New options for elderly
elderly patients with
with
newly diagnosed multiple myeloma
Thierry Facon
Lille University Hospital,
Lille, France
Faculty disclosure information
Consultant: No
Grant/Research Support: No
Speakers Bureau: Celgene, Janssen Cilag
Major Stock
Stock Shareholder: No
No
Period estimates of 10-year survival
of patients with
with MM
MM
Major age groups in defined calendar periods
from 1984 1986
to 2002 2004
50
Age, years
l(%)
40
< 50
30
esurviva
5059
e
20
6069
arrelativ
10
70 79
10
80
10-ye
0
198486
198789
199092
199395
199698 199901 200204
Calendar period
Brenner H, et al. Blood. 2008;111:2521-26.
Front-line treatment in
elderly patients with
with myeloma
myeloma
Alkylating-agent based
Dexamethasone based
Regimen Trial
Regimen
Trial
MPT
GIMEMA, IFM, NMSG,
Thal + Dex
ECOG, CC-5013-003,
HOVON
CEMSG
MPV
PETHEMA,VISTA
Len + Dex
SWOG, ECOG,
CC-5013-020/IFM 07
07-01
MPR
GIMEMA,CC-5013-015
CTD
MRC IX
Studies of MP vs MPT: patient
characteristics and MPT regimens
regimens
GIMEMA1,2
IFM 99-063
IFM 01-014
Nordic5
HOVON6
Patients, N (MPT, n)
331 (167)
447 (125)
232 (113)
362 (182)
344 (165)
Age
Median
72
69
79
74 (mean)
72
Range
6085
6575
7589
4992
NA
WHO 3 or 4 (%)
6
8
7
28
4
MPT regimen
Cycles, n
6
12
12
Until plateau Until plateau
Melphalan dosage
4 mg/m2
0.25 mg/kg
0.2 mg/kg
0.25 mg/kg
0.25 mg/kg
days 1
1 7
days 1
1 4
days 1
1 4
days 1
1 4
days 1
1 5
Thal dose, mg
100
up to 400
100
up to 400
200
Thal maintenance
+
--
++
1. Palumbo A, et al. Lancet. 2006;367:825-31. 2. Palumbo A, et al. Blood. 2008;112:3107-14.
3. Facon T, et al. Lancet. 2007;370:1209-18. 4. Hulin C, et al. J Clin Oncol. In press 2009.
5. Waage A, et al. Blood. 2007;110:32a:[abstract 78]; updated data presented at ASH 2007, 2008.
6. Wijermans R, et al. Blood. 2008;112:241:[abstract 649]; updated data presented at ASH 2007, 2008.
MP vs MPT: PFS and OS
GIMEMA1,2
IFM 99-063 IFM01-014
Nordic5
HOVON6
GIMEMA
IFM 99 06
IFM01 01
Nordic
HOVON
Median PFS, months
MP
15
18
19
14
10*
MPT
22
28
24
16
13
p value
0.0004
< 0.0001
0.001
TTP
< 0.001
Median OS, months
MP
48
33
29
39
30
MPT
45
52
44
29
37
p value
NS
0.0006
0.028
NS
NS
* Event free survival.
Significant.
In 5 of 5 studies, MPT was superior to MP in terms of PFS or TTP (or both)
In 2 of 5 studies, MPT was superior to MP in terms of OS
1. Palumbo
Palumbo A, et
et al
al. Lancet. 2006;11
2006;1 1:825
1
-31.
2. Palumbo A, et al. Blood. 2008;112:3107-14.
3. Facon T, et al. Lancet. 2007;370:1209-1218.
4. Hulin, et al. J Clin Oncol. 2009; in press.
5. Waage A, et al. Blood. 2007;110:[abstract 78].
6. Wijermans P, et al. Blood. 2008;112:[abstract 241]; updated data presented at ASH 2008.
MRC myeloma IX:
non-
non intensive pathway
Older, less fit patients (age > 65 years)
RANDOMIZATION
Patients, %
Zoledronic
Response
Clodronate
vs
id
ac
CTDa
MP
MP
vs
CTDa
CR
22.5
6
VGPR
47.5
9.5
RANDOMIZATION
No
PR
82 5
.
49
Thalidomide
vs
thalidomide
p < 0.001
CTDa: cyclophosphamide 500 mg orally, once weekly;
thalidomide 200 mg/day; dexamethasone 20 mg, days 14 and 1518
of a 28-day cycle
Morgan GJ, et al. Blood. 2007;110:[abstract 3593].
Morgan GJ, et al. Blood. 2008;112:[abstract 245].
