Waldenstrom'
Waldenstrom s Award
Thursday, February 26, 2009
Washington, D.C.
Brian G.M. Durie, M.D.
Los Angeles, CA
40 Years
A Timeline of Lessons Learned
Mayo
University
Cedars-Sinai,
Cli i
n c
i
fL
of
o L
d
on on
d
LA
Los
L
A
l
nge es
l
1969
1972
1989
1990
1992
2009
IMWG/Myeloma
University
International
University
Forum
of Arizona
Myeloma
Foundation
University of
Edinburgh,
Scotland
Key Points
Edinburgh- The Home of Anatomy
Mayo- Patient Care is #1
Univ. of Arizona- A Lab of My Own
Univ. of London- Running a Dept.
Los Angeles- "Dedicated to improving
the quality of life of myeloma patients
while working towards
towards prevention and a
cure."
Research Publications- Overview
RED = Will
W be briefly discussed
1975
Myeloma Staging System
1975
LI%: development and
and applications
0's 1976 Adria/BCNU for relapse
1977
Polyamines as disease markers
1978
OAF, cytokines and bone
197 1978 Myelomacolonies
colonies in
in soft
soft agar
agar
1980
Bone scans not useful
1980
Plateau phase defined
1980
Unscheduled DNA synthesis and drug resistance
s 1980 Unscheduled DNA synthesis and drug
s 1981 Cell mass calculated for BJ myeloma
1982
Amyloid production in soft agar
1983
In Vitro drug sensitivity and kinetics
980' 1984M
8
olecu
oular heterog
ogeneity in myeloma
1 1985 Diverse immunophenotypes: CD56/CALLA/Myelo Mono...
1986
Alpha2 interferon and alkylating agents in myeloma
1989
Antibody specificity of monoclonal proteins
1989
T-cell regulation of my
gyeloma growth
1975- My First Paper on Myeloma
Took
T
2 years to develop
First use of multivariate regression analyses in
myeloma. First presented at statistics conference in
France.
Lesson-
Lesson Applying new techniques
ttechniques can lead to
progress.
The Power of Regression
Top Clinical Features and Measured Myeloma Cell Mass...
Regression
P-value
% of total
coefficient x Parameter
multivariate
correlation
coefficient
(R2)
All cases (Total 71)
Myeloma cell
mass
Bone Lesions 1
0.601
(Cells x 1012
10 /m2
/m
+0 283
.
x bone
bone lesions
lesions
<0.01
79%
Light Chains 2
=
+0.031 x urine M-component
<0.01
10%
Hemoglobin
3
-0.058 x hemoglobin
<0.01
6%
Calcium
4
+0.051 x serum calcium
<0.05
3.6%
+0.028 x serum M-component
0.14
0.8%
[Serum Spike 5]
R2 = 0.72
99.4%
Serum creatinine
ccreatinine not correlated with
w
with measured
m
measured cell mass
m
mass.
...All Still Correlated with Survival in 2009
Plasma Cell LI%: 1975
Plasma Cell Labeling
LI% generally
gy low
[H]3
[H] Thymidine
High LI%: poor
prognosis
High grain count:
unscheduled DNA
synthesis: drug
resistance
Plateau: LI% = 0
Science 190:1093-1095, 1975
Lesson- Great test,
test but
New "HSARG" Method
not widely feasible.
Myeloma Clinic 1977*- 1989
Univ of Arizona
Diagnosis: New SWOG criteria
Staging: D/S
D/S staging
Kinetics: LI%; cyto/immunochemistry
Cytogenetics: F l
ull cytogenetics
l
pane
Serial computer monitoring of cell mass
Drug sensitivity testing:
b
Ham urger assay
Correlations in 106 patients
Sensitive/Sensitive
73%
Sensitive/Resistant
27%
Re
R sistant/Sensitive
sistant/Sensitiv
17%
Resistant/Resistant
83%
*Hamburger/Salmon 1977; Durie/Salmon 1983
Understanding Plateau Phase: 1980
Basis for treatment
selection in plateau phase.
