Total Therapy 3 (TT3) for Multiple Myeloma (MM): Contributions to Survival Outcomes of Dosing of
Maintenance Components Dexamethasone (D), Thalidomide (T) and Bortezomib (V)
Frits van Rhee1
Rhee , Bart Barlogie1
Barlogie , Jackie Szymonifka2
Szymonifka , Elias Anaissie1
Anaissie , Bijay Nair1
Nair , Sara Wa
W heed1
heed , Ya
Y zan Alsayed1
Alsayed , Nathan
Petty1, John D Shaughnessy Jr1, Antje Hoering2 and John Crowley2
1 Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences, Little Rock, AR;
2Cancer Research and Biostatistics, Seattle WA
Abstract
Results
The impact of cumulative dosing and premature drug
discontinuation (PMDD) of bortezomib (V),
Upper Tertile Glucocorticoid Receptor NR3C1
OS: Lower Tertile NR3C1 expression benefits from
Gene Expression improves OS and EFS
Dexamethasone and Thalidomide, but not Bortezomib
EFS: Lower Tertile NR3C1 expression benefits from
thalidomide (T) and dexamethasone (D) on overall
To
Total
tal Therapy
Therapy 3
Dexamethasone and Thalidomide, but not Bortezomib
thalidomide (T) and dexamethasone (D) on overall
3
Overall Survival
Lowest NR3C1
Middle NR3C1
Upper NR3C1
survival (OS), event-free survival (EFS), time to next
Univariate Analysis
Overall Survival
EventFree Survival
tertile (N=91)
tertile (N=92)
tertile (N=91)
Variable
n/N (%)
HR (95% Cl)
Pvalue
HR (95% Cl)
Pvalue
Variable
HR (95% Cl)
Pvalue
HR (95% Cl)
Pvalue
HR (95% Cl)
Pvalue
Eventfree Survival
Lowest NR3C1 tertile
Middle NR3C1 tertile
Upper NR3C1 tertile
therapy (TNT) and post-relapse survival (PRS) in Total
INDUCTION
VTDPACE x 2
(N=91)
(N=92)
(N=91)
B2M > 5.5 mg/L
65/303 (21%)
3.67 (2.33, 5.78)
<.001
3.45 (2.26, 5.26)
<.001
Dexamethasone during
0.57 (0.40, 0.79)
<.001
0.71 (0.48, 1.04)
0.081
1.38 (0.73, 2.60)
NS
induction (all stages of
Variable
HR (95% Cl)
Pvalue
HR (95% Cl)
Pvalue
HR (95% Cl)
Pvalue
Therapy 3 were examined, employing time-dependent
LDH 190 U/L
81/303 (27%)
3.12 (1.98, 4.89)
<.001
3.25 (2.14, 4.93)
<.001
induction combined, dg)
Dexamethasone during
0.85 (0.72, 1.02)
0.082
0.79 (0.67, 0.92)
0.002
0.91 (0.75, 1.11)
NS
Cytogenetic abnormalities
100/302 (33%)
2.80 (1.78, 4.41)
<.001
2.32 (1.53, 3.53)
<.001
Dexamethasone during
0.62 (0.46, 0.85)
0.003
0.72 (0.50, 1.05)
0.088
1.38 (0.75, 2.53)
0.302
methodology, relevant to induction, consolidation and
TANDEM
MEL200 x 2
consolidation (dg)
induction (all stages of
TRANSPLANT
Dexamethasone during
0.92 (0.85, 1.00)
0.045
0.94 (0.89, 1.00)
0.057
0.94 (0.87, 1.02)
NS
induction combined, dg)
GEP highrisk
40/275 (15%)
4.66 (2.83, 7.66)
<.001
4.50 (2.83, 7.16)
<.001
maintenance (dg)
maintenance phases. Univariately, OS and EFS were
Dexamethasone during
0.95 (0.82, 1.09)
NS
0.83 (0.72, 0.96)
0.012
0.87 (0.71, 1.06)
NS
GEP NR3C1 Lower tertile
91/274 (33%)
1.57 (0.97, 2.54)
0.068
1.83 (1.18, 2.83)
0.007
Bortezomib during
0.95 (0.83, 1.10)
NS
0.78 (0.69, 0.88)
<.001
0.92 (0.73, 1.15)
NS
consolidation (dg)
induction (mg)
longer in case higher
higher doses
doses wer
we e
r used
used of
of all
all agents
CONSOLIDATION
VTDPACE x 2
Bortezomib during
0.96 (0.85, 1.09)
NS
0.80 (0.71, 0.90)
<.001
0.92 (0.74, 1.14)
NS
agents
GEP NR3C1 uppe
up
r te
t rtile
91/274
91/
(33%
(
)
05
0. 6
56 (0 3
. 2
32, 0 99)
.
