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© 2009 OptumHealth Education
Phase III: Bortezomib + pegylated liposomal
doxorubicin vs bortezomib: Time to
progression
100
PLD + Bortezomib
80
9.3 months
sion-Free
60
Bortezomib
sProgres
65
6.5
t
mon h
ths
40
Patientof 20
Statistical analysis:
HR (95% CI) 1.82 (1.41-2.35)
P=0.000004
Percent
0
0
100
200
300
400
500
Days
APEX: TTP was 6.2 months
Orlowski et al. J Clin Oncol 2007;25:38923901

© 2009 OptumHealth Education
Summary of bortezomib induction regimens
Harousseau
Cavo
Sonneveld
Knop
VD vs VAD
VTD vs TD
PAD vs VAD
VCD
(n=223 vs 219)
(n=199 vs 200)
(n=75 vs 75)
(n=100)
(abstract 158)
(abstract 653)
(abstract 2776)
Results post-induction
CR + nCR
15% vs 7%
33% vs 12%
5% vs 1%
n/a
VGPR
39% vs 16%
61% vs 30%
42% vs 15%
50%
CR + PR
82% vs 65%
92% vs 78.5%
83% vs 59%
79%
Results post-ASCT
CR + nCR
40% vs 22%
54% vs 29%
23% vs 9%
n/a
VGPR
61% vs 44%
75% vs 53%
80% vs 50%
n/a
CR + PR
n/a
n/a
93% vs 80%
n/a
n/a: not available

© 2009 OptumHealth Education
Therapeutic Algorithm
Level of Evidence 1b (> 1 Randomized Trial)
Diagnosis
> 65 years
MPT
MP
>
5 randomized trials
MPV
MP
>
1 randomized trial
MPR
MP
under evaluation

© 2009 OptumHealth Education
Cyclophosphamide, Lenalidomide, Dexamethasone
CRd trial in Newly Diagnosed
yg
MM
Four 28-day cycles for 12 cycles or until ASCT in patients with SD
1
8
15
21 22
28
C
C
C
D
D
D
D
Lenalidomide

Cohort 1 (n=34), accrued from June 2006 to July 2007
Lenalidomide 25 mg/d, days 121; Dex, 40 mg/d, days 1, 8, 15, 22;
cyclophosphamide, 300 mg/m2 days 1, 8, 15

Cohort 2 (n=19), accrued due to need for cyclophosphamide dose
reduction in cohort 1
Treatment as per cohort 1, except cyclophosphamide 300 mg (fixed dose)
days 1, 8, 15

ASA or
or full
full anticoagulation
anticoagulation for
for all patients
patients
Kumar S et al. Blood. 2008;112:40 [abstract 91]; updated results presented at:
50th ASH Annual Meeting; December 69, 2008; San Francisco, CA

Cyclophosphamide, Lenalidomide,
© 2009 OptumHealth Education
Dexamethasone,
CRd trial: Response
Response at 4 cycles
Best response
90
80
70
% 60
50
58
58
53
se, 50
50
53
n
PR
n
40
CR/VGPR
Respo 30
20
35
26
26
25
26
32
10
0
Cohort
ohor 1
Cohort
ohor 2 All
Al patie
tients
ts Cohort
ohor 1
Cohort
ohor 2 All patie
tients
ts

34 patients went to stem cell collection

8 patients failed first attempt (3 salvaged with AMD3100, 1 salvaged with CTX, 4 did not reattempt/failed)

Median collection 7.0 × 106 CD34 cells/kg

11 patients have since gone to ASCT
Kumar S et al. Blood. 2008;112:40 [abstract 91]; updated results presented at:
50th ASH Annual Meeting; December 69, 2008; San Francisco, CA

© 2009 OptumHealth Education
Lenalidomide; Doxorubicin, Dexamethasone,
RAD trial: safety and efficacy
yy in relapsed MM patients
Response other than nCR or CR
100
nCR
87
CR
Grade 3 or 4
%*
80
adverse event
60
60
(%) 60
Neutropenia
44
nts 40
Thrombocytopenia
32
20
Peripheral
0
Patie
25
23
neuropathy
0
VTE
75
7.5
Group DL1 4

