1. I farmaci innovativi in Ematologia Bortezomib nel Mieloma Multiplo
Elena Zamagni Istituto di Ematologia ed Oncologia Medica “Seràgnoli” Università degli Studi di Bologna

2. NOVEL AGENTS TARGETING MM CELLS AND
THE BONE MARROW MILIEU
Cytokine production
Myeloma cells
Adhesion -
Angiogenesis A B D E C -
Kyle RA, NEWJ 2004 (modificata)

3. MECHANISM OF ACTION OF BORTEZOMIBX
Adapted from Adams J. Drug Discov Today 2003

4. BORTEZOMIB IN MULTIPLE MYELOMA AS…..
Induction and consolidation therapy in the context of ASCT in young patients
Up-front therapy in elderly patients
Salvage treatment in relapsed/refractory patients
Conditioning regimen and consolidation treatment in the context of allogeneic stem cell transplantation
Therapy of MM bone disease
Treatment of newly diagnosed and relapsed/refractory AL amyloidosis
Other strategies have been used to improve the outcome of ASCT
Among these strategies is double ASCT, which has been shown to be beneficial in patients not achieving a CR or VGPR following the first transplant
In addition, the transplant protocol has been further intensified, which has led to improvements in response rates and survival
Finally, novel agents are being introduced into the ASCT paradigm to further improve results

5. Current status: ASCT
In patients <65 years old, ASCT is the standard of care
- Superiority of a single ASCT over conventional chemotherapy
- Superiority of double ASCT over a single autotransplantation
Study n
Age
CR (%)
EFS OS
IFM 901
200
≤65
5 vs 22*
(7-year) 8% vs 16%*
(7-year) 27% vs 43%*
MRC VII2
401
8 vs 44*
19m vs 31m*
42m vs 54m*
IFM 943
399
 60
50 vs 42
(VGPR)
30m vs 25m*
58m vs 48*
Bologna 964
321
47 vs 33
35m vs 23m*
71m vs 65m
In patients <65 years old, ASCT is considered the standard of care, as randomized trials demonstrated the superiority of ASCT over conventional chemotherapy
The table summarizes important studies that compared conventional chemotherapy with ASCT
The first study comparing the two treatments was conducted by the French Myeloma Group and showed that high-dose therapy is superior to treatment with conventional chemotherapy
It is important to note that although 3 of the 4 studies listed here demonstrated a statistically significant superiority of ASCT over conventional chemotherapy, a recent update of the large US Intergroup trial could not show a significant difference between ASCT and conventional chemotherapy
1 Attal M et al, N Engl J Med Attal M et al, N Engl J Med 2003
2 Child A et al, N Engl J Med Cavo M et al, J Clin Oncol 2007
*Significant difference

6. ASCT: new treatment paradigm with novel agents
Introducing novel agents into ASCT
As induction therapy
• To maximize the speedy and degree of tumor reduction
• To increase the CR rate before and after ASCT(s)
• To apply ASCT(s) earlier and in a higher fraction of patients
As consolidation/mainteinance therapy
• To increase the final CR rate
• To reduce the risk of relapse
• To extend EFS and OS
Other strategies have been used to improve the outcome of ASCT
Among these strategies is double ASCT, which has been shown to be beneficial in patients not achieving a CR or VGPR following the first transplant
In addition, the transplant protocol has been further intensified, which has led to improvements in response rates and survival
Finally, novel agents are being introduced into the ASCT paradigm to further improve results

10. RESPONSE TO PRIMARY THERAPY
EBMT criteria (with added nCR and VGPR categories)
Cavo M. et al, ASH 2007

11. RESPONSE TO FIRST ASCT (MEL 200 mg/m2)
EBMT criteria (with added nCR and VGPR categories)
Cavo M. et al, ASH 2007

12. PBSC HARVEST
Median values (range)
Cavo M. et al, ASH 2007

13. RESPONSE (nCR) TO PRIMARY THERAPY ACCORDING TO GENETIC ABNORMALITIES
VTD 43 47 4 8 10 20 30 40 50 60
13 pos
t(4;14) pos
P<0.001
P=0.002
VTD vs TD
VTD TD 60
P=0.06
P=0.1 50 47
VTD 43 40 32 % 30 27 % 20 10
neg
pos
neg
pos
13
t(4;14)
Cavo M. et al, ASH 2007