Lesson- Myeloma is not
always actively growing.
Serum 2M: 1981-1990
OS
Overall
O
Survival
S
Lesson- Unexpectedly
S2
M reflects myeloma
2M reflects
biology.
biology
S2
M plus Albumin give
2M plus Albumin
excellent classification
(1986).
Osteoclast Activating Factors and Bone Disease:
1981
Lesson- Myeloma derived
factors trigger bone disease.
Greg Mundy went on to
identify several bone
resorptive factors.
Understanding Amyloid: 1982
NEJM 307:1689-1692, 1982
Lesson-
Lesson
Amyloid
synthesis
requires
myeloma cells
l
p us
macrophages.
Soft Agar Colony Growth and Disease Status: 1983
LI%
Lesson- LI%
reflects colony
growth and stem
cell renewal
Myeloma Heterogeneity: 1984
Morphology
Serial Genetics
Lesson-
Lesson Myeloma is
is
polyclonal manifesting
seq
se uential
q
clonal
evolution.
CD56 Positivity: A Novel Myeloma Phenotype
1985-1990
Collaboration with
Benjamin Van Camp
jp
Idea of CD56 positivity
initially rejected:
conside e
r d
ed "not
"not
possible"
Further data supplied
pp
Manuscripts accepted
Photograph from
Blood 76: 377-382, 1990.
rejected manuscript
used for cover photo.
Lesson- If you're right, you're right.
P-Glycoprotein MDR: 1988
·Development
·
of drug
resistant cell lines
·Start
·
of MDR trials
(Verapamil,
(V
Quinine, ...)
·Cyclosporine
·
was
w
was next
Research Publications- cont.
1999
SV40 molecular sequences in myeloma
2000
Efficacy of low dose thalidomide
2000
ALU RNA
RNA in myeloma plasma
plasma
2002
FDG-PET in myeloma
2002
Management guidelines for myeloma (IMWG)
2003
Classification for MGUS/myeloma
MGUS/myeloma (
... IMWG)
(IMWG)
2004
Time to progression key predictor
2005
ONJ and bisphosphonates
2005
Bortezomib for frontline therapy
2006
International uniform response criteria (IMWG)
2006
Role of anatomic/functional staging
2006
Frontline lenalidomide/dexamethasone:
thrombotitic complilicatitions
2008
Impact of age
2008
Frontline Bortezomib/Cytoxan/Dex
2009
Fully sequenced serum
serum DNA
SV40: 1999
22q 11.2 hot spot
for retro integration
ALU retro elements
include SV40
SV40
sequences
SV40 promoter
active even when
methylated
SV40 ALU RNA
circulates in plasma
microvesicles
Circulating RNA in Microvesicles in
Myeloma: 2000
EM
of microvesicle
·Acta Oncologica 39:789-796, 2000
·I
· n
In 70 patients the amount
amount and type
type of
of
Sample source: Dr. Brian Durie
plasma RNA Linked to active myeloma.
EM: Prof. Luc Montagnier
(Unpublished)
·RNA
·
fully
ful y sequenced from
from 4 separate
separate
patients. (GenBank# AF018254)
"Voyager RNA"
713 Nucleotide Plasma RNA Sequence: 2000
ALU
99% homology with ALU Sc (GenBank #U14571)
Role of FDG PET
Id
I entifies
d
active
activ myeloma
myeloma (vs
(vs. MGUS)
Best Nuclear
Extramedullary disease reflects poor
Medicine Paper
prognosis
pg
of 2002
Post-therapy residual disease indicates
poor prognosis
(1st
(1 Prize Aw
A ard)
w
Renewed uptake identifies relapse and
secondary cancer
The Start of IMWG Series 2003
C
R
Lesson-
A
CRAB
B
criteria key.
key
Lead Author: Dr.