Group DL5 +
* Reported in 69 patients.
G-CSF
(n = 20)
(n = 30)
Cyt
ti
ogene c b
a
lit
norma y
Pt
Pa iti t
en s, /
n
l
eva
b
ua l
ble (%)
(%)
PR, n
del(13q)
17/37 (46)
12
t(4;14)
4/25 (16)
3 (PD: 1)
del(17p)
6/31 (19)
2 (SD + PD: 2)
DL = dose level; G-CSF = granulocyte colony-stimulating factor; RAD = Revlimid®
Knop S, et al. Blood.
(lenalidomide), Adriamycin®, and dexamethasone; SD = stable disease.
2007;110 [abstract 2716].

© 2009 OptumHealth Education
Bortezomib, Cyclophosphamide, Dexamethasone,
VCD combinations in the relapsed/refractory setting
Phas
CR +
CR +
Bortezomib
n
EFS, PFS, OS
Reference
e
PR
nCR
+
EFS: 12
cyclophosphamid
Kropff
months
et al.
e
Br J
2
54
82%
16%
+ intermediate-
OS: not
Haematol
2007;138:330-
dose
reached @ 15
th
7
dex
months
+
Davies et al.
cyclophosphamid
Haematologic
e
1/2
16
75%
31%
PFS: 7 months
e
a 2007; 92:
+ dex
1149-1150
+
37
cyclophosphamid
1-year PFS
Reece et al.
1/2
(19 at
1/2
(
95%
50%
56%
JCO 2008;26:
e
dose
1-year OS 89%
4777-4783
+ prednisone
reported)

© 2009 OptumHealth Education
Bortezomib, Lenalidomide, and Dexamethasone
RVD trial in Newly Diagnosed
yg
MM
Eight 21-day cycles*
1 2
4 5
8 9
11 12
14
21
Bz
Bz
Bz
Bz
Dex
Dex
Dex
Dex
Lenalidomide
*Dex, 40 mg/d, days 1, 2, 4, 5, 8, 9, 11, 12; 20 mg/d, cycles 58, amended to
20 mg/10 mg cycles 14/58 based on safety data
· Patients achieving PR may proceed to ASCT after 4 cycles
· Maintenance therapy permitted in patients achieving SD using weekly
(days 1 and 8) schedule of Bort, and Dex on days 1, 2, 8, and 9
· Antithrombotic therapy with
with daily
daily ASA (81
(81 or 325 mg)
· Antiviral therapy as prophylaxis against herpes zoster
Richardson P et al. Blood. 2008;112:41 [abstract 92]; updated results presented at:
50th ASH Annual Meeting; December 69, 2008; San Francisco, CA

Bortezomib, Lenalidomide, and©2009OptumHealthEducation
Dexamethasone in Newly Diagnosed MM:
Response Data
Responses assessed by EBMT1 criteria and Uniform Criteria (UC)2
(modified to include nCR)3
EBMT/UC Response (N=65 Evaluable as of Nov
n (%)
2008)
CR
17 (26)
nCR
12 (18)
VGPR
20 (30)
PR
36 (55)
VGPR
48 (74)
PR
65 (100)
1. Bladé J et al. Br J Haematol. 1998;102:1115; 2. Durie BGM et al. Leukemia. 2006;20:1467
[published corrections in Leukemia. 2006;20:2220, Leukemia. 2007;21:1134]; 3. Richardson P et al. Blood.
2008;112:41 [abstract 92]; updated results presented at: 50th ASH Annual Meeting; December 69, 2008;
San Francisco, CA

