How to treat elderly pati
p
ents:
combination therapy
or sequencing
n
Antonio Palumbo, MD
Unive
Uersity
ty of
o Torin
o
o,
o, Tori
o no,
o, I, EU
Disclosures for
Palumbo Antonio, MD
Research Support/P.I.
No relevant conflicts of interest to declare
Employee
No relevant conflicts of interest to declare
Consultant
No relevant conflicts of interest to declare
Major Stockholder
No relevant conflicts of interest to declare
Speakers Bureau
No relevant conflicts of interest to declare
Honoraria
Celgene, Janssen-Cilag, Pharmion
Scientific Advisory Board
No relevant conflicts of interest to declare
Age-Adjusted
Age-Adjusted Therapy
Therapy
INCIDENCE:
2002
8.9/100.000
Full dose
Autologous
chemothe
chemoth rap
ra y
transplan
tr
t
ansplan
65 74
-
years
y
25 64
-
years
y
36%
31%
33%
75-
75 101
-
yea
ye r
a s
Reduced-
Reduced dose
cht
hemo
h
h
chemoth
the
chemoth ra
erap
ra y
Regione Piemonte, Assessorato Sanità 2006
Criteria for Diagnosis/ Start therapy
·
Serum and/or urine monoclonal protein
·
> 10% Bone marrow monoclonal plasma cells
biopsy
py proven
p
plasmocytoma
py
·
Myeloma-related organ dysfunction (1 or more)
(C) Hypercalcemia
e
(Ca >1
> 05m
10.5
g/
mg Lo
/L rU
or LN)
ULN)
(R) Renal insufficiency (creatinine >2 mg/ dL)
(A) Anemia ( Hb < 10 g/ dL or 2 g< normal)
(B) Bone disease
·
Doubling M- component in less than 2 months
Kyle RA et al. Leukemia (2009) 23, 3-9
Cytogenetic Data
Minimum panel required:
t (4
(4 1
; 4)
14), t (14
(14;16)
16 , 17
17 1
p 3
13 d l
e t
e i
tion
More comprehensive panel:
t (11;14
(11; ),
14) chromosome
chromosome 13
13 delet
dele ion,
tion, chromosome
chromosom 1 abnorma
abnorm liti
a
e
liti s,
s
hyperdiploid
Fonseca R et al. Leukemia (2009), 1-12
Open question
Treatment paradigm for patients in VGPR:
·Stop treatment:
No 2° transplantation
No consolidation / maintenance
· Is this right??
Bortezomib-Thalidomide-Dexamethasone
consolidation
in VGPR patients
patients
Responses after ASCT
Responses after VTD
PFS in PCR
VGPR 100%
VGPR 100%
negative patients
CR 22%
CR 66%
VGPR
CR
Mol CR
Ladetto et al. J Clin Oncol 2009 in press
months
Autologous stem cell
transplantation
for elderly patients
Autologous Stem Cell Transplantation
in Elderly Patients
Patients
Si
Survival Adva t
n age
Age 65-70 years
1.0
Age < 65 yr
OS
MP
MPT
MEL100
0.8
Mel 100
0.6
Age 65 yr
0.4
MP
0.2
P=0.008
P = .001
0.0
P=0.0
P0 1
.0
0
12
24
36
48
60
72
Time From Randomization, mo
Tandem MEL100
Barlogie B, et al. N Engl J Med.
Palumbo A, et al. Blood. 2004;104:
Facon T, et al. Lancet.
2006;354(10):1021-1030.
3052-3057.
2007;370(9594):1209-1218.
