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

1. Impact of Novel Therapies
In Multiple Myeloma
Jean-Luc Harousseau
Intergroupe Francophone du Myélome

2. Impact of novel agents in
younger patients

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 VTD
Harousseau et al. ASH/ASCO symposium during ASH 2008 Lokhorst et al. Haematologica 2008;93:124–7
Rajkumar 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. IFM 2005-01
Impact of achieving at least VGPR after
induction ≥ VGPR vs PR
RR p. Value
β2 mic (3mg/L) 1.54 0.01
1.32 0.23 p=0.0015
t(4;14) ± del (17p)
≥ VGPR vs PR 1.44 0.038
PFS
≥ VGPR PR
N=117 N=145
median 41m 33m

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. 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<.02
Avet-Loiseau et al., JCO online

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. CALGB trial
Registration Restaging Randomization
Days 90–100
Placebo
Stage 1-3, <70 years
Therapy at least 2 cycles Mel 200 CR
Stable 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. Median TTP: Not yet reached
Median TTP 25.5 mo
CALGB 100104, Nov 2009 Median Follow up is 12 months

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 relapse
Primary end-point: PFS.
Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide….

11. 1.00
0.75
IFM 2005-02 : PFS from randomization
p<10-7
0.50
0.25
P < 10-7
0.00
0 6 12 18 24 30 36
Placebo Revlimid

12. Impact of Novel Agents
in the ASCT paradigm
Best Intensive Approach
• Induction
- 3 or 4 courses of VTD (RVD ?)
• Maintenance with Lenalidomide

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. 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. 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. SCHEMA: BMT CTN
Lenalidomide
No
Consolidation Maintenance
Register
MEL VRD x 4 Lenalidomide
and
200mg/m2 Maintenance
Randomize
MEL Lenalidomide
200mg/m2 Maintenance

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. 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 21
Bz Bz Bz Bz
Dex Dex Dex Dex
Lenalidomide
MPD 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. 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
0
Attal NEJM 1996. Facon Lancet 2007. Child NEJM 2003. Palumbo Blood 2008. San Miguel NEJM 2008. Rajkumar lancet 2010

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. Impact of novel agents in
elderly patients

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. 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 risk
MPR-R 152 115 70 36 11 2 1
MPR 153 122 78 20 5 1 1
Palumbo A, et al. Blood. 2009;114:[abstract 613]; updated data presented at ASH 2009.

24. VMPT-VT vs VMP
VMP VMPT-VT P-value
Nb of pts 257 254
Med age 71 71
CR 24% 38% 0.008
CR+VGPR 50% 59% 0.03
3-yr PFS 40% 54% 0.006
3-yr OS 84% 86% 0.6

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. 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. 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. General Questions
1) Role of novel agents in poor-risk cytogenetics

29. General Questions
1 Role of novel agents in poor-risk cytogenetics
2 Which level of CR is needed to achieve long-term
remission?

30. Impact of immunophenotyping
at 3 months post-ASCT
RFS
1,0 p=0.0001
,9
,8
Relapse-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. General questions
1 Role of novel agents in poor-risk cytogenetics
2 Which level of CR is needed to achieve long-term
remission?
3 Which treatment at relapse when novel agents have
been used upfront ?

32. Pomalidomide
O O O O O O
H H
N N N
N O N O N O
O NH2 NH2 O
Thalidomide 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. 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. Carfilzomib
Carfilzomib is the first in a new class of selective and
irreversible proteasome inhibitors that are associated with
prolonged target suppression, improved antitumor activity
and low neurotoxicity
Tetrapeptide

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. 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. Panobinostat + Bortezomib Best Response
Dose escalation B2207 study in Relapsed MM pts
Clinical 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 1.3
PAN panobinostat; BTZ bortezomib
CR, IF-negative CR; VGPR, very good PR; PR, partial response; MR, minor response; SD, stable disease; PD, progress. disease; NA, no assessment
37

38. Panobinostat + Bortezomib Efficacy
Responses including in Bortezomib-Refractory Patients
100
90
80
Response rate (%)
70
60 MR
50
40 PR
30
VGPR
20
10 CR
0
All (n=47) BTZ refractory (n=15)

39. Phase 1b Elotuzumab plus Len/dex
Lonial ASCO 2010
Lenalidomide-Naїve
Total Patients (%) Patients (%)
Total (intent to 28 22
treat)
ORR (≥ PR) 23 (82) 21 (95)
CR 1 (4) 1 (5)
VGPR 7 (25) 6 (27)
15 (54) 14 (64)
PR
SD 4 (14) 1 (5)
PD 1 (4) 0
39

40. General questions
1 Role of novel agents in poor-risk cytogenetics
2 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. General Questions
SEARCHING FOR CURE …

42. General Questions
SEARCHING FOR CURE
… OR TREATING MM
LIKE A CHRONIC DISEASE

43. General Questions
SEARCHING FOR CURE
… OR TREATING MM
LIKE A CHRONIC DISEASE
The answer to this question may depend on
your definition of cure !!