多发性骨髓瘤诊断与治疗进展第二军医大学长征医院课件

多发性骨髓瘤诊断与治疗进展 第二军医大学长征医院 侯 健 EBMT/ABMTR/IBMTR关于MM的 疗效标准的修订（Blade 标准） 完全缓解（CR）需要达到以下全部几点： 1.免疫固定电泳检查血、尿M蛋白阴性，持续 6周 2.骨髓穿刺标本中浆细胞1.5 mg/dl，或2.8 mmol/L）。 没有达到CR的患者疾病进展的标准需至少达到 以下条件之一： 1.血清M蛋白增加25%，同时增加的绝对值必 须5g/L，至少一次重复检查确认 2.24小时尿轻链定量增加25%，同时增加的 绝对值必须大于200mg/24h，至少一次重复 检查确认 3.骨髓穿刺或骨髓活检标本中浆细胞数增加 25%，同时增加的绝对值必须大于10% 4.原有的溶骨损害或软组织浆细胞瘤体 积较前增大。 5.出现新的溶骨病变或软组织浆细胞瘤 ，（出现压缩性骨折不除外，也不作 为疾病进展的指标）。 6.出现其他原因不能解释的高钙血症（ 校正后的血清钙1.5mg/dl，或2.8 mmol/L） 关于Blad标准的思考 nCR或nCR是否意味着治愈或接近治愈 n5%浆细胞是多克隆还是单克隆 nASO-PCR nFCM n免疫组化 nFLC nFCM或ASO-PCR检测MRD阳性者其生存期远 远短于MRD阴性者 关于Blad标准的思考 n对于不分泌型、少分泌型骨髓瘤或者 M蛋白起始水平较低但治疗后复发的 患者，如何评估？如尿轻链 100MG/24H nFLC Light Chain Disease nPatients with light chain disease may not have a detectable protein on serum or urine electrophoresis Collect 24-hour urine samples for light chain quantitation nSome patients have “non- secretory disease” nDifficult to determine benefits of therapy Falk, RH et al. N. Engl. J. Med. 337:898-909, 1996. 1 Serum Free Light Chains nNew tests can more accurately measure free serum light chains (FLC) nCorrectly identified 224/224 patients with light chain disease n23/28 patients with “non-secretory” disease had abnormal values Adapted from http:/www.bindingsite.co.uk/freelite.asp. Bradwell, AR et al. Lancet 361:489-491, 2003. Drayson, M et al. Blood 97:2900-2902, 2001. Katzmann et al Clin Chem 2002 Following Free Light Chains nSerum FLCs drop in response to therapy nFLCs rise with disease progression Drayson, M et al. Blood 97:2900-2902, 2001. 1 Prognostic Value of FLCs ? nHalf-life is 2-6 hours, versus 20 days for IgG More rapid decline with successful treatment? nStudy of Actimid in relapsed/refractory myeloma A 50% drop in FLC ratio at day 7 predicted response or stable disease nMay also predict relapse after CR nIn 107 patients, 6/20 (30%) with an abnormal / ratio relapsed, vs. 9/87 (10%) of those with a normal value Patten, PE et al. Blood 102:449a, Abstract 1640, 2003. Sirohi, B et al. Blood 102:367b, Abstract 5195, 2003. 1 2 Combination therapies in relapsed or refractory multiple myeloma, and early use of bortezomib in elderly patients Jess San Miguel Background nSUMMIT bortezomib has notable activity in heavily pretreated patients FDA approval (May 2003) EMEA approval (June 2004) nCREST suggests a potential dose-response relationship May be less toxicities at lower dose Requires further exploration nAPEX demonstrated significant statistical improvement in time to progression for bortezomib vs high-dose dexamethasone control Largest randomized, myeloma trial ( 600 pts enrolled) Successful US/EU collaboration 万珂Velcade单药的II/III期临床资料 （在复发难治病人的疗效） Lonial Next steps nPatients with refractory disease: combination therapy* Cytotoxic agents Novel agents nFront-line therapy Pre- and post-transplant Elderly patients (MPV) nDifferent schedules and dosing regimens *Synergistic effect Synergistic effect of Synergistic effect of bortezomibbortezomib and and doxorubicin doxorubicin in doxorubicin-resistant in doxorubicin-resistant cell linescell lines Doxorubicin-resistant cell lines Doxorubicin-resistant cell lines can be induced to undergo can be induced to undergo apoptosis at a PS341 apoptosis at a PS341 concentration that is not toxic concentration that is not toxic to cells by itselfto cells by itself Mitsiades et al. Blood 2003;101:237780 Bortezomib combinations in refractory MM nBortezomib + pegylated liposomal doxorubicin1 nBortezomib + melphalan2 nBortezomib + thalidomide3 nBortezomib + thalidomide + liposomal doxorubicin4 nBortezomib + thalidomide + doxorubicin + dex5 1Orlowski et al. Blood 2005;105:3058-65. 