Dr Kyle
Response, Relapse, and Outcome: 2004
Lesson-
Progression Free
Survival is key.
key
Listening to Patients: 2005
NEJM 353(1): July
July 7,
7, 2005
Standardizing Response Criteria: 2006
· Clarified/improved response assessment
· Added VGPR
V
VGPR
· Included Freelite®
Freelite
Sequential IMWG Publications:
2003-2
003 009
2008 Serum Free Light Chain (SFLC) Guidelines
Lead Author: Angela Dispenzieri (Mayo)
Sequential Treatment Trials
1976
BCNU/Adriamycin (Univ of Az)
1977
Cycle-specific plateau treatment (Univ of Az)
1983
VMCP-VBAP ± levamisole (SWOG)
1985
Tamoxifen (Univ of Az)
1985
Interferon (Univ of Az), Poly (IC)-LC (Univ of Az)
1988
Verapamil/VAD (Univ
(Univ of Az)
1990
Prednisone maintenance (Univ of Az)
1991 Bisantrene (SWOG)
1996
Auto/Allo transplant (IBMTR)
1998
Low dose thalid
id
om e (C d
e
)
ars
2005
Frontline Velcade® (Aptium)
2006
Frontline chemo vs. transplant (SWOG)
2006
Frontline Revlimid®/Dex (SWOG
/(
)
2008
Frontline Thalidomide/Dex (SWOG)
Lesson- Improving
2008
Frontline Velcade®, Cytoxan®,
Dex... (Aptium)
outcomes is not
2009
S0777 RD/VRD
RD/VRD ± ASCT
(SWOG)...ongoing
easy!
What's New...Value of Fully Sequenced Serum DNA
Search Engine Results: "Voya
gy ger DNA" 2008
y = +0.73307
-21.19427xAluSg/x
+351.99346xL1MCc
+39.42443xDNA/MER1_type
+1595 14423
.
x(TT
(T A)
TA)n
-42.81081xAluJo/FRAM
-68.78752x(TG)n
+183 26275xMER44C
.
-
-
-
-
-
-
-
-
-
- 1.79
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
AluSg/x
0.621 0.847 1.169 0.342 0.615 0.326 0.008 1.253 2.023 1.036 0.237 248 1.807 0.710 1.705 1.368 0.539 1.288 2.466 2.162 0.084 1.678 0.194 1.531 1.489 2.245 1.622
- 2.198 2.009 1.548
1752 2847 4503 8363 8543 3176 8099 7780 7504 0036 8571 434 06855 1883 8852 0651 8502 0647 6754 4439 4973 4561 4709 2515 7915 2008 1690 2.298 8331 2254 1710
49
12
34
88
23
48
14
13
7
23
37
2
7
14
35
19
81
52
91
98
89
6
14
86
49
66
15 7873
84
64
19
-
-
-
-
- 1.25
-
-
-
-
-
-
Prognostic
L1MCc
0.778 2.289 0.563 0.626 2.024 2.543 0.194 1.257 0.097 0.611 1.436 813 1.561 0.358 1.205 0.266 0.229 1.436 0.238 1.014 1.436 2.295 3.568 0.968 0.099 0.900 0.958 0.823 0.543 0.740 0.553
2445 6502 1286 0490 8678 8951 2828 3934 3547 2096 4613 065 52760 0387 2203 4181 3683 4613 0788 9003 4613 8615 8311 5756 0118 6346 7883 4862 6962 3674 8597
26
66
06
93
2
66
89
87
66
37
81
1
2
92
21
38
42
81
63
75
81
67
16
29
45
01
86
25
08
46
24
DNA/MER1_typ
-
-
-
-
0.70
-
-
-
-
-
1 755 1 459
.
0 939
.
1 879
.
0 273
.
0 607
.
0 376
.
1 519
.
1 103
.
