How I Treat Transplant Eligible Myeloma Patients

Transcription

1 How I Treat Transplant Eligible Myeloma Patients Michele Cavo Seràgnoli Institute of Hematology, Bologna University School of Medicine, Italy Podcetrtek, Slovene, April 14 th, 2012

2 NEW TREATMENT PARADIGM FOR PATIENTS WHO ARE ELIGIBLE FOR AUTOTRANSPLANTATION (ASCT) Novel agents Induction therapy Autograft 1 ± 2 Consolidation Maintenance

3 GOALS OF NOVEL-AGENT-BASED ASCT(s) To enhance tumor reduction and increase the rate of CR - Induction - ASCT, either single or double - Post-ASCT consolidation therapy To reduce the risk of relapse and sustain durable CR Post-ASCT maintenance therapy To extend PFS and OS

4 NOVEL AGENT-BASED INDUCTION THERAPIES Thalidomidebased Lenalidomidebased Bortezomibbased Bortezomib + IMiD-based 2-drug combinations TD RD Rd VD 3-drug combinations TAD CTD RAD RCD BiRD PAD VCD VTD VRD 4-drug combinations VTDC RVDC

5 GOALS OF NOVEL-AGENT-BASED INDUCTION THERAPIES To enhance the depth of response up to the VGPR, ncr and CR level To quickly reverse disease-related complications, such as hypercalcemia, renal failure and anemia To ameliorate patient s symptoms To enable successful collection of PBSCs To minimize toxicities precluding subsequent ASCT Cavo et al. Blood 2011;117:

6 IMPORTANCE OF ACHIEVING HIGH-QUALITY RESPONSE TO VTD OR TD INDUCTION THERAPY Achievement of at least ncr prognosticates for extended PFS Progression-free survival Multivariate analysis ncr+cr Variable Relative risk (95% CI) p < ncr t(4;14) ± del(17p) 1.8 ( ) <0.001 Β2-m > 3.5 mg/l 2.0 ( ) < Months p= Failure to achieve at least ncr 1.6 ( ) Cavo et al, unpublished data

7 PHASE 3 STUDIES OF NOVEL AGENTS INCORPORATED INTO AUTOTRANSPLANTATION % INDUCTION % ASCT REGIMEN CR VGPR CR VGPR PFS OS TT2 + Thal vs NR NR 59 (3-yr)* NR 56% (5-yr)* 67% (5-yr)* TT2 no Thal 1 NR NR 42 (3-yr)* NR 45% (5-yr)* 65% (5-yr)* TAD + Thal vs 3 37* 14 54* 34 mo* 73 mo VAD + IFN * 12 44* 22 mo* 60 mo VD+Len±Len vs 6 38* 16* 54* 36 81% (3-yr) VAD+Len±Len 3 1* 15* 9* 37* 30 77% (3-yr) PAD+Bort vs NR 42* NR 61* 36 mo* HR = 0.73* VAD+Thal 4 NR 15* NR 36* 27 mo* Not reach. 1.Barlogie et al. N Engl J Med. 2006;354(10): Lokhorst et al. Blood 2010;115(6): Harousseau et al. J Clin Oncol. 2010;28(30): Sonneveld et al. Blood 2010;116(21). Abstract 40 * P value statistically significant

