Bortezomib Anthracyclines

1
Bortezomib Anthracyclines
2
OS From Time of Diagnosis in 6-yr Intervals
Based on Date of Diagnosis
Kumar SK et al. Blood. 2007 Nov 1 Epub ahead of
print
3
Levels of Evidence/Grades of Recommendation
Levels of Evidence Levels of Evidence
Ia Evidence obtained from meta-analysis of randomised controlled trials
Ib Evidence obtained from ?1 randomised controlled trial
IIa Evidence obtained from ?1 well-designed, non-randomised study, including phase II trials and case control studies
IIb Evidence obtained from ?1 other type of well-designed, quasi-experimental study, ie, studies without planned intervention, including observational studies
III Evidence obtained from well-designed, non-experimental descriptive studies. Evidence obtained from meta-analysis, randomised controlled trials, or phase II studies which are published only in abstract form
IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
Grades of Recommendation Grades of Recommendation
Grade A Evidence level Ia, Ib
Grade B Evidence level IIa, IIb, III
Grade C Evidence level IV
4
Therapeutic Algorithm
3 Relapse
2 Relapse
Diagnosis
1 Relapse
15 months
3 months
7 months
30 months
Single non cross-resist agent
Single non cross-resistant agent
Single n c-res agent
Combination regimen

5
Bortezomib Anthracycline Agents for RR MM
Bortezomib regimen Phase n CR PR CR nCR Reference
Doxil III 303 52 17 Harousseau et al. J Clin Oncol 2007 25(18S) Abstract 8002 (Oral Presentation)
adriamycin DEX (PAD) II 64 67 25 Palumbo et al. Ann Oncol 2008 19 1160-1165
liposomal doxorubicin DEX II 22 81 45 Gozzetti et al. Haematologica 2008 93(Suppl 1) Abstract 1111
liposomal doxorubicin DEX II 6 100 67 Pisani et al. Haematologica 2008 93(Suppl 1) Abstract 1106
CR VGPR nCR VGPR
6
Bortezomib Doxil
7
Bortezomib DOXIL DOXIL MMY-3001 Trial

• Phase III trial in Relapsed and/or Refractory MM
• Endpoints - Primary TTP Secondary OS, ORR,
  Safety
• Patients 646 pts
• Median age 62 yr (bortezomib, B), 61 yr
  (bortezomib DOXIL, BPLD)
• Prior therapies 1 line in 34 (each arm), 2
  lines in 66 (each arm)
• Dose and Schedule
• Stratification by ß2-microglobulin and response
  to initial therapy
• Pts randomised to
• B (n322) Bortezomib 1.3 mg/m2 days 1, 4, 8, 11
  for up to eight 21-day cycles
• BPLD (n324) Bortezomib as above DOXIL 30
  mg/m2 day 4
• Responding pts allowed to continue beyond 8
  cycles

Orlowski et al. J Clin Oncol 2007 25(25)
3892-3901 Harousseau et al. J Clin Oncol 2007
25(18S) Abstract 8002 (Oral Presentation)
8
Efficacy - Updated
By IMWG 2006 criteria
Orlowski et al. J Clin Oncol 2007 25(25)
3892-3901 Harousseau et al. J Clin Oncol 2007
25(18S) Abstract 8002 (Oral Presentation)
9
Time to Progression (TTP)
Orlowski et al. J Clin Oncol 2007 25(25)
3892-3901 Harousseau et al. J Clin Oncol 2007
25(18S) Abstract 8002 (Oral Presentation)
10
Overall Survival
100
Bortezomib PLD
80
Bortezomib
60
Percent of Subjects Alive
40
BPLD B
Censored Died 82 18 75 25
HR (95 CI) 1.41 (1.0021.97) P lt 0.05 HR (95 CI) 1.41 (1.0021.97) P lt 0.05 HR (95 CI) 1.41 (1.0021.97) P lt 0.05
20
0
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
Time (days)
Orlowski et al. J Clin Oncol 2007 25(25)
3892-3901 Harousseau et al. J Clin Oncol 2007
25(18S) Abstract 8002 (Oral Presentation)
11
Safety Grade 3/4 Adverse Events
Adverse Event B (n318) BPLD (n318)
Thrombocytopenia 17 24
Neutropenia 16 32
Peripheral Neuropathy 11 7
Anemia 10 9
Nausea/Diarrhea/Vomiting 7 14
Neuralgia 5 3
Asthenia 4 6
Cardiac Events 3 3
Fatigue 3 6
Febrile Neutropenia 2 3
Bleeding / hemorrhage 1 4
Anorexia lt1 2
Stomatitis lt1 2
Hand foot syndrome 0 6
Gr 3/4 AE of thromboembolic events 1 in each
arm SAE occurred in 33pts and 38 pts on B vs BD
respectively
Orlowski et al. J Clin Oncol 2007 25(25)
3892-3901 Harousseau et al. J Clin Oncol 2007
25(18S) Abstract 8002 (Oral Presentation)
12
Impact of Prior IMiD Therapy

