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Jointly sponsored by Postgraduate Institute for Medicine, the
International Myeloma Foundation, and Clinical Care Options, LLC
Multiple Myeloma:
Finding Your Way
gy Through the Treatment Maze--Selecting
the Best Treatment in the Era of Novel Agents
Friday, December 5, 2008
6:30 PM - 9:00 PM
Moscone Center
San Francisco, California
Supported by educational grants from Celgene, Genzyme Transplant, Lilly,
Millennium Pharmaceuticals, Inc., and Ortho Biotech.

Evidence
Evidence--Based
Based Approaches for
Transplantation-Ineligible Patients
At
Antonio Pal
b
um o
Div. Hematology, University of Torino, I, EU

Thal/Dex vs MP
in newly diag
dia
ygnosed MM
Time to progression
Overall Survival
Survival: pts > 75 yrs
Months
Months
Months
Ludwig, et al. Blood
Ludwig,
Prepublished
et al
online . IMW
Oct
2007
27, 2008

MPT: the current standard of care
in elderly p
ypatients
MP-Thal vs MP studies
Median PFS,
PFS
Median OS,
OS,
months
p-value
months
p-value
IFM 1
IFM
27.
27 5v
5
s
vs 17.
17 8
<0.
<0 0001
51.
51 6v
6
s
vs 33.
33 2
0.
0 0006
GIMEMA2
N/A
0.0006
N/A
N.S.
IFM 3
24.1 vs 19
0.001
45.3 vs 27.70.03
Nordic4
16 vs 14
N.S.
29 vs 33
N.S.
Hovon5
N/A
<0.001
N/A
N.S.
N/A= not available
availa
;
ble N.S.= not significant;
significa
1. Facon T, et al. Lancet. 2007;370:1209-18. 2. Palumbo A, et al. Lancet. 2006;367:825-31. 3. Hulin C, et al. Blood. 2007;110 [abstract 75]. 4.
Waage A, et al. Blood. 2007;110 [abstract 78]. 5. Wijermans P, et al. Haematologica. 2008;93 [abstract 0440].

MP-Thal: 35% reduced risk of progression (14%-50%)
ASCT: 25% reduced risk of prog
pgresion (4%-41%)
MP vs MP-Thal
MP-Thal*
MP-Thal vs
vs ASCT
ASCT
ASCT11
0.4
0.6
0.8
1.0
1.2
Hazard Ratio
13Facon et al. Lancet 2007; 370:1209-18. 36Palumbo et al. Lancet 2006;367:925-31. 37Hulin et al. J Clin Oncol 2007;25:abstract 8001.
38Gulbrandsen et al. Haematologica 2008;abstract 0209. 11Koreth J et al. Biol Blood Marrow Transplant 2007;104:3052-7

MPT in Elderly Patients: Grade 3/4 AEs
MPT (n=129)
MP (n=126)
Hematologic
P=0.001
Thrombotic
P=0.001
Neurologic
P=0.01
Infection
Cardiac
Early deaths*
0
102030
Patients, %
Palumbo A et al. The Lancet 2006 2007;370:1209-18

LMWH vs Warfarin vs ASA Prophylaxis
for thalidomide regimens:
Study design
Thalidomide regimens
VMP
(950 pts)
pts)
Random
ASA
WAR
LMWH
No
Aspirin
Warfarin
Enoxaparin
prophylaxis
100 mg/day
1.25 mg/day
40 mg/day
Rates of
of VTE
VTE
No prophylaxi
prophylax s
i
LMWH
WAR
WA
ASA
01
234
56
Palumbo et al EHA 2008; abs 0213
Patients (%)

MPV: the current standard of care
in transplant ineligible patients
52% reduced risk of progression
~36% reduced risk of death
100
100
VMP
90
)
90
VMP
)
(%
MP
80
%
MP
80
ent
t(
v
n
ve
70
eve 70
/o
60
ithout
w 60
w
50
nts
50
e
bjects
e
u
40
s
pati
40
of
of
30
30
20
entagec
rcentage
c
e 20
Median follow-up 25.9 months
eP
VMP: 3-year OS rate = 72%
Per
10
VMP: 24.0 months (83 events)
10
MP: 3-year OS rate = 59%
MP: 16.6 months (146 events)
0
HR=0.483, P<0.000001
HR = 0.644, p = 0.0032
0
03
6
9
12
15
18
21
24
27
0
2
4
6
8 10 1214 16 1820 2224 26 28 30 32 34 3638 40
Time (months)
Time (months)
San Miguel, et al. N Engl J Med. 2008;359:906-17.

VMP in Elderly Patients: Grade 3/4 AEs
VMP
MP
Neutropenia
Thrombocytopenia
DVT
PeripheralNeuropathy
Neuralgia
Infection
0
10
2030
4050
Pt
Pa i
tients, %
San Miguel, et al. N Engl J Med. 2008;359:906-17.

Response: MPT versus MPR
MPT
Overall
MPR
survival
Bt
Best response
70
60
Best response
100
n = 129*
n = 32^
60
50
75
50
40
53%
(%)
40
(%)
(%)
40
33
37%
30
29
50
tients
30
tients
24
tients
Pa
21
Pa
20
Pa
20
16
1
25
4
8
10
10
5
5
0
0
0
0
CR
VGPR
PR
MR
SD
0
510
15
20
25
CR VGPR PR
MR
SD
PD
or PD
months
*Palumbo A, et al. Lancet. 2006;367:825-31.
^Palumbo A, et al. J Clin Oncol. 2007;25:4459-65.

