Future Perspectives in Myeloma
Management
Kt
Kenne h
th C. A d
n erson, M.D.
Jerome Lipper Multiple
Multiple Myeloma
Myeloma Center
Center
Dana-Farber Cancer Institute
Harva
aard Med
e i
d ca
cal Sc
Schoo
o l
o

---

Ongoing MM Collaborative Model for Rapid
Translation
T
from
from Bench
Bench to Bedside
Four new FDA
approved drugs
Pharmaceuticals
Academia
Advocacy
NIH
FDA
NCI

---

Integration of Novel Therapy
gpy Into
Myeloma Management
Bortezomib, Lenalidomide,
Thalidomide, Doxil
Treatment of Relapsed/Refractory
MM (single agent/combinations)
Induction/First-line Therapy
Tl
Transpl
t
an /M
t/M i
a t
n enance

---

New Models
Models of Collaborative
Discovery in Myeloma
· Making Science Count for Patients
­ NCI Mouse Consortium (new mouse models)
­ Harvard Vaccine Center (new vaccines)
­ Broad/DFCI Chemical Genetics and Cancer
Drug Di
Discovery (new t
t
arge ed inhibitors)
­ DFCI Center for Applied Cancer Sciences
(new monoclonal antibodies)
antibodies)
­ Multiple Myeloma Research Consortium
(new preclinical and clinical
clinical collaborations)

---

Oncogenomics to Identify Targeted Therapies
Integrated
g
platform aCGH, SKY and expression profiling
profilin
55 MM Cell Lines; 73
73 Patient
Patient Samples
60
ence 40
e 20
0
20
recurr 40
46 amplicons - 658 NCBI genes
% 60
%
Chr.
Chr 11223344556677889910
10 11
11 12
12 13 15
17
19
21 X
Expressed Genes : 258
Functional validation of MM candidate genes.
New models
Small molecule
Monoclonal Abs
Carrasco et al. Cancer Cell,
Vaccines
2006 9:313-325

---

)
XBP-1s Transgenic Mouse Model of MM (NCI Mouse Model Consortium)
1
10
CONTROL
XBP-1s
lX
Bone Ly
Lytic
tic Lesions
m
XBP-1s
Ig(mg/
um
Ser
ry
ensitometD
Histology
Bone
Carrasco et al, 2006

---

Production of Vaccines Against MM
Antigens (Harvard Vaccine Center)
IGF-1
BCMA
RANKPEP
Sd
Syndecan-1
Caveolin 1
·
- HLA-A0201 binding
Cyclin D1
·
- 9mer or 10mer
Interg
egrin a8
a8
·
- proteasome cleavage
Amphiregulin
HLA-DOB
IL-5 receptor a
Prediction of 37 peptides
from 9 genes
RANK
POS.
N
SEQUENCE
C
MW (Da) SCORE
% OPT.
1
3
MG
KISSLPTQL
FKC
968.16
75
65.79%
2
38
LAL
CLLTFTSSA
TAG
924.08
67
58.77%
3
106
DLR
RLEMYCAPL
KPA
1077.34
64
56.14%
4
19
FCD
FLKVKMHTM
SSS
1116.43
61
53.51%
5
39
ALC
LLTFTSSAT
AGP
922.04
58
50.88%

---

DFCI Center for Applied Cancer Science
Targeting CD 138 In vivo in a Model of Human
MM in Human BM Milieu
Human
bone chip
7
B-B4-DM1
6
(150 g/Kg)
5
4
3
2
1
0
20
30
40
50
60
Days from cells injection
Bone chip
before
after 12 days

---

Blockade of Ubiquinated Protein Catabolism
Chemical Genetics and Cancer Drug Discovery (Broad/DFCI)
Protein
Ub
Ub
protein aggregates
(toxic)
Ub
Ub
Ub
Ub
26S proteasome
HDAC6
Trial of LBH alone
Bortezomib Ti l
f LBH
Ub
Ub
and with
Tubacin
LBH
HDAC6
LBH
Bortezomib
dynein
Ub
Ub
Lysosome
y
Aggresome
HDAC6
Ub Ub
dynein
Ub Ub
Ub
Ub
Microtubule
At
Aut
h
op agy
Hideshima et al, Clin Cancer Res;2005; 11: 8530
Catley et al, Blood 2006; 108: 3441-9.

