4prednisone 60 mg/m2 d1-4MPMelphalan 9 mg/m2 d1-4prednisone 60 mg/m2 d1-4RANDOMIZE9 x 6-week cycles

16、 (54 weeks) in both armsPrimary end point: TTPSecondary end points: CR rate, ORR, time to response, DOR, time to next therapy (TNT), OS, QoL (PRO)San Miguel et al. N Engl J Med 2008;359:90617Results：responseVMP (n=344)MP (n=338)P valueCR/PR82%50%.0001CR35%5%.0001Median TTR1.4 M4.2 M.0001Median TTP16

17、.6M24M0.0000013-year rate72%59%0.0032San-Miguel ASH 2007 presentation; Lederman, ASH 2007 IMF Multiple Myeloma Highlights for Physicians Mateous et al. Haematologica 2008; 93(4), 560-565结 论VMP 延长生存期Rapid and durable responses with CR rate of 30%Prolonged TTP and OSVMP 血液学毒性，腹泻和外周神经毒性1. Anderson et a

18、l. Leukemia 2008;22:2319VMP联合ThaVMPT Vs VMP in Elderly NDMM RANDOMIZAT IONNO MAINTENANCEMAINTENANCEBortezomib 1.3 mg/m2 IV on Days 1, 15;Thalidomide 50 mg/day continuouslyVMP Bortezomib 1.3 mg/m2 IV d1, 8, 15, 22* Melphalan 9 mg/m2 d1-4 Prednisone 60 mg/m2 d1-4 VMPT Bortezomib 1.3 mg/m2 IV d1, 8, 15

19、, 22* Melphalan 9 mg/m2 d1-4 Prednisone 60 mg/m2 d1-4 Thalidomide 50 mg/d continuously*64 VMP pts and 71 VMPT pts were treated with twice-wkly bortezomib.9 x 5-wk cycles in both armsUntil relapseVMPT vs VMP: Results*For pts who received wkly bortezomib with VMPT and VMP.Due to peripheral neuropathy.

20、VMPT, % (n = 177)VMP, %(n = 177)P ValueCR3521 .0001PFS at 3 yrs7156.13OS at 3 yrs9089.81Grade 3-4 peripheral neuropathy*22-Discontinuation34-Palumbo A, et al. ASCO 2009. Abstract 8515. Lenalidomide Plus Dexamethasone in 1st therapy NDMMECOG-E4A03 Ld VS LD：LD方案的CR/PR高，但Ld的PFS、OS略占优SWOG-0232 Ld优于DXM单药

21、，提高CR/RR率以及TTPJA Zonder et al. Blood 2007;110(11)Abstract 77.Rajkumar SV et al. ASH; 2007Addition of Lenalidomide to MP in NDMM Pts (Phase III)Palumbo A, et al. ASH 2009. Abstract 613.Primary comparison: continuous therapy with MPR vs MPOpen-labelextension/follow-upphasePatients withrelapsed/refract

22、orymultiple myeloma(N = 459)Melphalan 0.18 mg/kg on Days 1-4 + Prednisone 2 mg/kg on Days 1-4 + Placebo on Days 1-21 (n = 154)Lenalidomide 25 mg QD +DexamethasoneDisease progressionDouble-blind treatment phaseMelphalan 0.18 mg/kg on Days 1-4 + Prednisone 2 mg/kg on Days 1-4 + Lenalidomide 10 mg QD P

23、O on Days 1-21 (n = 153)Lenalidomidediscontinued,placebo addedMelphalan 0.18 mg/kg on Days 1-4 + Prednisone 2 mg/kg on Days 1-4 + Lenalidomide 10 mg QD PO on Days 1-21 (n = 152)ContinuedlenalidomidetherapyCycles 1-9 (28-day cycles)Cycles 10 +Addition of Lenalidomide to MP in NDMM: ResultsAddition of

24、 lenalidomide to MP plus maintenance lenalidomide reduced risk of progression by 50% vs MP alonePalumbo A, et al. ASH 2009. Abstract 613.PFSMos0510152025300255075100Patients Without Event (%)HR: 0.49995% CI: 0.330-0.755Log rank: P .001Median follow-up: 9.4 mosMedian PFSNot reached13.0 mosMPR-RMPRegi

