Impact of Novel Therapies      In Multiple Myeloma        Jean-Luc HarousseauIntergroupe Francophone du Myélome
Impact of novel agents in   younger patients
Summary of novel agent induction trials              (randomized studies)                 ≥ VGPR rates post-induction and ...
IFM 2005-01  Impact of achieving at least VGPR after         induction ≥ VGPR vs PR                      RR     p. Valueβ2...
VAD vs Vel/Dex induction for t(4;14) patients                   OS                               treatment       VAD      ...
t(4;14) with Bortezomib      EFS of 507 patients treated with Vel/Dex induction                                           ...
Impact of Novel Agents           in the ASCT paradigm                   Induction Treatment• Impact of CR/VGPR after Induc...
CALGB trial                    Registration          Restaging           Randomization                                    ...
Median TTP: Not yet reached                         Median TTP 25.5 moCALGB 100104, Nov 2009                        Median...
IFM 2005-02: Study design          Patients < 65 years, with non-progressive disease, ≤ 6                      months afte...
1.000.75       IFM 2005-02 : PFS from randomization                          p<10-70.500.25           P < 10-70.00       0...
Impact of Novel Agents        in the ASCT paradigm        Best Intensive Approach• Induction     - 3 or 4 courses of VTD (...
Questions for the near future• Will longer PFS with lenalidomide maintenance translate  into longer OS ? Survival after re...
IFM 2005 02 : Response during consolidation                  (n= 572)               PRE    POST     p value   CR (IF -)   ...
Consolidation with VTD• Patients: (n=39) with ≥VGPR after ASCT• Treatment:   – 4 cycles VTD, started within 6 months      ...
SCHEMA: BMT CTN                                       Lenalidomide                           No                       Cons...
Questions for the near future                  Key Question• With novel agents (MPT,MPV,Rd,RVD) it is  now possible to ach...
Phase I/II study on RVD in             newly diagnosed MM Up to eight 21-day cycles * 1 2          4 5        8   9     11...
ASCT plus novel agents                                 PFS          100           90           80           70            ...
IFM/DFCI Trial                     VRD x 3                        SC                    collection   VRD x 5              ...
Impact of novel agents in    elderly patients
Frontline therapy in elderly patients• MP is no longer the standard of care• New standards    - MPT > MP (1,2,3)    - MPV ...
MPR-R vs MPR                               47% reduced risk in PFS                              100                       ...
VMPT-VT vs VMP             VMP    VMPT-VT   P-valueNb of pts     257     254Med age       71       71CR            24%    ...
Frontline therapy in elderly patients• MP is no longer the standard of care• New standards    - MPT > MP (1,2,3)    - MPV ...
Questions for the near future- Will better PFS obtained with maintenance translate into  longer OS ?- Is maintenance neces...
MPT vs Revlimid-low dose Dexamethasone in Newly             Diagnosed Myeloma Patients, Aged >65 Years       Phase III int...
General Questions1) Role of novel agents in poor-risk cytogenetics
General Questions1 Role of novel agents in poor-risk cytogenetics2 Which level of CR is needed to achieve long-term  remis...
Impact of immunophenotyping                                     at 3 months post-ASCT                                     ...
General questions1 Role of novel agents in poor-risk cytogenetics2 Which level of CR is needed to achieve long-term  remis...
Pomalidomide   O   O                        O    O                            O    O                                      ...
Phase II of Pom/Dex in patients refractory                  to Lenalidomide• 35 patients - Median age 62 y              - ...
Carfilzomib    Carfilzomib is the first in a new class of selective andirreversible proteasome inhibitors that are associa...
Phase II study of Carfilzomib                100                                                              CR          ...
PX-171-004: Response Summary                100                                                               CR          ...
Panobinostat + Bortezomib Best Response                                    Dose escalation B2207 study in Relapsed MM ptsC...