• Pre-specified sub-analysis of the DOXIL MMY-3001
  trial
• Determine the efficacy and safety of PLD plus
  bortezomib versus bortezomib alone in patients
  with or without prior IMiD exposure

Bortezomib Bortezomib PLD
N 322 324
IMiD-naïve (n) 184 194
IMiD-exposed (n) 138 130
Orlowski et al. J Clin Oncol 2007 25(25)
3892-3901 Harousseau et al. J Clin Oncol 2007
25(18S) Abstract 8002 (Oral Presentation) Sonneve
ld et al. Cancer 2008 112 15291537
13
Impact of Prior IMiD Therapy on Response OS
Sonneveld et al. Cancer 2008 112 15291537
14
Impact of Prior IMiD Therapy on TTP

• In patients with prior IMiD therapy, TTP is
  significantly longer with BPLD vs. B (p0.018)
• Median TTP in patients treated with BPLDD is
  comparable between patient who received prior
  IMiD therapy (270 days) and those who did not
  (295 days)

Sonneveld et al. Cancer 2008 112 15291537
15
Phase III (MMY-3001)Bortezomib/PLD in Renal
Insufficiency

• Results PLD B resulted in numerically higher
  response and increased DOR vs B alone in RI

CrCl lt60 ml/min (RI) CrCl lt60 ml/min (RI) CrCl ?60 ml/min (normal) CrCl ?60 ml/min (normal)
PLDB (n88) B (n94) PLDB (n215) B (n216)
CR 1 3 6 2
VGPR 26 19 23 16
PR 48 38 41 41
ORR 49 42 47 44

• Both PLDB and B alone resulted in a steady
  statistically significant and clinically
  meaningful improvement in mean CrCl from baseline
  in the RI subgroups

• Safety Incidence of serious drug-related AE
  (SAE) for PLDB in RI vs normal renal function
  subgroups was 28 vs 19 respectively, (of note
  Gr ?3 anemia of 13 was higher in RI vs 8 in
  normal subgroup, hand-foot syndrome was lower in
  RI vs normal subgroups (1 vs 6, respectively)
• Safety profile of bortezomib alone was similar in
  both subgroups (RI vs normal) including SAE (16
  vs 14, respectively)
• Overall incidence of symptomatic cardiac AE was
  low and similar between the RI (9) and normal
  (7) for PLDB the rates were lower for pts
  receiving bortezomib alone (5 in both subgroups)

Blade et al. ASCO 2008, Abstract 8562
16
Phase III (MMY-3001)Bortezomib/PLD in Renal
Insufficiency

• Subgroup analysis of pts with renal insufficiency
  (RI) treated with PLDB or bortezomib alone
• Efficacy and safety of PLDB in MM pts with RI
  compared to pts with normal renal function pts
  with CrCl 30 mL/min were excluded from original
  study
• Patients
• 193 pts with RI (CrCl lt60 mL/min) mean age for
  PLDB arm was 67 yrs and bortezomib arm 66 yrs
• 453 normal pts (CrCl 60 mL/min) mean age for
  PLDB arm was 59 yrs and bortezomib arm 60 yrs
• Dose eight 21-day cycles
• B bortezomib 1.3 mg/m2 days 1, 4, 8, 11
• PLDB bortezomib as above PLD 30 mg/m2 day 4
• Results PLDB resulted in significantly longer
  median TTP vs B alone in RI (331 vs 199 days
  p0.002)