25、menORRCR VGPRPRMPR-R (n = 152), %77183245MPR (n = 153), %67133334MP (n = 154), %4951137P value .001 .001 .001-Thalidomide/DEX方案Thalidomide/DEXstudyregimenNRRTTP J Clin Oncol. 2008Rajkumar SV,et al. ECOG E1A00DEX/ThaDEX23523563%46% P0.00122.6M 6.5M P0.001Dex/ThaFDA May 26，2006EU Apr 21，2008 Thal-Dex

26、vs MP in Elderly NDMM (CEMSG Study)Thal 200-400 mg/d Dex 40 mg d1-4 and even d15-184-week cycle (n = 145)Patients with previously untreated MM(N = 289)Melphalan 0.25 mg/kg d1-4Prednisone 2.00 mg/kg d1-44- to 6-week cycle(n = 143)All patients received zoledronate 4 mg every 4 weeks*Odd cycle: treatme

27、nt on Days 1-4, 15-18; even cycle: treatment on Days 1-4.Ludwig H, et al. ASH 2007. Abstract 529.Thal-Dex vs MP: ResponseHigher RR with thal-dexCR/VGPR 48% vs 29%More rapid responseTime to response:6 vs 10 weeks (P .0001)Time to best response:16 vs 23 weeks (P .0002)Parameter, %TD(n = 145)MP(n = 143

28、)CR157nCR157VGPR1815PR2121MR1221SD418PD1510Ludwig H, et al. ASH 2007. Abstract 529.Thal-Dex vs MP : PFSLudwig H, et al. ASH 2007. Abstract 529.Rate Without ProgressionMonths05101520253035404550556065700.00.81.0Log rank test: P = .10MP: n = 141, 72 events;median: 20.7 monthsThal-Dex: n = 142

29、, 84 events;median: 16.7 monthsThal-Dex vs MP: OSLudwig H, et al. ASH 2007. Abstract 529.Log rank P = .024MP: n = 141, 47 events;median: 49.4 monthsThal-Dex: n = 142, 62 events; median: 41.5 months Median follow-up: 28.1 monthsSurvival (%)0.00.81.0Months0510152025303540455055606570Overall s

30、urvival：age结 论Thal/dex 方案TD方案的生存期短 (TD vs MP 41.5 vs 49.4M;P = .024)PFS相近 TD vs MP (16.7 vs 20.7M P = .10)不良反应： More grade 2-4 neuropathy, constipation, psychological events fewer grade 3/4 leukopenia and thrombocytopenia第1年死亡率高 (31 vs 17 deaths)Ludwig H, et al. ASH 2007. Abstract 529.干细胞移植支持下大剂量化疗H

31、igh dose chemotherapy since 1983Dose 100-200mg/m2ResponseMelphalan dose-response curveHDCT：1st reportedHigh dose Melphalan with ASCT standard of care in young ptsSuperior to CCTCR increased from 5 - 10% to 22 - 44%Remission extended from 18 to 30 monthsMST improvedHigh-dose therapy and autologous HS

32、CT are standard early treatment of patients with multiple myeloma. Tandem transplantation appears to provide additional benefit, particularly in patients with limited response to initial transplantation. Myeloablative allogeneic transplantation provides the only potential for cure, but has been larg

33、ely abandoned because of high mortality rates.解救治疗Thalidomide vs High-Dose Dex in Relapsed/Refractory Myeloma: OPTIMUM TrialN = 499 with progressive myeloma after 1-3 lines of therapyPrior thalidomide or lenalidomide not allowedRandomization to 1 of 3 thalidomide doses or dex 40 mg/day on Days 1-4,

34、9-12, and 17-20 of first four 28-day cycles then Days 1-4 of each cycle thereafterSignificant DOR benefit with all thalidomide doses vs dexNo OS benefitOutcomeThal 100 mg/dayThal 200 mg/dayThal 400 mg/dayDex 40 mg/dayORR (CR + PR), %20.718.021.524.6Median TTP, mos*6.01-yr OS, %80838280DOR,

