适合移植的多发性骨髓瘤患者治疗策略2012

RD, %
Response (≥ PR) in 4 cycles ≥ VGPR within 4 cycles Best overall response (≥ PR) ≥ VGPR CR (IF−) 79 42 81 50 13
Rd, %
68 24 70 40 10
p value
0.008 0.0001 0.009 0.040
97 100 126
Yes Yes/No No
Cancer 2006
NEJM 1996 Lancet 2006
常规化疗OS：联合化疗 vs MP方案
27 项随机试验; 6633名患者
100 0 90 80
– Allocated cct (% ± SD) – Allocated MP (% ± SD)
中国医学科学院血液病医院淋巴瘤 骨髓瘤中心
适合移植的MM治疗策略
邱录贵
中国医学科学院
血 液 病 医 院 血液学研究所
多发性骨髓瘤的常规化疗药物
• Class I: 糖皮质激素 • Class II: 细胞毒性药物
–烷化剂药物 – 长期低剂量给药或大剂量 –蒽环类抗生素 – 短期使用
初治患者常规化疗的缓解率欠佳
Macro
TD vs VAD2 4 months 204
Lokhorst
TAD vs VAD3 3 cycles 556
Morgan
CTD vs CVAD4 NA 251
≥ PR
Response after ASCT, % CR ≥ VGPR ≥ PR
76 vs 52
– – –
–
– 44 vs 42 –
75
9 40
• Remission depth greater with CTD (stringent CR) than with CVAD • CTD well tolerated, though there was a significant incidence of VTE • Maintenance thalidomide after ASCT provided PFS but not OS benefit
新药时代MM的治疗策略
Novel agents in MM
新型药物的应用显著提高了CR率和总缓解率
New options for patients eligible for transplantation
Induction regimens in the era of novel agents
CR or PR
Patients eligible for SCT can proceed to SCT
Arm 2
Lenalidomide 25 mg/day p.o., days 1–21 Low-dose dexamethasone 40 mg/day p.o., days 1, 8, 15, 22 Dexamethasone 160 mg per cycle (n = 222)
20 148 129
40 Mos 79 70
60 38 30
80 8 8
Attal M, et al. N Engl J Med. 1996;335:91-97. 2. Child JA, et al. N Engl J Med. 2003;348:1875-1883. Copyright © 1996 , 2003 Massachusetts Medical Society. All rights reserved
P = .03 by Wilcox test P = .04 by log-rank test Intensive therapy Standard therapy
OS (%)
25 0 0 15 30 45 Mos
Conventional dose
60
0 No. at Risk Intensive tx 201 Standard tx 200
1. Cavo M, et al. Blood.2005;106:35-39. 2. Macro M, et al. Blood.2006;108:[abstract 57]. 3. Lokhorst HM, et al. Blood.2010;115:1113-1120. 4. Morgan GJ, et al. Blood. 2007;110:[abstract 3593].
Four courses, every 28 days R A N D O M I Z A T I O N Arm 1
Lenalidomide 25 mg/day p.o., days 1–21 Standard-dose dexamethasone 40 mg/day p.o., days 1–4, 9–12, 17–20 Dexamethasone 480 mg per cycle (n = 223)
Owen RG, et al. Clin Lymphoma Myeloma. 2009;9 Suppl 1:S84 [abstract A546].
ECOG-E4A03: Len + standard- or low-dose Dex in newly diagnosed MM
Phase III, randomized study in newly diagnosed MM (N = 445)
Thalidomide-based induction vs VAD
Cavo
TD vs VAD1 Induction duration Patients, n Response before ASCT, % CR ≥ VGPR 10 vs 8 19 vs 14 -35 vs 13 3 vs 2 37 vs 18 20 vs 12 38 vs 26 4 months 200
Less than PR
Thal + Dex ×4 cycles
CR or PR or SD
Rajkumar SV, et al. Lancet Oncol 2010;11:29-37.
