1. Novel Treatment Applications for Newly Diagnosed Patients Eligible for Transplant
Evangelos Terpos, MD
Department of Clinical Therapeutics,
National and Kapodistrian University of Athens,
School of Medicine, Athens, Greece

2. When do we start therapy in MM?
Rajkumar et al. Lancet Oncol 2014;15:e

3. Issues in the Treatment of Young Myeloma Patients
In young fit patients (<65y) …to investigate therapeutic schemes with a cure in the horizon
Which regimen?
Duration?
Induction / Initial cytoreduction
Optimization?
Stem Cell Collection
Melphalan alone?
Single vs tandem?
High Dose Therapy ?
Maintenance Consolidation / 2nd ASCT

4. Long Term Follow up of Autotransplantation trials: Is cure possible?
Relapse Free at 10 years
Incorporation of novel agents in induction/consolidation improves outcomes after ASCT
Barlogie et al. J Clin Oncol 2010;8:

5. Novel Agent Regimens Improve CR and VGPR Rates Post-induction
CR rates post-induction
62%
62%
52%
52%
43%
42%
38%
37%
37%
31%
23%
19%
15%
14%*
15%
15%
13%
13%
13%
11% 6% 3%
*plus nCR
Zamagni et al. ASH 2009 (abstract 349); Morgan et al. Haematologica 2012;97: ; Lokhorst et al. Blood 2010;115: ; Boccadoro et al. J Clin Oncol 2011;29 (suppl) (Abstract 8020); Palumbo et al. ASH 2011 (Abstract 3069); Knop et al. ASH 2011 (Abstract 3967); Harousseau et al. J Clin Oncol 2010; 28(30): ; Sonneveld et al. J Clin Oncol 2012;30(24): ;
Einsele et al. Blood 2009; 114(22); Abstract 131; Cavo et al. Lancet 2010;376: ; Cavo et al. Blood 2012;120:9-19; Rosinol et al. Blood 2012;120(8): Moreau et al. Blood 2011;118(22):5752-8; Roussel et al ASH 2011 (Abstract 1872)

6. Novel Agent Regimens Improve CR and VGPR Rates Post-transplant
CR rates post-transplant
82%
74%
68%
60%
60%
58%
54%
54%
50%
42%
42%
37%
36%
35%
30%
25%
18%
14%
Zamagni et al. ASH 2009 (abstract 349); Morgan et al. Haematologica 2012;97: ; Lokhorst et al. Blood 2010;115: ; Boccadoro et al. J Clin Oncol 2011;29 (suppl) (Abstract 8020); Palumbo et al. ASH 2011 (Abstract 3069); Knop et al. ASH 2011 (Abstract 3967); Harousseau et al. J Clin Oncol 2010; 28(30): ; Sonneveld et al. J Clin Oncol 2012;30(24): ;
Einsele et al. Blood 2009; 114(22); Abstract 131; Cavo et al. Lancet 2010;376: ; Cavo et al. Blood 2012;120:9-19; Rosinol et al. Blood 2012;120(8): Moreau et al. Blood 2011;118(22):5752-8; Roussel et al ASH 2011 (Abstract 1872)

7. HOVON 65 MM / GMMG-HD4: Survival Data
In multivariate analysis, OS was better in the PAD arm (HR, 0.77; 95% CI: ; p=0.049).
HR 0.78 CI , p=0.01
median follow-up: 41 months
median follow-up: 74 months
Sonneveld et al. J Clin Oncol 2012;30:
Sonneveld et al. ASH 2013; abstract 404 7 7

8. Meta-Analysis: Phase 3 trials of bortezomib containing induction regimens
Impact of bortezomib induction on CR post induction
n=2086
Impact of bortezomib induction on overall survival
BCIR: bortezomib-containing regimens
Nooka et al. ASH 2011 (Abstract 3994), poster presentation

9. But which is the best bortezomib-based Induction? VCD or VTD?
GIMEMA MMY-3006
EMN-02
RANDOMIZATION
INDUCTION (three 21-d cycles)
BORT THAL-DEX
Bort 1.3mg/m2 twice weekly
Thal 100200mg/day
Dex 320mg/cycle
INDUCTION (three 21-d cycles)
THAL-DEX
Thal 100200mg/day
Dex 320mg/cycle
INDUCTION (three 21-d cycles)
VCD
PBSC COLLECTION
CTX+G-CSF
PBSC COLLECTION
CTX+G-CSF
RANDOMIZATION 1
TRANSPLANTATION
MEL 200
Thal 100md/day
Dex 160mg/cycle
TRANSPLANTATION 1 or 2
MEL 200
VMP
4 cycles
RANDOMIZATION 2
CONSOLIDATION (two 35-d cycles)
BORT-THAL-DEX
Bort 1.3mg/m2 once weekly
Thal 100mg/day
Dex 320mg/cycle
CONSOLIDATION (two 35-d cycles)
THAL-DEX
Thal 100mg/day
Dex 320mg/cycle
CONSOLIDATION (two 28-d cycles)
BORT-LEN-DEX
NO CONSOLIDATION
MAINTENANCE
DEX
MAINTENANCE
LEN until relapse
Cavo M et al. Lancet. 2010;379:2075 .
2. Cavo M et al. Blood. 2012;120:9.
HDM/ASCT at relapse