2 128
.
1 426
.
932 0 504
.
1 176
.
0 169
.
0 056
.
0 749
.
0 134
.
0 213
.
0 679
.
0 323
.
0 221
.
1 931
.
1 576
.
0 544
.
1 491
.
1 359
.
0 758
.
0 856
.
0 246
.
1 753
value of
/_ yp
e
1.755
.
0451 6819 7336 8938 0622 2023 2198 8762 2033 0935 4627 033 41446 8628 0189 8162 5424 3330 8895 2129 3988 9379 1047 8665 3977 3842 2395 7585 9527 7842 5184
of
84
39
76
28
57
76
31
93
11
14
2
8
4
54
38
95
05
52
99
63
89
32
11
29
67
3
15
1
33
88
68
-
-
-
-
-
-
-
-
-
(TTA)n
4.787 0.661 0.278 0.650 0.273 0.661 0.065 0.833 2.099 0.611 0.404 0.31 1.330 0.170 0.833 0.833 1.515 1.512 0.570 0.408 0.833 0.020 0.087 6.953 0.466 0.197
1.782 1.241 1.164 0.447
9147 8830 9746 4861 9076 3318 4398 5573 8572 5446 9237 044 53695 8179 5573 5573 5591 1528 0558 0534 5573 8656 9445 7853 1825 0568 0.199 9486 2470 3432 8588
28
72
74
42
51
27
21
12
16
78
65 477
1
66
12
12
19
6
28
83
12
62
76
41
96
38
711
71
38
4
19
ALU retro
-
-
-
-
-
-
- 1.77
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
AluJo/FRAM
0.083 2.515 0.487 1.085 0.510 0.993
0.186 0.408 0.807 1.212 841 0.705 0.974 1.615 0.679 0.027 0.180 1.242 0.611 1.326 1.112 2.201 0.857 1.501 0.820 1.389 1.719 1.124 1.687 0.463
3416 7605 2490 5503 8968 3658 0.858 4117 3849 4386 4542 559 38634 4938 0529 0606 3348 7147 4648 8093 2647 3300 9547 2352 4795 8013 7898 2262 1878 5382 9452
32
85
46
33
23
48 6734
41
22
32
83
4
4
95
15
08
41
33
97
44
09
98
59
39
13
76
55
87
48
58
1
-
-
-
-
-
-
-
-
0.47
-
-
-
-
-
-
elements
MER44C
0.684 0.684 0.994 0.004 0.254 0.684 0.684 0.002 0.684 0.092 1.216 648 0.814 1.108 0.065 0.275 0.179 0.684 1.201 1.214 0.684 0.210 0.684 0.168 0.938 1.370 1.418 0.507 0.962 3.457 0.684
8088 8088 1621 3097 0009 8088 8088 3296
396 8088 7182 2278 739 09886 9950 4369 6365 5039 8088 0773
03 9263
963 8088 7869 8088 0714 316
361 8179
89 5170
50 2367 2477 9916 8088
MER44C
33
37
14
37
3
3
1
344
17
7
5
77
83
57
38
3
89
43
3
94
337
09
43
04
43
48
44
3
Time
Understanding Voyager RNA and DNA...
DNA
methylation
Hi t
s one
modifications
Micro RNA
RNA
Silencing
...
...can lead to new treatments.
Innovation in Challenging Times
Many new drug targets are available
Investment in research and drug
development is crucial
CONSIDER
COST
COST
BENEFIT
Improved quality of life
Extended survival
Increased productivity
Reduced hospitalization/disabilities
Lesson: Improved outcomes are key.
key
Thank You
Susie, Ben and Imo
...and all my family and friends who have supported me over
the years
Bob Kyle- a colleague and very special friend
dl
...and my many, many co llleagues
d
an friends over 40
40 years
... "MYELOMOLOGISTS"
Many thousands of patients- my inspiration...
especially Michael Katz
Katz