Emerging treatment strategies in
Multip
Multi le
p My
pyeloma
Antonio Palumbo, MD
Diii
Division f
o Hemat l
o ogy
University of Torino
Torino, Italy
Elderly Patients
Patients
Autologous Stem Cell Transplant
in Elderly Patients
Survival Advantage
Survival Advantage
NO Survival Advantage
Age <65 years
Age 65-70 years
Age 65-75 years
1.0
MP
OS
MPT
MEL100
0.8
0.6
0.4
P = .001
0.2
0.00
122
1
4
22
36
3
486
4
07
86
2
07
Time From Randomization, mo
Tandem MEL200
Tandem MEL100
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.
Thal/Dex vs Melphalan/Prednisone
(MP) in Newly Diagnosed MM
Time to Progression
Overall Survival
Survival: Pts >75 Years
Months
Months
Months
Ludwig H, et al. Blood. 2008 Oct 27. [Epub ahead of print]
Ludwig, et al. IMW 2007
MPT: The Current Standard of Care
in Elderly Patients
Patients
MP-Thal vs MP Studies
Median PFS,
PFS
Median OS,
OS,
Months
P Value
Months
P Value
IFM 1
IFM
27.5 vs
vs 17.8
<.0001
51.6 vs
vs 33.2
.0006
GIMEMA2
N/A
.0006
N/A
NS
IFM 3
24.1 vs 19
.001
45.3 vs 27.7
.03
Nordic4
Nordic
16 vs 14
NS
29 vs 33
NS
Hovon5
N/A
<.001
N/A
NS
N/A= not available; N.S.= not significant
1. Facon T, et al. Lancet. 2007;370(9594):1209-1218. 22. 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.
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*
010
20
30
Patients, %
Palumbo A et al. The Lancet 2006 2007;370:1209-18
VTE is manageable and decreases after the
first 4 cy
c cles
y
of therapy
ypy with Len + Dex
ECOG-E4A03 study
MM-009 and MM-010:
subgroup analysis
analysis
30
4.0
RD
25,6
Grade 3: Len + Dex
Rd
3.5
Grade 3: Dex alone
)
s)
%
T
h
30
Grade 4: Len + Dex
Dex
(%
20,2
3.0
DV
20
Grade 4: Dex alone
VTE
2.5
of
2.0
ceof
azard
erson-mont
11,4
h
p
1.5
10
8,2
Inciden
100
verage
1.0
A
(per
0.5
0
0
Cycles 1­4
Later in the
0
3
6
9
12
15
18
21
treatment cour
course
se
Time (months)
()
High-dose Dex is itself a major VTE risk factor
Ishak J, et al. Blood. 2008;112:[abstract 3708]; updated data presented at ASH 2008.
Jacobus S, et al. Blood. 2008;112:[abstract 1740].
Low Molecular Weight Heparin vs Warfarin vs
ASA Prophylaxis for Thalidomide Regimens
Study Design
Thalidomide regimens
VMP
(950 pts)
Random
ASA
WAR
LMWH
No
Aspirin
Warfarin
Enoxaparin
Prophylaxis
100 mg/day
1.25 mg/day
40 mg/day
Rates of VTE
No prophylaxis
LMWH
WAR
WA
ASA
01
234
5
6
Patients (%)
(%
Cavo M, et al. Blood. 2008;112: Abstract 3017.
Individual and treatment-related risk
factors for
for DVT in
in MM
MM patients
patients
1. Concomitant chemotherapy
2. Use
Use of erythropoietin
3. High-dose corticosteroids
4. Central catheter
5. High tumoral mass
Increased
6. Immobilization
risk of DVT
7. Concomitant infection
8. Advanced age
9. Previous
Previous history of
of DVT
DVT or
high thromboembolic risk
1. Avoid
Avoid concomitant chemotherapy
2. Avoid erythropoietin (stop
Reduction
erythropoietin if Hb > 120 g/L)
of DVT risk
3. Give low-dose dexamethasone
(e.g. 40 mg/week)
Palumbo A, et al. Blood Rev. 2009;23:87-93.