14. Bortezomib + CHT prior to ASCT: phase II studies
PR /  VGPR
prior to ASCT (%)
CR + nCR
after ASCT (%)
Regimen
Reference n
Bortezomib
(1.3 or 1.0 mg/m2)
+ adriamycin
+ dexamethasone (PAD) 41
PAD 1: 95 / 29
PAD 2: 89 / 16
PAD1: 57
PAD 2: 42
Popat et al.
IMW 2007
Bortezomib
+ DOXIL® 63
58 / 16 -
Orlowski et al.
ASH 2006
Bortezomib
+ DOXIL®
+ dexamethasone 50
95 / 20 -
Belch et al.
IMW 2007
Bortezomib
+ DOXIL®
+ dexamethasone 40
92.5 /42.5
≥ VGPR 75 65
Jakubowiak et al.
IMW 2007
Bortezomib
+ DT-PACE
Barlogie et al.
BJH 2007
303
84* -
92 / 35
Bortezomib
+ Cyclo-dex
Reeder et al.
ASH 2007 33
* At 24 months

15. Toxicities with front line Bortezomib containing regimens
Neutropenia (Gr 3-4)
DVT and PE prophylaxis required PE
Gastrointestinal toxicity
Toxicity in presence of renal failure
Thrombocytopenia (Gr 3-4)
DVT PN
Uncommon
0-2%
Not reported
Yes No
Rare
Mostly reversible with dose modification
Bortezomib

16. Bortezomib dose modification for the management of PN
Severity of PN signs/symptoms
Modification of dose and regimen
Grade 1 (paresthesia and/or loss of reflexes without pain or loss of function)
No action
Grade 1 with pain or Grade 2 (interfering with function but not with ADLs)
Reduce bortezomib to 1.0 mg/m2
Grade 2 with pain or Grade 3 (interfering with ADL)
Withhold bortezomib until toxicity resolves then reinitiate at 0.7 mg/m2 and administer once per week
Grade 4 (permanent sensory loss interfering with function)
Discontinue bortezomib
SmPC Janssen-Cilag 2007
ADL, activities of daily living

17. Updated survival analysis of CREST
Overall survival
Bortezomib 1.3 mg/m2
Bortezomib 1.0 mg/m2
Jagannath et al. ASH 2007 (abstract 2717)

18. The role of bortezomib in the context of high-dose therapy with stem cell transplantation
CONCLUSIONS
Significantly higher response rate and CR+nCR rate after induction therapy with bortezomib containing regimens
Superior nCR rate with VTD is not adversely affected by t(4;14) or chromosome 13 deletion
Higher good-quality response with bortezomib containing regimens translates into a significantly higher probability of nCR or VGPR after the first ASCT
Primary therapy with bortezomib containing regimens does not adversely impair the efficiency of PBSC harvest
Relatively low toxicity profile, reflected by low discontinuation rate and absence of early deaths
Other strategies have been used to improve the outcome of ASCT
Among these strategies is double ASCT, which has been shown to be beneficial in patients not achieving a CR or VGPR following the first transplant
In addition, the transplant protocol has been further intensified, which has led to improvements in response rates and survival
Finally, novel agents are being introduced into the ASCT paradigm to further improve results

19. Median age at diagnosis: 68 yo
EPIDEMIOLOGY OF MM 2%
<40 yrs
38% 70 yrs
60%
40-69 yrs
more than 50% occur in people over the age of 71
more than 50% occur in people over the age of 71
Median age at diagnosis: 68 yo
Kyle et al. Best Pract Res Clin Haematol 2007;20(4):637-64

20. Melphalan/Prednisone vs poli-CHT and Dex containing regimens
Progression-free survival
Overall survival
27 studies
6633 patients
Survival (%)
Facon et al. Blood 2006;107(4):
Myeloma Trialists‘ Collaborative Group. J Clin Oncol 1998;16:3832–3842

21. MPV: phase I-II study Four 6-week cycles Bortezomib Rest period
Pazienti (n=60): età mediana 75aa
Four 6-week cycles
Day
–42
Bortezomib
Melphalan 9 mg/m2
Prednisone 60 mg/m2
Rest period
Five 5-week cycles
Day
–35
Bortezomib 1.0 mg/m2: 6 patients (Phase I)
Bortezomib 1.3 mg/m2: 6 patients (Phase I)
+ 48 patients (Phase II)
Total = 49 weeks of treatment
Mateos et al. Blood 2006;108:2165–2172

22. MPV: response rates e overall survivalOS
Best response:
median 7 cycles (2–9)
Median follow-up: 26 months
Survival rate at 38 months:
1.0
89% ORR
MPV: 85%
70%
0.8
60%
50%
45%
0.6
43% CR + nCR
40%
MP*: 49%
32%
0.4
* MP: Historical control
30%
20%
0.2
11%
11%
P<0.0001
10%
0.0 0%
CR IF-
CR IF+ PR SD 10 20 30 40
Mateos et al. Blood 2006;108:2165–2172
Mateos et al. Haematologica 2008;93(4):