10. VTD vs VCD: Response to induction therapy (intention-to-treat)
Cavo M, et al. ASH 2014, abstract #197. 10

11. VTD vs VCD: CR and ≥ VGPR rates in high risk subgroups of patients
Cavo M, et al. ASH 2014, abstract #197.

12. VTD vs VCD: CR and ≥ VGPR rates in low risk subgroups of patients
Cavo M, et al. ASH 2014, abstract #197.

13. VTD vs VCD: Collection of CD34+ cells
N° of evaluable pts
223
221
Median (IQR) x 106Kg
9.75 ( )
10.58 ( )
<2
2.25%
1.36%
2-3.9
3.60% ≥4
94.14%
97.29%
≥10
49.55%
57.92%
Cavo M, et al. ASH 2014, abstract #197. 13

14. peripheral neuropathy
VTD vs VCD: Hematological and neurological toxicities reported during induction therapy
VTD
VCD N° %
Any grade 3-4
hematological a.e. 12 5% 28
12%
Any grade 2-4
peripheral neuropathy 31
13% 21 9% 17 7% 4 2%
Cavo M, et al. ASH 2014, abstract #197. 14

15. VTD vs VCD: Conclusions
In comparison with VCD, VTD induction therapy was likely to
enhance the rates of CR and ≥ VGPR
induce more rapid responses
Grade 3-4 hematological toxicity was more frequent with VCD, while grade ≥ 2 PN rates were similar between the two regimens. However, grade ≥ 3 PN was likely to be higher with VTD
No difference between the two regimens was seen in terms of
early induction discontinuation rate
efficiency to mobilize PBSC
Cavo M, et al. ASH 2014, abstract #197. 15

16. VTD vs TD vs CC: PFS and OS from diagnosis
Median follow-up: 70.6 months
PFS OS
VTD: 56.1 m
TD: 29.2m
QT+V: 39.9m
p=0.005
p=NS
VTD TD
VBMCP/VBAD+V
Rosinol et al. ASH 2014 (Abstract 3457); poster presentation

17. Phase 2: dose-escalated Carfilzomib + Thal + Dex (CTd)
Objectives
Evaluate standard dose Carfilzomib (20/27 mg/m2)  + Thal + Dex induction, followed by HDM + ASCT, followed by CTd consolidation
Establish MTD of Carfilzomib in this combination
Induction
4 cycles
Intensification
1 cycle
Consolidation
4 cycles
Carfilzomib 20/27 mg/m2
days 1,2,8,9,15,16 of a 28 day cycle
Thal 200 mg
days 1-28 of a 28 day cycle
Dex 40 mg
days 1,8,15,21 of a 28 day cycle
HDM
200 mg/m2
ASCT
Carfilzomib 27 mg/m2
days 1,2,8,9,15,16 of a 28 day cycle
Thal 50 mg days 1-28 of a 28 day cycle
Dex 40 mg days 1,8,15,21 of a 28 day cycle
Sonneveld et al. ASH 2014 (Abstract 2118), poster presentation

18. CTd: Responses Dosing level of Carfilzomib Risk status by FISH and ISS
20/27 mg/m2
20/36 mg/m2
20/45 mg/m2
All pts
Standard risk
High risk
Pts, n 50 20 21 91 36 35
Response induction (%) CR 30 33 25 8 26
≥ VGPR 56 85 81 68 69 63
≥ PR 92 90 86 94
HDM (%) 28 40 38 64 76 71
100 95 96
Response consolidation (%) 58 70 67 66 89
Sonneveld et al. ASH 2014 (Abstract 2118), poster presentation

19. Novel Agent Induction for Transplant-Eligible Patients: Phase II Trials
Study
Treatment n
Outcomes
Safety
Richardson[1]
RVD 66
≥ VGPR: 67% 18-mo PFS: 75% 24-mo OS: 97%
Sensory neuropathy: 80% (mostly grade 1) Fatigue: 64% (mostly grade 1)
Jakubowiak[2]
CRd 53
≥ nCR: 62%
ORR: 98%
Only grade 1/2 PN
Khan (retrospective analysis of 3 trials)[3] RD
CRD
CyBorD 34
150
≥ VGPR, % 35 30 65
3-yr OS, % 88 79
Grade 3/4 toxicities least with CyBorD; most with CRD
More neuropathy with CyBorD vs RD and CRD
P = .0003
1. Richardson PG, et al. Blood. 2010;116:
2. Jakubowiak, et al. Blood. 2012;120: Khan ML, et al. Br J Haematol. 2012;156:

20. Panobinostat + RVD in Transplant-Eligible Pts with Newly Diagnosed Myeloma
Phase I/II trial evaluating the safety and efficacy of panobinostat + RVD in pts with NDMM
Panobinostat is a potent, nonselective HDAC inhibitor
RVD is highly active and one of the standard of care options in this setting
Objectives for this report
Determine MTD
Evaluate safety and ORR after 4 cycles
Shah J, et al. ASH Abstract 33.