Bortezomib based induction (PAD)
autologous stem cell transplantation
Lenalidomide
Lenalidomide bas
based
ed maintena
e
nce (LP
(LP-L)
PAD
PA
MEL100 - ASCT
A
LP
L
4 cycl
cy es
e
2 cycl
cy es
e
4 cycl
cy es
e
21-da
21-d y cycl
y e
PAD
PA
1
481
4
8
1
48111
21
B
B
B
B
PLD
Dex
28-da
28-d y cycl
y e
LP: Consolidati
t on
o
1
21
28
Lenali
Lena domide 25
2 mg/d
g
Predni
Predn sone
son 50 mg/
mg ev
e e
v r
e y other day
28-da
28-d y cycl
y e
L: Mainte
n nance
1
21
28
Lenali
Lena domide 10
1 mg/d
PAD: Bortezomib+ Doxorubicin+ Dexamethasone; MEL-100: Melphalan 100 mg/m2 ; LP: Lenalidomide+ Prednisone; L: Lenalidomide: B: Bortezomib;
PLD: Pegylated liposomal doxorubicin; Dex: Dexamethasone
Palumbo A, et al. J Clin Oncol. 2009 in press
Role of Maintenance
After Autologous Transplant
PAD-MEL100
MEL10 *
MEL100-
MEL100 LP-
LP L*
-
OS
n=83
n=8
n=50
n=5
80
80
86 %
66
60
60
81 %
43
38
40
40
40
20
20
20
13
10
4
2
0
0
0
0
CR VGPR
PR
SD
PD
CR
VGPR
PR
SD
PD
* Per protocol
Palumbo A, et al. J Clin Oncol. 2009 in press
Standard of care
for
elderly patients
patients
MPT (melphalan/prednisone/thalidomide)
Current Standard of Care
MPT vs MP Studies
Median PFS,
PFS
PFS
Median OS,
OS
OS,
OS
Months
P Val
V ue
Months
P Val
V ue
IFM 1
IFM
27.5 vs
v 17.
7 8
<.0001
51.6 vs
v 33.
3 2
.0006
GIMEMA2
A
N/A
.0006
N/A
NS
N
IFM 3
IFM
24.1 vs
v 19
.001
45.3 vs
v 27.
7 7
.03
.0
Nordic4
Nordic
16 vs
vvs 14
14
NS
29 vs
vvs 33
NS
Hovo
v n5
n
N/A
<.001
N/A
NS
N
N/A= not available; N.S.= not significant
1. Facon T, et al. Lancet. 2007;370(9594):1209-1218. 2
2. Palumbo A, et al. Lancet. 2006;367(9513):825-831. 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.
LMWH vs Warfarin vs Aspirin
for Thalidomide Induction Regimens
Standard Risk of VTE
Risk of VTE
Study Design
Study Desig
Thalidomide regimens
LMWH
(950 pts
pt )
Random
WAR
WA
ASA
ASA
WAR
LMWH
WAR
LMW
WAR
Aspi
p rin
Enoxapar
Enoxapa in
Warfarin
Warf
100
1
mg/day
1.25
1.2 mg/day
40
4 mg/day
y
01
23
45
67
8
Patients
n
(%)
%
High Risk of VTE
· previous VTE, infection, immobilization, CVC, doxorubicin
· previous VTE, infection, immobilization, CVC, doxor
LMWH is suggested
· LMWH is
· LMWH
ASA: Acety
Ac
l
ety salicy
l
lic
salicy
acid;
ac
LMW
LM
H:
H lo
l w mol
o ec
l
u
ec l
u ar
l
we
w ight
ig
hep
he a
p ri
r n;
i
VTE: veno
v
us
eno
th
t ro
r m
o b
m oe
b
m
oe b
m olis
b
m;
olis
CV
C C:
C centr
ce
a
ntr l ve
v n
e ou
o s cat
c het
at
er
het
Palumbo
Palumb , et
e al.
al EH
E A
H
2009
20
;
09 Abs
Ab 02
0 1
2 4
1 .
4
VMP (bortezomib/melphalan/prednisone)
Current Standard
Standa
of Care
Ca
52% reduced risk of progression
~36% reduced risk of death
100
100
VMP
90
VMP
90
MP
t
80
t
n
80
n
MP
n 80
ve
ve
E
E
70
70
60
60
Withouttsn 50
ctsWithout 50
atie
bje
a
u
40
fP
fS 40
eo
eo
30
tag
tag 30
20
ercenP
ercen
P
P 20
P
Medi
e
Med
Me an
diia
i n
a follow
follo -up 25
225 9
. mon
o
mo ths
nths
10
VMP: 3-year
y
OS rate = 72%
VMP: 24.0 months (83
(
ev
e en
e ts)
s
10
MP:
P 16.6
16. months (146 ev
e e
v n
e ts)
s
MP:
P 3-year
y
OS rate = 59%
0
HR=0.483, P<.000001
P
HR = 0.644, P = .0032
0
03
6
9
12
1
15
18
21
24
27
0 2 4 6 8 10
1 121
1
4
21 161
1
82
61
0
82 222
2
4
22 262
2
83
62
0
83 323
3
4
23 363
3
8
63 40
4
Time
i
,
me months
Time
i
,
me months
San Miguel JF, et al. N Engl J Med. 2008;359(9):906-917.
