Current US Experience with
Transplantation and Management of the
Newly Diagnosed Patient
Bart Barlogie, MD, PhD
Outline of Presentation
· Autotransplants as 1° therapy
· Salvage therapies for transplant
failures
Standard & new agents
Further transplants
· Salvage transplants for standard
therapy failures / relapses
Survival after Autotransplants
Single Tx vs SDT
Tandem vs Single Tx
100%
100%
TT2 2 Tx
80%
80%
MRC HDT Arm
S9321 HDT
60%
60%
TT1 2 Tx
S9321 VBMCP
40%
IFM90 HDT
40%
IFM94 2 Tx
Median Months
Median Months
54
43
MRC SDT Arm
20%
49
80
40
60
20%
IFM94 1 Tx
55
NR
55
56
IFM90 SDT
0%
0%
0
24
48
72
96
120
0
24
48
72
96
120
144
168
Months from Enrollment+ 180 Days
Months from Enrollment
Also see:Superiority of double over single autologous... - M Cavo abstract
abstract #536 Monday Dec 6 3:45pm
Single high-dose radiotherapy vs tandem high-dose... - H Einsel
Einsele
e; abstract #537 Monday Dec 6 4:00pm
3
Comparable survival in newly diagnosed myeloma... - J Crowley; abstract #539 Monday Dec 6 4:30pm
ISS Stage Discriminates Prognosis with
Both Standard & High-Dose Therapies
Standard Therapies
Autotransplants
Overall Survival by Treatment
Overall Survival by Treatment
High Dose Therapy Patients
Standard Dose Therapy Patients
100%
100%
Median
Median
Deaths / N
in Months
Deaths / N
in Months
ISS Stage I
201 / 753
111 (90,156)
ISS Stage I
1060 / 1554 55 (51,58)
80%
ISS Stage II
297 / 854
66 (61,73)
80%
ISS Stage II
1786 / 2303 40 (38,41)
ISS Stage III
303 / 625
45 (40,52)
ISS Stage III
1715 / 2068 25 (24,27)
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
Greipp PR, et al.: A new international staging system (ISS) for multiple myeloma (MM) from the International Myeloma Working Group. Blood 102 (11): A-664, 2003
Superior Survival in Untreated Myeloma
Receiving Total Therapy 1 vs Standard SWOG
146 Pairs Matched by B2M, Albumin & Age
Event-Free Survival
Overall Survival
100%
100%
80%
p < 0.0001
80%
p < 0.0001
60%
60%
Total Therapy I
40%
40%
Total Therapy I
20%
20%
SWOG Standard
SWOG Standard
0%
0%
0
5
10
15
0
5
10
15
Years from study registration
Years from study registration
Total Therapy 1 & 2: Schema
Induction
Transplant Consolidation Maintenance
VAD x 3
TT 1
MEL 200
None
Interferon
HD CTX
X 2
EDAP
231 patients accrued
VAD
TT 2
Randomize
DCEP
MEL 200
DPACE
Interferon
+/- THAL
X 2
Still
CAD
Blinded
668 patients accrued
DCEP
TT 2 More Effective & Safer than TT1
Overall Survival
Event-free Survival
100%
100%
80%
80%
TT 2
TT 2
60%
60%
40%
40%
TT 1
Deaths / N
Events / N
144 / 668
208 / 668
20%
20%
122 / 231
176 / 231
p = .06
p <.0001
TT 1
0%
0%
0
2
4
6
0
2
4
6
Years from Enrollment
Years from Enrollment
100%
100%
CR Duration
TTP & TRM
Events / N
80%
80%
144 / 231
TT 2
TT 1 TTP
123 / 668
60%
60%
25 / 231
11 / 668
TT 2 TTP
40%
40%
p <.0001
Events / N
20%
61 / 271
TT 1
20%
TT 1 TRM
61 / 87
p <.0001
p <.0001
0%
0%
0
2
4
6
0
1
2
3
4
5
TT 2 TRM
Years from CR
Years from Enrollment
Presence of CA Defines Malignant MM
Event-free Survival
Survival
Events / N @ 4-Yr
Deaths / N
@ 4-Yr
No CA: TT2 100 / 390
67%
No CA: TT2 60 / 390
79%
No CA: TT1 109/ 148
38%
No CA: TT1 70 / 148
65%
CA: TT2
93 / 197
40%
CA: TT2
72 / 197
50%
CA: TT1
63 / 74
23%
CA: TT1
49 / 74
55%
100%
100%
80%
80%
No CA: TT2
No CA: TT2