23. MPV: cytogenetic abnormalities
No influence of del13, del17p and IgH translocation on PFS e OS
Mateos et al. Haematologica 2008;93(4):

24. 9 x 6-week cycles (54 weeks) in both arms
VISTA: VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone
Randomized, international, phase III trial of VMP vs MP in previously untreated MM patients who were not candidates for HDT-ASCT
Patients: Symptomatic multiple myeloma/end organ damage with measurable disease
≥65 yrs or <65 yrs and not transplant-eligible; KPS ≥60%
682 pz
VMP
Cycles 1-4
Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
Cycles 5-9
Bortezomib 1.3 mg/m2 IV: days 1,8,22,29 R A N D O M I Z E
Primary Endpoint: TTP
Secondary Endpoints: CR rate, ORR, TTR, DOR, PFS, TNT, OS, QoL (PRO)
9 x 6-week cycles (54 weeks) in both arms
Response and progression assessed q3 weeks per
EBMT1 using central laboratory for M-protein quantification;
results reported in real time to investigator for evaluation MP
Cycles 1-9
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
1. Bladé et al. Br J Haematol 1998;102:
San Miguel et al. Blood 2007;110:Abstract 76 24

25. VISTA: response to therapy High CR with VMP
VMP, N=336
MP, N=331
p-value
M-protein*
M-protein
ORR (CR+PR)
82%
50%
<
CR (IF-)
35% 5% PR
46%
45%
VGPR (≥90% M-protein)
10%
EBMT1
71%
35%
30% 4%
40%
31%
N/A
*measured in serum or urine by centralized laboratory
1. Bladé et al. Br J Haematol 1998;102:
San Miguel et al. Blood 2007;110:Abstract 76 25

26. VISTA: time to progression ~52% reduced risk of progression on VMP
VMP: 24.0 months (83 events)
MP: 16.6 months (146 events)
HR = 0.483, p <
VMP MP
Number of patients at risk
MP:
VMP:
San Miguel et al. Blood 2007;110:Abstract 76 26

27. VISTA: overall survival ~ 40% reduced risk of death on VMP
Median follow-up 16.3 months
VMP: not reached (45 deaths)
MP: not reached (76 deaths)
HR = 0.607, p =
VMP MP
Number of patients at risk
MP:
VMP:
OS 2-years 82.6% in VMP vs 69.5% in MP
<75 years OS 2-years  84% in VMP vs 74% in MP
≥75 years OS 2-years  79% in VMP vs 60% in MP
Treatment related deaths on each arm: VMP 1%; MP 2%
San Miguel et al. Blood 2007;110:Abstract 76 27

28. VISTA: subgroup analysis
efficacy of VMP not influenced by age, renal function and cytogenetic abnormalities
Impact of age
Best M-protein response
Total
(N=336)
Age<75 Yrs
(N=230)
Age≥75 Yrs
(N=106)
CR (IF-)
35%
36%
33%
≥PR
82%
85%
74%
Impact of CrCl
Best M-protein response
Total
(N=336)
CrCl<60
(N=182)
CrCl≥60
(N=154)
CR (IF-)
35%
34%
≥PR
82%
81%
Impact of cytogeneticsFISH: any (t4-14, t14-16, -17p) vs None
Best M-protein response
Total
(N=165)
High Risk
(N=26)
Std Risk
(N=139)
CR (IF-)
32%
35%
≥PR
82%
81%
San Miguel et al. Blood 2007;110:Abstract 76

29. VMP: grade 3/4 (%) adverse events
VMP (n=340)
MP (n=337)
Gr 3
Gr 4
Neutropenia 30 10 23 15
Thrombocytopenia 20 17 16 14
Anaemia 3 8 GI 19 1 5
<1
Peripheral neuropathy 13
Fatigue 6
Pneumonia 2 4
Herpes Zoster
Risolution or improvement of PN in 75% of pts within a median time of 64 days
Low percentage of DVT in both arms of treatment (1%)
Serious adverse events: 45% for VMP vs 36% for MP
San Miguel et al. Blood 2007;110:Abstract 76 29

