Frontline Therapy in 2009
Washington, DC
August 8, 2009
Brian G.M. Durie, M.D.
What Will Be Discussed
Impact of new therap
ppies in 2009.
Current options for frontline therapy
Prognostic factors
Age
Stage
FISH/cytogenetics
Consider
FDA approved therapy
Phase III clinical trial results
New li
c ni l
ca tri l
a s currently accruing
FDA Approved New Drugs
Thalidomide (Thalomid®
(Thalomid )
Bortezomib (Velcade®
(Velcade )
Lenalidomide (Revlimid®
(
)
Doxil®
What impact has there
there been on outcomes?
Improving overall survival in myeloma
Impact
pact of
o tran
a sp
s lan
pa t a
tand nov
o el therap
a ies
pes
Ol
Overa l
ll
100
survival 1971
Diagnosis period
Median OS
2006
19711976
Last decade
45 months
1977 1982
80
Before last decade
30 months
19831988
p < 0.001
)
19891994
60
20012006
(%
19952000
s
2001 2006
40
Patient
65 years (60 vs 33 months)
20
> 65 years (32 vs 26
26 month
th )
s
0
0
20
40
60
80
100
120 140
Time (months)
Kumar SK, et al. Blood. 2008;111:2516-20.
Fundamental Philosophies*
CURE
Use all available options early in an attempt
to cure
a subset of patients
or
Use treatments sequentially in an attempt to
control myeloma
myeloma as a chronic
chronic disease with
with
recurrences
* Rajkumar: Mayo Clinic Proceedings 2008
CONTROL
Improving Survival at 2 Years
Phase III Clinical Trial Results
100%
90%
VMP, Rev d, MPR
80%
Thal/Dex or VAD + SCT
MPT
70%
60%
MP
50%
Staging and Prognostic Factors
Staging
Prognostic
Ft
Factors
Durie-Salmon
FISH
del 17p
ISS (S
t (4:14)
ISS (S 2
M/Alb)
2
t (14; 16)
Chromosomes
del 13
Hd
Hypo i
di l
p oid
idy
Molecular Prognostic Factors
1.0
All others including
t(11;14)
ity
P<0.001
i 08
0.8
13
0.6
robabil
Poor
24.7 mos
rp
Intermediate
42.3 mos
Good
51.0 mos
0.4
ivalv
t(4;14)
Sur 0.2
t(14;16)
-17p13
-
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Months
Fonseca et al Blood 101:4569, 2003
mSMART : Classification of Active MM
High-
High Risk
-
(25%)
Standard-
Standard Risk
-
(75%) *
FISHDel 17p
All others
others including:
17p
including:
t(4;14)*
Hyperdiploid
t(14;16)
t(11;14)
C t
y ogenetic Deletion 13
t(6;14)
Cytogenetic hypodiploidy
*Patients with
ith t(4;14), b2M<4 mg/l
/l and Hb10g/dl may have intermediate risk di
disease
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v5 Revised and updated: Jan 2009
Transplant Ineligible* Patients
"Old
Current
Curr
Standard"
Options
MP
MPT
VMP
Rev/Lo Dex
Thal/Dex
MPR
* Ineligible and/or not selected
Comparison of MPT , VMP,
Rev/Low Dex (
/(Rd) and MPR
MPT
VMP
Rd
MPR
Response
(> 50%)
76%
71%
71%
81%
> VGPR
47%
45%
42%
48%
Survival
1 year
88%
------
96%
95%
2y
2 ea
ye rs
83%
83%
88% (83%)* 90%
Toxicity
Thrombocytopenia
14%
37%
6%
24%
Neutropenia
48%
40%
19%
52%
PN
6%
14%
2%
0%
* Patients age > 65 years
mSMART Off-Study
Transplant Inelig
pgible
High Risk
Standard Risk*
MP + Bortezomib**
MP + Thalidomide** or Rd
Observation
Ob
i
servat on
*Bortezomib containing regimens preferred in
renal failure or if rapid response needed
Continuing Rd is an option for patients
responding well to induction with low toxicities;
** In patients in whom administration of
Dex is usually discontinued after first year
thalidomide or bortezomib is of concern,
consider MP or Rd
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v5 Revised and updated: Jan 2009
For Transplant Eligible Patients
"Old
Options"
Newer
Combinations
VAD
or
Velcade + Dex Combos*
Revlimid + Dex Combos**
Thal
Dex
* Phase III data; FDA approval
Transplant
Harvest
** Phase III data
Comparison of Options For Use in the
Tran
a sp
s l
p an
a t Sett
S
in
ett g
Response Rate
CR + VGPR
(> 50% regr.)