---

Gene Modulations Triggered
by Binding of MM Cells to BMSCs
Growth
Survival
BM
Drug resistance
MM
Adhesion molecules
stromal cells
Cytokines

---

BM Microenvironment Triggers Proteasome
Activity in MM Cells
MM cells
BMSCs
Chauhan et. al., 2006

---

Compartment
Compartment--specific
specific bioluminescence imaging (CS
(CS--BLI)
BLI)
High
High--throughput
throughput screening of MM with BMSCs (SPORE to CACS)
100
75
ival
Dex
rv 50
uS
No BMSCs
25
%
+HS--55 stroma
stroma
0
0.0
0.5
1.0
1.5
2.0
Dex (uM)
100
No BMSCs
75
+HS--55 stroma
stroma
Doxo
Luc+
Luc-
Myeloma
y
+
rvival 50
r
Myeloma cells
Stromal cells
Stromal cells
uS 25
%
0 0
10
20
30
40
50
60
Doxo
Dox (ng/mL)
Biolum signal
No signal
Biolum signal
100
75
Bortezomib
No BMSCs
rvival
No
50
r
+HS-
+HS 5s
5 trom
o a
m
u
stroma
S 25
%
0
McMillin et al. Oral presentation, IMW 2007 abs # S11
0
10
20
30
40
PS
PS--34
3 1
41 (nM)
(nM)

---

Plasmacytoid Dendritic Cells Promote the Growth
of MM Cells Ex-Vivo
* 4-5 fold increase in
CD138+
growth of MM cells
MM cells
* Increase in IL-1-, IL-6,
TNF- & VEGF
* NF-B induction
Myeloma Patient
Separation of MM cells
with CD138-magnetic beads
for further utilization
Co-culture
Proliferation/Propagation
of patient MM cells
Plasmacytoid
dendritic cells
Healthy donor or
Myeloma
My
patient
patient
Potential use for
In Vitro studies of
Genomics & Proteomic
deriving new MM cell lines
durg-efficacy/drug-resistance
studies
Chauhan et al., 2006

---

Growth of the MM Cell in the
MM
BM Microenvironment
migration
GSK-3
SC
FKHR
CD40
PKC
Survival
Caspase-9
Anti-apoptosis
Akt
NF-B
Cell surface
Cell cycle
cy
mTOR
targets
PI3-K
Bad
Bcl-xL
Survival
JAK/STAT3
Mcl-1
Anti-apoptosis
BAFF-R
Raf
MEK/ERK
proliferation
p
VEGFR
Bcl-xL
Survival
Cytokines
NF-B
IAP
Anti-apoptosis
Cyclin-D
Cell cycle
IL-6, VEGF
IGF-1, SDF-1
TNF
TNF
BAFF, APRIL
Proliferation
TGF
MEK/ERK
BSF-3
Anti-apoptosis
VEGF
p27Kip1
Smad, ERK
Adhesion
cytokines
NF-B
adhesion
LFA-1
molecules
ICAM-1
NF-
NF B
MUC-1
BMSC
NF-B
VCAM-1
Fibronectin
VLA-4
Hideshima T and Anderson KC. Nat Rev Cancer 2002, 2:927. Hideshima T et al. 2004, Blood 104:607

---

CS1 in
in Multiple
Multiple Myeloma
Myeloma
· Universal gene expression in multiple myeloma
· Confirmed CS1 protein expression by flow cytometry
and IHC with anti-CS1 antibodies
· Normal tissue
tissue staining
staining shows
shows exclusive
exclusive expression
expression
only in tissue plasma cells
Plasma ce
cells in normal
Multiple my
pyeloma cells
gut
in a plasmacytoma
Staining was performed with HuLuc63 humanized anti-CS1 monoclonal antibody

---

HuLuc63 Anti-
Anti CS
-
-1
- Antibody
Antibody Induces
Specific MM Cell Lysis
A
B
80
70
killing 60
CS1
fic 50
40
speci 30
% 20
10
0
0
1
10
0.0001
0.001
0.01
0.1
HuLuc63, g/ml
MM1R
MM1S
U266
CD19+B cells
Phase I trial ongoing in MM
CD19+B cells
Tai et al Blood, in press