Panobinostat + Bortezomib Efficacy             Responses including in Bortezomib-Refractory Patients                    10...
Phase 1b Elotuzumab plus Len/dex                   Lonial ASCO 2010                                           Lenalidomide...
General questions1 Role of novel agents in poor-risk cytogenetics2 Which level of CR is needed to achieve long-term  remis...
General QuestionsSEARCHING FOR CURE …
General QuestionsSEARCHING FOR CURE  … OR TREATING MM            LIKE A CHRONIC DISEASE
General QuestionsSEARCHING FOR CURE  … OR TREATING MM            LIKE A CHRONIC DISEASEThe answer to this question may dep...
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Impact of Novel Therapies in the Management of Multiple Myeloma

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Jean-Luc Harousseau, M.D., Professor of Hematology, Head, Dept. of Clinical Hematology, Director of the Cancer Center Rene Gauducheau, University of Nantes, France - Impact of Novel Therapies in the Management of Multiple Myeloma

Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

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Impact of Novel Therapies in the Management of Multiple Myeloma

  1. 1. Impact of Novel Therapies In Multiple Myeloma Jean-Luc HarousseauIntergroupe Francophone du Myélome
  2. 2. Impact of novel agents in younger patients
  3. 3. Summary of novel agent induction trials (randomized studies) ≥ VGPR rates post-induction and post-transplant Post-induction 76% Post-transplant 71% 57% 45-55% 49% 44-50% * 62% 30- 39% 42% 45% 15- 33% 16% 35% VAD TD VD RD TAD *Post-transplant data not available PAD VTDHarousseau et al. ASH/ASCO symposium during ASH 2008 Lokhorst et al. Haematologica 2008;93:124–7Rajkumar et al. ASCO 2008 (Abstract 8504); Sonneveld et al. ASH 2008 (abstract 653); IMW (abstract 152)ASH/ASCO symposium during ASH 2008 Cavo et al. ASH 2008 (abstract 158); IMW 2009 (abstract 451)
  4. 4. IFM 2005-01 Impact of achieving at least VGPR after induction ≥ VGPR vs PR RR p. Valueβ2 mic (3mg/L) 1.54 0.01 1.32 0.23 p=0.0015t(4;14) ± del (17p)≥ VGPR vs PR 1.44 0.038 PFS ≥ VGPR PR N=117 N=145 median 41m 33m
  5. 5. VAD vs Vel/Dex induction for t(4;14) patients OS treatment VAD Vel/Dex pvalue Vel/Dex (logrank) Patients 106 107 Deaths 70 20 0.0004 VAD Median OS (years) 2.87 ---* [IC 95%] [1.76 ; 3.48] [3.60 ; ---*]p=.0004
  6. 6. t(4;14) with Bortezomib EFS of 507 patients treated with Vel/Dex induction t(4 ;14) neg pos pvalue (logrank) Patients 396 106 t(4;14) neg Relapses 141 43 0.0178 t(4;14) pos Median EFS 2.90 2.32 (years) [IC 95%] [2.74 ; [1.49 ; 3.53] 2.95] p<.02Avet-Loiseau et al., JCO online
  7. 7. Impact of Novel Agents in the ASCT paradigm Induction Treatment• Impact of CR/VGPR after Induction• Induction with BTZ appears to partly overcome poor prognosis related to t(4,14)• The impact of 3-4 cycles of Len/Dex is less clear (no randomized study)• Triple combinations appears more effective ( VCD,PAD, VTD…VRD) with VGPR rates up to 50% before and 75% after ASCT VTD is currently the best induction regimen and its neurotoxicity is reduced by lower doses (Moreau ASCO 2010)
  8. 8. CALGB trial Registration Restaging Randomization Days 90–100 PlaceboStage 1-3, <70 yearsTherapy at least 2 cycles Mel 200 CRStable Disease or better PR≤1 year from Rx initiation ASCT SD Lenalidomide*2 x 106 CD34 cells/kg 10 mg/d with ↑↓ (5–15 mg) *Stratification based on Diagnostic B2M and IMiD Use during Induction
  9. 9. Median TTP: Not yet reached Median TTP 25.5 moCALGB 100104, Nov 2009 Median Follow up is 12 months
  10. 10. IFM 2005-02: Study design Patients < 65 years, with non-progressive disease, ≤ 6 months after ASCT in first line Randomization: stratified according to Beta-2m, del13, VGPR bConsolidation: Lenalidomide alone 25 mg/day p.o. days 1-21 of every 28 days for 2 months Arm A= Arm B= Placebo Lenalidomide (N=307) (N=307) 10-15 mg/d until until relapse relapsePrimary end-point: PFS.Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide….