0 046
.
05
0. 2
52 (0 3
. 1
31, 0 88)
.
00
0. 15
Bort
Bor e
t z
e om
z
i
om b
i during
0.99
0.9 (0.
0 97, 1.01)
1
NS
1.00 (0.99, 1.01)
NS
0.98 (0.
0 96, 1.01)
NS
015
inducti
t o
i n (mg
(m )
g
maintenance (mg)
during induction, consolidation (except T) and
Thalidomide during
0.51 (0.32, 0.80)
0.004
0.83 (0.46, 1.50)
NS
1.46 (0.65, 3.26)
NS
Completed transplant 20.37 (0.21, 0.62)
<.001
0.35 (0.21, 0.59)
<.001
Thalidomide during
0.49 (0.29, 0.83)
0.008
0.83 (0.44, 1.57)
NS
1.01 (0.42, 2.40)
NS
induction (all stages on
induction (all stages on
induction combined, dg)
maintenance (except V and T). The favorable OS and
MAINTENANCE
VRD
induction combined, dg)
Completed consolidation 10.38 (0.22, 0.67)
<.001
0.49 (0.29, 0.83)
0.008
Thalidomide during
0.85 (0.74, 0.98)
0.022
0.95 (0.85, 1.07)
NS
0.90 (0.76, 1.05)
NS
3YRS
Thalidomide during
0.86 (0.75, 0.98)
0.029
0.93 (0.85, 1.02)
NS
0.97 (0.86, 1.10)
NS
transplant (g)
consolidation (g)
EFS impact of D induction dosing provided the
Completed consolidation 20.45 (0.26, 0.78)
0.005
0.57 (0.34, 0.98)
0.043
Thalidomide during
0.97 (0.94, 1.01)
NS
1.00 (0.97, 1.02)
NS
0.98 (0.94, 1.02)
NS
maintenance (g)
rationale for examining the expression of glucocorticoid
receptor NR3C1, top-tertile levels of which significantly
prolonged
prolonged OS
OS and
and EFS and
and rendered outcom
outc
es
Total Therapy 3 Event-Free Surviva
omes
Total Therapy 3 OS
Overall Surviva
100%
independent of D and T dosing, while T and D but not
100%
Impact of VTD dosing during different treatment phases
V dosing were critical to outcome improvement in the
Variables Linked to Time to Next Treatment
Univariate Analysis
Overall Survival
EventFree Survival
80%
80%
low-tertile NR3C1 setting. PMDD of V was an
Variable
HR (95% Cl)
Pvalue
HR (95% Cl)
Pvalue
Multivariate Analysis
Time to Next Treatment
Bortezomib during induction
0.94 (0.90, 0.99)
0.008
0.96 (0.92, 1.00)
0.039
from Enrollment
60%
independent highly adverse feature for OS (hazard
60%
Variable
n/N (%)
HR (95% Cl)
Pvalue
Dexamethasone during induction (dg)
0.71 (0.56, 0.89)
0.004
0.75 (0.60, 0.94)
0.011
ratio, 6.44; p<0.001), while PMDD of both T and D
LDH 190 U/L
74/275 (27%)
1.62 (1.05, 2.49)
0.028
Dexamethasone during consolidation (dg)
0.85 (0.77, 0.93)
<.001
0.89 (0.81, 0.97)
0.007
40%
Cytogenetic abnormalities
95/275 (35%)
2.16 (1.42, 3.29)
<.001
40%
independently impa
im
rted
parted shorter
shorter TNT.
TNT. Absence
Absence of
of
Dex
De a
x meth
t aso
as ne
n mainte
n nance (dg
(d )
09
0. 3
93 (0 8
. 9
89, 0 97)
.
< 001
.
09
0. 7
97 (0 9
. 3
93, 1 00)
.
0 047
.
