初診多發(fā)性骨髓瘤治療進展

1、NDMM治療 楊永公,內(nèi)容提要,診斷（略）治療指征治療原則常用方案選擇特殊人群治療,治療指征—有癥狀MM,無癥狀MM 1)骨髓漿細胞≥ 60%。 2)血或尿輕鏈（ K和λ）比值≥ 100。 3）MR或Pet-CT顯示有一處骨質(zhì)破壞。有癥狀MM 1) CRAB 2)高粘度血癥、淀粉樣變性、反復(fù)感染（2008WHO),治療原則,有治療指征的MM患者應(yīng)早系統(tǒng)治療，包括誘導(dǎo)、鞏固治療（含造血干細胞

2、移植）以及維持治療。達到MR以上療效時可用原方案繼續(xù)治療，直到獲得最大程度的緩解，不建議在治療有效的病人變更治療方案；未達到MR患者應(yīng)變更治療方案。適合自體干細胞移植者，應(yīng)盡量用新藥誘導(dǎo)治療+造血干細胞移植。避免使用烷化劑和亞硝基脲類藥物。 適合臨床試驗者，應(yīng)考慮進入臨床試驗。,指南推薦,治療方案,,,,,,Use of DCEP as consolidation therapy after primary therapy di

3、d not have a significant impact on response rates,The incidence of severe adverse events reported was similar between the two groups.,Bortezomib/Doxorubicin/Dexamethasone,A benefit in terms of increased PFS was also obs

4、erved in patients with deletion of 17p13.,The rate of grade 2 to 4 peripheral neuropathy was higher in those treated with the bortezomib-containing regimen versus VAD (40% vs. 18%).,Bortezomib/Thalidomide/Dexamethasone,C

5、yclophosphamide/Bortezomib/Dexamethasone,Three phase II studies involving newly diagnosed patients with MM (n = 495) have demonstrated high response rates with CyBorD as primary treatment Reeder et al demonstrated an O

6、RR of 88% including a VGPR or greater of 61% and 39% CR/near CR with CyBorD as the primary regimen.,Cyclophosphamide/Bortezomib/Dexamethasone,German DSMM XIa study also demonstrated high responses with CyBorD as prima

7、ry treatment (ORR was 84%; with 74% PR rate and 10% CR rate). High response rates were seen in patientswith unfavorable cytogenetics。 EVOLUTION study, primary treatment with CyBorD demonstrated ORR of 75% (22% CR and 41

8、%≥VGPR), and one-year PFS rate was 93%.,,,Bortezomib,Bortezomib-based regimens may be of value in patients with renal failure, and in those with certain adverse cytogenetic features. Bortezomib treatment has been asso

9、ciated with an increased incidence of herpes zoster.peripheral neuropathy and gastrointestinal disturbance can be higher.,once-weekly schedule of bortezomib.,Reeder et al modified the regimen to a once-weekly schedule

10、of bortezomib. In the study, patients treated with weekly bortezomib achieved responses similar to the twice-weekly schedule (ORR 93% vs.88%, VGPR 60% vs. 61%). In addition, they experienced less grade ¾ adverse e

11、vents (37%/3% vs. 48%/12%),Lenalidomide/Dexamethasone,SWOG compared dexamethasone single agent with dexamethasone plus lenalidomide for patients newly diagnosed with MM.The lenalidomide plus dexamethasone arm showed imp

12、roved CR rate compared to dexamethasone alone(22.1% vs. 3.8%),Lenalidomide/Dexamethasone,In an open-label trial, 445 newly diagnosed patients with MM were randomly assigned to high-dose or low-dose regimens. The respons

13、e was superior with high-dose dexamethasone（79% VS 68%）However, the high response rates did not result in superior TTP, PFS, or OS.At 1-year interim analysis, OS was 96% in the low-dose dexamethasone group compared wit

14、h 87% in the high-dose group (P = .0002); 2-year OS was 87% versus 75%,Lenalidomide/Dexamethasone,52% patients on the high-dose regimen compared with 35% on the low-dose regimen had grade 3 or worse toxic effects in the

15、first 4 months, including DVT (26% vs. 12%); infections including pneumonia (16 vs. 9%); and fatigue (15% vs. 9%). The 3-year OS of patients who received four cycles of primary treatment with either dose followed by aut

16、ologous SCT was 92%,,Lenalidomide/Dexamethasone,A retrospective analysis of 411 newly diagnosed patients treated with either the lenalidomide and dexamethasone regimen (n = 228) or the thalidomide and dexamethasone regim

17、en (n = 183) was performed at the Mayo Clinic PR in RD 80.3% versus 61.2% with TD; VGPR rates were 34.2% and 12.0%, respectively. Patients receiving RD had longer TTP(median, 27.4 vs. 17.2 months; P = .019), longer PFS