8 PHASE 3 STUDIES OF NOVEL AGENTS INCORPORATED INTO AUTOTRANSPLANTATION % INDUCTION % ASCT REGIMEN CR VGPR CR VGPR PFS OS TT2 + Thal vs NR NR 59 (3-yr)* NR 56% (5-yr)* 67% (5-yr)* TT2 no Thal 1 NR NR 42 (3-yr)* NR 45% (5-yr)* 65% (5-yr)* TAD + Thal vs 3 37* 14 54* 34 mo* 73 mo VAD + IFN * 12 44* 22 mo* 60 mo VD+ Len ± Len vs 6 38* 16* 54* 36 81% (3-yr) VAD+ Len ± Len 3 1* 15* 9* 37* 30 77% (3-yr) PAD + Bort vs NR 42* NR 61* 36 mo* HR = 0.73* VAD + Thal 4 NR 15* NR 36* 27 mo* Not reach. VTD + VTD vs 19* 62* 42* 82* 68% (3-yr)* 86% (3-yr)* TD + TD 5 5* 28* 30* 64* 56% (3-yr)* 84% (3-yr)* VTD vs 35* 60* 46* 65* Not reach.* Not reach. TD 6 14* 29* 24* 40* 27 mo* Not reach. vtd vs 13* 51* 30* 61* Not reach. Not reach. VD 12* 35* 33* 54* Not reach. Not reach. 1.Barlogie et al. N Engl J Med. 2006;354(10): Lokhorst et al. Blood 2010;115(6): Harousseau et al. J Clin Oncol. 2010;28(30): Sonneveld et al. Blood 2010;116(21). Abstract 40 5.Cavo et al. Lancet 2010;379(9758): Rosiñol et al. Blood 2010;116(21). Abstract Harousseau et al. Blood 2009;114(22). Abstract 354. * P value statistically significant

9 PROGRESSION-FREE SURVIVAL Cavo et al. Lancet 2010;379(9758):

10 BORTEZOMIB + IMID-BASED INDUCTION REGIMENS INDUCTION REGIMEN RESPONSE POST-INDUCTION (%) RESPONSE POST-ASCT (%) CR VGPR CR VGPR PFS (months) OS (months) VRD not reported 75% (@ 18m) 97% (@ 18m) VRD not reported not reported VRD not reported 1 Richardson et al. Blood 2010; 116: Kumar et al. Blood 2012; [Published ahead of print March 15] 3 Roussel et al. Blood 2010; 116(21); Abstract 624, oral presentation at ASH 2010

11 LENALIDOMIDE-BASED REGIMENS ± AUTOTRANSPLANTATION 4 cycles Best response REGIMEN CR (%) VGPR (%) AEs grade 3 (%) EARLY DEATH (%) CR (%) VGPR (%) PFS OS RD vs NR 42* 52* 5* NR 87% (2-yr) Rd 1 NR 24* 35* 1* NR 75% (2-yr) 1.Rajkumar et al. Lancet Oncol. 2010;11(1): * P value statistically significant

12 NEW TREATMENT PARADIGM FOR PATIENTS WHO ARE ELIGIBLE FOR AUTOTRANSPLANTATION (ASCT) Novel agents Induction therapy Autograft 1 ± 2 Consolidation Maintenance

13 Aims of consolidation or maintenance therapy Consolidation Improve response/induce deeper response following therapy by administration of treatment for limited period Maintenance Maintain response achieved following therapy by administration of treatment for prolonged period Overall goal: prolong survival

14 STUDY DESIGN RANDOMIZATION INDUCTION (three 21-d cycles) VEL-THAL-DEX Vel 1.3mg/m 2 twice weekly Thal mg/day Dex 320mg/cycle INDUCTION (three 21-d cycles) THAL-DEX Thal mg/day Dex 320mg/cycle PBSC COLLECTION CTX TRANSPLANTATION MEL 200 Thal 100md/day Dex 160mg/cycle MEL 200 CONSOLIDATION (two 35-d cycles) VEL-THAL-DEX Vel 1.3mg/m 2 once weekly Thal 100mg/day Dex 320mg/cycle CONSOLIDATION (two 35-d cycles) THAL-DEX Thal 100mg/day Dex 320mg/cycle MAINTENANCE DEX

15 PROBABILITY TO UPGRADE FROM < CR TO CR WITH VTD AND TD AS CONSOLIDATION THERAPY AFTER ASCT TD: 17% VTD: 31% p = 0.030* *Pearson χ 2 significance probability

16 KAPLAN-MEIER CURVES FOR PFS FROM THE LANDMARK OF STARTING CONSOLIDATION THERAPY Cavo et al. Blood 2012; in press

17 COX REGRESSION ANALYSIS OF PFS FROM START OF CONSOLIDATION THERAPY UNIVARIATE ANALYSIS N pts High-risk subgroups VTD TD Hazard ratio 95% CI P-value t(4;14) and/or del(17p) positive del(13q) positive LDH >190 U/L β 2 -microglobulin >3.5 mg/l ISS stage MULTIVARIATE ANALYSIS Variable Hazard ratio 95% CI P-value β 2 -microglobulin <3.5 mg/l <.0001 Absence of t(4;14) and/or (17p) <.0001 Consolidation with VTD Cavo et al. Blood 2012; in press

