New Approaches to Myeloma Staging and
Front-Line Treatment Selection
Brian G. M. Durie, MD

HOW PATIENTS PRESENT 2004
BONE ISSUES
30%
ROUTINE PHYSICAL
25%*
ELEVATED urine/serum protein
15%
ANEMIA/FATIGUE
15%
INFECTION
3%
RENAL DYSFUNCTION
2%
MISCELLANEOUS
10%
* IMF: Myeloma Interactive 2004

DIAGNOSTIC WORK UP
Complete blood counts
Chemistry profile
SPEP: IFE/IEP
UPEP on 24 hr urine
Quant. Immunoglobulins * Serum FREELITE
Bone marrow asp/biopsy *
Skeletal survey
Cytogenetics/FISH
* MRI; PET; CT/PET

NEW CLINICAL CRITERIA **
MGUS PC < 10%; SPIKE < 3.0G/DL
Smoldering not MGUS or MM; D/S stage IA
Myeloma (MM*) 1 or more of
Calcium elevation (>10.5 g/dL)
Renal insufficiency (CREAT >2 mg/dL)
Anemia (Hb <10 or 2 g <Normal)
Bone disease (Lytic or Osteopenic)
* MM is same as Durie/Salmon stage IB plus stage II/III A/B
** British J. Haematol. 2003;121:749-757.

STAGING
Anatomic / Functional Staging
Durie & Salmon or variants
· Durie & Salmon Plus Imaging
Prognostic Factor Systems
International Staging System (ISS)
· Serum ß -microglobulin/Serum Albumin
2
New Molecular Approaches
RNA/DNA/Proteomics

STAGING WITH FDG PET
Multiple Myeloma FDG PET:
Severe Diffuse (D) and Focal (F) Disease
FL on PET & MRI:
F
F
D
F
D
D
F
D
D
D
FDG PET scan
MRI STIR
of thoracic spine
weighted of
thoracic spine

MRI-Defined Focal Lesions Affect Outcome
MRI
Overall Survival
Event-Free Survival
100%
100%
80%
80%
60%
60%
40%
40%
4-Year
4-Year
Events / N
Estimate
Events / N
Estimate
20%
0-4 Lesions
32 / 259
68%
20%
0-4 Lesions
49 / 259
68%
5-20 Lesions
25 / 136
54%
5-20 Lesions
39 / 136
54%
P = .0002
21+ Lesions
23 / 65
37%
P = .001
21+ Lesions
21+ / 65
37%
0%
0%
0123
4
5
0
1
2
3
4
5
Y e a r s A f t e r E n r o l l m e n t
Walker et al. ASH 2004. Abstract to be presented.

USES of FDG PET
Identify High Risk Myeloma at Baseline Staging
e.g., EFS 20% @12 months with extramedullary
disease (Durie et al. 2002.)
Identify True Complete Response at Restaging
or persistent disease e.g., median TTP < 9
months with persistent disease
Identify both intra- and extra-medullary at
relapse e.g. extra medullary disease in ~ 30% at
relapse

FDG PET: Severe Focal Disease
Torso
Extremities

PET 3-D IMAGING

ANATOMIC/FUNCTIONAL STAGING
Durie / Salmon "PLUS" System
Integration of Imaging
DURIE/SALMON
PLUS
MRI/PET*
upstage
STAGE
Number of lesions
I B
I
0 - 4
II A or B
II
5- 20
III A or B
III
> 20
*Bauer 2002
B: creatinine >2
Durie
2002
Walker 2003
and / or EMD on PET

ADDED BENEFITS OF PET
Detection of Occult Infection 15% of scans
at Little Rock: ~ 2,000 scans : ~300 infections
(half occult)
e.g., phlebitis, diskitis, lung, periodontal
Second Malignancies ~2-3% of scans
both Cedars-Sinai and Little Rock
e.g., breast, prostate, renal, melanoma,
thyroid, colon, ovarian, lung
Walker et al. ASH 2004. Poster to be presented.

PET vs. MRI for MONITORING
Cumulative Incidence of nCR/CR, PET Normalization, and MRI-CR
12-Month
Events/ N
Estimate
MRI-CR
12 / 59
17%
PET Normalization
30 / 59
54%
nCR / CR
12 / 59
61%
Walker et al. ASH 2004. Oral presentation to be presented.