CrCl lt60 ml/min (RI) CrCl lt60 ml/min (RI) CrCl ?60 ml/min (normal) CrCl ?60 ml/min (normal)
PLDB (n95) B (n98) PLDB (n229) B (n224)
TTP median days 331 (276-NA) 199 (161-218) 270 (221-331) 190 (169-230)
P-value 0.002 0.002 0.0007 0.0007
Blade et al. ASCO 2008, Abstract 8562
17
VELCADE DOXIL vs. VELCADE Sub-analysis
Bladè,Blood 2007 110 (Abstract 410)
18
Possible Therapeutic Algorithm
19
Conclusion

• Bortezomib PLD significantly improved TTP and
  OS in previously treated MM compared with
  bortezomib alone
• Benefits seen in clinically relevant groups,
  including those with prior IMiD use
• Response rate (CR VGPR) was also improved for
  bortezomib PLD compared with bortezomib alone
• Bortezomib PLD ORR 52, CR VGPR 30
• Bortezomib ORR 44, CR VGPR 20
• Safety and AE profile were predictable and
  manageable
• Incidence of thromboembolic events was low and no
  prophylaxis necessary

Sonneveld et al. Cancer 2008 112
15291537 Harousseau et al. J Clin Oncol 2007
25(18S) Abstract 8002 (Oral Presentation)
20
Bortezomib Adriamycin DEX (PAD)
21
Bortezomib Adriamycin DEX

• Open label study of 64 consecutive patients
  treated with PAD regimen.
• Dosing Schedule
• Bortezomib 1.3 mg/m2 (days 1, 4, 8, 11)
• Low dose dexamethasone 40 mg (days 14)
• Doxorubicin 20mg/m2 (days 1, 4) or pegylated
  liposomal doxorubicin at 30 mg/m2 (day 1).
• Median No. of prior therapies 2 (range 1-7).
• Median No. of PAD cycles 4 (range 1-6).

Palumbo et al. Ann Oncol 2008 19 1160-1165
22
Response Rates
All Patients (N64) PAD as 2nd Line Therapy (N15) PAD as 3rd Line Therapy (N24) PAD as 4-8th Line of Therapy (N25)
CR VGPR 25 27 25 24
CR IF- 9 13.5 4 12
VGPR 16 13.5 21 12
PR 42 53 38 40
SD 24 20 25 24
PD 9 0 12 12
Palumbo et al. Ann Oncol 2008 19 1160-1165
23
Survival

• Median follow up for surviving patients is 8
  months (range 1-21 months).
• 1-year EFS was 34
• 1-year OS was 66

Palumbo et al. Ann Oncol 2008 19 1160-1165
24
Safety
Palumbo et al. Ann Oncol 2008 19 1160-1165
25
Bortezomib Liposomal doxorubicin DEX
26
Bortezomib Liposomal doxorubicin DEX

• Open label study of 22 patients with RR MM
• Dosing Schedule
• Bortezomib 1.3mg/m2 days 1, 4, 8 11 every 21
  days
• PegLD 30mg/m2 on day 4
• DEX 40mg on days 1-4
• Five patients had MM disease previously
  refractory to anthracyclines (VAD therapy)
• Median of 4 lines of prior therapy (range 1-6)
• Patients received a median of 4 cycles of
  treatment (range 2-4)

Gozzetti et al. Haematologica 2008 93(Suppl 1)
Abstract 1111
27
Response Rates
ORR CR nCR VGPR PR
No. 18 8 2 4 5
81 36 9 18 23

• 4/5 VAD refractory patients obtained a response
• Median DOR was 7 months (range 2-12)
• 11/13 patients with ?VGPR maintained a response
  at a median of 8 months (range 4-12)

Gozzetti et al. Haematologica 2008 93(Suppl 1)
Abstract 1111
28
Bortezomib and dexamethasone as maintenance
Median time from diagnosis 41 months Salvage
therapy 8 courses of bortezomib containing
regimen Maintenance Bortezomib 1.3 mg/mq, days
1 and 15 Dexamethasone 20 mg, days 1-2 and 15-16
28-day cycle for a total of 6 cycles Response
improvement from PR 1/40 CR, 4/40 VGPR, Median
TTP 23 months (95CI 8-not reached) 1-year PFS
69 (95CI 50-82) 1-year OS 63 (95IC10-41).

