Ravi Vij MD Associate Professor Section of BMT and Leukemia
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Induction Therapy For Multiple Myeloma:
Two vs Three Drug Regimen and Role of Risk Stratification
Ravi Vij MDAssociate Professor
Section of BMT and LeukemiaWashington University School of Medicine
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Trends in Overall Survival of MM
Overall survival 1971–2006 Diagnosis period Median OS1996–2006 45 months1971–1996 30 months
(P<0.001)
Kumar SK, et al. Blood. 2008;111:2516-2520. Time from diagnosis (Months)
Surv
ival
0
0.2
0.4
0.6
0.8
1.0
0 20 40 60 80 100 120 140
2001–2006
1995–2000
2001–2006
1989–1994
1983–1988
1977–1982
1971–1976
OS, overall survival.
2
M
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CR and MM• Is CR an adequate surrogate for OS?
• Are all CRs as durable?
• Should we strive for CR pre-transplant?
• What is the role of HDCT for patients in CR pre-transplant?
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CR associated with OS prolongation in post-induction and post-transplant settings1-3
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.
Survival by response for 291 patients with MM (age <70 y) who received chemotherapy alone (left) and 375 who proceeded to ASCT (right) (CR vs PR or NR P<0.01)
Chemotherapy Alone Chemotherapy and ASCT
4
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> 65 yrs
> 75 yrs
Importance of CR in Elderly MM
Gay F et al. Blood. 2011;117(11):3025-3031)
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Approach to Treatment of MM
Clearly not a transplant candidate based on age, performance status
and comorbidity
Conventional Therapy
Potential transplant candidate
Non-alkylator based induction x 4 cycles
Stem cell harvest
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Bortezomib-Based Induction Prior to SCT
Trial Regimen NCR+VGPR Post-Induction (%)
CR+VGPR Post-ASCT (%) PFS P Value
Cavo et al, 2010VTD
vsTD
236
238
62*
28
82*
64
68% at 3 yr
56% at 3 yr .0057
Moreau et al, 2011IFM 2007/02
VDvs
vTD
99
100
36
49‡
58
74§
Median 30 months
Median 26 mo .22
*P <.001; †P =.001; ‡P =.05; §P =.02GMMG= 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.
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Fayers PM et alBlood.2011;118(5):1239-1247
MPT vs MP in Elderly MM
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Median survival:
MP 32.7 months (95% CI, 30.5-36.6 months)MPT 39.3 months (95% CI, 35.6-44.6 months).
HR 0.83 (95% CI: 0.73-0.94)P=0.004
Overall Survival
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Palumbo et al. N Engl J Med 2012;366:1759-69.
MPR vs MP in Elderly MM
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Study Regimen N ORR CR/nCR Outcomes
VISTASan Miguel et al.
Mateos et al.Phase III
VMPMP
344338
71%35%
33%4%
5 yr OS: 46%5 yr OS: 34.4%
UPFRONTNiesvizky et al.
Phase III
VMP/VelVTD/VelVD/Vel
30073%79%71%
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
Bortezomib in Transplant Ineligible MM
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UPFRONT Study
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MM-020: Len + Low-dose Dex vs MPT in Previously Untreated MM
Protocol CC-5013-MM-020/IFM 07-01. 2007; data on file, Celgene Corporation
Inclusion criteria•Previously untreated MM
•Age 65 years or not a candidate for transplantation
•No neuropathy of grade > 2
•CICr > 30 ml/min
• Lenalidomide 25 mg/day, days 1–21, every 28 days• Dexamethasone* 40 mg/day, days 1, 8, 15, 22, every
28 daysUntil PD
• Lenalidomide 25 mg/day, days 1–21, every 28 days• Dexamethasone* 40 mg/day, days 1, 8, 15, 22, every
28 days
18 four-week cycles or until PD
N = 1,590Centres in EU, Switzerland, USA and Canada
*In patients older than 75 years• Dexamethasone 20 mg/day• Thalidomide 100 mg/day• Melphalan 20 mg/kg/day
• Melphalan 0.25 mg/kg/day, days 1–4, every 42 days• Prednisone 2.0 mg/kg/day, days 1–4, every 42 days• Thalidomide* 200 mg/day, days 1–42, every 42 days
12 six-week cycles or until PD
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Conclusions• Three drug induction regimen are associated with higher CR
rates compared to two drug regimen.• In the transplant eligible population prospective trials have
shown a higher CR rate and PFS for two drug regimen. Follow-up is too short for analyses of OS.
• In the transplant ineligible population three drug regimes of thalidomide and bortezomib have a OS advantage compared with MP. Whether non-melphalan containing two drug regime may be equivalent is the subject of ongoing trials.
• We have entered an era of risk stratification for deciding therapy. However no consensus has emerged on treatment paradigms.