1、NDMM治疗 杨永公,内容提要,诊断（略）治疗指征治疗原则常用方案选择特殊人群治疗,治疗指征有症状MM,无症状MM 1)骨髓浆细胞 60%。 2)血或尿轻链（ K和）比值 100。 3）MR或Pet-CT显示有一处骨质破坏。有症状MM 1) CRAB 2)高粘度血症、淀粉样变性、反复感染（2008WHO),治疗原则,有治疗指征的MM患者应早系统治疗，包括诱导、巩固治疗（含造血干细胞移植）以及维持治疗。达到MR以上疗效时可用原方案继续治疗，直到获得最大程度的缓解，不建议在治疗有效的病人变更治疗方案；未达到MR患者应变更治疗方案。适合自体干细胞移植者，应尽量用新药诱导治疗+造血干细胞移植。避免使用
2、烷化剂和亚硝基脲类药物。 适合临床试验者，应考虑进入临床试验。,指南推荐,治疗方案,Use of DCEP as consolidation therapy after primary therapy did 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 incr
3、eased PFS was also observed 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,Cyclophosphamide/Bortezomib/Dexamethasone,Three phase II st
4、udies involving newly diagnosed patients with MM (n = 495) have demonstrated high response rates with CyBorD as primary treatment Reeder et al demonstrated an ORR of 88% including a VGPR or greater of 61% and 39% CR/near CR with CyBorD as the primary regimen.,Cyclophosphamide/Bortezomib/Dexamethason
5、e,German DSMM XIa study also demonstrated high responses with CyBorD as primary 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%VGP
6、R), 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 associated with an increased incidence of herpes zoster.peripheral neuropathy and gastrointest
7、inal disturbance can be higher.,once-weekly schedule of bortezomib.,Reeder et al modified the regimen to a once-weekly schedule 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
8、, they experienced less grade adverse events (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 improved CR rate compared to dexamethasone al
9、one(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 response was superior with high-dose dexamethasone（79% VS 68%）However, the high response rates did not result in superior TTP, PFS
10、, or OS.At 1-year interim analysis, OS was 96% in the low-dose dexamethasone group compared with 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
11、effects in the 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 autologous SCT was 92%,Lenalidomide/Dexamethasone,A retrospective ana
12、lysis of 411 newly diagnosed patients treated with either the lenalidomide and dexamethasone regimen (n = 228) or the thalidomide and dexamethasone regimen (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 receivin
13、g RD had longer TTP(median, 27.4 vs. 17.2 months; P = .019), longer PFS (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 of patie
14、nts 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 (10.4% vs. 0.9%, P 75岁)、国家和ISS分期(I或II vs III)强制抗血栓处理,FIRST, Frontline Investigation of Revlim
15、id and Dexamethasone versus Standard Thalidomide; ISS, International Staging System; LEN, lenalidomide; LoDEX, low-dose dexamethasone; LT, long-term; MEL, melphalan; MM, multiple myeloma; MPT, melphalan, prednisone, thalidomide; OS, overall survival; PD, progressive disease; PFS, progression-free su
16、rvival; Pred, prednisone; pt, patient; Rd, lenalidomide 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: 研究设计,aComplete cytogenetics profile for 762 pts (248
17、 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 performance status; FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; ISS, Internationa
18、l Staging System; MPT, melphalan, prednisone, thalidomide; pt, patient; Rd, lenalidomide plus low-dose dexamethasone; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles.,Patient characteristics were well balanced across all treatment arms,34,FIRST研究：患者基线特征,Benboubker L, et al. N Engl J Med
19、. 2014;371:906-917.,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)Hazard ratioRd vs. MPT: 0.72; P = 0.0006Rd vs. Rd18: 0.70; P = 0.0001,Time (months),FIRST 研究: PFS 1
20、00Median PFS,8060,Rd18 vs. MPT: 1.03; P = 0.7034940200,0,6,12,18,24,30,36,42,48,54,60,Facon et al. ASH 2013 (Abstract 2), oral presentation,内部资料，仅供医学药学专业人士参考，严禁翻印及传播,AMT, antimyeloma therapy; FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; MPT, melphalan, pr
21、ednisone, thalidomide; Rd, lenalidomide plus low-dose dexamethasone; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles; TTP, time to progression.,36,FIRST研究中期数据：中位随访37个月TTP和至第二次抗骨髓瘤治疗（AMT）的时间,Benboubker L, et al. N Engl J Med. 2014;371:906-917.,FIRST, Frontline Investigation of Revlimid a
22、nd Dexamethasone versus Standard Thalidomide; ITT, intent to treat; MPT, melphalan, prednisone, thalidomide; OS, overall survival; Rd, lenalidomide plus low-dose dexamethasone; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles.,37,FIRST研究中期数据：中位随访37个月，总生存率（OS）,Benboubker L, et al. N Engl
23、J Med. 2014;371:906-917.,Median follow-up 37 months,FIRST研究：中位随访45.5个月，Rd持续和Rd18 vs MPT组显示出显著的OS和PFS2优势,PFS2, time from diagnosis to second disease progression or death,Revlimid(lenalidomide). Summary of Product Characteristics. Celgene Europe Limited. Uxbridge, UK. February 2015.,FIRST研究：中位随访37个月和4
24、5.5个月结果比较,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(lenalidomide). Summary of Product Characteristics. Celgene Europe Limited. Uxbridge, UK. February 2015.,40,a Grade
25、3-4 AEs related to study medication were less frequent with Rd (70%) and Rd18 (60%) vs MPT (78%).b Diarrhea 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 D
26、examethasone versus Standard 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 Engl J Med. 2014;371:906-917.,FIRST研究：安全性,NDMM方案,BD(硼替佐米+地塞米松)
27、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+来那度胺+地塞米松),NDMM方案,经济情况特佳VRD经济情况好或一般VTD,VCD,PAD经济情况一般或差TCD,TCP,特殊患者NDMM方案,年龄80岁d or BzP肾损害硼替佐米为主的方案（来那度胺或沙利度胺也可）BD,BTD,BRD近期发生血栓事件硼替佐米为主的方案（在抗凝情况下来那度胺或沙利度胺也可）外周神经病变Len-dex一般情况差的患者Len-dex，单用dex不愿意住院的患者Len-dex,TD,CTP遗传学预后不良？含硼替佐米方案,谢 谢,