(> 90% regr.)
Dex
45%
16%
VAD
63%
19%
Thal / Dex
Dex (D)
65%
44%
Rev / dex (d)
70%
42%
Vel / Dex
80%
47%
VTD
85%
60%
mSMART Off-Study
Transplant Elig
pgible
High
g Risk
Standard Risk
4-6 cycles of bortezomib
4 cycles of Rd*
containing regimen (CBD, VRd, VTD etc)
Collect Stem Cells**
Collect Stem Cells
If not in CR, consider autologous stem
Autologous stem cell
OR
Continue
cell transplant (ASCT)
transplant (ASCT)
Rd
All pati
ti
t
en s receive Rd
Rd
If not in CR/VGPR after
til
If not in CR/VGPR
until
progression
1st ASCT, consider
consolidation (eg.,
second ASCT or IMiD)
* Bortezomib containing regimens preferred in
renal failure
failure or if rapid response
response needed
needed
Continuing Rd is an option for patients
(**If age >65 or > 4 cycles of Rd
responding well to induction with low toxicities;
Consider G-CSF plus cytoxan or plerixafor )
Dex is usually discontinued after first year
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v5 Revised and updated: Jan 2009
Primary Therapy Beyond 4 Cycles
What is the impact of long-
ti
term mai t
n
?
enance
Is this a safe option?
Longer-term results with
lenalidomide + dexamethasone
Mayo phase II
Stringent CR (sCR)
0% (4 cycles) 30% (30 months)
)%(
ingd
OS 93% at 4 years
responts
BiRD phase II
30% (30 months)
n
Cycles
) 100
Stringent complete response
Completed response
Patie
(%
80
Very good partial response
Partial response
ndingo 60
38%
67%
0% (4 cycles)
resp
40
20
VGPR or better
tientsaP 0 1 2 3 4 5 6 7 8 9101112131415161718192021222324252627282930313233
Lacy MQ, et al. Mayo Clin Proc. 2007;82:1179-84.
Niesvizky R, et al. Blood. 2008;111:1101-9.
Follow Up Results of ECOG Phase III Trial
Results of Primary therapy beyond 4 cycles with Rd
"Primary Rd"
Rd
(n=142)
Best Response
%
Overall Response Rate
89%
CR* (IF-)
22%
CR + VGPR
56%
Duration of Response
25 months
Grade
Gr
3 or more
mor non heme toxici
to
ty
t
27%
2 yr-Survival
93%
* *measured in serum or urine
Does multi-drug induction
improve outcomes?
outcomes?
Bortezomib, dexamethasone, cyclophosphamide,
lenalidomide (RV
(R CD):
VCD): phase I results
results from
from the
the
phase I/II, multi-centre EVOLUTION study
Response
n(
n %)
(%)
sCR
5 (20)
CR
9 (36)
(36)
VGPR
17 (68)
ORR 100%
PR
25 (100)
Kumar S, et al. Blood. 2008;112:[abstract 93];
updated data presented at ASH 2008.
Questions
Which combo is best?
Hd
How do we j d
u ge?
Is long term survival predictable??
Is transplant still needed for all
all patients?
Single/double auto?
Mini Allo?
Is intense upfront Rx better than sequential
Rx?
Transplant: Early vs. Later vs. None?
>3 or 4 Drug Combos vs. Simple Combos??