1. 2 lenalidomide in newly diagnosed multiple myeloma clinical update eha 2010 dr. oussama jradi
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Lenalidomide in Newly Diagnosed Multiple Myeloma
Clinical Update EHA 2010
DR. OUSSAMA JRADI
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• 3 major trials have demonstrated significant
superiority of maintenance, utilizing lenalidomide in
this setting.
ASCO and EHA 2010 re-defined the Meaning of Maintenance Treatment in Multiple Myeloma
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Is Longer Treatment Better?
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EHA 2010 – Yes, longer treatment is better in patients after autologous transplant!
EHA 2010 – Yes longer treatment is better in elderly patients not eligible for transplant!
Lenalidomide Maintenance after Autologous Transplantation for Myeloma:
First Interim analysis of a prospective randomized study of the Intergroupe
Francophone du Myélome
(IFM 2005-02 trial)
By Michel Attal, Gerald Marit, Denis Caillot, Thierry Facon, Philippe Moreau, Cyrille Hulin, Claire Mathiot, Hervé Avet-Loiseau, and Jean-Luc Harousseau.
for the IFM
IFM 2005-02: Study design
Patients < 65 years, with non-progressive disease, 6 months after ASCT in first line
Arm B=Lenalidomide
(N=307)10-15 mg/d until relapse
Primary end-point: PFS.Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide….
Phase III randomized, placebo-controlled trialN= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008
ASCT = autologous stem cell transplant. IFM = Intergroupe Francophone du Myelome.
Consolidation:Lenalidomide alone 25 mg/day p.o.
days 1-21 of every 28 days for 2 months
Randomization: stratified according to Beta-2m, del13, VGPR
Arm A=Placebo(N=307)
10-15 mg/d until relapse
IFM 2005 02 Trial: Patient characteristics Arm A (placebo)
N=307Arm B (Len)
N=307
• Age (y) 55 55
• Sex (M/F) 59% / 41% 55% / 45%
• ISSIIIIII
36%25%39%
30%24%46%
• Beta-2 m (≤3 / >3) 33% / 67% 30% / 70%
• Del 13 (present /eval) 40% 42%
• t(4-14) (present /eval) 7% 11%
• Del 17 (present /eval) 5% 7%
IFM 2005-02 : PFS from randomization
. Arm AN=307
Arm BN=307
P
Progression or Death 143 (47%) 77 (25%)
Median PFS (m) 24 (21-27) NA
3-year post rando PFS(i.e. 4-year post diag)
34% 68%
Hazard Ratio 1 0.46 < 10-7
IFM 2005-02 : PFS from randomization
0.0
00.2
50.5
00.7
51.0
0
0 6 12 18 24 30 36
Placebo Revlimid
p<10-7
P < 10-7
Rev
Placebo
PFS according to Response Pre-Consolidation
HR= 0.37 - CI 95% [0.25-0.58] HR= 0.54 - CI 95% [0.37-0.78]
PR or SD VGPR or CR
0.00
0.25
0.50
0.75
1.00
0 6 12 18 24 30 36
Placebo Revlimid
0.00
0.25
0.50
0.75
1.00
0 6 12 18 24 30 36
Placebo Revlimid
p<10-5 p=0.001
Grade 3-4 Adverse Events during Maintenance
AE (grade 4) Arm A Arm B
Anemia 0% 3% (2%)
Thrombocytopenia 3% 8% (3%)
Neutropenia 6% (1%) 31% (7%)
Febrile Neutropenia 0% 0.1%
Infections 4% 8%
DVT 0.3% 0.6%
Skin disorders 1% 4%
Fatigue 0.6% 2%
Peripheral Neuropathy 0.3% 0.4%
Neoplasia 0.9% 1%
Definitive Discontinuation for SAE: placebo = 4% vs lenalidomide = 6% (NS)
IFM 2005-02: First Interim Analysis (Cut off date 4th September 2009)
Maintenance therapy with Lenalidomide:• Is well tolerated:
Low discontinuation rate due to SAE (A=4%vs B=6%, NS)
No increased incidence of DVT or peripheral neuropathy
• Is superior to placebo:
54% reduction risk of progression (p < 10-7)
In all stratified subgroups (VGPR, ß2m, del 13)
A longer follow-up is required to appreciate the impact of Lenalidomide on OS (Final analysis: 8/2010)
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Lenalidomide
Treatment of elderly patients with newly diagnosed MM with MPR followed by R maintenance
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Secondary Comparison MPR-R vs. MPR
Addition of MPR arm per EMEA advice
MP
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
PBO: days 1-21
Primary Comparison MPR-R vs. MP
MPR
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21Placebo
Placebo
Phase III Study Schema
M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo.