2Berenson et al. Blood 2004;104:64a(abstract 209); 3Zangari et al. Blood 2003;102:236a(abstract 830); 4Chanan-Khan et al. Blood 2004;104:665a(abstract 2421); 5Hollmig et al. Blood 2004;104:659a(abstract 2399); Bortezomib in combination with melphalan in the treatment of relapsed or refractory MM: a phase I/II study James Berenson, Yang H, Swift R, Sadler K, Vescio R, Adams J, Schenkein D Oncology, Institute for Myeloma and Bone Cancer Research, CA, USA; Oncology, Oncotherapeutics, CA, USA; Cedars-Sinai Medical Center, CA, USA; Infinity Pharmaceuticals,Inc., MA, USA; Millennium Pharmaceuticals,Inc., MA, USA Cell lines and fresh MM cells: synergistic Cell lines and fresh MM cells: synergistic effect between effect between melphalanmelphalan and and bortezomibbortezomib Ma MH Clinic Cancer Res 2003 9:113644*At suboptimal concentration Bortezomib + melphalan: dosing schedule nMelphalan 0.0250.25 mg/kg orally days 1 4 nBortezomib 0.7 or 1.0 mg/m2 IV push, days 1, 4, 8 and 11 nRepeat every 4 weeks nMaximum of 8 cycles nExtension protocol for responding patients after 8 cycles Berenson et al. ASH 2004;104:64a(abstract 209) Bortezomib + melphalan: results n68% (19 of 28) patients responded; 43% CR + PR 7 % CR + 36% PR + 25% minor response (MR)7 % CR + 36% PR + 25% minor response (MR) Responses seen at all dose levels: Current dose 1.0 mg/m2 nResponses seen in patients who relapsed after bortezomib or melphalan nMedian TTP: 8 months nToxicities manageable, with grade 3/4 being hematologic : - - Grade 3 mostly due to myelosuppression (anemia in 3, thrombocytopenia in 4, neutropenia in 5 patients) and occurred in pts with baseline cytopenias. - Neuropathy in 2 patients Berenson et al. ASH 2004;104:64a(abstract 209) Bortezomib + thalidomide in advanced myeloma a phase I study Maurizio Maurizio ZangariZangari, Bart , Bart BarlogieBarlogie, , JeniferJenifer Prather, Jason McCoy, Prather, Jason McCoy, Paul Paul EddlemonEddlemon, Elias , Elias AnaissieAnaissie, , ChoonChoon- -KeeKee Lee, Guido Tricot, Lee, Guido Tricot, Raymond Raymond ThertulienThertulien, Frits van , Frits van RheeRhee Zangari M et al. Blood 2003;102:236a(abstract 830) Bortezomib + thalidomide in advanced myeloma a phase I study nBortezomib: Twice weekly iv push x 2 weeks followed by 10-day rest; administered on D1, 4, 8, 11 Arm 1: 1.0 mg/m2 IV push Arm 2: 1.3 mg/m2 IV push nThalidomide added at cycle 2 Arm 1: cohort 1: 50mg; cohort 2: 100mg; cohort 3: 150mg; cohort 4: 200mg Arm 2: cohort 5: 50mg; cohort 6: 100mg; cohort 7: 150mg; cohort 8: 200mg n Dexamethasone permitted if suboptimal response after 3 cycles 40mg PO with each bortezomib dose Zangari M et al. Blood 2003;102:236a(abstract 830) Bortezomib + thalidomide: patient characteristics 59%59% B B 2 2 M M 4mg/L4mg/L 97% 97% Prior Prior autotransplantautotransplant 78%78% Prior thalidomide Prior thalidomide 77%77% Prior Rx 5 lines Prior Rx 5 lines 52%52%del 13del 13 76%76% Abnormal Abnormal cytogeneticscytogenetics n n = 56 = 56 0%0% 10%10% 20%20% 30%30% 40%40% 50%50% 60%60% 70%70% 80%80% 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 Treatment cycleTreatment cycle Responding (%)Responding (%) 25%25% 50%50% 75%75% 90%90% 99%99% 100%100% Bortezomib + thalidomide for post-transplant relapse: results After 2 cycles, 55% ORR;After 2 cycles, 55% ORR; After 8 cycles, 22% CR OS: 21 m. Zangari M et al. Blood 2003;102:236a(abstract 830) Grade 1Grade 1 Grade 2Grade 2 Grade 3Grade 3 Grade 4Grade 4 Interim results: safety Results through 1.3 mg/m2/50 mg dose level ConstipationConstipation InsomniaInsomnia HeadacheHeadache AnorexiaAnorexia VomitingVomiting NeuropathyNeuropathy 