MPR: Grade 3/4 AEs
MPR*
P=0.001
Neutropenia
Thrombocytopenia
DVT
Peripheral-Neuropathy
Infections
020
40
60
Patients, %
*Melphalan 0.18 mg/kg,days 14; Prednisone 2 mg/kg,days 14; Lenalidomide 10 mg/day,days 121
Palumbo et al. J Clin Oncol. 2007;25:4459-65

CTD vs MP in Newly Diagnosed MM:
MRC Myeloma IX Study
Non-intensive: Post-induction
RANDOMIZATION
P<
P 0
<0 001
.
100
80
%
CTD
MP
es
35
MP
60
40
25
Respon
39
RANDOMIZATION
20
22,5
3,5
0
6
CTD (n=120)
MP (n=113)
Thal
+Thal
CR
VGPR
PR
CTD, cyclophosphamide, 500 mg po days 1, 8 and 15; thalidomide 50200 mg/day; dexamethasone 20 mg/day po days 14, 1518 q 4
wk
Morgan GJ et al. Blood. 2007;110:1051a [abstract 3593]

Prognostic factors
MPT
MPR
MPV
22--microg
microglob
lobulin
ulin > 3.5 mg/dL
Del 13; t(4:
t(4 1
: 4
1 )
4
t(4;1
; 4
1 ),
) t(14;
4 1
; 6)
6 , del 17p
100
)
90
(%
80
70
Standard risk
ent
High risk
v
60
te
50
uo 40
ith
30
Standard risk (N=142): 23.1 months (34 events)
w
20
High risk (N=26): 19.8 months (7 events)
HR=1.297 (95% CI: 0.55, 3.06), p=0.55

10
2
2--m > 3.5
3. mg/L
mg/
0
22--m
m 3.5
3. mg/L
mg/
Subjects
0
2
4
6
8
10121416 18 20 22 24 26
Time (months)
100
P = .19
)
90
%
80
t(
Standard risk
Months
n
70
ve
High risk
60
et 50
uo 40
ith
30
w
Standard risk (N=142): not reached (16 events)
20
High risk (N=26): not reached (3 events)
10
HR=1.009 (95% CI: 0.278, 3.663), p=0.99
0
ubjectsS
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30
Time (months)
Palumbo et al EHA 2008;abstract
Palumbo et al. Blood 2006;
San Miguel, et al. N Engl J Med.
0213
abstract 800
2008;359:906
2008;359:906--17.
17.

Age
Age--adjusted
adjusted therapy
Full dose
Autologous
chemotherapy
transplant
65-
65 75
-
years
25
25--64
64 years
31%
36%
33%
75
75--101
101 years
Reduced dose
chemotherapy
Regione Piemonte, Assessorato Sanità 2006,15

Early discontinuation
El
Early
ITT
Starting
Discontinuation,
doses
dose
%
MPT 1
200 mg/d
400 mg/d
45%
Thalidomide
in 52% pts
MPT2
100 mg/d
100 mg/d
41%
Thalidomide
VISTA3
1.3mg/m2
1.3mg/m2
34%
Bortezomib
d1,4,8,11
d1,4,8,1
d1,4,8,11
d1,4,8,1
1Facon et al. Lancet 2007; 370:1209-18. 2Palumbo et al. 2 Lancet 2006;367:925-31.
3San Miguel, et al. N Engl J Med. 2008;359:906-17

Age
Age--adjusted
adjusted doses
Further Dose
65-75 years
> 75 years
Redcution
Dt
Dexame h
thasone
40 mg
20 mg
10 mg
weekly
Melphalan
0.25 mg/Kg
0.18 mg/Kg
0.13 mg/Kg
days 1-4
Thalidomide
200 mg
100 mg
50 mg
per day
Lenalidomide*
25 mg
15 mg
10 mg
days
y 1-21
1.3 mg/m2
1.3 mg/m2
1.0 mg/m2
Bortezomib
bi-weekly
weekly
weekly
If a grade
grade 3-4 AE
AE occurs: 1. discontinue
discontinue therapy; 2. wait
wait for
for grade 1 AE; 3.
restart at a lower dose
Recommendations by A. Palumbo.
*Lenalidomide plus melphalan starting dose 10 mg/d

BiRD: continued therapy increases
the quality
ualit
qy of the response
St
S ringent CR
CR
CR
100
VGPR
PR
se
90
80
70
respon
60
a
)%50
(
with
40
30
ients
20
Pat
10
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 1617 18 19 20 212223 2425 26 2728 29 30 31 32 33
Cycles of treatment
Niesvizky R, et al. Blood. 2008;111:1101-9.

Autologous stem cell transplant
in elderly p
ypatients
Survival advantage
Survival advantage
NO Survival advantage
Age < 65 yr
Age 65-70 yr
Age 65-75 yr
1.0
MP
OS
MPT
0.8
MEL100
0.6
0.4
P= 0.001
0.2
0.00
12
1
243
2
64
43
8
64
60
6
72
7
Time From Randomization, mo
Tandem MEL200
Tandem MEL100
Tandem MEL100
Barlogie et al NEJM 2006;354:1021
Palumbo et al Blood 2004;104:3052
Facon Lancet 2007; 370:1209-18

Role of maintenance
after autologous transp
gplant
PAD
MEL100
LP
LP--L
L
INDUCTION
CONSOLIDATION
MAINTENANCE

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

Evidence
Evidence--Based
Based Approaches for
Transplantation-Ineligible Patients
At
Antonio Pal
b
um o
Div. Hematology, University of Torino, I, EU