GEP highrisk
40/275
1.74 (1.07, 2.85)
0.027
20%
adverse effects on PRS of dosing of any VTD
Premature dexamethasone discontinuation
2.47 (1.02, 5.98)
0.046
20%
5-Year
Thalidomide during induction (g)
0.63 (0.44, 0.90)
0.011
0.68 (0.50, 0.95)
0.021
5-Year
Events / N
Estimate
Deaths / N
Estimate
components and indeed a benefit from V supports the
Premature thalidomide discontinuation
4.04 (1.66, 9.81)
0.002
TT3 Event-Free Survival
89 / 303
69% (63,74)
Thalidomide during consolidation(g)
0.94 (0.89, 1.00)
0.0048
NS
NS
TT3 Overall Survival
76 / 303
72% (67,78)
0%
Achieved complete response
0.45 (0.29, 0.68)
<.001
0%
0
2
4
6
use up-front of all agents in a dose-dense and dose-
0
2
4
6
Years from Enrollment
Years from Enrollment
· Higher doses of V, T and D during induction improved OS and EFS
intense fashion, as practiced in TT3, toward
· Higher doses of T and D during consolidation improved OS (D and T) and EFS (D only)
maximizing myeloma survival.
· Higher doses of D during maintenance improved OS and EFS
Background & Methods
Conclusions
Acknowledgements
The impact of cumulative dosing and premature drug discontinuation (PMDD) of V,
T and dexamethasone D on overall survival (OS), event-free survival (EFS), time to
Total Therapy 3 Time to Next Treatment
Premature discontinuation of bortezomib adversely
next therapy (TNT) and post-relapse survival (PRS) in Total Therapy 3 were
·
Higher dosing of VTD during induction, consolidation (except T) and
100%
5-Year
examined, employing time-dependent methodology, relevant to induction,
affected both OS and EFS survival
maintenance (except V and T) impacted favorably on OS and EFS
Events / N Estimate
consolidation and maintenance phases.
TT3 Patients
116 / 303
41%
Multivariate Analysis
Overall Survival
EventFree Survival
80%
·
Top Terti
T
le ge
gene
ne exp
ex r
p ession
ression level
leve s
l of
of the
the gluc
glu ocorticoid
ocortico
recep
r
t
ecep or
o NR3C1
Mlti
i t Al i
Oll Si l
Et F
Si l
80%
The impact of cumulative dosing of VTD components on OS, EFS, TNT and PRS was
significantly prolonged OS and EFS and rendered these independent of
Variable
n/N (%)
HR (95% Cl)
Pvalue
HR (95% Cl)
Pvalue
addressed in relationship to the individual drugs in mg-per-protocol step or month of
D and T dosing
Creatinine 2 mg/dL
21/275 (8%)
2.09 (1.13, 3.87)
0.019
2.48 (1.42, 4.34)
0.001
60%
maintenance of V, T and D as continuous variables, applying actual doses taken
LDH 190 U/L
74/275 (27%)
1.98 (1.20, 3.26)
0.007
2.40 (1.52, 3.79)
<.001
·
Conversely, T and D were critical to OS and EFS improvement in the
through the end of induction and consolidation therapy and then serially by the end of
Cytogenetic abnormalities
95/275 (35%)
2.28 (1.37, 3.79)
0.001
1.85 (1.16, 2.95)
0.010
low Tertile NR3C1 setting
each month of maintenance.
40%
GEP Highrisk
40/275 (15%)
2.85 (1.69, 4.79)
<.001
3.01 (1.84, 4.94)
<.001
· This work was supported by NIH PO1 grant #CA558919
·
Premature discontinuation of V was an independent adverse feature
We also investigated the clinical consequences of PMDD of VTD components prior to
Premature bortezomib
6.44
<.001
1.59
0.087
discontinuation
(3.30, 12.57)
(0.93, 2.72)
20%
for OS (hazard ratio, 6.44; p<0.001)
the protocol-prescribed time lines.
· We acknowledge the Myeloma Institute Clinical and
Achieved complete response
0.41 (0.23, 0.72)
0.002
0.35 (0.21, 0.59)
<.001
Research staff for their hard work
·
Prematu
Pr
r
ematu e
r dis
di co
c n
o ti
tinu
n ati
at on
io of
of T and
an D conf
con erred
err
shor
sho ter Ti
Time to
- -Next
Nex
Kaplan-Meier statistical methods were used for OS and EFS, and the log-rank test
0%
Treatment
was used for comparisons. The impact of cumulative dosing of V, T and D on TNT
0
2
4
6
Years from Enrollment
and PRS was also examined. Multivariate modeling was used to determine which
·
There was no adverse effect of dosing on post relapse survival
baseline parameters and time-dependent drug dosages significantly affected the
supporting the use of all active agents up-front as applied in TT3
endpoints. Treating the drug dosages as continuous, time-dependent variables allowed
us to analyze the impact of the doses on outcomes for the entire population, unlike in
land-marking methodology in which only a population subset surviving the landmark
can be considered.

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