New Treatment Paradigms in Transplant-Eligible Myeloma Patients

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1 New Treatment Paradigms in Transplant-Eligible Myeloma Patients Michele Cavo Seràgnoli Institute of Hematology, Bologna University School of Medicine, Italy Turkey, March 1 st 2013

2 NEW TREATMENT PARADıGM FOR PATıENTS WHO ARE ELıGıBLE FOR AUTOTRANSPLANTATıON (ASCT) Novel agents Induction ASCT 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 IMPORTANCE OF ACHıEVıNG HıGH-QUALıTY RESPONSE TO VTD OR TD ınductıon THERAPY Achievement of at least ncr prognosticates for extended PFS Progression-free survival ncr+cr < ncr p= Months Variable Multivariate analysis Relative risk (95% CI) t(4;14) ± del(17p) 1.8 ( ) <0.001 Β2-m > 3.5 mg/l 2.0 ( ) <0.001 Failure to achieve at least ncr p 1.6 ( ) Cavo et al, unpublished data

5 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 Cavo et al. Blood 2011;117:

6 Cavo et al. Blood 2005;106:35-39 Rajkumar. Blood 2005;106:2-3

7 PHASE 3 STUDIES OF THALIDOMIDE-BASED INDUCTION REGIMENS INDUCTION N INDUCTION FIRST ASCT REGIMEN CYCLES % CR % VGPR % CR % VGPR TAD VAD CTD C-VAD Lokhorst et al. Blood 2010;15(6): Morgan et al. Haematologica 2012;97(3): per-protocol analysis

8 PHASE 3 STUDIES OF BORTEZOMIB-BASED INDUCTION REGIMENS INDUCTION N INDUCTION FIRST ASCT REGIMEN CYCLES % CR % VGPR % CR % VGPR VD VAD PAD 2 3 not rep. 42 not rep. 61 VAD 3 not rep. 15 not rep Harosseau et al. J Clin Oncol 2010;28(30): Sonneveld et al. Blood 2010;116(21)Abstract40 per-protocol analysis

9 PHASE 3 STUDIES OF BORTEZOMIB-THALIDOMIDE-BASED INDUCTION REGIMENS INDUCTION N INDUCTION FIRST ASCT REGIMEN CYCLES % CR % VGPR % CR % VGPR VTD TD VTD TD vtd VD Cavo et al. Lancet 2010;379(9758): Rosiñol et al. Blood 2010;116(21). Abstract Moreau et al. Blood 2011;117(11):

10 PHASE 2 STUDIES OF BORTEZOMIB-LENALIDOMIDE-BASED PRIMARY THERAPIES INDUCTION N INDUCTION ASCT REGIMEN CYCLES % CR % VGPR % CR % VGPR VRD not reported VRD not reported VRD Richardson et al. Blood 2010; 116: Kumar et al. Blood 2012; 119(19): Roussel et al. Blood 2010; 116(21); Abstract 624 best response

11 PHASE 2 STUDIES OF BORTEZOMIB-CYCLOPHOSPHAMIDE-BASED PRIMARY THERAPIES INDUCTION N INDUCTION ASCT REGIMEN CYCLES % CR % VGPR % CR % VGPR VCD (+ncr) 36.6 not reported CyBorD (+ncr) (+ncr) 74 VCD not reported VCD-mod not reported 1.Einsele et al. Blood 2009; 114(22); Abstract Reeder et al. Leukemia 2009; 23(7: ) 3.Kumar et al. Blood 2012; 119(19): response evaluated after 4 cycles

12 LENALIDOMIDE-DEXAMETHASONE UP-FRONT THERAPY ± AUTOLOGOUS TRANSPLANTATION 4 cycles Best response REGIMEN CR (%) VGPR (%) AEs grade 3 (%) EARLY DEATH (%) CR (%) VGPR (%) PFS OS RD vs NR NR 87% (2-yr) Rd 1 NR NR 75% (2-yr) 1.Rajkumar et al. Lancet Oncol. 2010;11(1):29-37.