  11. 11. 1.000.75 IFM 2005-02 : PFS from randomization p<10-70.500.25 P < 10-70.00 0 6 12 18 24 30 36 Placebo Revlimid
  12. 12. Impact of Novel Agents in the ASCT paradigm Best Intensive Approach• Induction - 3 or 4 courses of VTD (RVD ?)• Maintenance with Lenalidomide
  13. 13. Questions for the near future• Will longer PFS with lenalidomide maintenance translate into longer OS ? Survival after relapse ?• Optimal duration of maintenance ? - until progression - fixed duration - until best response (immunophenotypic remission?)• Role of consolidation ? - maintenance with/without consolidation - novel agents or second TX ?
  14. 14. IFM 2005 02 : Response during consolidation (n= 572) PRE POST p value CR (IF -) 13 % 19 % <0.0001 ≥ VGPR 58 % 68 % <0.0001 ATTAL ASCO 2010
  15. 15. Consolidation with VTD• Patients: (n=39) with ≥VGPR after ASCT• Treatment: – 4 cycles VTD, started within 6 months • Bortezomib: 1.6 mg/m2, days 1, 8, 15, 22 • Thalidomide: initial dose 50 mg/day, with increments up to 200 mg • Dex: 20 mg/day, days 1-4, 8-11, 15-18• Results: at 32 month median follow up CR increased from 15% post- auto to 49% post-conso, MR from 3% to 18% • Six patients achieved molecular remission; none had clinical relapse • 50 month PFS: 100% for patients with MR vs 62% for patients with no MR Ladetto et al. JCO 2010
  16. 16. SCHEMA: BMT CTN Lenalidomide No Consolidation Maintenance Register MEL VRD x 4 Lenalidomide and 200mg/m2 MaintenanceRandomize MEL Lenalidomide 200mg/m2 Maintenance
  17. 17. Questions for the near future Key Question• With novel agents (MPT,MPV,Rd,RVD) it is now possible to achieve up to 30%CR and up to 70% VGPR• In published trials median PFS are comparable to those achieved in the past with ASCT (24-28 months)• With prolonged treatment the CR/VGPR rate continues to increase (especially with Len which is well tolerated and administered orally)
  18. 18. Phase I/II study on RVD in newly diagnosed MM Up to eight 21-day cycles * 1 2 4 5 8 9 11 12 14 21Bz Bz Bz Bz Dex Dex Dex Dex LenalidomideMPD Len 25mg Vel 1.3mg Dex 20mg in Phase II (35 pts) • Overall response rate (66pts) 100% • CR 29 % (37 % for 35pts in the Phase II part) • CR+ VGPR 67% (74% in Phase II part) • 2-yr PFS 68% (no difference in 41 pts with ASCT) • 2-yr OS 95%
  19. 19. ASCT plus novel agents PFS 100 90 80 70 IFM 90 MRC7 60 Ld MPT Facon 50 MPT Palumbo MPV 40 RVD GIMEMA 30 20 10 0Attal NEJM 1996. Facon Lancet 2007. Child NEJM 2003. Palumbo Blood 2008. San Miguel NEJM 2008. Rajkumar lancet 2010
  20. 20. IFM/DFCI Trial VRD x 3 SC collection VRD x 5 Mel 200 + ASCT VRD x 2 Rev 1 year Rev 1 year(HDM + ASCT at relapse)
  21. 21. Impact of novel agents in elderly patients