---

Anti-BAFF Neutralizing Ab Prolongs Survival and
Inhibits Osteoclasts in SCID-Hu Model of MM
Control Animal
Anti-BAFF Ab-Treated
Survival in Days
70
CNT Isot.
BAFF
60
50
40
p=0.048
30
Ab(+)
20
10
Ab(-)
P<0.05
0
0
5
10
15
20
25
30
Days from treatment
Neri et al, Clin Can Res, 2007

---

MEK Inhibitor AZD6244 Specifically
Inhibits pERK and Induces Apoptosis
A
in MM Cells
AZD6244
-
- - -
+ + + +
AZD6244
AZD6244
0.01-10 µM
00 0.01-10 µM
IGF-1 0 5 10 30
0 5 10 30 min
pAKT
pERK
pERK
pAKT

-tubulin
-actin
IL6 stimulation CD40 activation
B
C
LD M
50
Patient MM cells
INA-6
0.485 + 0.013
120
MCCAR
0.7 + 0.024
100
MM1S
24.86 + 0.98
80
MM1R
25.312 + 1.23
60
RPMI8226
13.9 + 1.03
survival
40
%
DOX40
16.74 + 20
2. 5
05
20
0
LR5
7.5 + 0.945
0
0.02 0.2
2
20
28PE
28.7 + 1.368
28BM
0.92 + 0.034
AZD6244, µM
Tai et al , Blood 2007

---

AZD6244 Blocks Osteoclast
Differentiation
A
C
AZD6244
--
+
-
+
control
AZD6244
M-CSF+RANKL
-
+
+ +
+
hour
2
2
224 24
OCL
OCL
pERK
ERK
OCL
B
AZD6244 M
-
0.2
0.5
OCL
M-CSF+RANKL
+
+
+
cathepsin K
GADPH
cathepsin K/GADPH
2.0
1.2
0.6
ratio
AZD6244
AZD6244
Mature OCL
Bone
OCL precursor
resorption
Tai et al , Blood 2007

---

Novel Proteasome Inhibitor NPI-0052 Inhibits Human MM
Cell Growth and Prolongs Survival in a Murine Model
Phase I clinical trial in myeloma 11/06
Chauhan et al, Cancer Cell, 2005.

---

Phase 1 MMRC Clinical Trial of NPI-
0052
Study Design
N=1
N=1
N=1
*
01
0.1
02
0.2
04
0.4
mg/m2
mg/m2
mg/m2
· *A
l
cce
t
era d
e Tit
Tit ti
ra on Phase - c
ti
on nues t
a 1 t
p
per cohort with dose doubling until first G 2 drug-
related toxicity
· Thereafter, 3 pts enrolled per cohort and dose
escalation by Modified Fibonacci scale (50%,
40%, 33% and 25% increments)
,)

---

Proteasomal Active Site Specificity
20S proteasome
2
particle
-subunit
1
T
3
T
ring


caspase- trypsin-
Three distinct
like
like
N-ti
termi l

na
chymotrypsin-
4
7
threonine

like
protease active
T
sites
6
5
IC50s (nM)
Chymotrypsin-like
Caspase-like
Trypsin-like
Carlfizomib
6
2400
3600
Bortezomib
7
74
4200

---

Clinical Activity of Carfilzomib (PR-171)
1. Effective in Bortezomib resistance
2. Neuropathy not reported, dose related
thrombocytopenia
3. Dailily x 5 activity in MM
MM: 1MR
1MR, 1PR (45
(45 78d)
,
Discontinued to "treatment fatigue"
4. Daily x 2 activity in MM: 1MR, 4PR
4PR (100-
288+d) Thrombocytopenia, hypoxia
5. Two phase II trials in relap
ppsed refractory
MM in MMRC
Stewart et al, ASCO 2007

---

Proteasome: Present and Future Therapies
Potential
UB enzymes E1, E2 and
E3-UB-Ligases
Therapeutic Targets
Ub
ATPases/
Ub Ub
Cdc48
immunoproteasome
ATP
ADP
Poly-ubiquitinated proteins
(proteasome substrates)
19S
Six Proteolytic
activities
5, 5i
20S