ECOG-E4A03: phase III trial of Len + standard-dose Dex vs Len + low-dose Dex
研究
Rajkumar Goldschmidt
病 例
100 203
方案
Dex VAD DVd VMCP MP
CR/nCR
0% 3% 3% 5% 7%
CR+PR
50% 63% 43% 52% 48%
干细胞 采集
Yes Yes
参考文献
JCO 2006 ASH 2005
Rifkin IFM90 Palumbo
6 vs 1*
38 vs 15* 78.5 vs 63* 16 vs 9* 54 vs 37* 80 vs 77
5 vs 0*
33 vs 12* 80 vs 64* 15 vs 4* 59 vs 47* 92 vs 77*
* Significantly different For IFM 2005/01,response after first transplant is presented.Overall response, Including second transplant is > VGPR 68% VD vs 47% VAD and CR/nCR 39.5% VD vs 22.5% VAD. 1. Harousseau JL, et al. JCO 2010 in press. 2. Sonneveld P, et al. IMW 2009: [abstract 152].
IFM 2005-01 VD vs VAD1 Patients, n Response before ASCT, % 223 vs 218 HOVON-GMMG PAD vs VAD2 150 vs 150
CR
> VGPR > PR Response after ASCT, % CR > VGPR > PR
71 vs 57
14 vs 12 54 vs 44 84 vs 76
96 vs 83
58 vs 41 67 vs 43 99 vs 96
TAD vs VAD: significantly better ORR, EFS, and PFS (but not OS) with TAD EFS: 34 vs 22 months, P < .001; PFS: 34 vs 25 months, P < .001; OS: 73 vs 60 months, P = .77
ASCT与常规化疗比较：显著提高生存
100
IFM 90[1]
PFS (%)
100 75 50 25 0
MRC 7[2]
P < .001 by Wilcox test P < .001 by log-rank test Intensive therapy Standard therapy 20 124 90 40 Mos 55 25 60 27 9 80 5 3
1
2
3
4
5
6+
预期存活患者比例
70
60 50 40 30
24.4% 19.4% 23.0% 18.0% 1.4% SD 1.4 (log-rank 2P > .1; NS)
MP VBMCP VMCP VBAP ABCM MOCCA
ຫໍສະໝຸດ Baidu
20
10 0 1 2 3 4
5
6
年
Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16;12:3832
MRC Myeloma IX: preliminary results from intensive pathway study (CTD vs CVAD)
N = 1,114
Response Patients, % CTD CVAD
ORR
CR CR 100 days post-HDM
87
19 51
Combined induction regimens
VTD vs TD as induction regimen
Phase III trial: planned interim analysis
R A N D O M I Z A T I O N
Rajkumar SV, et al. Lancet Oncol 2010;11:29-37.
Len + Dex is a highly active pre-transplant induction regimen
Overall survival: transplant after induction therapy with 4 cycles of RD (50 pts) or Rd (40 pts)
100 80 Patients (%)
3-yr OS： 92%
RD Rd
60 40 20 0 0
6
12
18 24 Time (months)
30
36
42
Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.
Induction regimens based on bortezomib
– as consolidation only (not as ongoing maintenance)
• No significant differences in cytogenetic subgroups, except 17p−, in which thalidomide maintenance was significantly disadvantageous
IFM94: 双次ASCT提高长期生存
（N Engl J Med 2003;349:2495-502）
MM的常规治疗模式
初治诱导治疗
－常规化疗
适合移植者
不适合移植者
－非烷化剂药物
移植患者
短程诱导治疗（糖皮质激素） 大剂量化疗（烷化剂）
－烷化剂药物
非移植患者
长期低剂量 烷化剂 + 糖皮质激素
• 移植患者：短程诱导治疗后大剂量烷化剂治疗 • 非移植患者：长期烷化剂治疗12 -18个月
75
50 High dose 25 EFS (%) 0 0 15 30 Mos
0 No. at Risk Conventional dose Intensive tx 199 45 60 Standard tx 196
100 75 50
100
High dose
Survival (%)
75 50 25 0