VMP
VMP (bortezomib/melphala
zomib/melphalan/prednisone)
bortezomib: twice or once weekly infusion
VMP
VMP
VMP
Tw
T ice weekly
weekl
e
y
weekl
e
y
(N=344)
(N=130)
(N=177)
GIMEMA1
GIMEMA
PETHEMA2
PETHEMA
GIMEMA3
GIMEMA
CR
30%
22
2 %
20%
2- year
y
PFS
50%
74%
70%
Peripheral neuropaty
py
13%
5%
2%
Di
D sconti
nt nuati
t on
24%
8%
4%
1.San Miguel JF et al. Phase III Vista Trial. Blood 2008; 112:650; 2. Mateos MV et al Blood 2008; 112: 651;
3. Palumbo A. et al. Blood 2008; 112: 652
MPT (melphalan/prednisone/thalidomide) vs
MPR (melphala
(melphalan/prednisone/
(melphala
le
n/prednisone/ nalidomide
le
)
nalidomide
MPT1
MPR2
MPR
MPR
MPT1
Best response
Overall
Best response
survival
n = 129
n = 32
100
70
70
60
60
75
50
)
) 50
)
%
%
%
(
40
(
(
40
53%
nts
37%
ts 40
ts
ts
nts
37%
n
33
n 50
eti 30
tie
29
tie
tie
30
Pa
24
Pa
21
Pa
Pa
20
16
20
25
8
10
55
10
1
0
0
0
0
0
510
51
15
1
20
2
25
2
CR
C
VG
V PR
G
PR
MR
M
SD
PD
CR
C
VG
V PR
G
PR
MR
M
PDor
o
SD
th
mon s
th
1. Palumbo A, et al. Lancet. 2006;367(9512):825-831.
2. Palumbo A, et al. J Clin Oncol. 2007;25(28):4459-6445.
Treatment choice
Efficacy
MPT/MPR*
VMP§
MPT/MPR*
VMP
Standa
Stand rd risk
High risk
ri
Older
Younger
Safety
MPT*
MPR*
VMP§
MPT*
MPR*
VMP
Cytopenia
y
Neuropath
Neuropa y
DVT
Oral
Or
Ora
O l
Renal insuffic
insuffi iency
*MPT: melphalan/prednisone/thalidomide; MPR: melphalan/prednisone/lenalidomide;
§MPV: melphalan/prednisone/bortezomib; VTE: venous thromboembolism.
Future options
p
Combination therapy:
py
·4 drug combination to increase response
·Maintenance to improve remission dr
du ation
ration
Phase III randomized study:
VMPT (bortezomib/melphalan/prednisone/thalidomide)
versus
versu VMP
VMP
VMP (bt
bortezomib
bortezomib/l
ib/mel h
p
l
a
/
an
d
pre
i
n
)
/melphalan/prednisone)
sone
/melphalan/prednisone)
VMPT induction
Nine 5-week cycles
VT maintenance
Bortezomib 1.3 mg/m2 d 1 8 15 22
4-week cycles until progression
Melphalan
Melphalan, 9 mg/m2
mg/m (d 1-4)
Bortezomib 1.3 mg/m2
g
d 1 15
Prednisone 60 mg/m2 (d 1-4)
Thalidomide 50 mg/d continuously
Thalidomide 50 mg/day continuously
VMPT VT
VMP
70
70
60
60
55%*
%
50
50
45%*
%
s
s
39
39*
40
40
37
ient
* P < 0.01
ient
32
at
at
p 30
30
30
p
24
21*
21
of
of
20
20
%
16
16
%
10
10
6
2
0
0
0
CR
VGPR
PR
SD
PD
CR
VGPR
PR
SD
PD
Palumbo A et al. Blood 2008;112:652
Future options
·Single agent
·Sequential approach
·Fi
·Fri d
en l
dlyapproa h
c
Novel agents as primary treatment
safety
Grade
Gr
3 or
o 4 adve
adv rse
IFM
VISTA GIMEMA ECOG
events,
ev
%
MPT
MPV
MPR
Rd
Neutropenia
48
40
52
19
Thrombocyt
y openia
14
37
24
5.5
Anaemia
14
19
5
7
Neuropath
Neuropa y
613
0
1.5
DVT
12
1
5
9
Infection
10
7
95
9.5
7
Herpes zost
zos er
t
2.5
3
NR
NR
MPT: melphla
p
n/prednisone/thalidomide;
p; MPR: melphlan/pred
pp
nisone/lenalidomide;
MPV: melphlan/prednisone/bortezomib; Rd: lenalidomide/low dose dexamethasone
Moreau P, et al. Blood Rev. 2008;22:303-9.