18 NOVEL-AGENT-BASED CONSOLIDATION THERAPY AGENT / REGIMEN N CYCLES PROBABILITY TO UPGRADE RESPONSE (%) PFS OS Bortezomib vs 6 VGPR*: mos (median) no consolidation 1 / VGPR*: mos (median) VTD 2 4 CR: mo (median) 89% (3-yr) molecular CR: 15 > PFS > OS Lenalidomide 3 2 CR: 6 not eval. not eval. VGPR: 10 not eval. not eval. VTD 4,5 2 CR: 33 >PFS not sign. molecular CR: yes 1.Mellqvist et al. Haematologica 2011; 96(suppl 1). Abstract Ladetto et al, J Clin Oncol 2010;28: Attal et al. Blood 2009;114(22). Abstract Cavo et al. Blood 2010;116(21). Abstract Terragna et al. Blood 2010;116(21). Abstract 861. * P value statistically significant

19 NEW TREATMENT PARADIGM FOR PATIENTS WHO ARE ELIGIBLE FOR AUTOTRANSPLANTATION (ASCT) Novel agents Induction therapy Autograft 1 ± 2 Consolidation Maintenance

20 PHASE 3 STUDIES OF THALIDOMIDE MAINTENANCE Induct with Thal Improved PFS Improved OS Survival after relapse NO 1 Yes 39 m, 5.7 yr Similar in all groups NO 2 Yes Yes (3 yrs follow up) Similar in all groups YES 3 Yes Yes (7.2 yrs follow-up) Reduced OS after thal exposure YES 4 Yes No YES 5 Yes No YES 6 Yes No Reduced OS after thal exposure Reduced OS after thal exposure Reduced OS after thal exposure 1.Attal et al. Blood 2006;108: Spencer et al. J Clin Oncol 2009;27: Barlogie et al. N Engl J Med 2006;354: ; Blood 2008;112: ; J Clin Oncol 2010;28: Lokhorst et al. Blood 2010;115: Morgan et al. Blood 2010; 116(21). Abstract Stewart et al. Blood 2010; 116(21). Abstract 39

21 Morgan et al. Blood 2012;119:7-15 META-ANALYSIS OF STUDIES INCLUDING A THALIDOMIDE MAINTENANCE REGIMEN

22 THALIDOMIDE MAINTENANCE : CAVEATS In ASCT setting, benefit with thal maintenance seen in terms of PFS but not always of OS 1 Toxicity, particularly neurological, leading to discontinuation rates up to 60% 2 Shorter survival following relapse in patients with prior exposure to thal Selection of resistant clones? No benefit in patients with del(13q) and worse outcome in patients with del(17p) 2,3 1. Cavo et al. J Clin Oncol 2009; 27(32): e Attal et al. Blood 2006;108: Morgan et al. Blood 2012; 119(1);7-15.

23 PHASE 3 STUDIES OF LENALIDOMIDE MAINTENANCE Study Treatment Median follow-up PFS / TTP OS OS after relapse Len 44 mo IFM Len consolid - R Placebo 34 mo 24 mo No significant difference No significant difference (P<10-8 ) Len CALGB R 28 mo Placebo 48 mo 31 mo (P<0.0001) > Len NR 1.Attal et al. Blood 2010; 116(21). Abstract McCarthy et al. Haematologica 2011;96(suppl 1): S23 [IMW abstract]