35、mos12.7Kropff M, et al. ASH 2009. Abstract 959.*P = .017 vs dex.StudyRegimenN CR+PR (%)TTP（月）MST（月）MM-0091Len/DexDXM35159.4% 21.1%11.24.729.620.2APEX2Bortezomib HD- DXM 6996.23.529.823.7OPTIMUM3ThaDXM449NSDOR improvedNSNSSalvage therapy compared with DXM1. Weber et al. ASCO 2006, Abstract

36、 7521.2. Richardson et al. NEJM 20053 Kropff M, et al. ASH 2009. Abstract 959Molecular prognosisMolecular prognosisGood/average prognosis Hyperdiploidy t(11;14)(q32;q32): cyclin D1 upregulation t(6;14)(p25;q32)：cyclin D3 upregulationBad prognosis Hypodiploidy t(4;14)(p16.3;q32): FGFR3&MMSET upregula

37、tion t(14;16)(q32;q23): c-MAF upregulation Chromosome 1 abnormalities: 1q gains (overexpression CKS1B) 17q deletions, 13q deletions5004003002001000Time (d)Overall Survival0.000.250.751.000.50700600No t(4;14), no del(17p), low 2mOtherPatients 66 YearsT(4;14) or del(17p), and high 2mAvet-Loiseau H, et

38、 al, IMW 2007, Abstract S1.5.Genetics：IFM 99-02 studyCrCl 60 vs 60 mL/minSan Miguel et al. N Engl J Med 2008; 359:90617High-risk (t(4;14), t(14;16), del 17p) vs standard-risk cytogenetics by FISHTTPOSTime (months)Time (months)908070605040302010002468101214161820222426CrCI 60 mL/minCrCI 60 mL/minCrCI

39、 60 mL/min (N=159): 21.7 months (43 events)CrCI 60 mL/min (N=185): not reached (40 events)HR=0.666 (95% CI: 0.416, 1.066), p=0.09Subjects without event (%)Time (months)100908070605040302010002468101214161820222426Subjects without event (%)Time (months)1002830CrCI 60 mL/min (N=159): not reached (20 e

40、vents)CrCI 60 mL/min (N=185): not reached (25 events)HR=1.002 (95% CI: 0.516, 1.947), p=0.99CrCI 60 mL/minCrCI 60 mL/min1009080706050403020100024681012141618202224269080706050403020100024681012141618202224262830Subjects without event (%)Time (months)Subjects without event (%)Time (months)Standard ri

41、sk (N=142): 23.1 months (34 events)High risk (N=26): 19.8 months (7 events)HR=1.297 (95% CI: 0.55, 3.06), p=0.55Standard risk (N=142): not reached (16 events)High risk (N=26): not reached (3 events)HR=1.009 (95% CI: 0.278, 3.663), p=0.99Standard riskHigh riskStandard riskHigh risk100VMP in pts with

42、poor prognostic characteristicsManagement of Bone Disease in Multiple MyelomaMultiple Myeloma：Characteristic “punched-out” lesionsFour distinct forms of bone imagingThe solitary lesion (plasmacytoma)Diffuse skeletal involvement (myelomatosis)diffuse skeletal osteopenia（15%）Sclerosing myelomaCommon S

43、ites for Bone InvolvementSkull 40%Spine 66%NeckThoracicLumbarPelvis 30%Rib 45%Shoulders 40%Long bones 25%Spinal cord -compression can occur/Radio/topic460.htm#sectionIntroductionApproach to imaging in the management of myelomaPlain X radiographyCTMR imaging 99Technetium Bone scanPET、PET/CTInternatio

44、nal myeloma working group consensus statement and guidelines Conventional radiography still remains the gold standard of the staging procedure of newly diagnosed and relapsed myeloma patients. MRI gives information complementary to skeletal survey and is recommended in MM patients with normal conven

45、tional radiography and in all patients with an apparently solitary plasmacytoma of bone. Bone scintigraphy has no place in the routine staging of myelomaPET/CT or MIBI imaging are also not recommended for routine use in the management of myeloma patientsLeukemia. 2009 2010 ESMO guideEvaluation of ly

