bmt online journal club 11.19.14 palumbo et al, nejm 2014; 371:895-905
DESCRIPTION
Journal Club discussion of Palumbo et al, NEJM 2014; 371:895-905 - Autologous Transplant and Maintenance in Multiple MyelomaTRANSCRIPT
BMT Online Journal Club Gunjan L. Shah, MD MS November 19, 2014
Palumbo et al, NEJM 2014; 371:895-905
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Autologous Stem Cell Transplantation
Courtesy of Dr. Klein Attal, et al. NEJM 2003. Attal, et al, NEJM, 1996
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McCarthy, et al. Hematology (ASH Ed Book) 2013 Courtesy of Dr. Klein
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Lenalidomide Maintenance Therapy Study Attal NEJM 2012 McCarthy NEJM 2012
Design Prospective, Double blind
Prospective, Double blind
Patients 614, Age <65, 2006-2008 461, age <71, 2005-2009
Reg & Rand 6mo PostTx PreTx, 100d PostTx
Induction VAD 48% Borezomib/Dex 48%
Bortezomib 41% Lenolidomide 35% Thalidomide 45%
Consolidation DCEP 25% None
Transplant Mel 200, Tandem 25% Mel 200
PostTx Consol LenDex25 x21d, x2 (95%)
None
Maint Len10mg daily vs placebo
Len10mg daily vs placebo
PFS 41 vs 23 mo (p<0.001) 39 vs 21 mo (p <0.001)
OS 3yr: 80 vs 84% (p=0.29) 3y: 88 vs 80% (0.03)
Courtesy of Dr. Klein
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Continuous vs. Fixed-Duration Therapy Two phase 3 randomized trials
– RVMM209: lenalidomide-based induction, consolidation, followed by maintenance (CT) vs. lenalidomide-based induction, consolidation, no maintenance (FDT)
– GIMEMA0305: bortezomib-based induction followed by maintenance (CT) vs. bortezomib-based induction, no maintenance (FDT)
Palumbo A, et al. J Clin Oncol. 2014;32:abstr 8515.
GIMEMA MM0305 RVMM209 CT FDT CT FDT
(Median, mos) HR P (Median, mos) HR P From Diagnosis
PFS1 35 24 0.58 < 0.001 38 25 0.58 < 0.001
PFS2 59 42 0.69 0.003 63 49 0.69 0.015
OS NR 60 0.70 0.01 NR NR 0.68 0.047
From First Relapse
PFS 14 12 1.1 0.61 17 19 1.09 0.61
OS 26 28 0.99 0.94 47 42 1.0 0.99
PFS1: time from start of therapy to the occurrence of first relapse. PFS2: time from start of therapy to the occurrence of second relapse, incorporating the duration of both 1st and 2nd remission.
Courtesy of Dr. Comenzo
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Trial Design
Randomized
Open Label
Not Placebo Controlled
November 2007-July 2009, Data Cutoff April 30, 2013
62 Centers Italy & Israel
Palumbo et al, NEJM 2014; 371:895-905
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Patients
Symptomatic, measurable, newly diagnosed MM
< 65 years of age
KPS >= 60
Life expectancy longer than 6 months
ANC > 1500, Plt > 75,000
Normal cardiac and pulmonary function, CrCl >30
Palumbo et al, NEJM 2014; 371:895-905
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2 by 2 Factorial Design
Simple Randomization
1:1:1:1
Stratified by Age (<60 vs 61-65) ISS (I &II vs III)
Palumbo et al, NEJM 2014; 371:895-905
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Endpoints
Primary - Progression – Free Survival
Secondary - Overall survival, Overall response rate, Time to response, and Safety
Estimated from the time of enrollment and from the time when the random assignment was disclosed
Response - International Uniform Response Criteria for Multiple Myeloma
Palumbo et al, NEJM 2014; 371:895-905
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Statistics Auto vs MPR
Two-sided alpha error of 0.05 400 patients (200 per treatment group) enrolled Power of 85% to detect a hazard ratio of 0.62 in favor of Auto Corresponding to a 2-year PFS of 65% vs. 50%
Len Maintenance vs No Maintenance Two-sided alpha error of 0.05 Expected 240 patients (120 per treatment group) would be eligible for
maintenance Power of 80% to detect hazard ratio of 0.56 in favor of maintenance Corresponding to increase from 60% to 75% in 2-year PFS
Interim Analysis - O’Brien–Fleming design 1st: 65 progression events (40% of the expected number 2nd: 97 events (60% of the expected number)
Palumbo et al, NEJM 2014; 371:895-905
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Median duration of follow-up from the time of enrollment was 51.2 mo (range, 1 to 66).
Palumbo et al, NEJM 2014; 371:895-905
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Response Rates
High Dose Melphalan-Auto CR 15.7% after consolidation to 35.7% after maintenance
MPR CR 20% after consolidation to 33.8% after maintenance
Palumbo et al, NEJM 2014; 371:895-905
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5 yr OS: 78.4% vs 66.6% vs 70.2% vs 58.7%
Median PFS: 54.7m vs 37.4m vs 34.2m vs 21.8m
Survival
Palumbo et al, NEJM 2014; 371:895-905
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Median PFS: 43m vs 22.4 m PFS Hazard Ratio: 0.44 (95% CI 0.32-0.61) p<0.001
4 yr OS: 81.6% vs 65.3% OS Hazard Ratio: 0.55 (95% CI 0.32-0.93) p=0.02
Survival
Palumbo et al, NEJM 2014; 371:895-905
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Median PFS: 41.9m vs 21.6m PFS Hazard Ratio: 0.47 (95% CI 0.33-0.65) p<0.001
3 yr OS: 88% vs 79.2% OS Hazard Ratio: 0.64 (95% CI 0.36-1.15) p=0.14
Survival
Palumbo et al, NEJM 2014; 371:895-905
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Safety
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Conclusions
High-dose melphalan consolidation therapy followed by stem-cell transplantation associated with significant reduction in the risk of progression or death and increased OS.
Maintenance with lenalidomide was associated with a significantly reduced risk of disease progression or death independent of the consolidation regimen & comparable to prior maintenance studies.
Toxicity was manageable.
Palumbo et al, NEJM 2014; 371:895-905
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Limitations
Funding Source – Fondazione Neoplasie Sangue Onlus, Celgene
Only 68% of the enrolled patients were eligible to undergo the first randomization.
No discussion of eligibility to move on to consolidation or maintenance
No minimal residual disease testing.
No bortezomib.
Stratification based on ISS but few Stage III patients.
No placebo control.
No blind assessment of progression.
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Questions for Discussion
How do we use these data since everyone underwent tandem transplants which is uncommon in the US?
Should everyone get maintenance therapy since the ISS Stage III patients did not have even a PFS benefit?
How do we incorporate cytogenetic risk?
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Palumbo et al, NEJM 2014; 371:895-905
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PFS Palumbo et al, NEJM 2014; 371:895-905
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PFS Palumbo et al, NEJM 2014; 371:895-905
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OS Palumbo et al, NEJM 2014; 371:895-905
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OS Palu
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