CONFIRMATION OF REMISSION
Plasmacytomas
Pretreatment
3 months later

Serum Freelite Test
Use as for M-component
For Monitoring in Non-Secretory or
Hypo Secretory Disease
Response >50% Reduction (PR)
Complete Response- Normal direct
measurement and Ratio
Need to correct the numbers if
Creatinine > 2mg/dL

Value of Freelite Kappa/lamda Ratio
Survival time in patients with multiple myeloma who went into
complete remission by immunofixation electrophoresis
25
22
Abnormal kappa/lambda ratio
19
Normal kappa/lambda ratio
P<0.007
16
ts
360 days increased survival
en 13
tiaP 10
7
4
1
0
500
1000
1500
2000
2500
3000
Survival from diagnosis (days)

Prognostic Factors for Staging
International Staging System
M / S. Alb
2
Stage I
Low M < 3.5* plus
2
S. Albumin** > 3.5 G/DL
Stage II
M < 3.5 but low albumin < 3.5 or
2
M : 3.5 < 5.5
2
Stage III
High M > 5.5mg/DL
2
* mg/DL
Based upon 10-15 years follow-up
** Gm/DL

International Staging System
Asia / Europe / North America
Overall Survival by ISS
Asia
100%
Median
Deaths / N in Months
ISS Stage I
131 / 255 58 (47,64)
Asia
80%
ISS Stage II
159 / 240 38 (31,42)
ISS Stage III
181 / 246 24 (19,30)
60%
40%
20%
0%
North
0
24
48
72
96
120
144
168
192
216
Months from initial chemo treatment
Europe
Overall Survival by ISS America
Overall Survival by ISS
North America
Europe
100%
Median
100%
Median
Deaths / N in Months
Deaths / N in Months
ISS Stage I
591 / 747 55 (51,60)
ISS Stage I
539 / 1305 71 (65,75)
80%
ISS Stage II
1012 / 1146 40 (37,42)
ISS Stage III
943 / 1022 26 (24,29)
80%
ISS Stage II
912 / 1771 52 (49,55)
ISS Stage III
894 / 1425 32 (30,36)
60%
60%
40%
40%
20%
20%
0%
0%
0
24
48
72
96
120
144
168
192
216
0
24
48
72
96
120
144
168
192
216
Months from initial chemo treatment
Months from initial chemo treatment

THERAPY DECISIONS
Does the patient need therapy?
Will the patient and the doctor
consider high-dose chemotherapy
and stem cell transplant?

MULTIPLE MYELOMA TREATMENT
Biologic Age
< 70 years
> 70 years
Stem Cell
Melphalan/Prednisone
Transplant*
or combination
Early
Late
* Also single versus tandem

Initial Treatment Strategy
Induction
Consolidation
Maintenance
Induction:
High dose
Prednisone / Dexamethasone
· VAD or VDD
chemotherapy
Thalidomide + Dexamethasone
·Thal + Dex
· MP or MPT

MPT: New Effective Oral Regimen
Response to MPT (n = 42)
SAE were infection (26%) and DVT (19%)
Palumbo et al. ASCO 2004, Abstract 6549.

Front-line Bortezomib
(n=32)
Bortezomib
Bortezomib +/- Dexamethasone
100
88%
90
78%
80
(%)
70
Partial Response
60
Near Complete Response
Rate
50
41%
Complete Response
onse
40
p
30
Res
20
10
0
24
6
Cycle
Jagannath S, Durie BGM, et al. ASH 2004. Oral presentation to be presented.

PAD Regimen
Day
Cycle 1
1
48
11
15
18
21
Bortezomib 1.3 mg/m2
Dexamethasone 40 mg
Adriamycin
Day
Cycles 24
1
48
11
15
18
21
Bortezomib 1.3 mg/m2
Dexamethasone 40 mg
Adriamycin
Induction (4 cycles prior to transplantation)
Bortezomib 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11
Doxorubicin administered by continuous infusion or IV push to cohorts at
escalating dose levels (0, 4.5, 9.0 mg/m2/day) on days 14
Dexamethasone 40 mg p.o
· Cycle 1: days 14, 811, and 1518
· All subsequent cycles: days 14
Cavenagh et al. ASCO 2004. Abstract 6550.

SERUM/URINARY MYELOMA PROTEIN
RESPONSE by PAD CYCLE
120
Isotype
110
IgA
100
IgA
(%)
90
IgG
IgG
80
-LC
Protein
70
-LC
60
Mean ±
50
SEM
Myeloma
in
40
30
Change
20
10
0
Pre-Rx
#1
#2
#3
#4
Treatment Cycle
· M-protein levels decreased by a mean of 70% following cycle 1 of treatment
Cavenagh et al. ASCO 2004. Abstract 6550.

Front-line PAD Current Results
70% response with Cycle 1
Overall >PR rate of 95% after
4 cycles
81% CR, nCR, Very Good PR @
3 months post autotransplant
Cavenagh et al. ASH 2004. Abstract to be presented.

Current Frontline Options
Treatment
N
CR + NCR PR
Standard Dex
98 0
41%
VAd
95 0
41%
DVd
97 3%
40%
Thal + Dex
98 <5%
59%/ 69%
Bortezomib + 24 25%
63%
New
Dex
PAD
18 43%
44%
Cavenagh et al. ASCO 2004. Abstract 6550.

Document Outline