30. Bortezomib alone or Dexamethasone for relapsed MM
Bortezomib alone (n = 333)
APEX
8 cycles
1.3 mg/mq
Days 1, 4, 8, 11
Every 21 days
High-dose Dexamethasone (n = 336)
4 cycles
40 mg
Days 1-4, 9-12, 17-20
Every 35 days
5 cycles
3 cycles
3 cycles
1.3 mg/mq
Days 1, 8, 15, 22
Every 28 days
5 cycles
40 mg
Days 1-4
Every 28 days
International, randomized study in relapsed or refractory MM (N = 669) comparing single agent bortezomib to HD dexamethasone
Endpoints
Primary: TTP
Secondary: survival, response rate (RR), grade ≥ 3 infection, safety
Richardson P et al. NEJM 2005

31. 78% improvement in median TTP with bortezomibOS 1
0.8
0.4
0.2
Bortezomib
Dexamethasone
0.6 30 90
210
330
0.9
0.7
0.5
0.3
0.1 60
150
270
420
120
180
240
300
360
390
Time (days)
P < 0.001 1
0.8
0.4
0.2
0.6
0.9
0.7
0.5
0.3
0.1
Bortezomib
Dexamethasone 90
270
630
990
180
450
810
360
540
720
900
1080
1170
Time (days)
P =
29.8 mos
23.7 mos
78% improvement in median TTP with bortezomib
Superior survival despite > 62% of HD dex pts crossing over to bortezomib
1-yr survival rate: 80% vs 67%; P =
Richardson P et al. NEJM 2005

32. Del(13) in Multiple Myeloma
APEX: Matched-Pairs Analysis
Proportion of patients
1.0
0.8
0.2
0.5
120
240
HR (95% CI) = 9.31 (1.88, 46.06); P =
0.7
0.3
0.6
0.9
0.4
0.1 60
180
300
360
420
480
540
Del(13) (n = 12)
No deletion (n = 24)
Del(13) (n = 9)
No deletion (n = 17)
Time (days)
HR (95% CI) = 1.61 (0.35, 7.46); P = 0.79
Del(13) associated with poor survival in Dex-treated patients
Del(13) has no impact on survival in Bortezomib-treated patients
74/333 bortezomib patients had metaphase cytogenetics available – 11 del(13); 63 no del(13)
94/336 dex pateitns had metaphase cytogenetics available – 13 del(13); 81 no del(13)
Del(13) patients matched 1:2 with no del(13) patients
Of the 24 del(13) patients, only 21 were identified to have at least one corresponding match to the no del(13) patient population
Reference:
Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. ASCO 2005, Orlando FL. Abstract 6501.
Jagannath et al. Leukemia 2006

33. Treatment with Bortezomib of patients with renal failure
NF-KB activation related to impaired renal function
Half-life independent of renal clearance1
Short time to response (1.2 months)2,5
Reduces inflammation in myeloma kidney
Toxicity profile similar to that of patients with normal renal function3,5
Flexible even in dyalisis-dependent patients4,5
Apex trial: trend towards shorter TTP/OS in patients with renal failure as compared with others but p NS (OS significantly shorter in dex treated pts) 5
1. Mulkerin et al. ASCO 2006 (Abstract 2032)
2. Richardson P et al. Blood 2005;106: (Abstract 2547)
3. Jagannath S et al. Cancer 2005;103:1195–2000
4. Chanan-Khan et al. Blood 2007; 109:2604–2606
5. San Miguel J et al. Leukemia 2008

34. Bortezomib + DOXIL vs Bortezomib
Randomization
646 pts: relapsed and/or refractory MM
Stratifications:
1. B2M (≤2.5, >2.5 but ≤5.5, >5.5)
2. Response vs. PD on initial therapy
BZ 1.3 mg/m2 D 1, 4, 8, 11 every 21d for up to 8 cycles
Treated until: PD
Unacceptable toxicity
8 cycles administered (continued if MM still responding)
Primary endpoint: TTP
Secondary endpoint: OS, ORR, safety
BZ as above + Pegylated liposomal doxorubicin 30 mg/m2 on D4
Orlowski et al. J Clin Oncol 2007

35. Bortezomib + DOXIL vs Bortezomib
Time to progression
Overall survival
Orlowski et al. J Clin Oncol 2007

36. V-MPT at 1°Relapse/ MPT at diagnosis
Bortezomib day 1,4,15,22
Melphalan 0.18 mg/kg (4 days) 50 mg/month
Prednisone 2 mg/kg (4 days) 6 cycles
Thalidomide 50 mg/daily continuously
1°Relapse
Diagnosis 50 45
V-MPT (N = 14)
39%
MPT (N = 129)^
RR 79%
RR 80% 40
34% 35
43% 30 25
24%
36% %
21% 20 15
13%
26%
15%
17% 10 10 5% 5 0%
CR-
VGPR PR MR PD
CR-
VGPR PR MR PD
Palumbo A et al. Blood 2007
^Historical controls Lancet 2006;367:825