24 CRUDE INCIDENCE OF SPM n (%) Len (n = 306) IFM PBO (n = 302) Len (n = 216) Median follow-up 35 months 25 months CALGB PBO (n = 210) AML 3 (1.0) 2 (0.7) 4 (1.9) 0 MDS 2 (0.7) 0 3 (1.4) 0 MDS to AML B-ALL & Hodgkin lymphoma 6 (2.0) 0 2 (0.9) 0 Other hematol. malignancies Total* hematol. malignancies 11 (3.6) 2 (0.7) 9 (4.2) 0 Solid tumors 6 (2.0) 1 (0.3) 8 (3.7) 4 (1.9) Total* invasive SPMs 17 (5.6) 3 (1.0) 17 (7.9) 4 (1.9) Non-melanoma skin malignancies 4 (1.3) 2 (0.7) 2 (0.9) 2 (1.0) Total* all SPMs 19 (6.2) 5 (1.7) 19 (8.8) 6 (2.9)

25 CONCLUSIONS INDUCTION THERAPY - A triplet bortezomib-based regimen is likely to affect the highest rate of high-quality responses and should be considered a standard of care cycles represent a reasonable balance between efficacy and toxicity - BiPN is a major concern. Neurological toxicity might be significantly reduced by use of s.c. bortezomib ASCT - Outside clinical trials comparing early vs late ASCT, the preferred approach should continue to be ASCT up-front - High-dose therapy further enhances tumor reduction even in face of high CR rates affected by novel-agent-based induction regimens

26 CONCLUSIONS CONSOLIDATION THERAPY - Provides an incremental improvement in the rate of high-quality responses, up to the deepest level of molecular remission - Its impact on long-term clinical outcomes needs to be confirmed in prospective, randomized trials MAINTENANCE THERAPY - Lenalidomide reduces the risk of progression (60% range) and significantly prolongs TTP/PFS - Benefits with lenalidomide are seen regardless of β2 m, prior exposure to any of the novel agents, disease status at randomization, del (13q) - Does lenalidomide prolong OS?

27 NOVEL AGENTS ALONE VERSUS INTENSIVE THERAPY + NOVEL AGENTS: EUROPEAN INTERGROUP TRIAL (EMN02)

28 SUMMARY Although it is difficult to assess the impact of different treatment strategies (induction, ASCT, consolidation, maintenance) on clinical outcomes, PFS has been improved with new ASCT compared with old ASCT 1 New ASCT Old ASCT Treatment PFS Treatment PFS TAD + ASCT 1 + thal maint. 34 mos PAD + ASCT 1/2 + bort maint. 36 mos VD + ASCT 1/2 + len cons. and maint. 36 mos VAD + ASCT 1 + IFN maint. (Attal, 1996) VAD + ASCT 1 + IFN maint. (Child, 2003) VAD + ASCT 1 + IFN maint. (Cavo, 2007) 27 mos 30 mos 23 mos VTD + ASCT 1 + IFN/thal/bort+thal maint. 60% at 3 yrs VTD + ASCT 2 + VTD cons + dex maint. 68% at 3 yrs VAD + ASCT 2 + IFN maint. (Attal, 2003) 30 mos VAD + ASCT 2 + IFN maint. (Cavo, 2007) 35 mos 1 Cavo et al. Blood. 2011;117(23):

29 WHAT SHOULD BE THE TREATMENT GOAL IN MM PATIENTS? To achieve conventionally defined CR (not enough!) To eradicate the tumor clone or reduce it at the lowest detectable level To achieve immunophenotypic or molecular CR To achieve cure or at least long-term survival (>10 15 years) with good quality of life

30 PFS ACCORDING TO POST-ASCT PET/CT IN PATIENTS ACHIEVING CR Zamagni et al. Blood. 2011;118:

31 WHAT SHOULD BE THE TREATMENT GOAL IN MM PATIENTS? To achieve conventionally defined CR (not enough!) To eradicate the tumor clone or reduce it at the lowest detectable level To achieve immunophenotypic or molecular CR To achieve cure or at least long-term survival (>10 15 years) with good quality of life

32 PROGNOSTIC IMPACT OF MAINTAINING MOLECULAR REMISSION 6 MONTHS AFTER CONSOLIDATION THERAPY Terragna C et al unpublished data PFS MCR negative p = MCR positive H.R % CI ( ) p = Number at risk MCR negative MCR positive analysis time