MPT and cyclophosphamide studies:
conclusions
· Five studies (GIMEMA, IFM
IFM 99-
99 06
- , IFM 01-
01 01
- , Nordic,
HOVON) have shown that, compared with MP,
thalidomide plus MP (MPT) results in improved
response
t
ra es
d
an TTP or PFS (or b t
o h)
th)
· The 2 IFM studies have shown that, compared with
MP, MPT extends
extends OS by 15
15 18
months
· Preliminary analysis of the results of MRC IX indicates
findings
g consistent with those of MP vs MPT
MPT is a new standard of care for elderly patients with newly diagnosed myeloma
CTDa can also be considered a new standard of care
The EMEA approved front-line MPT in elderly MM patients in April 2008
VISTA: bortezomib as initial standard
therapy in multiple myeloma
Assessment with melphalan and prednisone
MPV
Cycles
Cy
14
Bortezomib 1 3
. mg/m2
mg/m i.v.
v days 1, 4, 8, 11
111, 22, 25, 29, 32
Melphalan 9 mg/m2
mg/m and prednisone 60 mg/m2
mg/m days 14
Cycles
Cy
59
Newly
Bortezomib 1.3 mg/m2
mg/m i.v.
i.v days 1, 8, 22, 29
y
Melphalan 9 mg/m2
mg/m
mg/m and prednisone 60
60 mg/m2
mg/m
mg/m days 14
diagnosed MM
patients;
9 × 6-week cycles (54 weeks) in both arms
age > 65 years
MP
Cycles
Cy
19
Melphalan 9 mg/m2
mg/m and prednisone 60 mg/m2
mg/m days 14
Primary end-point:
p
TTP
San Miguel JF, et al. N Engl J Med. 2008;359:906-17.
VISTA: time to progression
and overall survival
Time to progression
Overall survival
100
MPV
100
(%)
MP
80
80
ents
(%)
60
60
pati
40
40
t-free
Patients
Median follow-up: 16.3 months
n
MPV:
MPV 24 months (83 events)
MPV:
MPV not reached (45 deaths)
20
20
MP: 16.6 months (146 events)
MP: not reached (76 deaths)
Eve
HR 0.48, p < 0.001
HR 0.61, p = 0.008
0
0
0
3
6
9
12 15 18 21 24
27
0
3
6
9
12 15 18 21 24 27 30
Time (months)
Time ()
(months)
OS at 2 years
All patients: 82.6% in MPV vs 69.5% in MP
In patients < 75 years old: 84% in MPV vs 74% in MP
In patients 75 years old: 79% in MPV vs 60% in MP
Treatment-related deaths in each arm: MPV 1%, MP 2%
San Miguel JF, et al. N Engl J Med. 2008;359:906-17;
San Miguel JF, et al. Blood 2007;110:[abstract 76], updated data presented at ASH 2007
VISTA: conclusions
· MPV significantly prolongs survival and is superior
fl
for a lll pre-specified ffi
e cacy
d
en -poit
ints in th
the largest
MP-based phase III study
rapid and durable responses
pp
with high
g CR rate (33%)
prolonged TTP, time to next therapy or treatment-free interval,
and OS
· MPV d t
a a are consist t
en ltly superior across ll
a
prognostic subgroups
· MPV was
was well tolerated, with patients on
on therapy
therapy for
46 weeks
These results establish MPV as a new standard of care for
MM patients not eligible for ASCT
In 2008, the EMEA and FDA approved front-line bortezomib for
patients with previously untreated MM
San Miguel JF, et al. N Engl J Med. 2008;359:906-17.
Melphalan, prednisone, and lenalidomide
(MPR) treatment
treatment for newly diagnosed MM
· 54 patients, median age 71 years
· Results
MTD: melphalan 0.18 mg/kg + lenalidomide 10 mg/day (n = 21)
Response
Patients, %
Adverse events at
Patients, %
MTD, grade 3
CR
24
Neutropenia
52
VGPR
24
Thrombocytopenia
24
PR
33
DVT
5
SD
19
G-CSF support
43
MPR therapy is a promising first-line treatment for elderly MM patients
This study
study formed the basis
basis for
for the MM-
MM 015 and ECOG
ECOG E1A06
E1A06 trials
(MP vs MPR vs MPR + R, MPT vs MPR)
MPR + R = MPR + lenalidomide maintenance therapy;
MTD = maximum tolerated dose.
Palumbo A, et al. J Clin Oncol. 2007;25:4459-65.
