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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 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 : Study design Patients < 65 years, with non-progressive disease,  6 months after ASCT in first line Arm B= Lenalidomide (N=307) 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 trial N= 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) mg/d until relapse

IFM Trial: Patient characteristics Arm A (placebo) N=307 Arm B (Len) N=307 Age (y)55 Sex (M/F)59% / 41%55% / 45% ISS I II III 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 : PFS from randomization. Arm A N=307 Arm B N=307 P Progression or Death143 (47%)77 (25%) Median PFS (m)24 (21-27)NA 3-year post rando PFS (i.e. 4-year post diag) 34%68% Hazard Ratio10.46< 10 -7

IFM : PFS from randomization p<10 -7 P < Rev Placebo

PFS according to Response Pre- Consolidation HR= CI 95% [ ]HR= CI 95% [ ] PR or SD VGPR or CR p<10 -5 p=0.001

Grade 3-4 Adverse Events during Maintenance AE (grade 4)Arm AArm B Anemia0%3% (2%) Thrombocytopenia3%8% (3%) Neutropenia6% (1%)31% (7%) Febrile Neutropenia0%0.1% Infections4%8% DVT0.3%0.6% Skin disorders1%4% Fatigue0.6%2% Peripheral Neuropathy0.3%0.4% Neoplasia0.9%1% Definitive Discontinuation for SAE: placebo = 4% vs lenalidomide = 6% (NS)

IFM : 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 < ) 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

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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 1-21 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 RANDOMISATION Double-Blind Treatment Phase Disease progression Lenalidomide Continued 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) 1-9Cycles 10+

17 MPR-R N = 152 MPR N = 153 MP N = 154 Median age, years (range) 71 (65-87) 71 (65-86) 72 (65-91) Age distribution > 75 years 24% 25% ISS Stage I / II / III18 / 33 / 49%21 / 31 / 48%18 / 31 / 51% Median BM plasma cells35%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 Response a MPR-R N = 152 MPR N = 153 MP N = 154 P Value (MPR-R vs. MP) ORR77%67%50%<0.001 CR b 16%13%4%<0.001 ≥ VGPR c 32%33%12%<0.001 PR45%34%37%--- Progressive Disease0%1%0%--- Median time to first response, months21.93< Bladé J et al. Br J Haematol. 1998;102: a. As measured using EBMT criteria 1 b. Immunofixation negative with or without bone marrow confirmation c. VGPR: >90% reduction in M-protein

19 Progression-Free Survival Second Interim Analysis 58% Reduced Risk in PFS

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 1-21 Placebo 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 RANDOMISATION Double-Blind Treatment Phase Disease progression Lenalidomide Continued Tx 10 mg/day, days 1-21 Cycles (28-day) 1-9Cycles 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 MPR

24 Grade 3/4 AEs After Cycle 9 (Continuous Lenalidomide) DVT, deep vein thrombosis MPR-R N = 75 MP N = 94 Anemia0%5% Thrombocytopenia3%1% Neutropenia1%0% DVT3%0% Rash0% Fatigue1%0% Peripheral neuropathy0% 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

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