33 WHAT IS THE ROLE OF TRANSPLANTATION IN MM IN THE ERA OF NOVEL AGENTS?

34 NOVEL AGENTS ALONE VERSUS INTENSIVE THERAPY + NOVEL AGENTS: EUROPEAN INTERGROUP TRIAL (EMN02)

35 Kaplan Probability Meier estimate IMPORTANCE OF ACHIEVING HIGH-QUALITY RESPONSE TO VD OR VAD INDUCTION THERAPY Achievement of at least VGPR prognosticates for extended PFS Progression-free survival Multivariate analysis VGPR after induction Variable Relative risk (95% CI) t(4;14) ± del(17p) 1.5 ( ) p <VGPR after induction p< ISS stage 2 and ( ) < Best response < VGPR Response < VGPR 2.0 ( ) < ( ) < Months Moreau et al. Blood 2011;117:3041-4

36 PHASE III TRIAL: BORTEZOMIB MONOTHERAPY AS CONSOLIDATION (Nordic Myeloma Study Group [NMSG 15/05] trial) Induction (no bortezomib) + single or double ASCT (n=403) Randomization (3 months post-asct) (n=370) Bortezomib (n=188) 1.3 mg/m 2 IV Two 3-week cycles: days 1, 4, 8, 11 + Four 4-week cycles: days 1, 8, 15 (total 20 injections over 21 weeks) Observation (n=182) Primary objective: PFS Mellqvist et al. Haematologica 2011; 96 (s1): S31 (Abstract O-11); oral presentation at IMW 2011

37 RESPONSE RATES, PFS, OS MEDIAN FOLLOW-UP: 27 MONTHS Bortezomib Control p value post- ASCT best reported post- ASCT best reported CR/nCR 20% 45% 21% 35% VGPR 39% 71% 39% 57% PFS (months) 27% 20% OS 87% 87% NS Incidence of neuropathy CTC III Neuropathic pain 6% 0.5% Peripheral sensory neuropathy 5% 2% Mellqvist et al. Haematologica 2011; 96 (s1): S31 (Abstract O-11); oral presentation at IMW 2011

38 PHASE 3: VTD VS TD (GIMEMA STUDY) IMPACT OF VTD CONSOLIDATION Per-protocol analysis: n=321, received entire treatment program VTD TD p CR post-consolidation 61% 47% Upgrade to CR post-consolidation 30.4% 16.6% Landmark analysis from start of consolidation (30 months median follow up) 3-yr probability of relapse or progression 38% 52% yr PFS 62% 46% Frequency of grade 3/4 AEs comparable in both groups 9.3% VTD, 8.6% TD PN with VTD: 0.6% Skin rash, DVT: 0.6% in each group VTD arm: patients received 93% of planned doses of bortezomib and thal Cavo et al. ASH 2011 (Abstract 1871), oral presentation

39 ANALYSIS BY USE OF THE MCNEMAR S TEST OF PATIENTS WHO UPGRADED OR DOWNGRADED THEIR RESPONSE STATUS AFTER CONSOLIDATION THERAPY WITH VTD OR TD RESPONSE STATUS AFTER CONSOLIDATION VTD TD RESPONSE STATUS BEFORE CONSOLIDATION CR <CR Total CR <CR Total N pts N pts N pts N pts N pts N pts CR <CR Total P-value RESPONSE STATUS BEFORE CONSOLIDATION CR+nCR <ncr Total CR+nCR <ncr Total N pts N pts N pts N pts N pts N pts CR+nCR <ncr Total P-value Cavo et al. Blood 2012; in press

40 IMPACT OF ACHIEVING MOLECULAR REMISSION CONSOLIDATION FOLLOWING TRANSPLANT Ladetto J Clin Oncol 2010;28: n=39 in VGPR after ASCT, treated with 4 cycles VTD Post ASCT Post VTD consolidation IF - CR 15% 49% Molecular remission 3% 18% After consolidation 6 months after consolidation