18、(median, 26.7 vs. 17.1 months; P = .036), and better OS (median not reached vs. 57.2 months; P = .018),Lenalidomide/Dexamethasone,Grade 3 or 4 adverse events (57.5% vs. 54.6%, P = .568) were seen in a similar proportion

19、of patients in both groups Grade 3 or 4 toxicities of RD were hematologic, mainly neutropenia (14.6% vs. 0.6%, P < .001); the most common toxicities in TD were VTE (15.3% vs. 9.2%, P = .058) and peripheral neuropathy

20、 (10.4% vs. 0.9%, P < .001). Based on the results of this meta-analysis RD seems well-tolerated and more effective than TD,Bortezomib/Lenalidomide/Dexamethasone,Phase I/II study results have shown that primary therap

21、y with BRD is active and well tolerated in NDMMResponse rate is 100% with 74% VGPR or better and 52% CR/near CR.IFM 2008 trial, the ORR after primary treatment was 97% (13% sCR; 16% CR; and 54% ≥ VGPR),Bortezomib/Lenal

22、idomide/Dexamethasone,EVOLUTION trial evaluated VDC, VDR, and VDCR in previously untreated multiple myeloma (MM).(all arms) ≥ very good partial response was seen in 58%, 51%, 41%, and 53% (complete response rate of 25%,

23、 24%, 22%, and 47%) of patients (VDCR, VDR, VCD, and VCD-mod, respectively)No substantial advantage was noted with VDCR over the 3-drug combinations,其它方案,Thalidomide/DexamethasoneSingle-Agent Dexamethasone： selected gr

24、oup of patients (renal failure, hypercalcemia, cord compromise requiring radiation therapy,cytopenia)DVDCTP,部分2期及3期臨床試驗結(jié)果,,,Larocca et al. ASH 2013 (Abstract 687), oral presentation,Frailty score,數(shù)據(jù)來源于3個前瞻性多中心研究，869 例年

25、齡≥65歲或因存在合并癥不合適移植的初治MM患者， 中位年齡74歲（44%≥75歲），治療包括以硼替佐米為基礎(chǔ)的聯(lián)合方案、以來那度胺為基礎(chǔ)的聯(lián)合方案、以卡菲佐米 為基礎(chǔ)的聯(lián)合方案。,國外經(jīng)驗,Adapted from: Palumbo et al. N Engl J Med 2011;364(11):1046-60,,Larocca et al. ASH 2013 (Abstract 687), oral presentation,

26、,,,UPFRONT 研究：VD vs VTD vs VMP,初治不適合移植的骨髓瘤患者隨機入3個試驗組入選患者疾病標(biāo)準(zhǔn): 癥狀性骨髓瘤, 可測量病變,1°RANDOMIZATION,VD8 *21-day coursesV 1.3 mg/m2, d 1, 4, 8, 11; D 20 mg, d 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]),

27、 d 1, 2, 4, 5 [cycles 5–8],VTD8* 21-day courses V as before; T 100 mg/day, d 1–21; D as before,VMP8 21-day coursesV as before;M 9 mg/m2 ; d 1–4 every other cycleP 60 mg/m2, d 1–4 every other cycle,MAINTE

28、NANCEfive 35-day cyclesweekly V1.6 mg/m2, d 1, 8, 15, 22.,,,,,,,,,,,,The primary endpoint:PFS,Ruben Niesvizky, et al.Blood 2013 122:1966,ORR:VD 73% VTD 80% VMP70%CR/nCR 率：VTD(40%)略高于 VMP(32%)/VD(30%)VTD (PN) 的毒性大于V

29、MPPFS和OS：3組無差異,Considering efficacy and safety, VMP better than VTD for elderly MM patients,Nesvzky R ASH 2013 Abstract 1966,UPFRONT研究:結(jié)果,OS,VD14.7個月VTD15.4個月VMP 17.3個月 (VMP),VD49.8個月VTD51.5個月 VMP 53.1個月 (VMP),33,分

30、組：年齡 (≤ 75歲 vs > 75歲)、國家和ISS分期(I或II vs III)強制抗血栓處理,FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; ISS, International Staging System; LEN, lenalidomide; LoDEX, low-dose dexam

31、ethasone; LT, long-term; MEL, melphalan; MM, multiple myeloma; MPT, melphalan, prednisone, thalidomide; OS, overall survival; PD, progressive disease; PFS, progression-free survival; Pred, prednisone; pt, patient; Rd, le

32、nalidomide plus low-dose dexamethasone; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles; THAL, thalidomide; Tx, treatment.Benboubker L, et al. N Engl J Med. 2014;371:906-917.,FIRST/MM020研究: 研究設(shè)計,aComplete