Benevolo et al personal communication
29
Bortezomib Liposomal doxorubicin DEXfor
Newly Diagnosed Patients
30
GIMEMA Italian Myeloma Network

• BORTEZOMIB, PL-DOXORUBICIN, DEXAMETHASONE (PAD)
• AUTOLOGOUS STEM CELL TRANSPLANT (MEL100)
• LENALIDOMIDE - PREDNISONE (LP)
• IN ELDERLY NEWLY DIAGNOSED MYELOMA

Palumbo Antonio1, Falco Patrizia1, Corradini
Paolo2, Crippa Claudia2, Patriarca Francesca2,
Rossini Fausto2, Offidani Massimo2, Liberati
Anna Marina2, Petrucci Maria Teresa2, Boccadoro
Mario1 1Myeloma Unit, Divisione di
Ematologia, Università di Torino, Torino, I, EU,
2GIMEMA, Italian Myeloma Network, I, EU.
31
Treatment ScheduleINDUCTION
PAD-MEL100-LP-L
L
PBSC Mobilization (CyclophosphamideG-CSF)
MEL-100 ASCT
LP
PAD
4 cycles
2 cycles
2 cycles
4 cycles
PAD BortezomibPegylated DoxorubicinDexamethaso
ne MEL100 Melphalan100 mg/m2 LP
Lenalidomide Prednisone L Lenalidomide
32
Treatment Schedule CONSOLIDATION AND MAINTENANCE
33
Response Rate PAD vs PAD-MEL100
PAD 4 Cycles n86
PAD MEL100 n51
of patients
of patients
CR/ nCR
VGPR
PR
MR
SD
PD
CR/ nCR
VGPR
PR
MR
SD
PD
34
Response Rate PAD-MEL100 vs PAD-MEL100-LP
PAD MEL100 LP n34
PAD MEL100 n51
of patients
of patients
CR/ nCR
VGPR
PR
MR
SD
PD
CR/ nCR
VGPR
PR
MR
SD
PD
35
Response Rate PAD-MEL100 vs DAV-MEL200
of patients
36
PAD-MEL100-LP vs DAV-MEL200
PAD-MEL100-LP Median Follow-up 13.6 months
n86 DAV-MEL200 Median Follow-up 26.5 months
n124
PFS
OS
PAD-MEL100-LP
PAD-MEL100-LP
DAV-MEL200
DAV-MEL200
of patients
of patients
P0.01
P0.46
months
months
Historical control Palumbo et al. Blood
2007108 abs727
37
PFS PAD-MEL100-LP according to prognostic
factors
?2-microglobulin
age
?2mg lt 3,5
Age lt 70
?2mg gt 3,5
Age gt 70
of patients
of patients
P0.10
P0.08
months
months
t(414)
del(13)
No del(13)
t(414)
No t(414)
del(13)
of patients
of patients
P0.5
P0.61
months
months
38
Conclusions
DAV-MEL200 VD-MEL200 PAD-MEL100
CR 15 33 53
gt VGPR 36 55 88
EFS _at_ 2 years 63 NA 83
OS _at_ 2 years 85 NA 92
Historical control Palumbo et al. Blood
2007108 abs727 Harousseau et al.
Haematologica 2006 911498
39

• BORTEZOMIB, MELPHALAN,
• PREDNISONE AND THALIDOMIDE
• (VMPT)

40
V-MPT at 1 RelapseMPT at Diagnosis
V-MPT (N14)
MPT (N129)
1 Relapse
Diagnosis
45
50
57
39
45
40
40
35
36
36
35
30
30
25
21


25
21
21
21
20
20
15
13
15
15
10
10
5
5
5
0
0
0
CR-
VGPR
PR
MR
SD-PD
CR-
VGPR
PR
MR
SD-PD
Palumbo et al,Lancet 2006367825
41
STUDY DESIGN
9 V-MP courses
random
diagnosis
9 V-MPT courses
42
VMP vs VMPT Grade 34 peripheral neuropathy
Patients
43
Conclusion

• Bortezomib PLD significantly improved TTP and
  OS in comparison with bortezomib alone
• Benefits seen in clinically relevant groups
• prior IMiD use
• Prior Doxorubicin use
• Renal insufficiency
• High risk patients t(414), del(17)
• Treatment strategies
• Bortezomib Dexamethasone
• Rechallenge
• Bortezomib Doxorubicin Dexamethasone