13 DESIGN OF PHASE III TRIALS INCORPORATING NOVEL AGENTS INTO ASCT STUDY INDUCTION N ASCT CONSOLIDATION MAINTENANCE HOVON-50 MRC IX IFM HOVON 65/GMMG-HD4 GIMEMA MMY-3006 PETHEMA/GEM IFM TAD VAD CTD CVAD VD VAD PAD VAD VTD TD VTD TD VBMCP/VBAD/Vel vtd VD Thal IFN +/- Thal 1 or 2 Len +/- Len 1 or VTD TD /- Len or vtd Vel Thal Dex Dex IFN-α2b vs Thal vs Vel+Thal +/- Thal or Len

14 IMPACT OF NOVEL AGENTS INCORPORATED INTO ASCT(s) ON CLINICAL OUTCOMES Rate of high-quality responses ( VGPR, CR-nCR) to ASCT PFS and OS Novel agents have been also incorporated after ASCT as consolidation and/or maintenance therapy The contribution of different treatment phases to clinical outcomes cannot be easily evaluated

15 PHASE 3 STUDIES OF NOVEL AGENTS INCORPORATED INTO AUTOTRANSPLANTATION TREATMENT INDUCTION ASCT % CR % VGPR % CR % VGPR PFS OS TAD 1 + Thal maint mo 73 mo VAD + IFN maint mo 60 mo CTD mo not reach. ± Thal maint. C-VAD mo 63 mo VD 3 + Len cons not rep mo 81% (3 yr) VAD ± Len maint not rep mo 77% (3 yr) PAD 4 + Vel maint. not rep. 42 not rep mo not reach. VAD + Thal maint. not rep. 15 not rep mo not reach. per-protocol analysis 1.Lokhorst et al. Blood 2010;15(6): Morgan et al. Haematologica 2012;97(3): Harosseau et al. J Clin Oncol 2010;28(30): Sonneveld et al. Blood 2010;116(21)Abstract40

16 PHASE 3 STUDIES OF NOVEL AGENTS INCORPORATED INTO AUTOTRANSPLANTATION TREATMENT INDUCTION ASCT % CR % VGPR % CR % VGPR PFS OS VTD 1 + VTD cons % (3-yr) 86% (3-yr) TD + TD cons % (3-yr) 84% (3-yr) VTD 2 + IFN vs Not reach. Not reach. VT vs Thal TD maint mo Not reach. vtd 3 + Len or vtd mo Not reach. cons and Thal VD or Len maint mo Not reach. 1.Cavo et al. Lancet 2010;379(9758): Rosiñol et al. Blood 2010;116(21). Abstract Moreau et al. Blood 2011;117(11):

17 NEW TREATMENT PARADıGM FOR PATıENTS WHO ARE ELıGıBLE FOR AUTOTRANSPLANTATıON (ASCT) Novel agents Induction ASCT 1 ± 2 Consolidation Maintenance

18 AıMS OF CONSOLıDATıON AND MAıNTENANCE THERAPY Consolidation To improve the rate and depth of response achieved following therapy Maintenance To maintain response achieved following therapy by administration of treatment for limited period by administration of treatment for prolonged period Overall goal: prolong survival

19 GIMEMA MMY-3006 PHASE 3 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

20 GIMEMA MMY-3006 PHASE 3 STUDY: IMPACT OF VTD CONSOLıDATıON ON OUTCOMES VTD TD p CR before consolidation 48.7% CR post-consolidation 60.6% 46.6% Upgrade to CR post-consolidation 30.5% 16.7% Landmark analysis from start of consolidation (30 months median follow up) 3-yr PFS 60% 48% Cavo et al. Blood. Prepublished online April 12, 2012 Per-protocol analysis: 321 patients Frequency of grade 3/4 AEs comparable in both groups 10.6% VTD, 9.3% 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

21 KAPLAN-MEIER CURVES FOR PFS FROM THE LANDMARK OF STARTING CONSOLIDATION THERAPY Cavo et al. Blood. Prepublished online April 12, 2012

22 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. Prepublished online April 12, 2012

23 NOVEL-AGENT-BASED CONSOLıDATıON THERAPIES 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: 15% 49% 60 mo (median) 89% (3-yr) molecular CR: 3% 18% > PFS > OS Lenalidomide 3 2 CR: 14% 20% not eval. not eval. VGPR: 58% 67% not eval. not eval. 1.Mellqvist et al. Haematologica 2011; 96(suppl 1). Abstract Ladetto et al, J Clin Oncol 2010;28: Attal et al. Blood 2010;116. Abstract 310. * P value statistically significant

