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 Protocol High dose therapy is a standard treatment for young patients with myeloma. However, a residual disease, responsible for relapse, is always present after single or double transplantation. Effective maintenance treatment would be required However……!
Maintenance TT for Myeloma Chemotherapy: NO ! (SWOG: Arch Intern Med 75; Alexanian: Blood 78; Belch: Br J Cancer 88) Interferon: NO ! Mandelli, N Engl J Med 1990: Yes Barlogie, JCO 2006 (US Intergroup): No Corticosteroids: NO ! Berenson, Blood 2002: Yes (survival and duration of response) ShusTik, JCO 2004: No survival improvement Alexanian, Am J hematol 2000: IFN = Corticoïdes Thalidomide …..
Maintenance therapy with thalidomide after ASCT * CR + VGPR rates. Barlogie B, et al. Blood 2008. Attal M, et al. Blood. 2006 Spencer A, et al. J clin Oncol. 2009
IFM 99 02 : EFS According to del 13 Del 13 - Del 13 + Thal + Thal + Thal - (n = 391) NS P = 0.001 Thal - Thal -
IFM 99 02 : EFS According to Response at Random Response at Random < 90% Response at Random ≥ 90% Thal + Thal + Thal - Thal - NS P < 0.0003 Thal - (n = 391) Consolidation rather than maintenance Explanation: 68% of PN responsible for short duration of TT ?
IFM 2005-02 Protocol: Rationale • Lenalidomide was an attractive candidate: • Oral agent • Active among patients who had failed HDT, • Without neurological complications, • Effective and safe when administered for a long time
IFM 2005-02: Study design Phase III randomized, placebo-controlled trial N= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008 Patients < 65 years, with non-progressive disease, 6 months after ASCT in first line Randomization: stratified according to Beta-2m, del13, VGPR Consolidation: Lenalidomidealone 25 mg/day p.o. days 1-21 of every 28 days for 2 months Arm A= Placebo (N=307) until relapse 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…. ASCT = autologous stem cell transplant. IFM = Intergroupe Francophone du Myelome.
The IFM 2005 02 trial: First Interim Analysis • Primary endpoint: PFS • Powered to show a improvement in 4-year PFS: 37.5% vs 50% • 572 / 614 patients received consolidation • According to the first amendment (9/2006) • Responses and progressions confirmed by Medical Monitor • First interim analysis: 12/2009, • Cut off date: 4th september 2009 , • Median follow up: 24 mo post random, 34 mo post diagnostic • DMC suggested to unblind the study • Significant difference of PFS in favour of arm B • Patients will continue treatment in their initial treatment arm
IFM 2005 02 : Responsea during consolidation (n= 572) a IMW Criteria b Mc Nemar test
IFM 2005 02 : Best Responsea (N=614) a IMW Criteria
IFM 2005-02 : PFS from randomization Rev Placebo P < 10-7
PFS according to Response Pre-Consolidation VGPR or CR PR or SD Rev Rev Placebo Placebo p<10-5 p=0.001 HR= 0.37 - CI 95% [0.25-0.58] HR= 0.54 - CI 95% [0.37-0.78]
PFS according to initial ß2-m ß2-m 3 mg/l ß2-m > 3 mg/l Rev Rev Placebo Placebo p<10-5 p=0,0002 HR= 0.38 - CI 95% [0.23-0.65] HR= 0.50 - CI 95% [0.36-0.69]
PFS according to cytogenetic With del 13 Without del 13 Rev Rev Placebo Placebo p=0.0001 p=0.003 HR= 0.45 - CI 95% [0.30-0.67] HR= 0.53 - CI 95% [0.35-0.81]
PFS according to induction regimen VAD VD Rev Rev Placebo Placebo p=0.0001 p=0.0005 HR= 0.47 - CI 95% [0.32-0.69] HR= 0.47 - CI 95% [0.30-0.72]
Grade 3-4 Adverse Events during Maintenance 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)