1010202030304040505060607070 ArthralgiaArthralgia FeverFever NauseaNausea DiarrheaDiarrhea FatigueFatigue EventsEvents Zangari M et al. Blood 2003;102:236a(abstract 830) Summary and conclusions nResponse: remarkably high ( PR 75% with 20% nCR) nResponse apparent within 2 cycles nResponse is independent of CA13 nLack of synergistic toxicity with bortezomib + thalidomide up to 150 mg regarding Myelosuppression Neuropathy Zangari M et al. Blood 2003;102:236a(abstract 830) Bortezomib + doxorubicin hydrochloride + thalidomide + dexamethasone (VATD) is an effective regimen in patients with refractory or relapsed MM Klaus Hollmig, Julie Stover, Giampaolo Talamo, Athanasios Fassas, Choon-Kee Lee, Elias Anaissie, Guido Tricot, Bart Barlogie Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA Hollmig et al. Blood 2004;104:659a(abstract 2399) VATD: treatment nBortezomib 1.0 or 1.3 mg/m2 days 1, 4, 8, and 11 nDoxorubicin 2.5 to 5 mg/m2/day, continuous infusion days 1 4 and 912 nThalidomide 50 or 100 mg/day days 112 nDexamethasone 20 or 40 mg/day days 1 4 and 912 Hollmig et al. Blood 2004;104:659a(abstract 2399) VATD: results n20 patients evaluable for toxicity, 16 evaluable for response (prior resistance: 90% to bortezomib, 60% to thalidomide combinations VT, VTD, DT-PACE) n12% CR, 12% nCR, 31% PR nAt 11 months median follow-up, 13 patients are alive, 6 of whom were previously resistant to VTD (possible synergy with anthracyclines) n60% grade 3 thrombocytopenia Hollmig et al. Blood 2004;104:659a(abstract 2399) nCombination regimens achieve higher response rates than single-agent bortezomib nCombinations overcome resistance to bortezomib nOutstanding issues Optimal combinations Dose levels and scheduling Summary of combination data in relapsed or refractory MM CR+PR Combination regimen 45 65% SUMMIT-APEX27-38% Next steps *Synergistic effect nPatients with refractory disease: combination therapy* Cytotoxic agents Novel agents nFront-line therapy -Pre- and post-transplant -MPV in elderly patients nDifferent schedules and dosing regimens A phase I/II study of bortezomib + melphalan and prednisone in elderly untreated patients with MM M. V. Mateos,1 J. Blad,1 J. Diaz Mediavilla,1 J. J. Lahuerta,1 M. J. Terol,1 J. Hernndez,1 M. J. Moro1, J. Bargay,1 J. M. Ribera,1 J. De Larubia,1 A. Sureda,1 D. Carrera,1 F. de Arriba,1 L. Palomera,1 M. Hernndez,1 J. Garca Laraa,1 A. Alegre,1 F. Prper,1 P. Rivas,1 D. L. Esseltine,2 D. Schenkein,2 J. F. San Miguel1 1Hematology, Grupo Espaol de MM (GEM/PETHEMA), Spain 2Millennium Pharmaceuticals, Inc., Cambridge, MA, United States Mateos et al. Blood 2004;104:943a(abstract 3462) V-MP: background and rationale nMelphalan and prednisone combination Gold standard of treatment for elderly patients with MM Response rate: 5060% (CR rare), progression-free survival (PFS): 18 months, overall survival (OS): 3 years nBortezomib Significant activity as monotherapy in patients with relapsed, refractory myeloma1,2 In vitro synergy in combination with cytotoxic agents such as melphalan3,4 Activity in combination with melphalan using reduced doses of each agent in patients with relapsed or refractory MM5 1Richardson et al. N Engl J Med 2003;348:260917 2Jagannath et al. Br J Hematol 2004;127:16572 3Ma et al. Clin Cancer Res 2003;9:113644 4Mitsiades et al. Blood 2003;101:237780 5Berenson et al. Hematol J 2004:5(Suppl 2):S130 Bortezomib+melphalan+dexamethasone DEXA+PS341+MELP 0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1 CONTROL DEXA MELP PS341 MELP+PS341 MTT uptake (A570) DEXAMETHASONE 100 nM MELPHALAN 1 mM BortezomibBortezomib (PS341) 2 nM V-MP: objectives nPrimary