41 LENALIDOMIDE AND BORTEZOMIB/ LENALIDOMIDE-BASED CONSOLIDATION Study details IFM Len consolidation (2 mos) Maintenance randomization: Len vs placebo n=572 Response data CR (IF ) 14% 20% < VGPR 58% 67% < p IFM VRD induction ASCT VRD consolidation (2 cycles) Len maintenance n=31 Preconsolidation Postconsolidation Postinduction Post- ASCT Postconsolidation scr 17% 36% 39% CR 6% 6% 9% VGPR 39% 26% 36% Consolidation: upgraded response in 26% 1 Attal et al. Haematologica 2011; 96 (s1): S23; oral presentation at IMW Roussel et al. ASH 2011 (Abstract 1872), poster presentation

42 PHASE 3 STUDIES OF THALIDOMIDE MAINTENANCE Induct with Thal Improved PFS Improved OS Survival after relapse NO 1 Yes 39 m, 5.7 yr Similar in all groups NO 2 Yes Yes (3 yrs follow up) Similar in all groups YES 3 Yes Yes (7.2 yrs follow-up) Reduced OS after thal exposure YES 4 Yes No YES 5 Yes No YES 6 Yes No Reduced OS after thal exposure Reduced OS after thal exposure Reduced OS after thal exposure 1.Attal et al. Blood 2006;108: Spencer et al. J Clin Oncol 2009;27: Barlogie et al. N Engl J Med 2006;354: ; Blood 2008;112: ; J Clin Oncol 2010;28: Lokhorst et al. Blood 2010;115: Morgan et al. Blood 2010; 116(21). Abstract Stewart et al. Blood 2010; 116(21). Abstract 39

43 PFS according to Response Post-ASCT CR Not in CR Rev Rev p=0.021 p< Placebo Placebo Placebo Revlimid Placebo Revlimid HR= CI 95% [ ] HR= CI 95% [ ] Attal M, et al. Blood. 2010;116:[abstract 310].

44 Probability CALGB : Overall survival 1.0 Follow-up to 04/17/ P = deaths in the lenalidomide arm and 39 deaths in the placebo arm ITT Analysis with a median follow-up from transplant of 28 months. Placebo Lenalidomide Time since ASCT (days) McCarthy P, et al. Haematalogica. 2011;96(suppl 1): S23 [IMW abstract].

45 CRUDE INCIDENCE OF SPM n (%) Len (n = 306) IFM PBO (n = 302) Len (n = 216) Median follow-up 35 months 25 months CALGB PBO (n = 210) AML 3 (1.0) 2 (0.7) 4 (1.9) 0 MDS 2 (0.7) 0 3 (1.4) 0 MDS to AML B-ALL & Hodgkin lymphoma 6 (2.0) 0 2 (0.9) 0 Other hematol. malignancies Total* hematol. malignancies 11 (3.6) 2 (0.7) 9 (4.2) 0 Solid tumors 6 (2.0) 1 (0.3) 8 (3.7) 4 (1.9) Total* invasive SPMs 17 (5.6) 3 (1.0) 17 (7.9) 4 (1.9) Non-melanoma skin malignancies 4 (1.3) 2 (0.7) 2 (0.9) 2 (1.0) Total* all SPMs 19 (6.2) 5 (1.7) 19 (8.8) 6 (2.9)

46 WHAT IS THE ROLE OF TRANSPLANTATION IN MM IN THE ERA OF NOVEL AGENTS?

47 IMID-BASED INDUCTION REGIMENS: EARLY VERSUS LATE ASCT REGIMEN STUDY DETAILS RESULTS RD vs Rd 1 TD or Rd 2 Retrospective analysis of phase 3 ECOG E4A03 study Retrospective analysis of 290 patients treated with TD or RD Patients < 65 years old 3-year OS Early transplant (n=68): 94% Late transplant (n=141): 78% Patients treated with TD 4-year OS Early transplant (n=82): 68% Late transplant (n=41): 64% Patients treated with Rd 4-year OS Early transplant (n=91): 82% Late transplant (n=76): 86% 1 Siegel et al. Blood 2010;116(21); Abstract 38 2 Kumar et al. Cancer 2011 (Epub ahead of print)