© 2009 OptumHealth Education
Phase III Study of Bortezomib, Melphalan, Prednisone
(VMP) ± Thalidomide (VMPT) in Newly Diagnosed MM
VMP
R
Bortezomib 1.3 mg/m2 IV
A
days 1,8,15,22*
Newly
NO MAINTENANCE
N
Melphalan 9 mg/m2 and
diagnosed
D
prednisone 60 mg/m2 days 14
symptomatic
sy
MM
O
M
65 yr or
9 × 5-wk cycles in both arms
Until relapse
I
<65 yr and not
Z
transplant-
VMPT
A
eli ibl
g
e
Bt
Bortezomib
ib 13
1.3 mg/ 2
/m IV
T
MAINTENANCE
days 1,8,15,22*
(N=393)
I
Bortezomib 1.3 mg/m2 IV
Melphalan 9 mg/m2 and
O
days 1,15
prednisone 60 mg/m2 days 14
N
Thalidomide 50 mg/d
Thalidomide 50 mg/d
continuously
ti
l
continuous y
*61 VMP patients and 70 VMPT patients were treated with biweekly infusions of bortezomib
Palumbo A et al. Blood. 2008;112:243 [abstract 652]; updated results presented at:
50th ASH Annual Meeting; December 69, 2008; San Francisco, CA

© 2009 OptumHealth Education
VMPT vs VMP in Newly Diagnosed MM: Efficacy
50
55%*
VMPT Best Response
50
VMP Best Response
45
N=177
45
N=177
39
Median 5 cycles
Median 5 cycles
40
39
40
40
37
35
32
35
45%*
30
30
s(%)
(%)
24
25
25
21
20
20
Patients
16
Patient
16
15
15
10
10
6
5
2
5
0
0
0
CR
VGPR
PR
SD
PD
CR
VGPR
PR
SD
PD
VMPT
VMP
P Value
Time to next therapy @ 36 mo, %
80
78
.56
PFS @ 36 mo, %
74
70
.28
*P<.001
OS @ 36 mo, %
88
87
.75
Palumbo A et al. Blood. 2008;112:243 [abstract 652]; updated results presented at:
50th ASH Annual Meeting; December 69, 2008; San Francisco, CA

© 2009 OptumHealth Education
Bortezomib, Dexamethasone, Cyclophosphamide,
Lenalidomide (VDCR) in Newly Diagnosed MM
Phase I EVOLUTION Trial
Dose escalation of Cy: eight 21-day cycles
1
4
8
11
14 15
21
B
B
B
B
Dex
Dex
Dex
Cy
Cy
Lenalidomide
Maintenance therapy: four 42-day cycles
1
8
15
22
42
B
B
B
B
Bort 1.3 mg/m2 IV; Dex 40 mg po; Len 15 mg po; Cy dose-escalating 100500 mg/m2 po

Prophylactic antibiotics, acyclovir, and anticoagulants as required

Eligible patients could undergo ASCT after 4 cycles
Kumar S et al. Blood. 2008;112:41 [abstract 93]; updated results presented at:
50th ASH Annual Meeting; December 69, 2008; San Francisco, CA

© 2009 OptumHealth Education
VDCR in Newly Diagnosed MM: Response rate
Dos
Remain
Best Unco
c nfirm
o
ed
Dos
Remain
ed
Patients
e
Cy Dose,
Enrolle
Treate
on
Response, N=25
Undergoin
Leve
mg/m2
d
d
Treatmen
g ASCT
CR
VGPR
l
t
PR
(sCR)
(nCR)
1
100
3
3
3
0
2 (2)
1

2
200
4
4*
1
0
1 (1)

3
3
300
4
4*
1
0
2 (1)
2 (1)

4
400
8
7
41
2
3
2
5
500
7
7*
N/A
52 (1)
2
3
Total
26
25
9
6
9 (5)
8 (1)
8
Recommended dose of Cy was 500 mg/m2
CR 36%
> VGPR 68%
*1 patient not evaluable for DLT per protocol 1 patient excluded (did not receive study treatment due to a heart problem); 1
other patient not evaluable for DLT per protocol
Patients have not undergone sufficient cycles (4)
Kumar S et al. Blood. 2008;112:41 [abstract 93]; updated results presented at:
50th ASH Annual Meeting; December 69, 2008; San Francisco, CA