24 AıMS OF CONSOLıDATıON AND MAıNTENANCE THERAPY Consolidation To improve the rate and depth of response achieved following therapy Maintenance To maintain response achieved following therapy by administration of treatment for limited period by administration of treatment for prolonged period Overall goal: prolong survival

25 PHASE 3 STUDIES OF THALIDOMIDE MAINTENANCE AFTER ASCT(s) Thal+pamidronate vs Pamidronate vs None 1 Thal + pred vs Pred 2 Thal vs No Thal 3 Thal vs IFN 4 Thal vs None 5 Thal+pred vs None 6 Induction with thal Treatment ASCT Maintenance duration No Double ASCT until PD No Single ASCT 12 months Yes/No Double ASCT until PD Yes/No Single or double ASCT until PD Yes/No Single ASCT/ Non-intensive Tx until PD No Single ASCT until PD 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 2012; 119(1): Stewart et al. Blood 2010; 116(21). Abstract 39

26 PHASE 3 STUDIES OF THALIDOMIDE MAINTENANCE AFTER ASCT(s) 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 Reduced OS after thal exposure YES 5 Yes No Reduced OS after thal exposure YES 6 Yes No Not reported 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 2012; 119(1): Stewart et al. Blood 2010; 116(21). Abstract 39

27 OS BENEFıT WıTH THALIDOMIDE MAINTENANCE: META-ANALYSıS OF RANDOMIZED STUDıES Morgan et al. Blood 2012; 119: 7-15

28 THALIDOMIDE MAINTENANCE AFTER ASCT(s) : 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 high-risk cytogenetics 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.

29 PHASE 3 STUDIES OF LENALIDOMIDE MAINTENANCE AFTER ASCT(s) Study Treatment Median follow-up PFS OS IFM Len consolid Len 41 mo 73% (4 yrs) - R 45 mo Placebo 23 mo 75% (4 yrs) (p<0.001) Len 46 mo 88% (3 yrs) CALGB R 34 mo Placebo 27 mo 80% (3 yrs) (p<0.001) (p=0.03) 1. Attal et al. NEJM 2012;366(19): McCarthy et al. NEJM 2012;366(19):

30 IFM : EFS and OS (as of October 2011) PROGRESSION-FREE SURVIVAL OVERALL SURVIVAL STOP LEN 41 mos median* 23 mos median* Lenalidomide: 73% at 4 yrs Placebo: 75% at 4 yrs *40 vs 23 months after including SPM as an event Attal et al. NEJM 2012;366(19):

31 IFM : HR FOR PFS BY PATIENT SUBGROUP Age < vs 55 yr Gender β 2 -m vs > 3mg/L Del(13q) neg vs pos Induction VAD vs VD < VGPR vs at Attal et al. NEJM 2012;366(19):

32 CALGB : PFS and OS (as of October 2011) PROGRESSION-FREE SURVIVAL OVERALL SURVIVAL 46 mo. median 27 mo. median Lenalidomide: 88% at 3 yrs Placebo: 80% at 3 yrs *43 vs 27 months after including SPM as an event 86 out of 128 patients without PD in the placebo group crossed over to lenalidomide maintenance after study unblinding McCarthy et al. NEJM 2012;366(19):

33 SECOND PRIMARY MALIGNANCIES IFM (as of Oct 2011) CALG (as of Feb 2012) Attal et al. NEJM 2012;366(19): McCarthy et al. NEJM 2012;366(19):

34 CUMULATIVE INCIDENCE OF SPMs IFM (as of Oct 2011) CALG (as of Feb 2012) Attal et al. NEJM 2012;366(19): McCarthy et al. NEJM 2012;366(19):

35 Secondary Cancers in Myeloma Potential Factors Leukemogenic potential of conventional therapy Alkylating agents o Latency 5-10 years o Often with loss of all/part of chromosomes 5 and/or 7 Topoisomerase II inhibitors (doxorubicin, etoposide) o Latency 1-5 years. o Often with translocation of 11q23. Concomitant XRT increases risk Potential contribution of high-dose therapy + ASCT Low incidence MDS/AML with VAD induction and ASCT 1 FISH studies in Hodgkin s and non-hodgkin s lymphoma indicate MDS changes present before ASCT in most cases 2,3 1 Govindarajan R, et al. Br J Haematol 1996; 95: ; 2 Abruzzese E, et al. Blood 1999; 94: ; 3 Lillington DM, et al. J Clin Oncol 2001; 19:

36 Secondary Cancers in Myeloma Potential Factors Increased risk appears intrinsic to plasma cell disorders Higher risk of MDS/AML and non-melanoma skin cancer in patients with myeloma and MGUS 1 1 Mailankody W, et al. Blood 2011; 118:

37 HOVON 65/GMMG-HD4 MM STUDY DESIGN MM Stage II or III, Age Randomization 3 x VAD 3 x PAD CAD + GCSF CAD + GCSF MEL PBSCT MEL PBSCT GMMG MEL PBSCT Allogeneic Tx GMMG MEL PBSCT Thalidomide 50 mg/day for 2 years maintenance Bortezomib 1.3 mg/m 2 / 2 weeks for 2 years maintenance

38 HOVON 65/ GMMG-HD4 STUDY: PFS FROM ASCT 100 HR = 0.82 ( ), P=0.08 Cumulative percentage B: PAD A: VAD A: VAD B: PAD 10 Nov :15:14 0 A: VAD B: PAD At risk: N F months Sonneveld et al. Blood. 2010;116:[abstract 40].

39 ALLOGENEIC SCT IN THE NOVEL AGENT ERA Over the last 10 years a reduced-intensity conditioning (RIC) regimen in preparation for allo-sct preceded by ASCT (tandem AUTO-ALLO) has become a widely accepted procedure The role of ALLO-SCT as part of up-front therapy for MM continues to remain controversial in the novel agent era higher risk of relapse/progression in comparison with that previously reported with myeloablative treatments relatively high TRM and morbidity, particularly cronic GVHD

40 COMPARISONS OF DOUBLE ASCT WITH AUTO-ALLO SCT Lokhorst et al. JCO 2010;28:4521

41 EBMT STUDY PFS OS Bjorkstrand et al. JCO 2011;29:3016

42 Krishnan et al. Lancet Oncol. 2011;12:1195 BMT CTN 0102 STUDY PFS / STANDARD RISK OS / STANDARD RISK PFS / HIGH-RISK OS/ HIGH-RISK

43 CONCLUSIONS INDUCTION THERAPY - Novel-agent-based induction regimens affect unprecedented rates of CR that rival those previously seen with ASCT preceded cy conventional CHT. - A triplet bortezomib-based regimen is likely to yield the highest rate of high-quality responses and should be considered a standard of care - 3 to 6 cycles represent a reasonable balance between efficacy and toxicity - BiPN is an issue: it may adversely influence patient s QoL, but generally does not have a major impact on patient s ability to complete the induction therapy and to receive subsequent ASCT - Neurological toxicity might be significantly reduced by use of s.c. bortezomib

44 CONCLUSIONS 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 - The role of single vs. double ASCT in the novel agent era needs to be prospectively addressed in the context of randomized clinical trials

45 CONCLUSIONS CONSOLIDATION THERAPY - Provided an increase in the rate of high-quality responses, up to the deepest level of molecular CR after ASCT and in several studies was associated with extended PFS, thus contributing to the better outcome seen with the entire treatment program - Its impact on long-term clinical outcomes needs to be confirmed in prospective, randomized trials

46 NOVEL AGENTS ALONE VERSUS NOVEL AGENTS + INTENSIVE THERAPY: EMN 02 TRIAL

47 CONCLUSIONS MAINTENANCE THERAPY - Thalidomide has not been widely accepted - Lenalidomide dramatically reduced the relative risk of progression (50% range) and significantly prolonged TTP/PFS in comparison with placebo - Benefits with lenalidomide wee seen regardless of β2 m,prior exposure to any of the novel agents as part of induction, disease status at randomization and del (13q) - The risk of SPMs associated with lenalidomide maintenance is outweighed by improved clinical outcomes

48 CONCLUSIONS ALLOGENEIC SCT - Convincing evidence is lacking that tandem AUTO-ALLO (RIC- ALLO) as part of up-front therapy for MM improves the outcome compared with (double) ASCT, particularly in high-risk patients - Novel agents incorporated into the entire treatment program (before and after AUTO-ALLO SCT) and more effective conditioning regimens in preparation for ALLO SCT to reduce the risk of relapse are warranted - as up-front therapy for patients with ultra-high-risk disease - as salvage therapy at first early relapse (sensitive-treatment patients) in the context of controlled clinical trials