60%
60%
No CA: TT1
CA: TT2
40%
40%
CA: TT2
No CA: TT1
CA: TT1
20%
No CA: TT1
No CA: TT2 v TT1 p <.0001
20%
No CA: TT2 v TT1 p = 0.009
CA: TT2 v TT1 p = 0.03
CA: TT1
0%
CA: TT2 v TT1 p = 0.9
0%
0
2
4
6
0
2
4
6
Years from Enrollment
Years from Enrollment
Pre-transplant CA Present in 20%
Imparts Grave Prognosis
in Entire Arkansas Autotransplant Series
100%
N
Median
80%
1469
58 mos
346
16 mos
60%
No CA < 3 mos
from 1st Tx
40%
CA < 3 mos
from 1st Tx
20%
P < .0001
0%
0
2
4
6
8
10
12
14
Survival from 1st Transplant (Years)
Pre-Transplant Characteristics
Related to Length of EFS
100%
80%
60%
Overall Survival
964 / 2098
58 mos
40%
Event-Free Survival
20%
1152 / 2098
30 mos
0% 0
5
10
15
Years from 1st Transplant
PERCENT OF PATIENTS EVENT-FREE FOR:
Factor Prior to
> 10 yr
5 10 yr
< 5 yr
1st Transplant
(n=30)
(n=69)
(n=1083)
p
CA
7%
17%
43%
<0.001
LDH > 190
0%
13%
21%
0.014
IgA Isotype
3%
13%
23%
0.009
Age >60
3%
26%
36%
<0.001
Total Therapy 1
50%
35%
12%
<0.001
TT 2: Suppression of CA & Achieving CR
Pre-transplant Both Improve Survival
Suppression of CA
Induction CR
100%
No CA / CR
100%
No CA Pre-Rx
No CA / No CR
No CA Pre-Tx
80%
80%
CA / CR
60%
60%
CA Pre-Rx
No CA Pre-Tx
No CA Pre-Rx
CA Pre-Tx
CA / No CR
40%
40%
CA Pre-Rx
20%
CA Pre-Tx
20%
p= <.001
p< .0001
0%
0%
0
2
4
6
0
2
4
6
Years from 1st Transplant
Years from First Transplant
TT 2: Molecular CR (CDR3 PCR)
Regardless of Presence of CA
~ 80% with Clinical CR
< 10% with Clinical PR
0
6
12
18
24
30
36
42
Months
PCR negative
PCR positive
0
6
12
18
24
30
36
42
Months
Induction
Tx-1
Tx-2
Consolidation
Maintenance
High frequency of molecular remissions (m-CR) in MM patients ... G Tricot abstract # 933 - Saturday Dec 4 6:00pm
TT2: Survival Can Be Predicted by
Gene Expression Profiling
1.0
0.8
37 Deaths among 316
0.6
Good-Risk Patients
0.4
p < .000001
22 Deaths among 35
0.2
High-Risk Patients
0.0
02
10
0
30
40
50
Months from Start of Total Therapy 2
Elevated expression of CKS1B is highly correlated with short survival in myeloma
J Shaughnessy abstract #77 Sunday Dec 5 5:30pm
Total Therapy 3
Year 1
Year 2
Monthly VDT
0
V-DTPACE
Years 3 - 4
1
V-DTPACE
PBSC
Monthly
2
MEL200 # 1
THAL + DEX
THAL + DEX
3
Stop Treatment
4
THAL + DEX
5
MEL200 # 26
Characteristics (n = 106)
7
THAL + DEX
Median age
61 yr
8
Albumin < 3.5
20%
9
V-DTPACE
10
B2M > 4
40%
THAL + DEX
11
CRP > 4
50%
months
12
V-DTPACE
CA
25%
TT 3: Co-target MM + Microenvironment
GEP
VEL
day
4
3
2
1
0
1
2
VDT-PACE 3
4
56
7
VEL + THAL:
PR
Activates PTEN in MM
Normalizes ME
VEL V+T THAL
DEX
REVMEL
80%
Myeloma ME
Normal ME
60%
VEL + THAL (n=81)
40%
VEL (n=48)
20%
THAL (n=169)
48 hr post-Rx GEP
of purified MM cells
P = .0002
0%
0
2
4
6
8
Pre-Rx +48 hr
Months to PR
V + T combined induce PTEN
Cumulative M-Protein Responses
Total Therapy 3
99% Reduction
100%
25%
100%
TT 3
80%
50%
75%
99%
80%
60%
60%
TT 2
40%
40%
20%
20%
P = .02
0%
0%
0
2
4
6
8
0
3
6
9
12
Months from Start of Therapy
Months from Start of Therapy
TT 1: Salvage Therapy for 95 Relapses
Salvage Regimen
N
Survival
%
HR
p
DEX +/- THAL
13
CA at relapse
40%
3.5
<.0001
Chemotherapy +/- DEX - THAL
51
B2M >4 at relapse
28%
3.0
<.0001
Further transplant
31
R2= 36%
N
Med
100%
40
6.0 yr
45
1.3 yr
80%
10
0.7 yr
60%
No CA / Low B2M
40%
P < .0001
20%