33、cytogenetics profile for 762 pts (248 in continuous Rd, 261 in Rd18, and 253 in MPT); high-risk defined as t(4;14), t(14;16), or del(17p).CrCl, creatinine clearance; ECOG PS, Eastern Cooperative Oncology Group perform

34、ance status; FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; ISS, International Staging System; MPT, melphalan, prednisone, thalidomide; pt, patient; Rd, lenalidomide plus low-d

35、ose dexamethasone; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles.,Patient characteristics were well balanced across all treatment arms,34,FIRST研究：患者基線特征,Benboubker L, et al. N Engl J Med. 2014;371:906-917.

36、,Patients (%),72 wks,Rd (n= 535),25.5 mos,20.7 mos21.2 mos,RdRd18MPT,535541547,400391380,319319304,265265244,218167170,168108116,1055658,553028,1976,221,000,Rd18 (n= 541)MPT (n= 547)Hazar

37、d ratioRd vs. MPT: 0.72; P = 0.0006Rd vs. Rd18: 0.70; P = 0.0001,Time (months),FIRST 研究: PFS 100Median PFS,8060,Rd18 vs. MPT: 1.03; P = 0.7034940200,0,6,12,18,24,30,36,42

38、,48,54,60,Facon et al. ASH 2013 (Abstract 2), oral presentation,內(nèi)部資料，僅供醫(yī)學(xué)藥學(xué)專業(yè)人士參考，嚴禁翻印及傳播,,AMT, antimyeloma therapy; FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; MPT, melphala

39、n, prednisone, thalidomide; Rd, lenalidomide plus low-dose dexamethasone; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles; TTP, time to progression.,36,FIRST研究中期數(shù)據(jù)：中位隨訪37個月TTP和至第二次抗骨髓瘤治療（AMT）的時間,Benboubker

40、L, et al. N Engl J Med. 2014;371:906-917.,,FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; ITT, intent to treat; MPT, melphalan, prednisone, thalidomide; OS, overall survival; Rd

41、, lenalidomide plus low-dose dexamethasone; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles.,37,FIRST研究中期數(shù)據(jù)：中位隨訪37個月，總生存率（OS）,Benboubker L, et al. N Engl J Med. 2014;371:906-917.,Median follow-up 37 months,

42、FIRST研究：中位隨訪45.5個月，Rd持續(xù)和Rd18 vs MPT組顯示出顯著的OS和PFS2優(yōu)勢,,PFS2, time from diagnosis to second disease progression or death,Revlimid(lenalidomide). Summary of Product Characteristics. Celgene Europe Limited. Uxbridge, UK..

43、 February 2015.,FIRST研究：中位隨訪37個月和45.5個月結(jié)果比較,1. Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371:906-17 2. Revlimid

44、(lenalidomide). Summary of Product Characteristics. Celgene Europe Limited. Uxbridge, UK.. February 2015.,40,a Grade 3-4 AEs related to study medication were less frequent with Rd (70%) and Rd18 (60%) vs MPT (78%).b Diar

45、rhea occurred in 21 (4%), 18 (3%), and 8 (2%) of patients treated with Rd, Rd18, and MPT, respectively.AE, adverse event; DVT, deep vein thrombosis; FIRST, Frontline Investigation of Revlimid and Dexamethasone versus S

46、tandard Thalidomide; MPT, melphalan, prednisone, thalidomide; PE, pulmonary embolism; Rd, lenalidomide plus low-dose dexamethasone; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles.Benboubker L, et al. N E

47、ngl J Med. 2014;371:906-917.,FIRST研究：安全性,,NDMM方案,BD(硼替佐米+地塞米松)    PAD (硼替佐米+阿霉素+地塞米松) BCD（硼替佐米+ CTX+地塞米松    BTD(硼替佐米+沙利度胺+地塞米松)  BRD(硼替佐米+來那度胺+地塞米松),NDMM方案,經(jīng)濟情況特佳——VRD經(jīng)濟情況好或一

48、般——VTD,VCD,PAD經(jīng)濟情況一般或差——TCD,TCP,特殊患者NDMM方案,年齡＞80歲——Ｒd or BzP腎損害——硼替佐米為主的方案（來那度胺或沙利度胺也可）BD,BTD,BRD近期發(fā)生血栓事件——硼替佐米為主的方案（在抗凝情況下來那度胺或沙利度胺也可）外周神經(jīng)病變——Len-dex一般情況差的患者——Len-dex，單用dex不愿意住院的患者——Len-dex,TD,CTP遺傳學(xué)預(yù)后不良——？含硼替佐米