49 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 VAD + ASCT 1 + IFN maint. (Attal, 1996) 27 mos PAD + ASCT 1/2 + bort maint. 36 mos VAD + ASCT 1 + IFN maint. (Child, 2003) 30 mos VD + ASCT 1/2 + len cons. and maint. 36 mos VAD + ASCT 1 + IFN maint. (Cavo, 2007) 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):

50 WHAT SHOULD BE THE TREATMENT GOAL ın MM PATıENTS? 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

51 Progressive reduction in tumor cell mass throughout induction, ASCT, consolidation and maintenance therapy 1 kg 1x10 12 Tumor cells 1x10 6 Induction Transplant Consolidation Maintenance Detection limit of Immunophenotyping and Polymerase chain reacdtion 0 Time

52 FISH cytogenetics and immunophenotypic CR for the prediction of early relapse of patients in CR after ASCT TTP OS Paiva B et al. Blood 2012;119:

53 Impact of MRD detection by flow cytometry on clinical outcomes after high-dose tx and ASCT PFS OS % % 30% Median: 71 months Median: 37 months % Medians: not reached 0 P< P= years Months Months 5 years MRD negative (n=94) MRD positive (n=53) Paiva et al. Blood. 2008;112:

54 PROGNOSTıC ımpact OF MAıNTAıNıNG MOLECULAR REMıSSıON 6 MONTHS AFTER CONSOLıDATıON THERAPY PFS MCR negative MCR positive p = H.R % CI ( ) p = Number at risk MCR negative MCR positive analysis time Terragna C et al unpublished data

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

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

57 Impact of MRD detection by PCR techniques on clinical outcomes after high-dose tx and ASCT p = PFS H.R % CI ( ) p = MCR negative MCR positive Number at risk MCR negative MCR positive analysis time Terragna C et al, EHA 2011, oral presentation

58 Thalidomide maintenance and OS: Meta-analysis of randomized studies Morgan GJ, et al. Blood. 2012;119:7-15.

59 Number of patients with at least one SPM (10/2011) Lenalidomide (N= 306) Placebo (N= 302) Total (N= 608) Hematologic malignancies (%) 13 (4.2) 5 (1.7) 18 (3.0) AML/MDS 5 4 ALL 3 0 Hodgkin lymphoma / Non-HL 4 / 1 0 / 1 Solid tumours (%) 10 (3.3) 4 (1.3) 14 (2.3) Esophageal / Colon 4 0 Breast 2 0 Lung / Sinus 1 1 Kidney / Prostate 3 2 Melanoma 0 1 Non-Melanoma skin cancers (%) 5 (1.6) 3 (1.0) 8 (1.3) Total (%) 26* (8.5) 11** (3.6) 37 (6.1) Attal et al N Engl J Med 2012.

60 IFM : Risk Factors for SPM Factors (Multivariate Analysis) P value Treatment (Placebo vs Len) 0.03 Age (<=55 y vs >55 years) 0.02 Sex (M vs F) 0.03 ISS (I +II vs III) Cumulative dose of Len Consolidation only < 12 m m >24 m HR P Courtesy by M. Attal

61 Secondary Cancers with Lenalidomide Maintenance: Considerations Small increase in incidence, but... o IFM study included skin cancers o CALGB study had several cases even before starting drug EMA released statement in Sept 2011 o The benefit-risk balance for lenalidomide remains positive within its approved patient population but advises doctors of the risk of new cancers as a result of treatment with the medicine x 3.98 new cancers per every 100 patient-years with lenalidomide compared with 1.38 cases without lenalidomide in the approved population x Risk of secondary cancers was increased four-fold with the use of lenalidomide in newly diagnosed individuals Other factors likely contribute to these observations 1 Press Release 23 Sept 2011, European Medicines Agency,

62 MDS-Associated Cytogenetic Abnormalities (CA) after High-Dose Melphalan and ASCT for Myeloma 105/3077 developed MDS CA Transient in 72 MDS in 21; AML in 5 Predictors Age Lower CD34+ cell yields Predictors for TT2 and TT3 Early onset MDS CA-- longer time from dx and lower platelet count before ASCT Late onset MDS CA post- ASCT consolidation chemotherapy No effect of thalidomide 1 Barlogie B, et al. Blood 2008; 111:

63 Secondary Malignancies Potential Factors Possible relationship to immunomodulatory effects of lenalidomide: Meta-analysis of 74 RCTs of anti-tnfα monoclonal antibody therapy showed relative risk of 2.09 for non-melanoma skin cancers and 0.99 for all other cancers 1 Risk of skin cancers and lymphoma is higher in organ transplant recipients 2 Updated analyses of secondary cancers in myeloma patients treated with ASCT, IMiDs and bortezomib ASH 2011 abstracts # s 678, 823, 996, 2933, Askling J, et al. Pharmoepidemilo Drug Saf 2011; 20: Metcalfe MJ, et al. Can Resp J 2010; 17: e7-13

64 NOVEL-AGENT-BASED CONSOLıDATıON 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

65 RESPONSE TO DIFFERENT TREATMENT PHASES IN THE PER- PROTOCOL POPULATION, ACCORDING TO CENTRAL ASSESSMENT VTD (n=160) TD (n=161) P-value After second ASCT CR 78 (48.7%, ) 65 (40.4%, ).131 CR/nCR 101 (63.1%, ) 88 (54.7%, ).123 After consolidation therapy CR 97 (60.6%, ) 75 (46.6%, ).012 CR/nCR 117 (73.1%, ) 98 (60.9%, ).020 Cavo et al. Blood 2012; in press

66 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)

67 TREATMENT PARADıGM FOR PATıENTS WHO ARE ELıGıBLE FOR AUTOTRANSPLANTATıON (ASCT) Induction therapy Autograft 1 ± 2 Maintenance VAD DEX DEX IFN

68 NEW TREATMENT PARADıGM FOR PATıENTS WHO ARE ELıGıBLE FOR AUTOTRANSPLANTATıON (ASCT) Novel agents Induction therapy Autograft 1 ± 2 Consolidation Maintenance

69 GOALS OF NOVEL-AGENT-BASED ınductıon THERAPıES 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:

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

71 IMPORTANCE OF ACHıEVıNG HıGH-QUALıTY RESPONSE TO VTD OR TD ınductıon THERAPY Achievement of at least ncr prognosticates for extended PFS Progression-free survival ncr+cr ncr+cr < ncr < ncr p= p= Months Variable Multivariate analysis Relative risk (95% CI) t(4;14) ± del(17p) 1.9 ( ) <0.001 Β2-m > 3.5 mg/l 1.8 ( ) <0.001 Failure to achieve at least ncr p 1.7 ( ) Cavo et al, unpublished data NUOVA

72 PHASE 3 STUDIES OF THALIDOMIDE-BASED INDUCTION REGIMENS INDUCTION N INDUCTION FIRST ASCT REGIMEN CYCLES % CR % VGPR % CR % VGPR TD 1 4 not rep. 35 not rep. 60 VAD 4 not rep. 13 not rep TD 2 4 not rep. 25 not rep. 44 VAD 4 not rep. 7 not rep Cavo et al. J Clin Oncol 2009;27(30): Macro et al. Blood 2006;108. Abstract 57

73 PHASE 3 STUDıES OF NOVEL AGENTS ıncorporated ınto AUTOTRANSPLANTATıON % 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

74 PHASE 3 STUDıES OF NOVEL AGENTS ıncorporated ınto AUTOTRANSPLANTATıON % 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

75 EFFECT OF NOVEL AGENTS ON STEM CELL COLLECTION Thalidomide Adequate collection of stem cells 1,2 Bortezomib Not cytotoxic to bone marrow Successful mobilization and adequate collection of PBSC with variety of induction regimens 3-5 REGIMEN Priming therapy Collected CD34+ (x10 6 /kg) VD 4 G-CSF 6.8 VTD 5 CTX + G-CSF Breitkreutz et al. Leukemia 2007;21: Cavo et al. Blood 2005;106: Kumar et al. Blood 2009;114: Moreau et al. Leukemia 2010;24: Cavo et al. Lancet 2010;376:

76 EFFECT OF NOVEL AGENTS ON STEM CELL COLLECTION Lenalidomide Cytotoxic effect on bone marrow Evidence of decreased stem cell yield after lenalidomide exposure Recommendation: - Collection of PBSC within 4 months of initiation of therapy - Mobilization with G-CSF + cyclophosphamide after 4 months of therapy and/or in patients aged 65 years Kumar et al. Blood 2009;114:

77 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

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80 Attal et al. NEJM 2012;366(19): IFM : EFS (as of October 2011)

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83 Avet-Loiseau et al. JCO 2010;28:

84 Avet-Loiseau et al. JCO 2010;28: