初诊多发性骨髓瘤治疗进展

NDMM治疗杨永公内容提要n 诊断（略）n 治疗指征n 治疗原则n 常用方案选择n 特殊人群治疗治疗指征 有症状 MMn 无症状 MM1)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。n 有症状 MM1) CRAB2)高粘度血症、淀粉样变性、反复感染（2008WHO)治疗原则n 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。n 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。 避免使用烷化剂和亚硝基脲类药物。n 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 ratesThe incidence of severe adverse events reported was similar between the two groups.Bortezomib/Doxorubicin/Dexamethasone A benefit in terms of increased 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 n Three phase II studies involving newly diagnosed patients with MM (n = 495) have demonstrated high response rates with CyBorD as primary treatmentn 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/Dexamethasone 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%VGPR), and one-year PFS rate was 93%.Bortezomibn Bortezomib-based regimens may be of value in patients with renal failure, and in those with certain adverse cytogenetic features. n Bortezomib treatment has been associated with an increased incidence of herpes zoster.n peripheral neuropathy and gastrointestinal disturbance can be higher.once-weekly schedule of bortezomib.n Reeder et al modified the regimen to a once-weekly schedule of bortezomib.n In the study, patients treated with weekly bortezomib achieved responses similar to the twice-weekly schedule (ORR 93% vs.88%, VGPR 60% vs. 61%). n In addition, they experienced less grade adverse events (37%/3% vs. 48%/12%)Lenalidomide/Dexamethasone n SWOG compared dexamethasone single agent with dexamethasone plus lenalidomide for patients newly diagnosed with MM.n The lenalidomide plus dexamethasone arm showed improved CR rate compared to dexamethasone alone(22.1% vs. 3.8%)Lenalidomide/Dexamethasone n In an open-label trial, 445 newly diagnosed patients with MM were randomly assigned to high-dose or low-dose regimens.n The response was superior with high-dose dexamethasone（ 79% VS 68%）n However, the high response rates did not result in superior TTP, PFS, or OS.n 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 n 52% patients on the high-dose regimen compared with 35% on the low-dose regimen had grade 3 or worse toxic effects in the first 4 months, including DVT (26% vs. 12%); infections including pneumonia (16 vs. 9%); and fatigue (15% vs. 9%).n The 3-year OS of patients who received four cycles of primary treatment with either dose followed by autologous SCT was 92%,Lenalidomide/Dexamethasone n A retrospective analysis 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 Clinicn 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 (median, 26.7 vs. 17.1 months; P = .036), and better OS (median not reached vs. 57.2 months; P = .018)Lenalidomide/Dexamethasone n Grade 3 or 4 adverse events (57.5% vs. 54.6%, P = .568) were seen in a similar proportion of patients in both groupsn 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 .001).n Based on the results of this meta-analysis RD seems well-tolerated and more effective than TDBortezomib/Lenalidomide/Dexamethasone n Phase I/II study results have shown that primary therapy with BRD is active and well tolerated in NDMMn Response rate is 100% with 74% VGPR or better and 52% CR/near CR.n IFM 2008 trial, the ORR after primary treatment was 97% (13% sCR; 16% CR; and 54% VGPR)Bortezomib/Lenalidomide/Dexamethasone n EVOLUTION trial evaluated VDC, VDR, and VDCR in previously untreated multiple myeloma (MM).n (all arms) very good partial response was seen in 58%, 51%, 41%, and 53% (complete response rate of 25%, 24%, 22%, and 47%) of patients (VDCR, VDR, VCD, and VCD-mod, respectively)n No substantial advantage was noted with VDCR over the 3-drug combinations其它方案n Thalidomide/Dexamethasonen Single-Agent Dexamethasone： selected group of patients (renal failure, hypercalcemia, cord compromise requiring radiation therapy,cytopenia)n DVDn CTP部分 2期及 3期临床试验结果Larocca et al. ASH 2013 (Abstract 687), oral presentationFrailty score数据来源于 3个前瞻性多中心研究， 869 例年 龄 65岁 或因存在合并症不合适移植的初治 MM患者， 中位年 龄 74岁 （ 44%75 岁 ），治 疗 包括以硼替佐米 为 基 础 的 联 合方案、以来那度胺 为 基 础 的 联 合方案、以卡菲佐米 为基础的联合方案。国外 经验Agent Dose level 0 Dose level 1 Dose level 2 Bortezomib 1.3 mg/m2 twice / wkd 1,4,8,11 / 3 wks 1.3 mg/m2 o