46、tic bone lesions. Full skeleton X-ray survey is recommended. Optional MRI provides greater details and is recommended if spinal cord compression is suspected.The skeletal survey postero-anterior (PA) view of the chestantero-posterior (AP) and lateral views of the cervical spine, thoracic spine, lumb

47、ar spine, humeri and femora,AP and lateral view of the skull and AP view of the pelvisother symptomatic areas should be specifically visualized with appropriate views Bone Cell Stimulation in MalignancyMultiple myelomaOsteolytic solid tumors including breast cancerOsteoclastsOsteoblastsMultiple myel

48、oma vs. bone metastasesEventMyelomabone metastasesInvolvement of intervertebral discs NoInvolvement of mandible NoInvolvement of vertebral pedicles NoAssociated paraspinal soft tissue mass NoIsotope bone scanFrequentlyNegativeFrequently positiveCancer Imaging (2004)Clinical Consequences of Cancer-In

49、duced Bone LesionsPathological fracturesNonvertebralVertebral compressionSpinal cord compression/collapseRadiation therapySurgery to boneHypercalcemiaBone pain Use of analgesics Quality-of-life effectsSurvivalSkeletal-related eventsPercentage of patients with each type of SRE (placebo group)EventBre

50、ast cancer24 monthsProstate cancer24 monthsMyeloma21 monthsLung cancer21 monthsTotal SREs68%49%51%48%Radiation to bone43%33%34%34%Pathologic fractures52%25%37%22%HCM13%1%9%4%Surgery to bone11%4%4%5%Spinal cord compression3%8%2%4%The oncologist 2004Treatment of bone disease SurgeryInterventional Radi

51、ologyRadiotherapyRadioisotopesMedicine bisphosphonatesSteroidsOpiates/NSAIDSAntitumor therapyDenosumab？Bisphosphonates Relative R1 R2 potencyEtidronateOH CH3 1ClodronateCl Cl 10PamidronateOH(CH2)2 NH2 100AlendronateOH(CH2)3 NH2 1000RisedronateHCH2 N 5000Ibandronate OH (CH2)2-N-(CH2)4-CH3 10,000 CH3

52、Zoledronic acidOHN N 100,000OHR1OHR2OHPCPOOHOInhibitors of bone lossPotency varies greatly depending upon R1 andR2 side chainsnon NN甲羟戊酸途径 双膦酸盐vs安慰剂Meta-analysis 2002观察项目 （研究数目）双膦酸盐对比安慰剂 (病例数) OR（95可信区间）p值死亡事件 (10) 1,079 vs 1,048 0.99 (0.88 to 1.12) 0.9椎体骨折 (7) 575 vs 541 0.59 (0.45 to 0.78) 0.0001非

53、椎体骨折 (6) 708 vs 681 1.05 (0.77 to 1.44) 0.7高钙血症 (8) 1,044 vs 1,002 0.76 (0.56 to 1.03) 0.07疼痛(8) 657 vs 624 0.59 (0.46 to 0.76) 0.00005胃肠道反应 (6) 853 vs 836 1.28 (0.95 to 1.74) 0.11Meta analysis：Efficacy of Clodronate, Pamidronate, and ZoledronateReduction in All Skeletal-Related EventsReduction in P

54、athologic FracturesReduction in Radiation to Bone or Bone SurgeryReduction in HypercalcemiaNone of the bisphosphonates was associated with a reduction in overall mortalityno clear advantage of one drug over the others was observedClinical Therapeutics/2009Approved Indications for Different Bisphosph

55、onatesIndicationHCMBreast CancerMultipleMyelomaProstateCancerOther SolidTumorsClodronate？PamidronateZoledronic acidIbandronate = European registration = Global registrationASCO 2007 Clinical Practice Guideline Update on the Role of Bisphosphonates in Multiple Myeloma对X平片或其它影像显示溶骨性破坏或脊髓压迫者 推荐 帕米膦酸钠 90mg（over 2 hours） 唑莱膦酸 4mg（over 15 min） 每3-4周一次唑莱膦酸发生下颌骨坏死的危险性为帕米膦酸9.5倍氯屈膦酸作为替代选择，可口服或静脉使用轻重度肾功不全者（ccr 30-60ml/min)，唑莱膦酸需减量