Sequential Use of Novel
At
Agents in I d
n ucti
tion Th
Therapy
for Multiple My
pyeloma
Joan Bladé
XII International Myeloma Workshop
Washington, March 1, 2009
CP1123175-17
Survival from Onset of Treatment of
Multiple Myeloma
100
80
60
Placebo
Surviving
(%)
40
20
Urethane
0
0
10
20
30
40
50
Months
Holland, et al., 1966, Blood 27(3):335
CP1123175-18
MM. First Report on
Melphalan Therapy*
· Evaluation of new chemotherapeutic agents
in the treatment of multiple myeloma. L-
Phenylalanine mustard (NSC-8806)
* Bergsagel DE
DE et
et al
al. Cancer Chemother Rep
Rep 1962; 21: 87 99
-
.
MM. First Trial on Cyclophosphamide
Therapy*
· Ml
Mul il
tiple myeloma. A
l
na ysis of
l
cyc
h
op osphamid
ide
therapy in 165 Patients
* Korst DR et al (by the Midwest Cooperative
Chemotherapy Group). JAMA 1964; 180: 758 762
-
.
MM. Melphalan vs Cyclophosphamide
Trials*
·No significant differences in response rate
and overall survival
* Rivers SL and Patno ME. JAMA 1969; 207:1328-1334.
Witts LI et al (MRC trial)
trial). Br Med J 1971; 1:640
1:640 641
-
.
A Comparison of the Effect of
Prednisone (PDN) and a Placebo
Placebo in
the Treatment of Multiple Myeloma*
PDN
(40 mg/d
mg/d x
Placebo
p value
24 weeks)
No. patients
25
22
Serum globulin
28%
4%
0.036
decrease >15
>15 g/L
Significant Hb
26%
0%
0.001
* Mass RE. Cancer Chemother Rep 1962; 46:257-9.
Treatment for MM: Combination
Chemotherapy with Diff
Dif erent
Melphalan Dose Regimens *
Nº. of
Response
Regimen
patients
p
rate
Daily melphalan
35
19%
Intermittent melphalan
69
35%
Melphalan + alternate
alternate day PDN
28
65%
Melphalan + concurrent PDN
51
73%
* Alexanian R et al. JAMA 1969; 208:1680-5.
Combination Chemotherapy
Regimens Compared with MP
VBMCP
VCMP/VBAP
VBMCP/VBAD
VAD-like
ABCM
ASCT: Standard of Care for Younger Patients
ith
w
MM since 1990s
Patients Eligible and Non-eligible for ASCT
PATIENTS ELIGIBLE FOR HDT/ASCT
ASCT in MM:
Induction with Old Drugs (I)
· CR rate 35%
· Longer EFS
· Longer OS in some studies
ASCT in MM with Induction with
Old Drugs
· Long term outcome
Total Therapy I: 16/231 patients in continued
CR after a median follow-up of 12 y
pyrs*
Single ASCT: 11/95 patients in
in continued
continued CR
from 8 to 15 yrs**
*Barlogie et al, BJH 2007
** Rovira et al, EBMT Meeting 2009
Pre and Post-ASCT CR Rate with Novel
Id
Inducti
tion R
i
eg mens*
Regimen
Pre-ASCT
Post-ASCT
Thal/Dex
6%
23-34%
Vel/Dex
12%
33%
PAD
PA -
D 1
24%
43%
VTD
21-30%
43-49%
Total Therapy III**
-
56% at 2 yrs
*Cavo t
e l
a , ASH 2008; R i
os ñ
iñ l
o t
e l
a , ASH 2008; R i
os ñ
iñ l
o t
e l
a , JCO 2007;
Popat et al, BJH 2008; Barlogie et al, BJH 2007.
**VTD-PACE + Tandem ASCT + VTD/TD
Multidrug Pre-ASCT Induction (VTD,
VRD, PAD, VTD-PACE) or Gentle
Induction (i.e., alternating VEL/DEX)?
· Longer EFS?
· Longer OS?
· Superior long term
-
outcome (cure rate)?
rate)?
PATIENTS NON-ELIGIBLE FOR HDT/ASCT
Expanding Treatment Options for Front-
line Therapy of Eld
Eld l
er y P ti
a ents with
ith MM
Alkylating agent-based
Dexa-based
· MPT (GIMEMA, IFM,
NMSG, HOVON)
· Thal/Dex (ECOG,
Celgene 003,
· MPV (PETHEMA,
CEMSG)
VISTA)
· L/
Len D
/Dex (SWOG
· MPR (GIMEMA)
(SWOG,
ECOG, Others)
· CTD (MRC IX)
Unprecedented CR Rate with Novel plus Old
Drugs in Non-transplant Candidates
Regimen
CR rate (%)
MPT1,2
MPT
15
MPR3
24
MPV4
30
Rev/Dex5 or BIRD6
22-37
1Palumbo et al, Lancet 2006
5Lacy et al, Mayo Clin Proc 2007
2Facon et al, Lancet 2007
6Niesvizky et al,
y, Blood 2008
3Palumbo et al, JCO 2007
4San Miguel et al, NEJM 2008
MM. Impact on
o Su
S rviv
u
al of
o Fron
o t-line Treatment
with Novel Agents in Elderly Patients
· Longer EFS/PFS
· Longer OS in some studies
· Long-term outcome?
· Cure rate?
Impact of novel agents on outcome
in newly diagnosed
diagnosed disease
Overall survival
survival from
from diagnosis
diagnosis
1.0
1971-76
1977-82
08
0.8
1983 88
-
1989-94
1994-00
0.6
2001-06
vival
Sur
0.4
0.2
0.0
0
20
40
60
80
100
120
140
Time
Kumar et al. Blood 2008; 111: 251620
Improvements in survival of young
patients
Period estimates of 10-yr survival by major age groups in defined calendar
periods
50
45
(%) 40
<50
40
35
30
5059
vesurvival 25
v
20
relati 15
6069
10
7079
-year
5
80+
10
5
0
1984
1987
1990
1993
1996
1999
2002
1986
1989
1992
1995
1998
2001
2004
Calendar period
Improvements in survival for elderly patients expected with longer follow up of
ongoing trials
Brenner et al. Blood 2008;111:252126
Expected Long-term Survival of Patients
Diagnosed with Multiple Myeloma in
2006-2010*
· Projected 5-and 10 years relative survival
significantly improved in patients < 45 yrs.
· Survival projections hardly exceed estimates
from traditional survival analysis for older
patients
*Brenner et al, Haematologica, 2009
Tailored/Sequential Therapy for
Elderly Patients with MM
"Aggressive" disease
MPV
"Non-
Non aggressive"
aggressive disease
MPT
Poor cytogenetics
MPV
Renal failure
Ve
V l/Dex
e
History of peripheral neuropathy Len-based
Vl
Very e d
lderly
MPT (Th
(Th l
a 100
/d)
mg
Logistics
MPT/ Len-based
Disease Evolution
St
Sequen iti l
a Th
Therapy
45
M/P
40
Dex
35
Len/Dex
30
einot 25
-pr
Vel
Mm 20
ru
Se
15
10
IF-
IF
IF+
IF
EP+
5
0
7/98
9/99
9/00 8/01 11/02 9/03
4/04 10/04 10/05 10/06 10/07 10/08 2/09
Time
Current Expectations for Multiple
Myeloma
Are we closer to
Chronic??
or
Cure??
Future Workshops!!!