MPR-R
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21
RA
ND
OM
ISA
TIO
N
Double-Blind Treatment Phase
Diseaseprogression
LenalidomideContinued Tx
Lenalidomide
(25 mg/day) +/-
dexamethasone
Open-Label Extension/Follow-Up Phase
N=459, 82 centers in Europe, Australia
Stratified by age (≤ 75 vs. > 75 years) and stage (ISS 1,2 vs. 3)
10 mg/day,days 1-21
Cycles (28-day) 1-9 Cycles 10+
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MPR-R N = 152
MPR N = 153
MPN = 154
Median age, years (range)71
(65-87)71
(65-86)72
(65-91)
Age distribution > 75 years
24% 24% 25%
ISS Stage I / II / III 18 / 33 / 49% 21 / 31 / 48% 18 / 31 / 51%
Median BM plasma cells 35% 38% 35%
• 459 patients randomised between Feb 2007 and Sept 2008– 180 patients ongoing (MPR-R: 73; MPR: 54; MP: 53)
ISS, International Staging System
Patient Characteristics
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Best Response
Best Overall Responsea MPR-R N = 152
MPR N = 153
MP N = 154
P Value(MPR-R vs. MP)
ORR 77% 67% 50% <0.001
CRb 16% 13% 4% <0.001
≥ VGPRc 32% 33% 12% <0.001
PR 45% 34% 37% ---
Progressive Disease 0% 1% 0% ---
Median time to first response, months 2 1.9 3 <0.001
1. Bladé J et al. Br J Haematol. 1998;102:1115-1123.
a. As measured using EBMT criteria1
b. Immunofixation negative with or without bone marrow confirmation
c. VGPR: >90% reduction in M-protein
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Progression-Free SurvivalSecond Interim Analysis
58% Reduced Risk in PFS
HR 0.423 95% CI [0.330, 0.755]
Logrank P<0.001
MPR-R
MP
Median PFS
Not reached
13.0 months
0 5 10 15 20 25 300
25
50
75
100
PFS Time (months)
0 5 10 15 20 25 300
25
50
75
100
PFS Time (months)
Pat
ien
ts w
ith
ou
t E
ven
t (%
)
Median follow up: 21 mos
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Primary Analysis MPR-R vs. MP
MPR
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21Placebo
MPR-R vs. MPR Secondary Comparison
M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo.
MPR-R
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21
RA
ND
OM
ISA
TIO
N
Double-Blind Treatment Phase
Diseaseprogression
LenalidomideContinued Tx
10 mg/day,days 1-21
Cycles (28-day) 1-9 Cycles 10+
Secondary Comparison MPR-R vs. MPR
Addition of MPR arm per EMEA advice
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MPR-R vs. MPR Landmark PFS Analysis After Cycle 9
69% Reduced Risk in PFS
No. at Risk
MPR-R 75 40 17 3 1
MPR 81 21 8 1 1
HR 0.31495% CI [0.126, 0.476]
Logrank P<0.001
0 5 10 15 200
25
50
75
100
PFS Time (months)
Pat
ien
ts w
ith
ou
t E
ven
t (%
)
MPR-R
MPR
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Grade 3/4 AEs After Cycle 9 (Continuous Lenalidomide)
DVT, deep vein thrombosis
MPR-R N = 75
MPN = 94
Anemia 0% 5%
Thrombocytopenia 3% 1%
Neutropenia 1% 0%
DVT 3% 0%
Rash 0% 0%
Fatigue 1% 0%
Peripheral neuropathy 0% 0%
• Overall toxicity in maintenance phase is rather low: Grade 3/4 < 5%
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Conclusions MPR-R in Elderly NDMM
• Continuous lenalidomide is superior to regimens of limited duration
• MPR-R is superior to MP– Higher and more rapid responses– 50% reduced risk of progression
• Favorable safety profile– Grade 4 neutropenia: 36% (febrile neutropenia: <7%)– No Grade 3/4 peripheral neuropathy (Grade 2: 1% )– Low discontinuation due to AE: 16%
• MPR-R is a new standard treatment option for elderly patients
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