VMP: The Current Standard of Care
in Transplant Inelig
Ineli
pgible Patients
52% reduced risk of progression
~36% reduced risk of death
100
100
90
VMP
VMP
90
MP
t
80
t
n
MP
n 80
ve
ve
E
E
70
70
60
60
Without
Without
50
50
atients
bjects
a
u
P
40
Sf
of
40
ge
eo
30
ta
tag 30
en
20
ercP
ercen
P
P 20
P
Median follow-up 25 9
. months
months
10
VMP: 3-year OS rate = 72%
VMP: 24.0 months (83 events)
10
MP: 16.6 months (146 events)
MP: 3-year OS rate = 59%
0
HR=0.483, P<.000001
HR = 0.644, P = .0032
0
03
6
9
12
15
18
21
24
27
0 2 4 6 8 10 1214 161820 2224 26 2830 32 34 3638 40
Time, months
Time, months
VMP = bortezomib/melphalan/
San Miguel JF, et al. N Engl J Med. 2008;359(9):906-917.
prednisone
VMP in Elderly Patients: Grade 3/4
AEs
VMP
MP
Neutropenia
Thrombocytopenia
DVT
PeripheralNeuropathy
Neuralgia
Infection
010
20
30
40
50
Pt
Pa i
tients, %
San Miguel, et al. N Engl J Med. 2008;359:906-17.
GIMEMA, VMPT vs VMP
Best Response
VMPT
VMP
N=221
N=229
70
70
Median No. of cycles 5
Median No. of cycles 5
60
60
51%*
§ P < 0 0001
51%*
.
50
50
* P = 0.06
§
40
fpatients 40
42%*
36
fpatients
35
f
33
o
o%
%
30
30
§
21
21
20
18
20
16
20
9
10
10
1
1
0
0
CR
VGPR
PR
SD
PD
CR
VGPR
PR
SD
PD
Palumbo et al ASCO 2009
VMP: Twice-weekly or weekly infusion?
VMP
VMP
VMP
biweekly
Mix
weekly
(N=42)
(N=19)
(N=116)
CR
27%
23%
20%
Pi
Peri h
p
l
era sensory
14%
16%
2%
neuropathy
Neuralgia
12%
10%
3%
Discontinuation
24%
22%
10%
MPT (melphalan/prednisone/thalidomide) vs
MPR (melphalan/prednisone/lenalidomide)
((melphalan/prednisone/lenalidomide)
MPT
MPR
MPR
Best response
Best response
Overall
n = 129*
survival
n = 32^
70
60
100
60
50
75
50
)
)
)
40
53%
(%
40
(%
(%
40
ts
33
n
37%
ts
ts
37%
n 30
29
n 50
30
24
Patie
21
Patie
Patie
20
20
16
1
25
4
10
8
10
55
0
0
0
0
CR VGPR PR
MR
SD
CR VGPR PR MR SD
PD
0
510
15
20
25
or PD
months
*Palumbo A, et al. Lancet. 2006;367(9512):825-831.
^Palumbo A, et al. J Clin Oncol. 2007;25(28):4459-6445.
MPR: Grade 3/4
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 A. et al. J Clin Oncol. 2007;25(28):4459-4465.
Incidence of haematological AEs declines
during lenalidomide treatment
MM-009 and MM-010 subgroup analysis: Len + Dex
Nt
Neut
i
ropen a
Thrombocyt
i
open a
4.0
4.0
Grade 3: Len + Dex
Grade 3: Len + Dex
3.5
Grade 3: Dex alone
3.5
Grade 3: Dex alone
-months)
-months)
n
Grade 4: Len + Dex
Dex
n
Grade 4: Len + Dex
Dex
3.0
3.0
Grade 4: Dex alone
Grade 4: Dex alone
perso
2.5
perso 2.5
2.0
2.0
er100
er100
(p
1.5
(p 1.5
1.0
1.0
ehazard
ehazard
0.5
0.5
verag
0
verag
A
0
A
0
3
6
9
12
15
18
21
0
3
6
9
12
15
18
21
Time (months)
Time (months)
Treatment interruptions and dose reductions also declined during follow-up
Ishak J, et al. Blood. 2008;112:[abstract 3708];
updated data presented at ASH 2008.
Management of haematological adverse
events with Len + Dex treatment
Adverse event
Action
Ot
On h
the fi
first day f
o a new
l
cyc e Wi
Withh
thhold
ld treatment until grade 1
Platelets < 75,000/L or
Reinitiate at lower dose*
ANC < 1,500/L
During the cycle
Start G-CSF
ANC < 500/L
Wi
W thhold treatment
treatment
Reinitiate next cycle at lower dose*
During the cycle
Withhold treatment and
Platelets < 25­50,000/L
anticoagulation
Reinitiate next cycle at lower dose*
* Lenalidomide: 5 mg dose reduction.
Palumbo A, et al. Blood Rev. 2009;23:87-93.