48 IFM/DFCI 2009 study Newly diagnosed MM patients (SCT candidates) Randomize, stratification ISS & FISH VRD x 3 Induction VRD x 3 CY (3g/m 2 ) MOBILIZATION Goal: 5 x10 6 cells/kg Collection CY (3g/m 2 ) MOBILIZATION Goal: 5 x10 6 cells/kg Melphalan 200mg/m 2 * + ASCT VRD x 2 Lenalidomide 12 mos Consolidation Maintenance VRD x 5 Lenalidomide 12 mos SCT at relapse MEL 200 mg/m2 if <65 yrs, 65 yrs 140mg/m 2

49 MORE SENSITIVE TECHNIQUES ARE REQUIRED TO DETECT THE DEPTH OF RESPONSE BEYOND THE LEVEL OF CR Bone marrow level Clonality of PC and k:λ FLC ratio STRINGENT CR (scr) 1 Multiparametric flow cytometry IMMUNOPHENOTYPIC CR 2 Qualitative and quantitative RT-PCR MOLECULAR CR 3,4 Outside bone marrow MRI 5 PET-CT 6 1. Durie et al, Leukemia 2006;20: Paiva et al, Blood 2008;112: Terragna et al, Blood 2010;116(21). Abstract Ladetto et al, J Clin Oncol 2010;28: Barlogie, Blood 2006; 108: Zamagni et al, Blood 2010;116(21). Abstract 369

50 PROGNOSTIC IMPACT OF ACHIEVING MOLECULAR REMISSION AT DAY +70 AFTER CONSOLIDATION THERAPY Terragna C et al unpublished data PFS MCR negative p = MCR positive H.R % CI ( ) p = Number at risk MCR negative MCR positive analysis time

51 PFS ACCORDING TO SUV MODIFICATION POST INDUCTION P= SUV basal >4.2, post-ind.< 4.2 SUV basal >4.2, post ind. > % at 4 yrs 42% at 4 yrs months Zamagni et al, Blood 2011;118. Abstract 826

52 PFS ACCORDING TO SUV MODIFICATION POST ASCT P= 0.04 SUV basal >4,2, final < 4.2 SUV basal >4,2, final > % at 4 yrs 21% at 4 yrs months

53 NEW TREATMENT PARADIGM FOR PATIENTS WHO ARE ELIGIBLE FOR AUTOTRANSPLANTATION (ASCT) NOVEL AGENTS Induction therapy Autograft 1 ± 2 Consolidation Maintenance Have novel agents incorporated into ASCT opened the doors for a risk-adapted strategy?

54 TD FAILED TO OVERCOME THE POOR PROGNOSIS RELATED TO THE PRESENCE OF t(4;14) PROGRESSION-FREE SURVIVAL

55 PHASE 3: MPR VERSUS TANDEM ASCT Induction Consolidation Maintenance n=402 Rd (four 28-d cycles) Lenalidomide 25 mg/d, d1-21 Low-dose dex 40mg/d, d 1,8,15,22 R A N D O M I Z E n=202 MPR (six 28-d cycles) Melphalan 0.18 mg/kg/d, d 1-4 Prednisone 2 mg/kg/d, d 1-4 Len 10 mg/d, d 1-21 n=200 MEL 200 Tandem Mel 200mg /m 2 plus stem cell support R A N D O M I Z E No maintenance Maintenance Len 10 mg/d, d d course until relapse Primary end point: PFS Palumbo et al. ASH 2011 (Abstract 3069), poster presentation

56 Palumbo et al. ASH 2011 (Abstract 3069), poster presentation PHASE 3: MPR VERSUS TANDEM ASCT Median follow up 26 mos MPR (n=202) MEL 200 (n=200) p CR 20% 25% 0.49 VGPR 60% 58% yr PFS 54% 73% < yr OS 87% 90% yr PFS Standard-risk pts 46% 78% High-risk pts 27% 71% Pts who achieved CR 66% 87% <0.001 Pts who achieved PR 56% 77% <0.001 Gr 3/4 neutropenia 55% 89% <0.001 Gr 3/4 infections 0% 17% <0.001 Gr 3/4 GI toxicity 0% 21% <0.001 DVT 2.44% 1.13% 0.43 Second tumors 0.5% 1.5% 0.12