20S
1, 1i
2, 2i
19S
Free Ub
for
li
re-cyc ng
Degraded protein
26S PROTEASOME

---

Rationally Based Combination
Combination
Therapies
· Bortezomib and Hsp 90
· Lenalidomide and mTOR
inhibitor
inhibitor
· Bortezomib and doxil
· Lenalidomide and Anti-
Bortezomib and NPI 0052
CD40 antibody
· Bortezomib and NPI-0052
antibody
· Bortezomib and perifosine
· Lenalidomide and doxil
· Bortezomib and LBH 589
· Lenalidomide and
· Bortezomib and Smac
HuLuc63
· Bortezomib and Smac
peptides
· Lenalidomide and LBH 589
· Bortezomib and Bcl 2
· Lenalidomide and
inhibitor
perifosine
38
· Lenalidomdide and
· Bortezomib and p38 MAPK
inhibitor
Bevacizumab
· Bortezomib and HuLuc63
· Lenalidomide and Vaccine
Lenalidomide and Bortezomib

---

Preclinical Rationale for
Combination Therapy in Clinical Tr
T ials
r
Low-dose bortezomib enhances and restores
sensitivity to DNA damaging chemotherapy
(doxorubicin)
120
100
(-)
vival
Dox
v
80
(+)
80
60
sur% 40
20
0
02
0
2
5
10
10
Bortezomib (nM)
Mitsiades et al. Blood 2002;101:2377

---

Phase III study: Pegylated liposomal
doxorubicin/ bortezomib compared
compared with
bortezomib
R
alone in relapsed/refractory MM
A
N
Bortezomib 1.3 mg/m2 days 11, 4, 8, 11 every
D
21 days for up to 8 cycles
O
M
Primary endpoint: TTP
646 patients with
I
relapsed and/or
Secondary: OS, ORR, safety,
Z
refractory myeloma
resource utilization
Z
A
T
Bortezomib as above + Pegylated liposomal
I
doxorubicin 30
30 mg/m2
mg/m on day 4
O
N
Stratifications:
2m(2.5, >2.5 but 5.5, >5.5)
2m ( 2.5,
2.5 but 5.5,
Response vs. progression on initial therapy
Harousseau et al Abstract 8002

---

Superior Time to Progression with
Combination of Bortezomib and
PLD
100
PLD + Bortezomib
80
9.3 months
ession-Free
60
Progr
Bortezomib
atientsP 0
65
6.5
t
mon h
ths
of
Percent 204
Statistical analysis:
HR (95% CI) 1.82 (1.41-2.35)
0
p = 0.000004
0
100
200
300
400
500
Days
Harousseau et al Abstract 8002

---

Combination of Revlimid + Bortezomib
50
Patient Cells
40
Revlimid
100
0 uM
5 uM
ldeath
ontrol 80
c
30
%
cel
60
%
40
20
20
10
0
0
10
20
Bortezomib (nM)
0
Mitsiades et al. Blood 2002; 99: 4525.

---

Bortezomib and Lenalidomide Therapy
Lenalidomide induces
induces caspase 8 mediated
mediated apoptosis
apoptosis of
of MM
MM
cells in BM in vitro and in vivo; Dex (caspase 9)
enhances response
Synergistic MM cell toxicity of lenalidomide with
Bortezomib in vitro and
and in vivo (dual apoptotic
apoptotic signaling)
Phase I-II trials show that majority (58%) of patients
refractory to
to either
either agent
agent alone respond to the
combination
Phase I-II trials show 100% response with 71% CR/VGPR
when used as initial therapy.
Richardson et al, ASCO 2008

---

Akt Inhibitor Perifosine Enhances
Bortezomib-Induced Cytotoxicity in MM Cells
Bt
Bortezomib
ib
Bortezomib
048h
p-Akt
caspase
Akt
Perifosine
Akt
apoptosis anti-apoptosis
8h
24h
CP
BP+B
120
Perifosine (M)
p-JNK1/2
100
0
5
caspase-8
80
7.5
CF
60
PARP
control
CF
40
%
C: control
20
B: Bortezomib (10 nM)
0
05
7.5
P: Perifosine (5 M)
Bortezomib (nM)
Clinical trial of Bortezomib and Perifosine
ongoing
Hideshima et al. Blood 2006; 107: 4053-52

---

Novel therapy combinations with
bortezomib to treat multiple
myeloma
Drug
Drug class
Results
Author
Abstract
no
Perifosine
Alkyphospholipid plus
56% ORR
Richardson
1170
(KRX-
(KRX 0401)
proteasome inhibtor
inhibtor
31% SD
et al
SD
et .
plus
bortezomib