  22. 22. Frontline therapy in elderly patients• MP is no longer the standard of care• New standards - MPT > MP (1,2,3) - MPV > MP (4) - Len/dex > Len /dex (5)• Maintenance therapy prolongs PFS - Low-dose lenalidomide (MM015 Palumbo ASH 2009) - Velcade-based combinations (Mateos ASH 2009, Boccadoro ASCO 2010)• Weekly velcade is better tolerated than bi-weekly VMPT-VT vs VMP (Mateos ASH 2009, Boccadoro ASCO 2010) Facon Lancet Oncol 2007, Palumbo Blood 2008, Hulin JCO 2009 San Miguel NEJM 2008, Rajkumar Lancet Oncology 2010
  23. 23. MPR-R vs MPR 47% reduced risk in PFS 100 Median PFS MPR-R Not reached Patients without event (%) MPR 13.2 months 75 50 HR 0.530 95% CI 0.350–0.802 Log-rank p = 0.002 25 0 0 5 10 15 20 25 30 PFS duration (months)Number at riskMPR-R 152 115 70 36 11 2 1MPR 153 122 78 20 5 1 1Palumbo A, et al. Blood. 2009;114:[abstract 613]; updated data presented at ASH 2009.
  24. 24. VMPT-VT vs VMP VMP VMPT-VT P-valueNb of pts 257 254Med age 71 71CR 24% 38% 0.008CR+VGPR 50% 59% 0.033-yr PFS 40% 54% 0.0063-yr OS 84% 86% 0.6
  25. 25. Frontline therapy in elderly patients• MP is no longer the standard of care• New standards - MPT > MP (1,2,3) - MPV > MP (4) - Len/dex > Len /dex (5)• Maintenance therapy prolongs PFS - Low-dose lenalidomide (MM015 Palumbo ASH 2009) - Velcade-based combinations (Mateos ASH 2009, Boccadoro ASCO 2010)
  26. 26. Questions for the near future- Will better PFS obtained with maintenance translate into longer OS ?- Is maintenance necessary after all induction treatments (MPT, MPV, Ld) ?- Optimal duration of maintenance ?- Role of alkylating agents
  27. 27. MPT vs Revlimid-low dose Dexamethasone in Newly Diagnosed Myeloma Patients, Aged >65 Years Phase III international study / MM-020, IFM 2007-01, FIRST study MPT 12 cycles MP at 6-week interval + Thal at 200 mg/day, stopped at end of MP 1 Rev + low-dose Dex.N = 1590 Rev 25mg/day, days 1-21 ; Dex 40 Primary 1 endpoint: mg/day, days 1,8,15, 22 PFS 18 cycles at 4-week interval 1 Rev + low-dose Dex. same schedule as above Given until progessive disease
  28. 28. General Questions1) Role of novel agents in poor-risk cytogenetics
  29. 29. General Questions1 Role of novel agents in poor-risk cytogenetics2 Which level of CR is needed to achieve long-term remission?
  30. 30. Impact of immunophenotyping at 3 months post-ASCT RFS 1,0 p=0.0001 ,9 ,8Relapse-free survival ,7 NR — <0.01% MM-PC ,6 — 0.01% to 1% MM-PC ,5 40m — ≥ 1% MM-PC ,4 ,3 23m ,2 ,1 0,0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Months from immunophenotypical analysis Updated Paiva et al Blood 2008
  31. 31. General questions1 Role of novel agents in poor-risk cytogenetics2 Which level of CR is needed to achieve long-term remission?3 Which treatment at relapse when novel agents have been used upfront ?
