1

2

Lenalidomide in Newly Diagnosed Multiple Myeloma

Clinical Update EHA 2010

DR. OUSSAMA JRADI

3

• 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

4

Is Longer Treatment Better?

5

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)

14

Lenalidomide

Treatment of elderly patients with newly diagnosed MM with MPR followed by R maintenance

15

16

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+

17

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

18

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

19

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

22

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

23

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

24

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%

25

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

26