Relapse and the
Search for a Cure
September 16, 2009
St. Petersburg, Russia
Brian G.M.
G.M. Durie, M.D.
What We Learn From Relapse
Some myeloma cells persist and regrow despite
prior treatment
These cells are partly or completely resistant to
prior drugs
drugs
Finding new treatment that works in this setting
can both
both produce
produce a response
response...
and may ultimately
lead to a
cure
Outcomes at Relapse
No necessarily poor over time
With new agents
agents..
· Best response ever can occur
·Longest response ever can occur
Planning for future options is always
important
What is Relapse?
Regrowth of myeloma
Increase in M-protein in blood/urine
"Biochemical Relapse"
New CRAB ft
features
"Clinical Relapse"
p
Understanding Relapse
Can be
be single
single lesion or multiple sites
In bone/out of bone
On/Off treatment different
Important to consider:
Prior response(s)
Length of response(s)
Number of prior treatments
Risk Category
gy: B2M, FISH, LDH, ...
2 ,,
,
Monitoring Issues
M
-protein: Blood/Urine
FLC: Serum Free Light Chain
Imaging: MRI / PET/CT
Ri

k
s A
t
ssessmen : FISH /
Chromosome Testing
Bone Marrow
Supportive Care Issues
Individual Co-Morbidities or Co-Factors
Infection
Blood Clots
Neuropathy
py
Kidneys
Bones
Other Medical Problems
Costs / Reimbursement
What to do at relapse?
IMID, Bortezomib or Combinations?
Sequencing versus Combinations
Combinations ?
Transplant
T
role ?
New Drugs
Drugs ?
Clinical trials ?
Patient Profile and Treatment Choice
Dexamethasone
Thalidomide
Lenalidomide Bortezomib
Oral
++
+
-
Intravenous
+-
-
+
Neuropathy
-++
+/-
++
DVT/PE
-++
++
-
Hyperglycemia
+++
-
-
-
Herpes Zoster
+
--
++
Varicella
Myelosuppression
-+
++
-
Thrombocytopenia
-
+
++
+++
Psychological
+++
+
-
-
disorders
Tolerability in Renal
+++
+++
-
+++
Failure
Sleep disturbance
++
++
-
-
IMID, Bortezomib or Combinations at
relapse
eapse ?
In most studies combinations win out
2 > 1
(e.g.
(g Rev/d
/ ex
d
versus
u Dex)
3>2
3 > 2
(MPV versus MP, MPT
MPT versus MP,
MPR versus MP, VTD versus
TD
etc.)
But toxicities
toxicities also increase
increase
IMID, Bortezomib or Combinations at
relapse
eapse ?
Things to Consider
Disease tempo : combination preferable if
rapid relapse and in younger patitients
Prior therapy response and side effects
Time since last therapy
Practical details - preference, g
pgeogra
g ph
p y,
y
access, compliance, diabetes, renal function,
neuropathy, genetic risk
"The definition of insanity
is doing the same thing
gg
over and over again and
expecting
pg different
results"
So what about another transplant?
