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Sergio Giralt defends the PRO position

To Maintain or Not to Maintain The Answer is Yes And Lenalidomide is the Right Choice. Sergio Giralt defends the PRO position. So we will just proceed with the discussion Arguing and debating are survival strategies. Disclosures. Grant Support Celgene Millenium Onyx Honoraria Celgene

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Sergio Giralt defends the PRO position

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  1. To Maintain or Not to Maintain The Answer is Yes And Lenalidomide is the Right Choice Sergio Giralt defends the PRO position

  2. So we will just proceed with the discussion Arguing and debating are survival strategies.

  3. Disclosures • Grant Support • Celgene • Millenium • Onyx • Honoraria • Celgene • Millenium • Onyx • Novartis • Sanofi/Genzyme • Most important I am a transplanter

  4. Case 1 55-year-old female presents with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/L Workup reveals 30% plasma cells Cytogenetic diploid IgA kappa peak of 3.2 β2M of 3.0 Receives 4 cycles of Bz/Thal/Dex Followed by Auto SCT on day 60 documented stringent CR Case 2 55-year-old female presents with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/L Workup reveals 30% plasma cells Cytogenetic t(4;14) IgA kappa peak of 3.2 β2M of 3.0 Receives 4 cycles of Bz/Thal/Dex Followed by Auto SCT on day 60 documented paraprotein peak of 0.4 g/dL Tales of Two Cases

  5. What are our options? Traditional IMID + Proteosome Inhibitor Era IMID Thalidomide Lenalidomide Pomolidomide Proteosome inhibitor Bortezomib Carfilzomib • No maintenance • 24 months PFS • Until recently the standard • Maintenance interferon • Maintenance steroids • Maintenance alkylators

  6. Maintenance with IFN after ASCT Comparable Survival in MM In a study of 899 patients, HDT (melphalan 140 mg/m2 + TBI 12 Gy)vs standard dose VBMCP therapy showed no benefitfor IFN maintenance IFN (121) ASCT (261) VBMCP (255) Allograft (39) Responders No IFN (121) VAD  4 (813) Barlogie B, et al. J Clin Oncol. 2006;24:929-36.

  7. Comparable survival in MM with or without IFN p = NS • 52% of VBCMP patients had salvage ASCT 59% of whom had a PR (median OS 30 months) vs 23 months in patients who received non-transplant salvage therapy (p = 0.13) Barlogie B, et al. J Clin Oncol. 2006;24:929-36.

  8. Overall Survival With Maintenance Thalidomide Post-ASCT 0.1 0.2 0.5 1 2 5 10 Favors Thalidomide Favors Control 0.1 0.2 0.5 1 2 5 10 Favors Thalidomide Favors Control Badros AZ. J Natl Compr Canc Netw. 2010;8 Suppl 1:S21.

  9. Three Trials to Guide Us • IFM • CALGB 100104 • GIMENA MEL VS MPR

  10. CALGB 100104 Schema Registration Restaging Days 90–100 Randomization Mel 200 ASCT Placebo D-S Stage 1-3, < 70 years > 2 cycles of induction Attained SD or better  1 yr from start of therapy > 2 x 106 CD34 cells/kg CR PR SD Lenalidomide* 10 mg/d with ↑↓ (5–15 mg) * provided by Celgene Corp, Summit, NJ Stratification based on registration -2M level and prior thalidomide and lenalidomide use during Induction. Primary Endpoint: powered to determine a prolongation of TTP from 24 months to 33.6 months (9.6 months)

  11. CALGB 100104: Updated TTP Estimated HR=0.51 (95% CI = 0.39 to 0.66), 146/229 events (64%) on placebo 104/231 events (45%) on lenalidomide ITT Analysis with a median follow-up from transplant of ~48 months p<0.001 Median TTP: 50 months versus 27 months with 86 of 128 non-progressing placebo patients receiving lenalidomide at study un-blinding in Jan 2010 CALGB 100104 IMW 2013 follow up to January 7, 2013

  12. CALGB 100104: Updated OS Estimated HR=0.61 (95% CI = 0.41 to 0.87) 69/229 (30%) deaths on placebo 47/231 (20%) deaths on lenalidomide CALGB 100104 IMW 2013 follow up to January 7, 2013 ITT Analysis with a median follow-up from transplant of ~48 months. p= 0.008, Median OS: not reached versus 73 months

  13. CALGB 100104: Updated OS, 12 mo crossover Estimated HR=0.57 (95% CI = 0.40 to 0.83), 68/210 (32%) deaths on placebo 48/250 (19%) deaths on lenalidomide 63/183 (34%) deaths on placebo 53/277 (19%) deaths on lenalidomide CALGB 100104 IMW 2013 follow up to January 7, 2013 Analysis including placebo patients crossing over within 12 months of randomization on lenalidomide arm with a median follow-up of ~48 months. p= 0.003

  14. CALGB 100104 TTP Lenalidomide Stratification Median TTP Stratified by Prior Lenalidomide Use Placebo No Prior Len, 27 mo; Placebo Prior Len, 28 mo; LenNo Prior Len, 46 mo, Len Prior Len, Not reached CALGB 100104, January 2013 Subset analysis, ITT IMW 2013

  15. CALGB 100104 OS Lenalidomide Stratification Median OS Stratified by Prior Lenalidomide Use Placebo No Prior Len, 73 mo; Placebo Prior Len, Not reached; LenNo Prior Len, Not reached; Len Prior Len, Not reached CALGB 100104, January 2013, Subset analysis, ITT IMW 2013

  16. Phase 3 IFM 2005-02: Lenalidomide as Consolidation/Maintenance Post-ASCT Consolidation Lenalidomide: 25 mg/d Days 1–21/month 2 months Lenalidomide: 10–15 mg/d until relapse N=614 First-line ASCT <65 years ≤6 months No PD Lenalidomide: 25 mg/d Days 1–21/month 2 months Placebo until relapse Primary end point: PFS Attal M et al. Blood. 2009;114:Abstract 529.Attal M et al. J Clin Oncol. 2010;28: Abstract 8018.

  17. PFS According to Response Preconsolidation PR or SD VGPR or CR 1.00 1.00 0.75 0.75 0.50 0.50 0.25 0.25 P<10-5 P=0.001 0.00 0.00 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Len Placebo Len Placebo HR = 0.37 - CI 95% [0.25–0.58] HR = 0.54 - CI 95% [0.37–0.78] Attal M et al. Blood. 2009;114: Abstract 529.Attal M et al. J Clin Oncol. 2010;28: Abstract 8018.

  18. CALGB 100104: OS Response at Randomization Median OS Stratified by Response Placebo CR, 83 mo; Placebo Not in CR, 66 mo; LenCR, Not reached, Len Not in CR, Not reached CALGB 100104, January 2013 Subset analysis, ITT IMW 2013

  19. In Summary • Three trials have shown that post SCT therapy with lenalidomide prolong PFS • All trials show tolerability but increased in Second Primary Malignancies (SPM’s) a concern. • The benefit is regardless of response and prior exposure to lenalidomide. • Data is emerging that the benefit may be greater when started earlier after the SCT • One trial has shown a survival advantage with the others not yet being reported • FOR NOW LEN MAINTENANCE SHOULD BE CONSIDERED THE STANDARD OF CARE.

  20. ACKNOWLEDGEMENTS “New” Myeloma Service at MSKCC Adult BMT Service at MSKCC Nurses, Fellows. Pharm D’s Patients and their families Advanced Cellular Therapies (CAR and CTL’s)

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