Thalidomide + dexamethasone vs MP
in elderly patients with
with MM
MM
· 289 patients, median
median age 72
· Treatment
first randomization: thalidomide + dexamethasone versus
melphalan + prednisolone, 9 cycles
· thalidomide 50400 mg/day + dexamethasone 40 mg/day
· melphalan 0.25 mg/kg + prednisolone 2 mg/kg
mg/kg
second randomization: thalidomide + interferon alfa versus
interferon alfa
· Rl
Results
d
an
l
conc
i
us on
thalidomide + dexamethasone yielded higher response rates
but was associated with more adverse events in older patients
and shorter overall survival
Ludwig H, et al. Blood. [Epub ahead of print 2008 Oct 27].
Len + high-dose Dex vs Len + low-dose Dex
in patients with newly diagnosed myeloma
ECOG-E4A03 trial design
Len + hig
hi h-dose
g
Dex,
Dex 4 cy
c cles
y
,y
,
cles cycle
length 28 days
Len 25 mg/day,
mg/day days 121
Patients with
Dex 40 mg/day,
mg/day days 14, 912, 1720
newly diagnosed
MM
(n = 445)
Len + low dose Dex, 4 cycles
L2
Len
L
25
2
/
mg d
//day
/d ,
ay days
d
1 21
Dex 40 mg/day,
mg/day days 1, 8, 15, 22
Primary end-point: response rate
andd
d adverse events
Rajkumar SV, et al. Blood. 2007;110:[abstract 74].
ECOG-E4A03: adverse events
RD, %
Rd, %
Adverse event, grade 3
p value
(n = 223)
(n = 220)
DVT or PE
25
11
< 0.001
Infection or pneumonia
16
8
0.019
Cardiac ischaemia
3
0.5
0.068
Any non-haematological
66
46
< 0.001
adverse event (grade 3)
Adverse events
events of
of any type
27
17
0 022
.
(grade 4)
Early death (< 4 months,
5
0.5
0.003
all patients)
Rajkumar SV, et al. J Clin Oncol. 2008;26:[abstract 8504].
Updated data presented at ASCO Annual Meeting, 2008.
Len + high-dose Dex vs Len + low-dose Dex in
patients with newly diagnosed
diagnosed myeloma
Survival rate in patients 65 years old
Patients,
2-Year survival probability
n
(95% CI)
RD
119
0.67 (0.560.77)
p = 0 009
.
Rd
114
0.82 (0.740.91)
Rajkumar SV, et al. Blood. 2007;110:[abstract 74].
Efficacy of Len + low-dose Dex in patients
with newly diagnosed
diagnosed myeloma
Primary Rd beyond 4 cycles
Patients, %
(n = 142)
CR + PR
89
CR (IF-
(IF )
22
CR + VGPR
56
2-Year survival
93
Rajkumar SV, et al. J Clin Oncol. 2008;26:[abstract 8504].
Updated data presented at ASCO Annual Meeting, 2008.
FIRST: lenalidomide + low-dose Dex vs
MPT (IFM
(IFM 07-
07 01)
Lenalidomide 25 mg/day,
mg/day days 121; every 28 days
Dexamethasone*
Dexamethasone 40 mg/day,
mg/day days 1, 8, 15, 22;
Until PD
Inclusion criteria
every 28 days
Previously
untreated MM
Eighteen
Lenalidomide 25 mg/day,
mg/day days 1
1 21;
every 28 days
Age 65 years or
4-week
Dexamethasone*
Dexamethasone 40 mg/day,
mg/day days 1, 8, 15, 22;
not a candidate for
cycles or
every 28 days
transplantation
until PD
No neuropathy of
Melphalan*
Melphalan 0.25 mg/kg/day,
mg/kg/day days 14, every 42 days
Twelve
grade > 2
6-week
Prednisone 2.0 mg/kg/day,
mg/kg/day days 14, every 42 days
cycles or
Thalidomide*
Thalidomide 200 mg/day,
mg/day daily through 42-
42 day cycle
until PD
N = 1,590
* In patients older than 75 years:
dexamethasone 20 mg/day,
melphalan 0.20 mg/kg/day,
thalidomide 100 mg/day.
Primary end-point: progression-free survival
Elderly patients with
newly diagnosed MM
· Symptomatic treatments
treatments remain
remain essential
essential
· Highest doses of drugs are not always optimal
dexamethasone
MPR dose-escalating study
· Avoid excessive adverse events
careful treatment monitoring
dose-reduction guidelines
particularly in
in patients with
with poor performance status
status and
in early stages of treatment
· Quality of life is important