Continued treatment is associated with longer OS
Lenalidomide 25 mg d 1-21
Dexamethasone 40 mg d 1,8,15,22
OS: 4 mont
mon hs treatmen
trea
t
tmen
OS:
O
12 mont
mon hs
t
treatmen
trea
t
tmen
100
100
Rd
)%
) 80
80
RD
)
Rd
%
ts(
s( 60
60
3-Year OS rate
RD
ent
atien
79%
ent
P
40
40
Pati
3-Year OS rate
Pati
20
> 55%
20
p = NS
0 0
6
121
1
82
21
4
82
30
3
36
0
36
3
0
6
12
1
182
1
4
82
303
3
6
03
Time (months)
Time (months)
Number at risk
Number at risk
RD 54
50
43
39
36
20
14
RD 108
108
103
97
90
67
44
Rd
39
37
33
30
27
19
11
Rd 140
140
139
133
128
95
51
RD: Lenalidomide+ Dexamethasone; Rd: Lenalidomide + low dose dexamethasone
Rajkumar SV, et al. Joint ASH/ASCO symposium at ASH 2008.
Adjusted therapy
Full dose
Reduced dose
chemotherap
a y
chemotherap
a y
65-75 years
y
>75
7 years
y
Normal
Norm :
al
Normal
Norm :
al
· Cardiac
Cardi
· Cardiac
Cardi
· Pulmonary
· Pulmonary
· Live
Liv r
· Live
Liv r
· Rl
Renal f
t
unc i
ttion
ti
· Rl
Renal f
t
unc i
ttion
ti
<65
<6 years
y
65-75 years
y
Abnormal:
Abnormal
Abnormal:
bnormal
· Cardiac
Cardi
· Cardiac
Cardi
· Pulmonary
· Pulmonary
· Live
Li r
· Live
Li r
· Renal function
func
· Renal function
func
Recomm
Recomm
endations
endations
by
by A
A. . Palumbo
Palumbo.
Age-Adjusted
Age-Adjusted Doses
Further
Furthe Dose
Dos
65-75 Year
Yea s
r
>75
>7 Years
Year
Redc
Red ution
ut
Dexamet
Dexame has
ha one
s
40 mg
20 mg
10 mg
weekly
Melphala
Melphal n
0.25 mg/k
mg/ g
0.18 mg/k
mg/ g
0.13 mg/k
mg/ g
days
y 1-4
Thalidomide
200 mg
100 mg
50 mg
per day
Lenalidomide
Lenalidomid *
25 mg
15 mg
10 mg
days
y 1-21
1.3 mg/m2
mg/m
1.3 mg/m2
mg/m
1.3 mg
m /m2
g/m
Bortezom
Bort
ib
ezom
Ti
Tw
T ice
i -w
-
kl
ee y
kl
Wk
Wee l
kly
Ti
Tw
T ice
i -mo
m
thl
n
y
If a grade 3-4 AE occurs: 1. discontinue therapy; 2. wait for grade 1 AE;
3. restart at a lower dose
*Lenalido
d mide
m
plu
p s melphalan star
t ting dose
o
10 mg/d
Recommendations by A. Palumbo.
AE: ad
a ve
v rs
r es
s
eve
ev n
e ts
Therapeutic Algorithm
Level of Evidence 1b
1b (>
( 1 Randomized
Randomized Trial)
Trial)
MPT
>
MP
5 randomiz
randomi ed
e tria
tri ls
MPV
>
MP
1 randomiz
randomi ed
e tria
tri l
MPR
MP
1 randomized trial
>
MP
1 randomized tria
>
Other options
VMP
Bortezomib/thalidomide maintenance
VMPT
Rd
Until progression