Define the appropriate dose of bortezomib in combination with conventional melphalan and prednisone Determine the efficacy of this regimen (response rate) nSecondary Assess potential superiority of this regimen vs historical controls with melphalan and prednisone alone Evaluate efficacy in terms of PFS and OS Assess safety and tolerability V-MP: major eligibility criteria nInclusion Symptomatic MM with measurable disease Age 65 years No previous chemotherapy for MM Platelet count 100 x 109/L, hemoglobin 8 g/dL, absolute neutrophil count (ANC) 1.0 x 109/L Corrected serum calcium 14 mg/dL Serum creatinine 2 mg/dL nExclusion grade 2 PN, HIV positivity, hepatitis B surface antigen positivity, active hepatitis C infection, New York Heart Association Class III or IV heart failure, uncontrolled angina Day 1 2 3 4 8 11 22 25 29 32 3342 V-MP: treatment schedule Day 1 2 3 4 8 15 22 2335 Bortezomib Melphalan 9 mg/m2 Prednisone 60 mg/m2 Four 6-week cycles Four 6-week cycles Five 5-week cycles Five 5-week cycles Bortezomib Melphalan 9 mg/m2 Prednisone 60 mg/m2 Rest period Rest period Total = 49 weeks of treatment Total = 49 weeks of treatment V-MP : Results nPhase I: 12 patients have been enrolled and all data have been reviewed nPhase II: 42 patients have been enrolled n35 out of the 54 enrolled patients have just completed the first cycle and are evaluable for efficacy 54 out of the 60 planned patients have been enrolled V-MP: Toxicities (Phase I ) nNo DLT as defined in the protocol * nOther non-DLT Grade 34 toxicity Two patients with grade 3 neutropenia (ANC 0.6 109/L) One patient: grade 3 thrombocytopenia (28 109/L) at day 32 One serious adverse event : pulmonary embolism, probable septic shock with death at day 11 nOther non-DLT Grade 12 toxicities Most common: nausea, constipation, diarrhea, fever, zoster infection, anorexia, peripheral neuropathy, neutropenia, anemia, thrombocytopenia. Grade 2 ocular neuropathic pain *Dose limiting toxicity (DLT): treatment-related grade 3-4 nonhematologic or grade 4 hematologic toxicity during the first 6-week cycle V-MP: Response Rates (N=35) MP (x6) : ORR 41% (3% MP (x6) : ORR 41% (3% nCRnCR, 38% PR) Hernandez, Br J H, 2004, 38% PR) Hernandez, Br J H, 2004 After 1st cycle 69% 0%3% 66% 14% 17% Best MC response 91.5% 23% 8.5% 60% 3% 5.5% V-MP: Comparative Safety Data (%) 46 51 48 24 37 13 36 24 33 27 42 24 V-MP 12 14 30 10 13 8 10 APEX 9723Anemia 31Neutropenia 302913Thrombocytopenia 141123PN 11Infection -Rash/pruritis 18246Asthenia 3-41Anorexia 2-40Constipation 7543Diarrhea 6-58Nausea 7-29Vomiting SUMMITV-MPSUMMIT/CREST GRADE 3GRADE 1-2 V-MP: Reduction of Dose Due to AEs Safety Population (N=54) n8 patients: Reduction of Velcade dose due to peripheral neuropathy 3 pts : reduction at 1 mg/m2 for: neuropatic pain grade 2 5 pts : reduction at 0.7 mg/m2 for: neuropathic pain grade 2 plus peripheral sensory neuropathy grade 1 in 3 pts and peripheral sensory neuropathy grade 3 in 2 pts n2 patients: Reduction of Velcade dose due to diarrhea 2 pts : diarrhea grade 3 at 1.0 mg/m2 n3 patients: Discontinuation of Velcade due to peripheral neuropathy 2 pts after 1 cycle due to neuropathic pain grade 3 and peripheral sensory neuropathy grade 3, and 1 pt after 2 cycles due to peripheral neuropathy grade 4 V-MP: conclusions nThe combination of bortezomib with Melphalan- Prednisone induces a high reponse rate in de novo elderly MM patients (ORR: 91% with 31% CR/nCR) nToxicities are manageable: most grade 3/4 side effects are hematological (neutropenia, thrombocytopenia) or peripheral neuropathy VISTA: a large randomized international trial of Velcade -MP vs