---

Blockade of Ubiquinated Protein Catabolism
Protein
Ub
Ub
protein aggregates
(toxic)
Ub
Ub
Ub
Ub
26S proteasome
HDAC6
Trial of LBH alone
Bortezomib Ti l
f LBH
Ub
Ub
and with Bortezomib
Tubacin
LBH
HDAC6
LBH
dynein
Ub
Ub
Lysosome
y
Aggresome
HDAC6
Ub Ub
dynein
Ub Ub
Ub
Ub
Microtubule
At
Aut
h
op agy
Hideshima et al, Clin Cancer Res;2005; 11: 8530
Catley et al, Blood 2006; 108: 3441-9.

---

Trials of LBH589 in MM
· Phase II, single agent study currently
accruing
­ At least 2 prior regimens
­ Response rate endpoint
endpoint
­ Patients will receive oral LBH589 on Days 1,
3, 5 each week
· 2 Combination phase IB studies to start in
2007
­ LBH589 + bortezomib
­ LBH589 + lenalidomide + dexamethasone

---

Novel therapy combinations with
bortezomib to treat multiple myeloma
Drug
Drug class
Results
Author
Abstract
no
Suberoylanilide
Histone deacetylase
n=17
Weber et
1172
hydroxamic acid
(HDAC) inhibitor plus
plus
4P
4 R
PR, 2
al
2
.
(SAHA) plus
proteasome inhibitor
MR, 11SD
bortezomib
n=16
n16
Badros et
1168
1
1nCR, 7PR, al.
6SD
Romidepsin plus
HDAC inhibitor
inhibitor plus
plus
n=7
n7
Prince et al. 1176
1
bortezomib
proteasome inhibitor
1 CR, 3 PR,
1 MR

---

Apoptotic Signaling of NPI-0052 vis-à-vis
Bortezomib
Bortezomib
NPI-0052
Bax/Bak-/-
Caspase-8, and -3
Mitochondria
Smac
Cyto-c
Caspase -9, and -3
Caspase-9, and -3
Apoptosis

---

Combination of Bortezomib and NPI-0052 Inhibits
Human Plasmacytoma Growth in
Immune-Deficient BNX Mice
Control
Treated
Chauhan, Blood 2007

---

Lenalidomide Induces Increased anti
anti--
CD40 induced
iinduced ADCC Against
Autologous MM Cells
Clinical Trial in MM in 2007
Patient 1
Patient 2
Patient 3
60
**
50
**
25
** **
50
40
**
20
lysis
40
15
fic
30
f
30
*
*
10
20
20
*
5
Speci
10
*
*
10
con
%
0
0
0
on
gG
40
de
+L
med
gG
40
de
+L
on
gG
SGN-40
alidomide
g
+L
c
I
S+
I
S+
c
I
len
S
med
con
SGN-
con
SGN-
med
con
lenalidomi
lenalidomi
Tai et al. Cancer Res 2005, 65: 7896-7901.

---

Conclusions and Future Directions
1. A new
new treatment paradigm targeting
targeting both the
the
tumor cell and its microenvironment has
already markedly
yy improved OR, CR, EFS and
OS.
2. Oi
Ongoing
i
oncogenom c
d
an
t
pro eomic studi
dies
are informing clinical protocol design and
identifying novel therapeutic targets
targets.
3. Future moleculary based rationally
yy designed
g
combination therapies (ie immunomodulatory
drug, proteasome inhibitor, hsp 90 inhibitor,
HDAC inhibitor, and MoAb) will achieve durable
CR in the majority of patients.

