Donna E. Reece, M.D.
Princess Margaret Hospital
27 February 2009
Multiple Myeloma
y
in Canada
Incidence 4/100,000
2,000/yr in Canada
Prevalence
6500/yr in Canada
Median age 65 yrs
Canadian Cancer Statistics; 2007. Available at www.cancer.ca
Canadian Collaborative Trials
NCIC-CTG Trials
MY.07--elderly newly
yy diagnosed patients
MY.10--post-ASCT maintenance
MY.11--elderly newly diagnosed patients
[MY.12--Phase II aurora kinase inhibitor]
National investigator-initiated trial
Bortezomib-based therapy in newly-diagnosed t(4;14)
disease
Industry i t
n ernatiti
l
ona h
p ase III trials
APEX
MM090 leading
--
contrib
contrib t
u or
tor
MM020--FIRST trial
MY.07: Induction Therapy in Elderly MM
Randomized comparison of melphalan 9 mg/m2 days
1-4 + prednisone or dex day
pys 1-4 (MP vs Mdex)
(), and
maintenance with dex vs observation
1996-2003, n=585
Mdex arm stopped early due to more adverse events
No difference in PFS (MP 1.8 yrs and Mdex 1.9 yrs;
p=0 2
. )
2)
No difference in OS (MP 2.5 yrs and Mdex 2.7 yrs;
p=0.3)
p)
Dex maintenance had better PFS but not OS
Median PFS 2.8 vs 2.1 yrs; p= 0.0002
Median OS 4.1 vs 3.8 yrs; p=0.4
Shustik C, et al. Br J Haematol 2007; 136: 203-11.
MY.11: Lenalidomide + Melphalan for
Pi
Previ
l
ous y U t
n
t
rea d
e Eld
Eld l
er y MM
MM P t
a iti t
en s
Primary Objectives
Objectives
To determine the optimum doses of Mel + Len not requiring dose
modifications or routine G-CSF over first 3 cycles
To
To evaluate the
the CR rate after 6 cycles
Original design--randomized phase II trial of
Mel 9 mg/m2
g
days 1-4 and Len 10 mg day
gys 1-21 vs
Mel 9 mg/m2 days 1-4 and Len 20 mg days 1-21
28 day cycle; dex maintenance
DLT
DL = 2 dose reductions
reductions of
of Len or 1 of
of Mel
Mel
Safety run-in of 6 pts for Mel9Len10
4 of 4 pts experienced
pp
DLT with 1 death
White D, et al. Blood 2007; 110: abstract 189
MY.11: Redesign
Randomized phase II of M4L15 and M6L10
If neither arm tolerable
tolerable, single
single arm
arm testing of:
of:
Melphalan 5 mg/m2 days 1-4 + Len 10 mg days 1-21
(M5L10)
28 day cycle; dex maintenance
Sft
Safety
if
run-in of 6 pts at both
th dose levels
White D, et al. Blood 2007; 110: abstract 189
MY.11
11: Redesign
Redesign
Run-in Phase
Regimen
N
# pts with DLT in 1st
SAEs
Response
3l
3 cycles (#
id
episodes)
t
ra e
M4L15
6 4 (5 gr 3-4 neutropenia
13 PR
1 gr 4 thrombocytopenia)
thrombocytopenia)
1S
1 D
SD
M6L10
6 3 (4 gr 3-4 neutropenia;
23 PR
2 gr 3-4t
4 h
th
b
rom ocyt
i
open )
a
2S
2 D
SD
White D, et al. Blood 2007; 110: abstract 189
MY.11: Redesign
Phase IIII Trial
Trial of Mel 5 + Len 10 (N=
(N 35)
Median age 73.4 yrs; 63% ISS stage II-III
Hematologic toxicity:
toxicity:
Grade 3-4 anemia in 11/34 (32%)
Grade 3-4 neutropenia in 27/34 (79%)
Grade 3-4 thrombocytopenia in 11/34 (32%)
Dose attenuations (DLT) occurred in 20/27 (74%)
evaluable pts
DLT hematologic in 18/20 (90%)
Anti-myeloma activity was modest
In 10 evaluable pts: no CRs were seen after 6 cycles
6 PRs were seen after 6 cycles (60%)
No VGPRs
In 22 evaluable pts: 11 PRs were seen after 2 cycles (50%)
White D, et al. Blood 2008; 110: abstract 2767
MY.11: Summary
Phase II Trial of Mel 5 + Len 10
Routine G-CSF required for this regimen
Anti-myeloma activity was modest but need for
dose modifi
difications li it
m d
e assessment
Absence of prednisone may have affected
Ml
Myelosuppression
Response rate
Results of MPR trials
trials awaited
awaited with
with interest
ECOG E1A06: MPT vs MPR
MM015: MP vs MPR vs
vs MPR
MPR + len
len maintenance
White D, et al. Blood 2007; 110: abstract 189
MY.10 Randomized Phase III Trial of
Thalidomide + Prednisone
Prednisone vs Observation
after ASCT
Activated in 2002
Target N=324
Enrollment completed last
last month
month
Thalidomide 200 mg per day +
prednisone 50 mg q 2 days for 4
years vs observation
Primary outcome overall survival
96 events required for completion
Interim analysis at 28
24, 48 and
72 events
# events met in Dec 2008 for
3 d
3r ii
interim
l
ana ysis
MY.10:Randomized Phase III Trial of
Th lid
a
id
om e + P d
re i
n sone vs Ob
Ob
i
servat on
after ASCT
Parameter
Arm A (n=165)
Arm B (n=160)
Median age
57.8
57.7
Male
108 (65%)
106 (66%)
ECOG PS 0
65 (39%)
33 (21%)
Ig subtype
IgG
96(58%)
103 ( 64)
IgA
39 (24%)
33 (21%)
IgD
2 (1%)
1 (1%)
Light chain
24 (15%)
20 (13%)
CR after ASCT
24 (15%)
20 (13%)
Stage III at diagnosis
80 (48%)
84 (53%)
Any lytic lesions
111 (67%)
115 (72%)
Thalidomide Maintenance after ASCT
Author/Year
N
Thalidomide dose (mg)
PFS/
Overall
/duration
EFS
Survival
Attal/2006
597
Thal 200 (median dose) vs obs
++
/progression
Spencer/2006
243
Thal 200 + pred vs pred/
++
12 months
Abdelfeki/2008*
140
Thal 100/
++
6 months
Maiolini/2008
212
Thal 200 + dex vs dex/
+NS
12 months
Barlogie/2006*
668
Thal 400/
+
NS
progression
Morgan/2008*
--
--
+
NS
NCIC/2009
325
Thal 200 + pred vs obs/
??