Group
# of patients
Median PFS post
2nd ASCT
Entire Cohort
79
18.5 months
1st Transplant
2nd Transplant
<24 months
15
12.7 months
24-36
th
mon s
30
17.0
t
mon h
ths
>36 months
34
32.6 months
Wt
Wor h
th C
i
ons d
idering
New Proteasome Inhibitors
Unique chemistry drives selectivity and prolonged inhibition
Carfilzomib
O
O
H
H
H
O
O
N
N
O
N
N
N
N
H
H
H
O
O
O
O
Proteasome (Thr)
N
H
O
O
H
Irreversible
HO
Bortezomib
OH
HN
H
B
O
OH
H
O
R
N
N
B
CH
N
OH
H
CH
Thr or Ser protease
O
HN
N
O
Slowly reversible
Single Agent Anti-tumor Activity
Carfilzomib
100
6.5%
CR
14%
18%
VGPR
10%
PR
14%
MR
s
SD
ts
32%
c
14%
PD
e
47%
NE (TLS)
ubj 50
fs
16%
o
36%
%
ORR:
18%
26%
ORR:
57%
35.5%
14%
ORR:
65
6. %
5%
18%
18%
7%
0
3.2%
All
Bortezomib
Bortezomib
Subjects
Exposed
Naive
(N = 31)
(N = 17)
(N = 14)
90% of responses occurred by the end of Cycle 2
Low Rate of Treatment Emergent
Periph
ep er
e al
a Neu
e r
u opat
opa h
t y
· 73% had a prior history of drug or disease related neuropathy
· 32% had Grade 1/2 neuropathy at baseline*
30
No study discontinuations for
peripheral neuropathy
neuropathy
20
(N=31)
Peripheral Neuropathy does not
ts
limit dose or duration of therapy
c
bjeus 10
of%
6.5%
3.2%
0%
0
Gr1
Gr2
Gr3
()
(n=2)
()
(n=0)
()
(n=1)
Neuropathy AEs
*Grade Based on physical assessment at
screening (NCI-CTC scale)
Data through March 2009
Molecular Structure of Thalidomide,
Len
e ali
a domide an
a d Pomali
a domide
O
O
O
O
O
H
O
H
N
N
N
N
O
N
O
N
O
O
NH
O
2
NH
2
2
Thalidomide
Lenalidomide
Pomalidomide
(CC-4047)
Structurally similar, but functionally different
b t
o h
th qualit ti
a vely and
tit
quan
ati
tively
Phase II Trial of Pomalidomide +
Dex
e am
a eth
et ason
aso e in Rel
e apsed
apsed MM
Study Goals:
To assess the response rate and duration of
remission with Pom/dex in patients with
relapsed or refractory myeloma.
To assess the toxicity, overall survival and
progression free survival of Pom/dex in this
patient population.
Best Response
Confirmed
N=
N 60
=60
Response
sCR
1 (2%)
ORR 58%
Median follow-up
VGPR
14 (23%)
4 months
PR
20 (33%)
CR +VGPR
(33%)
SD
11 (18%)
25%
PD
13 (22%)
()
NE
1 (2%)
Among the first 37 patients, there were 13 lenalidomide refractory
patients, with responses seen in 29%
Patient case
69 year old male
Pomalidomide Response
IgG M-spike 3.0;
Progression on Len/dex; started
started Len/dex
Pom/dex; M-spike 2 5 labeling
started Len/dex
Pom/dex; M spike 2.5,
index was 2.2%.
PR; M-spike 1.5
M-spike 0.7
Bone Disease and BHQ880
Anti-DKK-
DKK 1 Antibody
Antibody
A Phase Ib multicenter dose-determination study, with
an adaptive, randomized, placebo-controlled, double-
bli d
n
h
p ase II,
i
us ng
i
var ous
t
repea ed IV doses f
o
BHQ880 in combination with zoledronic acid in
relapsed or refractory
py myeloma
y
patients with prior
skeletal-related event
Anti-DKK1 activity in MM models
INA-6 implanted SCID-hu mice
BHQ880 inhibits MM tumor
12500
Control
growth
BHQ880
rrugateu
growth
10000
s
BHQ880 inhibits MM-induced
7500
tumor
bone loss
­
5000
g/ml)p(
Systemic MM1S-Luc model
2500
80
*
0
shuIL-6R
)
*
0
7
14
21
28
M
*
V
M
V
70
*
Days from treatment
*
SE
MM1S-Luc
BV/T
+
Healthy tibia
inoculated
%
60
ean
(M
50
New Drugs: Where are we in 2009?
180 drugs reported in lab studies
About 30 in trials
About 3 or 4 seem to work
Some Drugs Under Testing
AUY922
TAK901 / MLN8237
CEP070 / MLN9708
TKI258 / Dasatinib
Obatoclax
SCH900105 / SGN40 / 1877S
Summary
Survival is improving with
with introduction
introduction
of IMIDs and Proteasome Inhibitors
Combination therapies likely to
to
dominate care
Trials for high
high risk
risk disease
disease required
Individualized approach required
Moving Forward Every Patient Needs Help
We
We just don't always
always
know where the help
will come from.
...nor whi h
c
treatments will lead to
li
long remi
i
ss on...or a
cure.