多发性骨髓瘤诱导治疗: 两药VS三药治疗方案和危险分层的作用 Ravi Vij MD 副教授 骨髓移植和白血病专业 华盛顿大学医学院

MM总生存期的趋势 M 总生存期1971–2006 1996–2006 45 个月 1971–1996 30 个月 (P<0.001) 1.0 诊断周期 中位 OS 1996–2006 45 个月 1971–1996 30 个月 (P<0.001) 0.8 2001–2006 OS, overall survival. 0.6 生存率 0.4 Trends in Overall Survival of MM Kumar et al studied survival in 387 patients who were treated at the Mayo Clinic from 1971–2006 and experienced a first relapse after ASCT Patients were divided into 2 cohorts, those with a relapse date on or before December 31, 2000 and those with a later relapse date Median overall survival (OS) was longer for patients who relapsed after 2000 compared with those who relapsed prior to this date (23.9 vs 11.8 months) Improved outcome of patients with MM has been observed in recent years, both in the relapsed setting as well as at diagnosis Reference Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516-2520. 1971–1976 1989–1994 0.2 1977–1982 1995–2000 1983–1988 2001–2006 20 40 60 80 100 120 140 距离诊断时间(月) Kumar SK, et al. Blood. 2008;111:2516-2520.

CR与MM CR足够替代OS吗？ 所有的CRs都是看作持久的吗？ 移植前是否力求达到CR ？ HDCT在CR患者移植前的作用是什么？

CR与诱导后和移植后OS延长相关 只接受化疗 化疗和移植 CR associated with OS prolongation in post-induction and post-transplant settings Assessing the prognostic impact of achieving CR has been difficult because of the use of different definitions of CR.1 [Harousseau/p3139/c2/para3/lines1-3] Although not all studies show a correlation between CR and OS in MM, CR generally indicates patients who are likely to live longer.2 [Wang/p500/fig1] Many studies have demonstrated that CR is usually associated with longer overall survival.1[Harousseau/p3140/c2/para1/lines1-9] These findings have been demonstrated in both the postinduction and posttransplant settings.3[Lahuerta/p5778/table3] 1. Harousseau J-L et al. Blood. 2009;114(15):3139-3146. 2. Wang M et al. Bone Marrow Transplant. 2010;45(3):498-504. 3. Lahuerta JJ et al. J Clin Oncol. 2008;26(35):5775-5782. 291例（年龄<70岁）MM患者只接受化疗，375例化疗后接受移植（右），比较两种情况生存率与缓解程度的关系(CR vs PR or NR P<0.01) 1. Lahuerta et al. J Clin Oncol. 2008;26(3):5775-5782. 2. Alexanian et al. Bone Marrow Transplant. 2001;27:1037-1043. 3. Wang, et al. Bone Marrow Transplant. 2010;45(3):498-504.

CR对老年MM患者的重要性 > 65岁 > 75岁 Gay F et al. Blood. 2011;117(11):3025-3031)

MM的治疗方法 不适合移植的患者 考虑年龄，身体状况，并发症 常规治疗 适合移植的患者 4个周期非烷化剂 诱导治疗 干细胞采集

CR+VGPR Post-Induction (%) 基于硼替佐米的移植前诱导治疗 Trial Regimen N CR+VGPR Post-Induction (%) CR+VGPR Post-ASCT (%) PFS P Value Cavo et al, 2010 VTD vs TD 236 238 62* 28 82* 64 68% at 3 yr 56% at 3 yr .0057 Moreau et al, 2011 IFM 2007/02 VD vTD 99 100 36 49‡ 58 74§ Median 30 months Median 26 mo .22 *P <.001; †P =.001; ‡P =.05; §P =.02 GMMG= German Multiple Myeloma Group; SCT = stem cell transplant; CR = complete response; VGPR = very good partial response; PAD = bortezomib (V)/AD; T = thalidomide; VAD = vincristine, doxorubicin (A), dexamethasone (D); vTD = reduced-dose bortezomib. Cavo M, et al. Lancet. 2010;376:2075-2085. Harousseau JL, et al. J Clin Oncol. 2010;28:4621-4629. Sonneveld P, et al. ASH Annual Meeting Abstracts. 2010;116(21):40. http://web.educationalconcepts.net/Newsletter/MMY015AE1/MMY015AE1.pdf. Accessed July 17, 2012. Moreau P, et al. Blood. 2011;118: 5752-5758.

老年MM患者：MPT vs MP Fayers PM et alBlood.2011;118(5):1239-1247

总生存期 中位生存期: MP组：32.7个月 (95% CI, 30.5-36.6 个月) MPT组：39.3个月 (95% CI, 35.6-44.6个月). HR 0.83 (95% CI: 0.73-0.94) P=0.004

老年MM患者：MPR vs MP Palumbo et al. N Engl J Med 2012;366:1759-69.

硼替佐米治疗不适合移植MM患者 Study Regimen N ORR CR/nCR Outcomes VISTA San Miguel et al. Mateos et al. Phase III VMP MP 344 338 71% 35% 33% 4% 5 yr OS: 46% 5 yr OS: 34.4% UPFRONT Niesvizky et al. VMP/Vel VTD/Vel VD/Vel 300 73% 79% 31% 36% 34% ORR: overall response rate; CR: complete response; nCR: near complete response; OS: overall survival; TTP: time to progression; PFS: progression free survival; VMP: Bortezomib-melphalan-dexamethasone; MP: Melphalan-Prednisone; VTP: Bortezomib-thalidomide-dexamethasone; VTD: bortezomib-thalidomide-dexamethasone; VD: bortezomib-dexamethasone; VMPT-VT: bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance

前期研究

MM-020:来那度胺 +低剂量地塞米松 vs MPT治疗初治MM患者 来那度胺 25 mg/天, 1–21天, 每28天 地塞米松* 40 mg/天, 1, 8, 15, 22天, 每28 天 到 PD为止 入组标准 初治MM 年龄 65岁或不适合移植的MM 神经病变不大于 2级 CICr > 30 ml/min 来那度胺25 mg/天, 1–21天,每28天 地塞米松* 40 mg/天, 1, 8, 15, 22天, 每28天 18个周期或直到PD 马法兰 0.25 mg/kg/天, 1–4天, 每42 天 泼尼松 2.0 mg/kg/天, 1–4天,每42 天 沙利度胺* 200 mg/天, 1–42天每42 天 MM-020 study design: lenalidomide plus low-dose dexamethasone given until PD or for 18 four-week cycles versus melphalan, prednisone, and thalidomide for 12 six-week cycles in patients with previously untreated multiple myeloma who are either ≥ 65 years old or not candidates for stem cell transplantation. ClCr = creatinine clearance; MM = multiple myeloma; PD = progressive disease. Celgene Corporation. Protocol CC-5013-MM-020/IFM 07-01. 2007; data on file. 12个六周或直到PD N = 1,590 多中心：欧盟,瑞典, 美国，加拿大 * 对于大于75岁的患者： 地塞米松20 mg/天 沙利度胺100 mg/天 马法兰20 mg/kg/天 Protocol CC-5013-MM-020/IFM 07-01. 2007; data on file, Celgene Corporation

结论 三药诱导方案和两药方案相比与有更高的CR率。 在适合移植患者的前瞻性研究中，两药方案显示出更高的CR率 和PFS，随访太短无法分析OS。 对于不适合移植的患者，沙利度胺和硼替佐米的三药方案OS优 于MP，其是否与不含有马法兰两药方案等效是临床试验的课 题。 我们已经进入了一个危险分层决定治疗的时代，然而治疗模式 尚未达成共识。