  32. 32. Pomalidomide O O O O O O H H N N N N O N O N O O NH2 NH2 OThalidomide Lenalidomide Pomalidomide (CC-4047) Structurally similar but functionally different, both qualitatively and quantitatively Teo SK, et al. Drug Discov Today. 2005;10:107-14.
  33. 33. Phase II of Pom/Dex in patients refractory to Lenalidomide• 35 patients - Median age 62 y - 15 pts with mSMART high-risk - Median number of prior Tt 6 - 100% Len , 100% Btz , 77% SCT• Best response - VGPR 5 (14%) - PR 6 (17%) - MR 8 (23%)• Median PFS 8 months Lacy M ASCO 2010
  34. 34. Carfilzomib Carfilzomib is the first in a new class of selective andirreversible proteasome inhibitors that are associated withprolonged target suppression, improved antitumor activity and low neurotoxicity Tetrapeptide
  35. 35. Phase II study of Carfilzomib 100 CR 6.5% 18% 14% VGPR 10% PR MR 29%% of subjects SD PD 45% NE (TLS) 50 59% 3% 36% ORR: 26% 6% 57% ORR: 14% 35.5% ORR: 6.5% 18% 3% 18% 7% 0 All Bortezomib Bortezomib Subjects Exposed Naive (N = 31) (N = 17) (N = 14) 90% of responses occurred by the end of Cycle 2
  36. 36. PX-171-004: Response Summary 100 CR 6.5% 18% 14% VGPR 10% PR MR 29%% of subjects SD PD 45% NE (TLS) 50 59% 3% 36% ORR: 26% 6% 57% ORR: 14% 35.5% ORR: 6.5% 18% 3% 18% 7% 0 All Bortezomib Bortezomib Subjects Exposed Naive (N = 31) (N = 17) (N = 14) 90% of responses occurred by the end of Cycle 2
  37. 37. Panobinostat + Bortezomib Best Response Dose escalation B2207 study in Relapsed MM ptsClinical benefit (≥ MR) in 13/17 at cohort 3 and 6 level 10 9 8 Number of patients NA 7 PD 6 SD 5 4 MR 3 PR 2 VGPR 1 CR 0 Co.1 Co. 2 Co. 3 Co. 4 Co. 5 Co. 6 PAN mg 10 20 20 30 25 20 BTZ mg/m2 1.0 1.0 1.3 1.3 1.3 1.3PAN panobinostat; BTZ bortezomibCR, IF-negative CR; VGPR, very good PR; PR, partial response; MR, minor response; SD, stable disease; PD, progress. disease; NA, no assessment 37
  38. 38. Panobinostat + Bortezomib Efficacy Responses including in Bortezomib-Refractory Patients 100 90 80Response rate (%) 70 60 MR 50 40 PR 30 VGPR 20 10 CR 0 All (n=47) BTZ refractory (n=15)
  39. 39. Phase 1b Elotuzumab plus Len/dex Lonial ASCO 2010 Lenalidomide-Naїve Total Patients (%) Patients (%)Total (intent to 28 22treat)ORR (≥ PR) 23 (82) 21 (95) CR 1 (4) 1 (5) VGPR 7 (25) 6 (27) 15 (54) 14 (64) PRSD 4 (14) 1 (5)PD 1 (4) 0 39
  40. 40. General questions1 Role of novel agents in poor-risk cytogenetics2 Which level of CR is needed to achieve long-term remission?3 Which treatment at relapse when novel agents have been used upfront ? 4 What is the best strategy ? - all active agents upfront ? - sequential use of active agents ?
  41. 41. General QuestionsSEARCHING FOR CURE …
  42. 42. General QuestionsSEARCHING FOR CURE … OR TREATING MM LIKE A CHRONIC DISEASE
  43. 43. General QuestionsSEARCHING FOR CURE … OR TREATING MM LIKE A CHRONIC DISEASEThe answer to this question may depend on your definition of cure !!

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