CTD (cyclophosphamide/thalidomide/dex)
vs MP in Newly Diag
Dia
ygnosed MM:
MRC Myeloma IX Study
Nonintensive: Post-induction
RANDOMIZATION
P<.001
100
80
%
CTD
MP
60
35
sponse,
40
25
Re
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, 15­
18 q 4 wk
Morgan GJ, et al. Blood. 2007;110: Abstract 3593.
Len + standard- versus low-dose Dex in
elderly patients
patients with
with newly
newly diagnosed MM
ECOG-E4A03: survival rate in patients aged 65 years
Patients,
2-Year survival probability
n
(95% CI)
RD
119
11
06
0. 7
67 (05
(0. 6
56 0
­ .77) p = 0.009
Rd
114
0.82 (0.74­0.91)
Rd = Len + low-dose Dex;
RD = Len + standard-dose Dex.
Rajkumar SV, et al. Blood. 2007;110:[abstract 74].
FIRST: phase III trial of Len + low-dose Dex
versus MPT
MPT (IFM 07-01; MM-
MM 020)
Ili
it i
Lenalidom
Lenalido ide
m
25 mg/day,
mg/day days 1­21 of every
Inclusion criteria
R
28-day cycle
Until disease
· Previously
A
Dexamethasone
Dexamethason *
e 40 mg/day,
mg/day days 1, 8, 15, 22
progression
untreated MM
N
of every 28-day cycle
D
· Age 65 years
O
Lenalidom
Lenalido ide
m
25 mg/day,
mg/day days 1­21 of every
Eighteen
or not eligible
28-day cycle
M
4-week
for a transplant
Dexamethasone
Dexamethason *
e 40 mg/day,
mg/day days 1, 8, 15, 22
I
of every 28-day cycle
cycles
· No neuropathy
Z
py
of grade > 2
A
Melphalan*
Melphalan 0.25 mg/kg/day,
mg/kg/day days 1­4 of every
T
42-day cycle
·Cl
> 30 mL/min
Twelve
Cr
I
Prednisone 2.0 mg/kg/day,
mg/kg/day days 1­4 of every
6-week
O
42-day cycle
cycles
Thalidomide* 200 mg/day,
mg/day daily through every
N
N = 1,590
42-day cycle
Centres in EU,
*In patients aged > 75 years: Dex 20 mg/day,
Switzerland, USA,
melphalan 0.20 mg/kg/day, thalidomide 100 mg/day
and Canada
Primary end-point: PFS
Cl
= creatinine clearance.
Trial NCT00689936. Available from: www.clinicaltrials.gov.
Cr
Novel agents as primary treatment:
efficacy
Median
CR +
CR +
EFS or
or
Study
n
age, years
VGPR, %
PR, %
TTP
Median
MPT1
IFM 99-06
125
69
47
76
28 months
Median
MPT2,3
MPT vs MP
167
72
29
69
22 months
Median
MPV45
MPV4,5
VISTA
VIST
337
71
41
74
24 months
Median
MPR6
MPR
54
71
48
81
30 months
ECOG-E4A03
2-Year OS
Rd7
114
65
56
89
65 years
82%
Not
CTDa8,9
MRC Myeloma IX
NA
73
48
83
reported
1. Facon T, et al. Lancet. 2007;370:1209-18. 2. Palumbo A, et al. Lancet. 2006;367:825-31. 3. Palumbo A, et al. Blood. 2008;112:3107-14. 4. San Miguel JF, et al. N Engl J Med.
2008;359:906-17. 5. San Miguel JF, et al. Blood. 2008;112:[abstract 650]. 6. Palumbo A, et al. J Clin Oncol. 2007;25:4459-65. 7. Rajkumar SV, et al. Blood. 2007;
110:[abstract 74]; updated data presented at ASH 2007. 8. Morgan GJ, et al. Blood. 2007;110:[abstract 3593]. 9. Owen RG, et al. Presented at IMW 2009 [abstract 547].
Novel agents as primary treatment:
safety
Grade 3 or 4 adverse events,
IFM
VISTA
GIMEMA
ECOG
%
MPT
MPV
MPR
Rd
Neutropenia
48
40
52
19
Thrombocytopenia
14
37
24
5.5
Anaemia
14
19
5
7
Neuropathy
6
13
0
1.5
DVT
12
1
5
9
Infection
10
7
95
9.5
7
Herpes zoster
2.5
3
NR
NR
Moreau P, et al. Blood Rev. 2008;22:303-9.
