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

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

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

Tales of Two Cases 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

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

VAD  4 (813) ASCT (261) VBMCP (255) Allograft (39) Responders IFN (121) No IFN (121) In a study of 899 patients, HDT (melphalan 140 mg/m 2 + TBI 12 Gy) vs standard dose VBMCP therapy showed no benefit for IFN maintenance Maintenance with IFN after ASCT Comparable Survival in MM Barlogie B, et al. J Clin Oncol. 2006;24:

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) Comparable survival in MM with or without IFN CR (%) PR (%) PFS (months) OS (months) ASCT p = p = 0.8 VBCMP IFN2359 − IFN18 Barlogie B, et al. J Clin Oncol. 2006;24:

Overall Survival With Maintenance Thalidomide Post-ASCT Badros AZ. J Natl Compr Canc Netw. 2010;8 Suppl 1:S21. Study or SubcategoryLog[HR] (SE) HR (Random) 95% CI Barlogie Attal Spencer Abdelkefi Total (95% CI) (0.1451) (0.2207) (0.3086) (0.4126) 0.98 [0.74, 1.30] 0.56 [0.36, 0.86] 0.32 [0.17, 0.58] 0.69 [0.31, 1.54] 0.61 [0.37, 1.01] Test for heterogeneity: Chi 2 =12.93, df=3 (P=.005), I 2 =76.8% Test for overall effect: Z=1.93 (P=0.05) Favors ThalidomideFavors Control Study or SubcategoryLog[HR] (SE) HR (Random) 95% CI Attal Spencer Abdelkefi Total (95% CI) (0.2207) (0.3086) (0.4126) 0.56 [0.36, 0.86] 0.32 [0.17, 0.58] 0.69 [0.31, 1.54] 0.49 [0.32, 0.74] Test for heterogeneity: Chi 2 =3.01, df=2 (P=.22), I 2 =33.6% Test for overall effect: Z=3.38 (P=.0007) Favors ThalidomideFavors Control

Three Trials to Guide Us IFM CALGB GIMENA MEL VS MPR

D-S Stage 1-3, < 70 years > 2 cycles of induction Attained SD or better  1 yr from start of therapy > 2 x 10 6 CD34 cells/kg Placebo Lenalidomide* 10 mg/d with ↑↓ (5–15 mg) Restaging Days 90–100 Registration CALGB Schema CR PR SD 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) Mel 200 ASCT * provided by Celgene Corp, Summit, NJ Randomization

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 IMW 2013 follow up to January 7, /229 events (64%) on placebo 104/231 events (45%) on lenalidomide CALGB : Updated TTP Estimated HR=0.51 (95% CI = 0.39 to 0.66),

CALGB 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 69/229 (30%) deaths on placebo 47/231 (20%) deaths on lenalidomide CALGB : Updated OS Estimated HR=0.61 (95% CI = 0.41 to 0.87 )

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

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

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

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

HR = CI 95% [0.25–0.58]HR = CI 95% [0.37–0.78] PFS According to Response Preconsolidation Attal M et al. Blood. 2009;114: Abstract 529. Attal M et al. J Clin Oncol. 2010;28: Abstract Len Placebo PR or SD VGPR or CR P<10 -5 P= Len Placebo

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

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.

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