BMT Online Journal Club 11.19.14 Palumbo et al, NEJM 2014; 371:895-905

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)

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Median duration of follow-up from the time of enrollment was 51.2 mo (range, 1 to 66).

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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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