21. Panobinostat + RVD: Phase I Dose Escalation
Lenalidomide
Bortezomib (SC)
Dex
Panobinostat
DLT
Cohort -1
15 mg
1.0 mg/m2
20 mg
10 mg
Cohort 1
25 mg
1.3 mg/m2
0/6
Cohort 2
2/6
MTD included
1 pt with grade 4 PLT, grade 3 diarrhea, grade 4 hypocalcemia
1 pt with grade 3 diarrhea without supportive care; resolved immediately with supportive care, lasting < 12 hrs
19/20 additional pts enrolled in dose expansion
MTD without supportive care: panobinostat 10 mg, bortezomib 1.3 mg/m2, lenalidomide 25 mg, and dexamethasone 20 mg
Shah J, et al. ASH Abstract 33.

22. Panobinostat + RVD: Response Rates After 4 Cycles of Therapy
Outcome, n (%)
Pts Completing 4 Cycles of Therapy
(n = 22)
ORR (≥ PR)
21 (95)
nCR/CR
11 (50)
VGPR
6 (27) PR
4 (18) SD
1 (5)
Historical RVD therapy at 4 cycles CR: 10% to 23%
No effect of panobinostat on stem cell collection or mobilization
No unexpected posttransplantation toxicity
Shah J, et al. ASH Abstract 33.

23. Panobinostat + RVD: Safety
AE, n
Grade 1
Grade 2
Grade 3
Grade 4
Hematologic AEs
Anemia 17 10 4
Neutropenia 5 7 3 1
Thrombocytopenia 12 8
Leukopenia 2 6
Nonhematologic AEs
Alanine aminotransferase 11
Alkaline phosphatase 9
Aspartate aminotransferase
Constipation
Diarrhea
Dyspnea
Nausea
Edema (limbs)
Fatigue
Peripheral sensory neuropathy 15
Shah J, et al. ASH Abstract 33.

24. Our Approach for Patients Eligible for ASCT
VTD x 4 cycles
<10% of patients fail to proceed to stem cell collection
Mobilization with cyclophosphamide 2.5 g/m2 + G=CSF
Single large volume leukapheresis to collect >6x106 CD34+ cells/kg to allow support of two high dose therapies (in less than 10% of patients we need a second day)
High dose melphalan (200 mg/m2) immediately after leukapheresis with infusion of one half of the collection after 24 hours
Cryopreservation of the other half for salvage high dose therapy if TTP from first high dose therapy >18 months

25. Summary: Induction regimens
Novel agents improve PFS when used as induction before ASCT
Bortezomib and dexamethasone should be part of the induction regimen (VTD, VCD, PAD, VRD)
3-drug regimens better than 2-drug regimens (VTD better than VCD)
4 cycles considered standard (more in responding patients?)
4-drug regimens NO better than 3-drug regimens but associated with increased toxicity (role for monoclonal antibodies?)

26. What is the Role of Transplantation in MM in the Era of Novel Agents
What is the Role of Transplantation in MM in the Era of Novel Agents? Could ASCT be Delayed and Administered at First Relapse?

27. Patients younger than 65 yrs of age with NDMM
MPR vs tandem MEL200 ± Lenalidomide Maintenance in NDMM: Phase III Trial
Second Randomization
Patients younger than 65 yrs of age with NDMM
(N = 402)
Lenalidomide maintenance 28-day courses until PD
First Randomization
MPR six 28-day courses
(n = 202)
No maintenance
Lenalidomide + Dexamethasone four 28-day courses
Lenalidomide maintenance 28-day courses until PD
MEL200 2 courses
(n = 200)
No maintenance
Primary endpoint: PFS
Other endpoints: efficacy, safety
Palumbo et al. N Engl J Med 2014;371:

28. MPR vs MEL200 ± Lenalidomide Maintenance: MPR vs MEL200 PFS and OS
Progression-free survival
Overall survival
Median PFS
MPR
22.4 months
MEL200
43 months
4-year OS
MPR
65.3%
MEL200
81.6% 70 25 50 75
100 10 20 30 40 60 25 50 75
100
Months 10 20 30 40 60 70
MEL200, melphalan 200 mg/m2; MPR, melphalan/prednisone/lenalidomide; OS, overall survival, PFS, progression-free survival.
HR 0.44, 95% CI , P <.0001
HR 0.55; 95% CI ; P = 0.02
Months
Palumbo et al. N Engl J Med 2014;371:

29. ASCT vs CC + lenalidomide
Gay et al. ASH 2014 (Abstract 198); oral presentation

30. ASCT produces better results than CC+R
Mel200-ASCT
CC+R P
Median PFS1
41 months
26 months
<
4-year PFS2
71%
52%
0.002
4-year OS
84%
0.008
OS subgroup analysis:
Gay et al. ASH 2014 (Abstract 198); oral presentation

31. Gay et al. ASH 2014 (Abstract 198); oral presentation

32. Conclusions
Mel200-ASCT vs CC+R significantly prolongs PFS1, PFS2, and OS in comparison with CC+R
ASCT as salvage therapy may not be feasible in all patients
The major benefit of Mel200-ASCT vs CC+R was shown in patients with good prognosis
→ Intensified treatment to prolong OS
Bad prognosis patients require more effective treatment
Gay et al. ASH 2014 (Abstract 198); oral presentation

33. Summary for ASCT ASCT at first remission remains the standard approach
The patient is more fit to tolerate intensive and repetitive therapies earlier in the disease course
ASCT is associated with long treatment-free interval & good QoL
Relapses after MEL200 are sensitive to novel agents…… but we don´t know the opposite: Mel200 after long term exposure to novel agents
Ongoing clinical trials will define the role of late transplant in patients treated with novel agents
Our centre: N=340
After 2000
Median survival : 8.8 years
Before 2000
Median survival: 4 years

34. What are the data to support the use of consolidation therapy?

35. Single versus double ASCT in MM IFM94 trial
VGPR after first ASCT
Absence of VGPR after first ASCT
P<0.001
P=0.7
Attal et al. N Engl J Med 2003;349:

36. Bortezomib Monotherapy as Consolidation: Results
Median follow-up: 38 months
Beneficial effect of bortezomib consolidation on PFS only seen in patients not achieving at least VGPR after ASCT
Bortezomib
Control
p value
Improvement of response from PR to ≥ VGPR
57%
36%
0.007
Median PFS
27 months
20 months
0.05
Incidence of neuropathy CTC ≥ III
Neuropathic pain > grade 2 6% 1%
< 0.006
Sensory neuropathy > grade 2 5%
< 0.04
Mellqvist et al. Blood 2013;121:

37. Updated analysis of Phase 3 Gimema-MMY-3006 study
Randomization
Induction (three 21-day cycles)
Bortezomib-Thal-Dex (VTD)
V 1.3 mg/m2 d1, 4, 8, 11
T 200 mg daily
D 320 mg/cycle
Induction (three 21-day cycles)
Thal-Dex (TD)
T 200 mg daily
D 320 mg/cycle
Double ASCT
Consolidation (two 35-day cycles)
Bortezomib-Thal-Dex (VTD)
V 1.3 mg/m2 once-weekly
T 100 mg/d through d 1 to 70
D 320 mg/cycle
Consolidation (two 35-day cycles)
Thal-Dex
T 100 mg/d through d 1 to 70
D 320 mg/cycle
Maintenance: Dex
Cavo et al. Lancet 2010;376(9758):
Cavo et al. Blood 2012;120(1):9-19
Cavo et al. ASH 2013 (Abstract 2090), poster presentation

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%
0.012
Upgrade to CR post-consolidation
30.4%
16.6%
0.030
Landmark analysis from start of consolidation (30 months median follow up)
3-yr probability of relapse or progression
38%
52%
0.039
3-yr PFS
60%
48%
0.025
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. Blood 2012;120:9-19

39. Median follow-up: 65 months
VTD TD P
PFS
57 months
42 months
0.0012
5-year OS
80%
73% ns
PFS2 at 5 years
76%
63%
0.0124
Time to next treatment
40 months
31 months
0.0137
Median treatment-free interval
26 months
16 months
0.016
OS after first relapse
36 months
VTD superior to TD in terms of extended PFS2, time to subsequent anti-MM therapy and treatment-free interval
VTD induction and consolidation did not select bortezomib- resistant clones at the time of relapse
Tacchetti et al. ASH 2014 (Abstract 196); oral presentation

40. Take home messages
Induction treatment with a triplet containing bortezomib: possibly VTD or VRD the best options
Novel agents, i.e. carfilzomib (KTD) or panobinostat (P-VRD) are used in clinical trials in an attempt to improve the results of induction treatment
High dose melphalan post ASCT remain the “standard of care” for eligible patients
Consolidation with VTD increases responses and survival

41. Thank you