48 months
* Thalidomide given before and after ASCT
ASCT in t(4;14) Myeloma
· Translocation between heavy Ig
gene locus and MMSET + FGFR3
· Found in 15% of patients by FISH
Study
N
# ASCT
Median PFS
Median OS
(mos)
(mos)
1
Chang/2004
16
1
9.9
18.3
Gertz/20052
26
1
8.2
18.8
M
/
oreau 20073
/2007
100
2
21
41
1Chang et al. Bone Marrow Transplant 2005;36:793; 2Gertz et al. Blood 2005;106:2837;3Moreau et al.
Leukemia 2007 2007;21:2024
Tr
T eatment of
of Progressive
Progressive t(4;14) MM
Regimen
N
Response
p
Median
Median
rate
TTP (mos)
OS (mos)
Cyclophosphamide
11
0 (63% SD)
--
--
+ predi
dnisone/MP1
/MP
Thalidomide or
17
41%
4.7
--
dex1
dex
Bortezomib +/-
6
67%
10.5
15.5
steroids2
Lenalidomide +
28
79%
8.0
23.7
dex3
1Jaksic W, et al. J Clin Oncol 2003; 23:7069; 2 Chang H, et al. Leuk Res 2007; 31:779-782; 3Bahlis N, et al.
Blood 2008;112:abstract #1731.
t(4;14) Canadian Trial
Doxil + Bortezomib + Dex (DBd)
induction x 4 cycles
Assessment
Elective stem cell
No Progression
harvest
Cybor-P Post-Remission x 8 cycles
Weekly bortezomib 1.5 mg/m2
Weekly po cyclophosphamide 300 mg/m2
yp
y
p
p
g
Prednisone 100 mg q d days
Dex maintenance
CYBOR-P in Relapsed/Refractory MM
Bortezomib
Days\
N
Response rate
1 year
Toxicity
dose
28 day
(CR)
PFS
cycle
1.3 mg/m2
1,4,8,11
6
100% (50%)
--
gr 2 PN
17%
gr 3 ANC
17%
gr 3 pl
40%
1.5 mg/m2
1,8,15
13
85% (54%)
83%
gr 2 PN
0
gr 3 ANC
1.3%
gr 3 pl3
l
3 9
. %
9%
Cyclophosphamide given at a dose of 300 mg/m2 days 1,8,15 and 22
Prednisone 100 mg given q 2 da
da s
y on a 28
28 da
day sched le
u
Reece D, et al. J Clin Onol 2008; 26: 4777-4783
t(4;14) Study: Statistical
Statistical Considerations
· Gf
Goal is prolongation of TTP from 12 to 21 months
· 36 patients required for an 80% power in a two-sided
comparison
· Drop-out rate assumed to be 20%; therefore, 45
patients needed
· Fixed follow-up time of 24 months
· Interim analysis p
yplanned after 12 patients have
completed post-induction CyBorP
Canadian t(4;14) Trial
Trial open since September 2008
6 centers
95 patients screened
8 positive for t(4;14)
6 entered
1 referred after 3 months of therapy
1 asymptomatic
asymptomatic myeloma
Acknowledge
Acknowledg men
e
t
men s
t
CTG-NCIC
PMH Myeloma Team
Dr. Ralph Meyer
Dr. Christine Chen
Erica Hartnett
Dr. Suzanne Trudel
Canadian hematologists
Dr. Vishal Kukreti
Dr. Darrell White
Dr. Peter Anglin
DN
Dr. i
Nizar B h
a li
hlis
DK
Dr. Keith
ith St
St
t
ewar
Dr. Andy Belch
Myeloma nurses
Dr. Chaim Shustik
Shustik
Ml
Myeloma research
Dr. Michael Kovacs
coordinators
Dr.
Dr David
David Swzacjer
Giovanni Piza Rodriguez
Dr. Tony Reiman
Myeloma patients