High B2M / CA
High B2M or CA
0%
0
2
4
6
8
10
Survival after Relapse (years)
TT 2: Shorter Survival after
Relapse on THAL Arm
Characteristics of TT 2 Failures
Survival from TT 2 Failure
100%
Similar standard baseline parameters
80%
No THAL
Higher CKS1B with THAL at baseline
60%
n = 67
Higher PC % with THAL at relapse
40%
THAL
20%
p= .0004
n = 47
0% 0
12
24
36
48
60
Months from TT 2 failure
THAL
THAL +
Regimens
N = 67
N = 47
p
THAL + DEX
27%
12%
0.06
Survival after TT 2 Failure
VEL + THAL +/- DEX
24%
24%
NS
MULTIVARIATE
HR
p
DTPACE +/- VEL
15%
33%
0.03
LDH > 190 @ relapse
2.8
.0006
3rd Autotransplant
5%
10%
NS
Months on study
0.9
.01
PR
35%
21%
0.2
THAL arm
4.4
.0002
Improvement
54%
26%
0.009
Post-Transplant Salvage Therapies
THAL
REV
VEL
VEL+THAL
Variable
n=128
n= 62
n=40
n=76
p
LDH > 190 U/L
23%
47%
40%
43%
0.002
> 5 yr prior Rx
24%
47%
50%
36%
0.03
B2M > 4 mg/L
31%
44%
43%
51%
0.04
CA
66%
71%
80%
80%
0.1
Higher PR Rate with VEL+THAL
Survival after Salvage
100%
100%
80%
VEL +
VEL +
80%
VEL
THAL
THAL
60%
60%
n = 76
VEL
40%
REV
40%
n = 51
THAL
VEL
THAL
20%
20%
n = 40
REV
n =128
P < .0001
0%
0%
0
2
4
6
8
0
24
48
72
96
Months to PR
Months of Therapy
VTD + Metronomic ADR (2.5mg/m2 x 14d)
Characteristics (n=20)
M-Protein Responses
0%
LDH > 190
55%
B2M > 4
55%
PRIOR AUTOTRANSPLANT
85%
> 1 prior AutoTx
50%
PRIOR NEW AGENTS
50%
THAL
100%
VEL
95%
VTD
45%
CA
83%
100%
Serum M
Urine M
SF-Lambda SF-Kappa
Bortezomib (VelcadeTM ) + AdriamycinTM + Thalidomide + Dexamethasone (VATD) as an effective eegimen in patients
with multiple myeloma (MM) K Hollmig et al abstract #77 Sunday Dec 5 6:00pm Halls DE
3rd Transplant for Salvage (N = 98)
MULTIVARIATE ANALYSIS: SURVIVAL FROM Tx #3
Variable
%
HR
p
Years 2nd to 3rd Tx
NA
0.8
0.001
Albumin < 3.0 mg/dL
20
2.6
0.0003
B2M > 3.0 mg/L
47
1.8
0.01
SURVIVAL FROM 3RD TRANSPLANT
100%
80%
2nd 3rd Tx
Albumin
Median
> 3 yr
AND
> 3 g/dL
21 mos
60%
< 3 yr
OR
< 3 g/dL
10 mos
40%
< 3 yr
AND
< 3 g/dL
3 mos
20%
p< .0001
0%0
12
24
36
48
60
72
84
96
Months from 3rd Autotransplant
Timing of 3rd Transplants (CA 76%)
Alive
Dead
autotx
mini-allotx
allotx
mini-MUD
MUD
0
12243648
60728496
108
120
132
144
156
1st/2nd tx
Months from 1st Autologous Transplant
Partial Response to Induction Therapy
Irrelevant to Post-Transplant Survival
S9321 Primary Therapy
ARK Salvage Therapy
VBMCP Arm
Transplant Arm
100%
100%
100%
80%
80%
80%
60%
60%
60%
40%
40%
40%
20%
20%
Deaths / N Median
Deaths / N Median
20%
Deaths / N @5 yrs
P = .3
P = 1.0
At Least PR 102 / 184
61 mos
96 / 182 58 mos
P = .5
No Response
54 / 95
38%
No Response 14 / 25
63 mos
11 / 24
NR
At Least PR
32 / 56
39%
0%
0%
0%
0
2
4
6
8
10
0
2
4
6
8
10
0
2
4
6
Months from VBMCP
Years from 1st Transplant
Years from Salvage Transplant
Summary & Conclusions
· Doubling of survival with MEL-based autotransplants
· Marked efficacy of new agents (THAL, VEL) and
combinations (VTD) in end-stage myeloma
· Progress in myeloma therapy linked to skillful
combination of MEL-based autotransplants + new
agents for induction and / or maintenance
· "Malignant Myeloma", best defined by metaphase
cytogenetic abnormalities (superseded by gene
array?), deserves international effort to eliminate major
cause of early disease-related mortality
Document Outline