Microsoft PowerPoint - Brown=BartelASCO06012009.ppt

Prognostic Implications of Comprehensive Imaging with PET-CT,
MRI and X-rays, and Their Biological and Molecular Correlates in
Multiple Myeloma (MM) Treated with Total Therapy 3 (TT3)
Bartel TB,1 Brown TLY,1 Haessler J,2 Shaughnessy J,3 Angtuaco E,1 Anaissie F,3 van Rhee F,3 Walker R,4 Crowley J,3 Barlogie B.3
1Department of Radiology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR; 2Cancer Research and Biostatistics, Seattle, WA; 3Myeloma
Institute for Research and Therapy, UAMS, Little Rock, AR; 4Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN
BACKGROUND
METHODS
RESULTS
·
Detection of osteolytic lesions on metastatic bone
Study subjects:
Patient Lab/Molecular Characteristics:
SUV>4.1 in most metabolical y active FL on PET and
survey (MBS) is the historical gold standard for imaging
239 treatment-naïve patients with MM presenting Feb
· LDH > upper limit of normal in 23%
MRI-FL>7 conferred poorer EFS (Fig. 4).
diagnosis in multiple myeloma (MM); though MBS has
2004 July 2006, with Zubrod performance score < 3
· B2M > 3.5mg/L in 45%, > 5.5mg/L in 22%
Figure 4.
limited sensitivity and can not distinguish active from
unless due to MM-related pain (median follow-up 43 m)
EFS by PET-FL max SUV in those with > 0 PET-FL at baseline
EFS by MRI-FL
· Metaphase cytogenetic abnormalities in 34%
100%
100%
inactive lesions
Figure 1.
· GEP-defined "high-risk" disease in 14%
80%
80%
· Magnetic resonance imaging (MRI) detects diffuse and
Imaging protocols:
A
D
60%
60%
Figure 2.
40%
40%
focal bone disease in MM patients prior to development
MBS--digital radiograph:
Significant
30-Month
30-Month
20%
Events / N
Estimate
20%
Events / N
Estimate
GEP proliferation index >= 10
a PET-FL max SUV <= 4.1 at Baseline
11 / 58
84% (75,94)
a MRI FL <= 7 at Baseline
39 / 171
83% (77,89)
of osteolysis detectable on MBS, may differentiate active
axial skeleton, extremities
correlations were
b PET-FL max SUV > 4.1 at Baseline
36 / 96
72% (63,81)
b MRI FL > 7 at Baseline
25 / 68
72% (61,83)
Logrank P-value = .05
Logrank P-value = .03
GEP proliferation subgroup
0%
0%
0
12
24
36
48
60
0
12
24
36
48
60
from inactive disease, and is likely the most sensitive
to include hands and feet
observed between
GEP low bone subgroup
Months from enrollment
Months from enrollment
GEP high-risk
modality for diagnosing small bone lesions
MRI--axial skeleton with
B
E
imaging findings
CRP >= 8mg/L
STIR-wt, spin-echo, gradient
Shorter EFS and OS if PET-FL>3 in those with GEP-
and B2M, LDH, &
LDH >= 190U/L
PET-FL > 3
MRI-FL > 7
B2M > 5.5mg/L
· Positron emission tomography (PET) with F-18 labeled
echo (T2), and gad-enhanced
MBS-OL > 2
defined low risk, while all high-risk faired poorly (Fig. 5).
GEP-derived
FL-SUV > 3.9
B2M >= 3.5mg/L
CT-OL > 50
fluorodeoxyglucose (FDG) has been recently evaluated
spin echo sequences (+/- fat
parameters (Fig. 2).
-4
-3
-2
-1
0
1
2
3
Figure 5.
Log(OR)
in MM, as it may detect transition from active to inactive
suppression)
Log odds ratio (OR) and 95% confidence intervals for lab
EFS by GEP-defined risk and baseline PET-FL
OS by GEP-defined risk and baseline PET-FL
C
F
100%
100%
associations with imaging parameters. MBS-OL= osteolytic
disease earlier than MRI, and whole-body acquisition
FDG PET-CT--Multidetector
lesion on MBS; CT-OL= osteolytic lesion on CT portion of
80%
80%
PET-CT study; MRI-FL= focal lesion on MRI; PET-FL=focal
allows for global bone and soft tissue evaluation; addition
CT (no IV contrast) + PET
Shorter OS and EFS
lesion on PET portion of PET-CT study; FL-SUV = maximum
60%
60%
SUV of most metabolically active focal lesion on PET.