---

United Nations Against Myeloma
Kenneth Anderson
Iris Breikeutz
Pl Ri h d
Ruben Carrasco
Paul Richardson
Carrasco
Robert Schlossman
Dharminder Chauhan
QuickTimeý Dz
QuickTimeTM and a
GIF êLí£ÉvÉçÉOÉâÉÄ
TIFF (Uncompressed) decompressor
ÇTMDZÇÃÉsÉNÉ`ÉÉǾå©ÇÈÇ...ÇÕïKóvÇ-ÇÅB
Steven Treon
are needed to see this picture.
Paola Neri
QuickTimeý Dz
GIF êLí£ÉvÉçÉOÉâÉÄ
ÇTMDZÇÃÉsÉNÉ`ÉÉǾå©ÇÈÇ...ÇÕïKóvÇ-ÇÅB
Nikhil Munshi
Giovanni Tonon
China
Irene Ghobrial
Marc Raab
Canada
Greece
Noopur Raje
Teru Hideshima
QuickTimeý Dz
Deborah Doss
Simona Blotta
GIF êLí£ÉvÉçÉOÉâÉÄ
ÇTMDZÇÃÉsÉNÉ`ÉÉǾå©ÇÈÇ...ÇÕïKóvÇ-ÇÅB
Kathleen Colson
QuickTimeý Dz
QuickTimeý Dz
GIF êLí£ÉvÉçÉOÉâÉÄ
GIF êLí£ÉvÉçÉOÉâÉÄ
ÇTMDZÇÃÉsÉNÉ`ÉÉǾå©ÇÈÇ...ÇÕïKóvÇ-ÇÅB
James Bradner
ÇTMDZÇÃÉsÉNÉ`ÉÉǾå©ÇÈÇ...ÇÕïKóvÇ-ÇÅ
Mary McKenney
Ruben Carrasco
Austria
Kim Noonan
Patrick Hayden
Noonan
J
Hayden
Japan
Ti
Taiwan
Marybeth Nelson
Hiroshi Ikeda
QuickTimeý Dz
Kathy McCormick
Steffen Klippel
GIF êLí£ÉvÉçÉOÉâÉÄ
QuickTimeTM and a
ÇTMDZÇÃÉsÉNÉ`ÉÉǾå©ÇÈÇ...ÇÕïKóvÇ-ÇÅB
Muriel Gannon
QuickTimeý Dz
TIFF (Uncompressed) decompressor
GIF êLí£ÉvÉçÉOÉâÉÄ
ÇTMDZÇÃÉsÉNÉ`ÉÉǾå©ÇÈÇ...ÇÕïKóvÇ-ÇÅB
Merav Leiba
are needed to see this picture.
Diane Warren
Joseph Negri
Doug McMilli
UK
Andrea Freeman
an
Germany
Turkey
Leslie Lai
Constantine Mitsiades
QuickTimeý Dz
Laura Lunde
Nicholas Mitsiades
GIF êLí£ÉvÉçÉOÉâÉÄ
QuickTimeý Dz
ÇTMDZÇÃÉsÉNÉ`ÉÉǾå©ÇÈÇ...ÇÕïKóvÇ-ÇÅB
Edie Weller
GIF êLí£ÉvÉçÉOÉâÉÄ
ÇTMDZÇÃÉsÉNÉ`ÉÉǾå©ÇÈÇ...ÇÕïKóvÇ-ÇÅB
Yutaka Okawa
QuickTimeý Dz
GIF êLí£ÉvÉçÉOÉâÉÄ
ÇTMDZÇÃÉsÉNÉ`ÉÉǾå©ÇÈÇ...ÇÕïKóvÇ-ÇÅB
Melissa Farrell
Klaus Podar
Farrell
Italy
Steven Hayes
Samantha Pozzi
India
Australia
Brendan Connel
Masood Shammas
QuickTimeTM and a
TIFF (Uncompressed) decompressor
Katie Loftus
Tanyel Kiziltepe
QuickTimeý Dz
QuickTimeý Dz
are needed to see this picture.
Amy Potenza
GIF êLí£ÉvÉçÉOÉâÉÄ
GIF êLí£ÉvÉçÉOÉâÉÄ
ÇTMDZÇÃÉsÉNÉ`ÉÉǾå©ÇÈÇ...ÇÕïKóvÇ-ÇÅB
Yu-Tzu Tai
ÇTMDZÇÃÉsÉNÉ`ÉÉǾå©ÇÈÇ...ÇÕïKóv Ç-ÇÅB
Sonia Vallet
Shannon Viera
Vallet
Israel
Christine Rubio
USA
Ajita Singh
Ireland
Lisa Popitz
Mohan Brahmandan
Jeffrey Sorrell
Weihua Song
Mariateresa Fulcinitti

---

Improvement in EFS in childhood
ALL as a model for MM
N.B. Not due to new drugs but to new combinations
1980s
1970s
1960s
1950s
Pui, NEJM 1995; 332: 1618

---

"Cure is growing old and dying from something else"

---