© 2009 OptumHealth Education
Phase II Trial of Lenalidomide, Melphalan, Prednisone,
and Thalidomide (RMPT)
() in Relapsed/Refractor
p
y MM
Melphalan
Prednisone
Lenalidomide
Thalidomide
Cohort
(mg/kg) po
(mg/kg) po
(mg/d) po
(mg/d) po
1 (n=22)
()
0.18
2
10
50
2 (n=22)
0.18
2
10
100
1 2 3 4
21
28
Melphalan
Prednisone
L
lid
ena
id
om e
Thalidomide
q 28 days for 6 cycles. Low-dose aspirin (100 mg/d) as prophylaxis for DVT
MAINTENANCE: 28-day cycles until progression
1 2 3 4
21
28
Lenalidomide 10 mg/d
Palumbo A et al. Blood. 2008;112:321 [abstract 868]; updated results presented at:
50th ASH Annual Meeting; December 69, 2008; San Francisco, CA

© 2009 OptumHealth Education
Phase II Trial of RMPT in Relapsed/Refractory MM:
Response
p
vs MivPT and VMPT
RMPT (N=44)
MivPT (N=24)1
VMPT (N=30)2
Historical control
Historical control
50
43
50
50
50
42
40
40
40
29
(%)
27
30
30
30
20
22
23
20
20
17
20
17
17
17
13
12
Patients
10
10
10
2
0
0
0
0
CR/nCR VGPR PR
SD
PD
CR-
VGPR
PR
MR
SD-PD
CR-
VGPR
PR
MR
SD-PD
MivPT1, %
VMPT2, %
RMPT, %
CR
0
17
13
VGPR
12
44
33
PFS @ 1 yr
20
65
55
OS @ 1 yr
60
76
66
1. Palumbo A et al. Eur J Haematol. 2006;76:273; 2. Palumbo A et al. Blood. 2007;109:2767
Palumbo A et al. Blood. 2008;112:321 [abstract 868]; updated results presented at: 50th ASH Annual
Meeting; December 69, 2008; San Francisco, CA

© 2009 OptumHealth Education
PAD Induction, MEL-100, Len/Prednisone Consolidation, and
Len Maintenance
Maintenance in Elderly Patients
Patients With
With Newly
Newly Diagnosed MM
PADMEL-100LPL
PBSC Mobilization
MEL-100
PAD
LP
L
(Cyclophosphamide + G-CSF)
ASCT
4 cycles
2 cycles
2 cycles
4 cycles
PAD = bortezomib + pegylated doxorubicin + dexamethasone; MEL-100 = melphalan100 mg/m2;
LP = lenalidomide + prednisone; L= lenalidomide
21-day cycle
PAD
1
4
8
11
21
B
B
B
B
PLD
2
2
B = bortezomib 1.3 mg/m2; PLD = pegylated doxorubicin 30 mg/m ;
Dex*
Dex = dexamethasone 40 mg/d *Dex days 14, 811, 1518 on cycle 1
28-day cycle
LP: Consolidation
1
21
28
Lenalidomide 25 mg/d
Prednisone 50 mg/every other day
28-day cycle
L: Maintenance
1
21
28
Lenalidomide 10 mg/d
Palumbo A et al. Blood. 2008;112:65 [abstract 159]; updated results presented at:
50th ASH Annual Meeting; December 69, 2008; San Francisco, CA

© 2009 OptumHealth Education
PAD vs PADMEL-100 vs PADMEL-100LP vs
PADMEL-
MEL 100LP
LP L: Response Rate
Rate*
100
100
100
100
90
90
90
90
95%
80
80
80
80
73
89%
s 70
70
70
70
60%
59
87%
60
60
60
60
47
50
Patient
50
43
44
50
50
40
36
40
40
40
of
30
30
%
30
30
30
%
22
20
13
20
12
20
20
9
10
3
10
10
10
5
1
1
0
2
0
00
0
0
0
0
CR VGPR PR
SD
PD
CR VGPR PR
SD
PD
CR VGPR PR
SD
PD
CR VGPR PR
SD
PD
PAD 4 Cycles
PADMEL-100
PADMEL-100LP
PADMEL-100LPL
(n=102)
(n=77)
(n=56)
(n=40)
*Per protocol
Palumbo A et al. Blood. 2008;112:65 [abstract 159]; updated results presented at:
50th ASH Annual Meeting; December 69, 2008; San Francisco, CA

© 2009 OptumHealth Education
Preliminary Conclusions
3 drug
drug combos
combos seem superior to
to 2 drug combo
Unclear which is the best 3 drug combo
VMPT double the CR rate of VMP
Randomized studies are needed