of computed tomography (CT) in hybrid PET-CT systems
(10-15 mCi dose FDG); both
(not shown) when
40%
40%
30-Month
30-Month
Events / N
Estimate
Deaths / N
Estimate
a Low-risk/PET-FL <= 3
19 / 129
91% (85,96)
a Low-risk/PET-FL <= 3
14 / 129
94% (89,98)
may improve detection of lysis above that of MBS
b Low-risk/PET-FL > 3
20 / 55
75% (63,86)
b Low-risk/PET-FL > 3
15 / 55
78% (67,89)
from skull vertex-toes
Figure 1. Positive MRI (B) and PET-CT (C) focal lesion in
MBS-OL>2, PET-FL>3, or (+) extramedullary disease
20%
20%
c High-risk/PET-FL <= 3
5 / 13
62% (35,88)
c High-risk/PET-FL <= 3
5 / 13
69% (42,96)
d High-risk/PET-FL > 3
13 / 19
42% (20,64)
d High-risk/PET-FL > 3
10 / 19
63% (41,85)
the left humerus not visible by MBS (A). Limited field-of-view
and sequences on standard MRI study for MM (D) poorly
(EMD) (Fig. 3); MRI-FL>7 did not significantly affect OS.
P-value: a v c=0.01, b v d=0.01, a v b=0.0006, c v d=0.22
P-value: a v c=0.002,b v d=0.06,a v b=0.003,c v d=0.43
0%
0%
0
12
24
36
48
60
0
12
24
36
48
60
Months from enrollment
Months from enrollment
visualize liver extramedullary disease seen on PET-CT (E).
Subsequent dedicated MRI of the liver (F) visualizes liver
Figure 3.
EMD.
STUDY OBJECTIVE
Lab examinations:
OS by MRI-FL
OS by MBS-OL
M-protein, Ig profile, free light chains, -2-microglobulin
100%
100%
· To determine if baseline findings on MBS, MRI and
(B2M), CRP, albumin, LDH; flow cytometry & cytogenetics
80%
80%
60%
60%
CONCLUSIONS
PET-CT can predict outcomes in patients with untreated
of marrow aspirate and biopsy; gene expression profiling
40%
40%
MM who were subsequently enrolled in the TT3
(GEP) analysis of CD138(+) plasma cells and unseparated
30-Month
30-Month
Deaths / N
Estimate
Deaths / N
Estimate
· Severity of imaging findings on MBS, MRI and PET-
20%
20%
a MRI-FL <= 7 at Baseline
31 / 171
87% (81,92)
a MBS-OL <= 2 at Baseline
26 / 164
89% (84,94)
regimen
marrow biopsy samples from iliac crest or focal lesion
b MRI-FL > 7 at Baseline
19 / 68
79% (70,89)
b MBS-OL > 2 at Baseline
24 / 75
75% (65,84)
Logrank P-value = .10
Logrank P-value = .003
0%
0%
CT inversely correlates with outcome in MM
0
12
24
36
48
60
0
12
24
36
48
60
Months from enrollment
Months from enrollment
OS by PET-FL
OS by presence EMD at baseline
· Even in patients with low-risk disease by GEP, PET-
Total therapy 3 (TT3) = induction (2 cycles VDT-PACE [bortezomib,
Statistical analysis:
100%
100%
80%
80%
FL number can identify a subgroup with inferior
dexamethasone, thalidomide + 4-d cont infusion cis-platin,doxorubicin,
· Kaplan-Meier used to estimate overall survival (OS) and
cyclophosphamide, etoposide] with peripheral blood stem cell collection after
60%
60%
prognosis
1st cycle), tandem transplantation with melphalan 200mg/m2 consolidation with
event-free survival (EFS); group comparisons by log-rank
40%
40%
2 cycles dose-reduced VDT-PACE, & maintenance x 3 yrs with monthly VTD
·
OS and EFS measured from date of registration until
30-Month
30-Month
·
Overall, this data suggests an important role for
for yr 1 and thalidomide + dexamethasone yrs 2 & 3
20%
Deaths / N
Estimate
20%
Deaths / N
Estimate
death from any cause or disease relapse, respectively
a PET-FL <= 3 at Baseline
22 / 157
90% (86,95)
a -EMD at Baseline
43 / 225
87% (82,91)
b PET-FL > 3 at Baseline
28 / 82
73% (64,83)
b +EMD at Baseline
7 / 14
50% (24,76)
Logrank P-value = .0002
Logrank P-value = .002
advanced imaging in patients with MM as complimentary
0%
0%
0
12
24
36
48
60
0
12
24
36
48
60
· Uni- and multivariate analyses using Cox regression
Months from enrollment
Months from enrollment
to lab and clinical evaluations