TTP with Len + Dex is consistent regardless of
the extent of renal impairment
No RI
RI,
d
me i
dian TTP 11
11 3
.
t
mon h
ths
p = 0.54
100
Mild RI, median TTP 12.1 months
p = 0.62
p = 0.15
Moderate RI, median TTP 11.4 months
Severe RI, median TTP 7 9
. months
80
(%) 60
tsn
40
Patie
20
0
010
20
30
Time to progression (months)
Weber D, et al. J Clin Oncol. 2008;26:[abstract 8542];
updated data presented at ASCO 2008.
Dosing recommendations for patients
with renal insufficiency
insufficienc
Renal function impairment
Lenalidomide dosage
Mild
25 mg/day (full dose)
(ClCr 50 ml/min)
Moderate
10 mg/day*
(30 ClCr < 50 ml/min)
Severe
15 mg every
gy 48 hours
(ClCr < 30 ml/min, dialysis not required)
End-stage renal disease
5 mg/day; on dialysis days the
(ClCr < 30 ml/min, dialysis required)
dose should be administered
after the dialysis
* Dose may be increased to 15 mg/day after 2 cycles if patient has no response
to treatment.
Revlimid® SmPC
Prognostic Factors
MPT
MPR
MPV
22--microglobulin
microglobulin > 3.5 mg/dL
Del 13; t(4:14)
t(4;14), t(14;16), del 17p
100
90
80
)
70
(%
Standard risk
60
High risk
ent
50
tev
40
ithou
30
w
Standard risk (N = 142): 23.1 months (34 events)
20
High risk (N = 26): 19.8 months (7 events)
ects
10
HR = 1.297 (95% CI: 0.55, 3.06), P = .55
22--m > 3.5 mg/L
mg
0
Subj
22--m
m 3.5 mg/L
mg
0
2
4
6
8
10121416
1820
22
24
26
Time (months)
100
P = .19
90
80
)
Months
%
70
(
Standard risk
60
High risk
vente 50
40
ithout
30
w
Standard risk (N = 142): not reached (16 events)
20
High risk (N = 26): not reached (3 events)
ects
10
HR = 1.009 (95% CI: 0.278, 3.663), P = .99
Subj
0
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30
Time (months)
Palumbo A, et al. Haematologica.
Palumbo A, et al. Blood. 2006;108: Abstract 800.
2008;92(auppl 1): Abstract 0213.
San Miguel JF, et al. N Engl J Med. 2008;359(9):906-917.
Age-Adjusted Therapy
Fu
F ll
u dose
Autol
Auto
uto ogous
ogous
o
chemotherapy
transplant
65-75 years
25
25--64
64 years
31%
36%
33%
75
75--101
101 years
Reduced-
Reduced dose
chemotherapy
Regione Piemonte, Assessorato Sanitą 2006,15
Early Discontinuation
ITT
Starting
Early
Doses
Dose
Discontinuation, %
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
d1,4,8,11
1. Facon T, et al. Lancet .2007; 370(9594):1209-1218. 2. Palumbo A, et al. Lancet. 2006;367(9512):825-
831. 3. San Miguel J, et al. N Engl J Med. 2008;359(9):906-917.
Age-
Age Adjusted
-
Doses
Further Dose
65-75 Years
>75 Years
Redcution
Dexamethasone
40 mg
20 mg
10 mg
weekly
Melphalan
02
0. 5
25 mg/kg
mg/kg
01
0. 8
18 mg/kg
mg/kg
01
0. 3
13 mg/kg
mg/kg
days 1-4
Thalidomide
200 mg
100 mg
50 mg
per day
Lenalidomide*
25 mg
15 mg
10 mg
days 1-21
1.3 mg/m2
g
1.3 mg/m2
g
1.0 mg/m2
g
Bt
Bortezomib
ib
biweekly
weekly
weekly
If a grade 3-4 AE occurs: 1. discontinue therapy; 2. wait for grade 1 AE;
3. restart
restart at a lo
lo e
w r
er dose
*Lenalidomide plus melphalan starting dose 10 mg/d
Recommendations by A. Palumbo.
BiRD: Continued Therapy Increases
the Quality of the Response
Stringent CR
CR
100
VGPR
PR
e,%
90
e
80
70
Respons
60
50
a
40
with
30
ents
20
e
10
Pati
0
1
2
3
4
5
6
7
8
9 10 11 1213 14 15 1617 18 19 20 2122 23 24 25 26 2728 29 30 31 32 33
Cycles of Tr
T eatment
r
Niesvizky R, et al. Blood. 2008;111:1101-1109.
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
MPR
MP
under evaluation