37. Bortezomib combinations for relapsed/ refractory MM ASH 2007
Bortezomib regimen
Phase n
CR + PR
CR + nCR
Abstract*
+ low-dose melphalan, dex
1/2 53
78%
34%
Popat et al. (abstract 2713)
+ mel, prednisone, thal, defibrotide 24
42%
(16% VGPR)
not stated
Palumbo et al. (abstract 2715)
+ bendamustine, prednisone 2 46
61%
15%
Poenisch et al. (abstract 2723)
+ doxorubicin, dex
+ thal/dex 35
93%
68%
Lee et al. (abstract 2731)
+ thal, DOXIL, dex
+ thal maintenance 20
80%
40%
Offidani et al. (abstract 2729)
+ lenalidomide, dex 27
79%
(includes MR)
33%
(includes VGPR)
Richardson et al. (abstract 2714)
*Abstracts from Blood 2007;110

38. Davies & Morgan et al. Haematologica 2007
Bortezomib combinations for relapsed/ refractory MM selection of studies published in
Bortezomib regimen
Phase n
CR + PR
CR + nCR
Reference
+ cyclophosphamide,
dex
Retrosp 16
75%
31%
Davies & Morgan et al. Haematologica 2007
+ intermediate-dose
dex,
cyclophosphamide 2 54
82%
16%
Kropff et al.
BJH 2007
+ melphalan,
prednisone,
thalidomide
1/2 30
67%
17%
(43% CR + VGPR)
Palumbo et al. Blood 2007
+ Doxil 3
646
44%
18%
Orlowski et al.
JCO 2007
+ thal-dex 85
63%
22%
Pineda-Roman et al.
Leukemia 2008
+ doxil, thal,dex 42
81% nr
Ciolli et al.
BJH 2008

39. Novel therapy combinations with bortezomib
Drug class
Abstract*
Tanespimycin
Hsp90 inhibitor
Richardson et al. ASH 2007
Suberoylanilide hydroxamic acid (SAHA)
Histone deacetylase (HDAC) inhibitor
Weber et al. ASH 2007
Badros et al. ASH 2007
Romidepsin
HDAC inhibitor
Prince et al. ASH 2007
Tipifarnib (R115777)
David et al. ASH 2007
LBH (Panobinostat)
Sezer et al. EHA 2008
CNTO 328
Anti-Interleukin (IL-6) monoclonal antibody
Manges et al. ASH 2007
Perifosine (KRX-0401)
Alkyphospholipid
Dasatinib
Tyr kinase inhibitor
Wildes et al. ASH 2007

40. Bortezomib retreatment in relapsed MM: a retrospective multicenter survey
Retrospective survey of 49 patients in 15 centers
Median of 4 therapies prior to first bortezomib treatment
Safety profile in line with first treatment
Initial treatment
Retreatment
ORR
100%
63% CR
12%
10%
Time to response (median)
3.2 months
3.0 months
Dex added
39%
62%
Treatment-free interval (median)
6.6 months
4.1 months
TTP
10.9 months
6.7 months
Hrusovsky et al, ASH 2007

41. BORTEZOMIB IN MULTIPLE MYELOMA CONCLUSIONS
Rapidity of action, no renal and cardiac toxicity
Peripheral neuropathy mostly reversible with dose modification
Response not influenced by high risk cytogenetic abnormalities
Other strategies have been used to improve the outcome of ASCT
Among these strategies is double ASCT, which has been shown to be beneficial in patients not achieving a CR or VGPR following the first transplant
In addition, the transplant protocol has been further intensified, which has led to improvements in response rates and survival
Finally, novel agents are being introduced into the ASCT paradigm to further improve results
Optimal use as induction regimen in young and elderly patients and as salvage treatment

42. BORTEZOMIB IN MULTIPLE MYELOMA OPEN ISSUES
Duration of response
Role and schedule of maintenance treatment-efficacy of retrieve
Combination with new drugs/chemotherapy
Long term results in patients with poor prognosis
In combination or in alternative to ASCT in young patients? Role of double ASCT?
Other strategies have been used to improve the outcome of ASCT
Among these strategies is double ASCT, which has been shown to be beneficial in patients not achieving a CR or VGPR following the first transplant
In addition, the transplant protocol has been further intensified, which has led to improvements in response rates and survival
Finally, novel agents are being introduced into the ASCT paradigm to further improve results