Consolidation Therapy with Bortezomib, Thalidomide and Dexamethasone (VTD) Regimen After ASCT in Myeloma Patients Who Do Not Receive
Bisphosphonates Reduces Bone Resorption and RANKL/OPG Ratio but Seems to Have No Effect On Bone Formation and Angiogenesis
Evange
gelos
os Terpos1
pos , Dimitri
,t os
os Christou
stoulas1
as , Magda
agdalini Migkou1
ou , Maria Ga
Gavriatopou
atopoulou1
ou , Ath
t anas
asios
os Papat
a
h
pat eodo
eodorou2
ou , Evangelos Eleuth
eut erakis-Papaiakovou1
ou , Efstat
,sta hi
t os
os Manios1
os , Efstat
,sta hi
t os
os
Kastritis1, Christos Papadimitriou1 and Meletios A. Dimopoulos1
1Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece; 2Department of Medical Research, 251 General Air Force Hospital, Athens, Greece
Introduction
Results
· Bortezomib (V) monotherapy is associated with increased osteoblastic activity, reduced
· So far, 32 patients have completed the first block of VTD,
osteoclast function and decreased angiogenesis in relapsed/refractory myeloma (MM).
while 16 patients have completed both VTD blocks.
· The co-administration of zoledronic acid in all reported studies to-date may suggest a
· Just before VTD administration, 10 patients were in CR (4 in
synergistic stimulation on osteoclast/osteoblast interactions by the two agents but has not
sCR), 14invgPRand 8 inPR.
allowe
allow d
e the independent evaluation of V on bone metabolism.
metabolism
· Alth
Al
h
oug
most
f
o these p ti
a
t
en swere r td
ated as
PR
vg
or
· Furthermore, the combination of V with other agents, such as thalidomide (T), melphalan
better, they had increased serum levels of sRANKL (p=0.037),
(M) and dexamethasone (D), although it reduced osteoclast activity, it did not enhance
Dkk-1 (p=0.001), CTX (p=0.002), TRACP-5b (p<0.001), VEGF
osteoblast function.
(p<0.001), bFGF (p<0.001), ANG (p=0.006) and reduced levels
of Angp-1/Angp-2 ratio (p<0.001) compared to 18 healthy
Aim of the Study
controls of similar age and gender, indicating sustained
osteoclast and angiogenic activity despite minimal tumor load.
The aim of this study was to evaluate the effect of VTD consolidation on bone metabolism
· Levels of sRANKL and Dkk-1 positively correlated with
resorption markers (p<0.01).
and angiogenesis in MM patients who underwent high-dose M followed by ASCT.
Materials & Methods
· The first block of VTD resulted in a significant reduction of sRANKL (p=0.001),
Methods
sRANKL/OPG
RANKL/OP
(p=0 005
.
)
005 , CTX (p=0 001
.
)
001 , TRACP
TRAC
5
- b
5
(p=0 032
.
)
032 , bt
but
l
a so
f
o bALP
p=0.005
p=0.001
· In this prospective study, only patients in first remission or with primary refractory disease to
(p=0.022) and OC (p=0.02), while Dkk-1 and the majority of angiogenic cytokines
p=0.001
p=0.01
p=0.027
p=ns
showed no alterations (only Angp-1/Angp-2 ratio had a borderline increase,
p=0.005
one frontline treatment were included.
p=ns
p=0.044).
p=0.001
· Patients did not receive any bisphosphonate during or post-ASCT as well as throughout the
· After the first block of VTD, 39% of patients improved their status of response;
period of VTD consolidation.
however alterations of the studied molecules were irrespective of further response
or not improvement.
· VTD started on day 100 after ASCT:
p=0.012
· Before the administration of the 2nd block of VTD, RANKL, RANKL/OPG and
·V was administered at a dose of 1.0 mg/m2 on days 1,4,8,11
p=ns
p=0.008
p=0.037
p=0.02
p=ns
p=ns
p=0.022
p=ns
CTX were reduced compared to values after the first block of VTD (p=0.01, p=0.027
and p=0.005, respectively). These parameters were further reduced after the
·T was given at a dose of 100 mg/day, po, on days 1-21 and
completion of the study (p<0.05).
·D at a dose of 40 mg/day on days
day 1­
1 4 of a 21-
21 day cycle
cy
.
· On the contrary, Dkk 1
- was
wa increased
a
between
w
the end of the first block of VTD
and the initiation of the 2nd (p=0.008) but was reduced after the 2nd block of VTD
· Patients received 4 cycles of VTD (first block), were followed without treatment for
(p=0.037).
p<0.001
p=ns
p=ns
100 days and then received another 4 cycles of VTD (2nd block).
p=ns
p=ns
p<0.001
p=0.044
· OC had no further alterations, while bALP was increased before the 2nd block of
p=ns
p<0.001
· Patients were assessed for skeletal-related events (SREs) throughout the period of the
VTD (p=0.012) and showed no changes thereafter.
study (12 months).
· VEGF
VE
,
GF ANG,
ANG and Angp-
Angp 1/Angp
1
-
/Angp 2 wer
we e
r
increased during the resting period
· Bone remodeling was studied by the measurement of the following serum indices before
between the two VTD blocks and remained unchanged thereafter.
and after each block of VTD (4 measurements for each patient): i) osteoclast regulators
Conclusion
[sRANKL and osteoprotegerin (OPG)], ii) osteoblast inhibitor dickkopf-1 (Dkk-1), iii) bone
· The results of this ongoing study suggest that VTD consolidation post-ASCT, without the
resorption markers (CTX and TRACP-5b) and iv) bone formation markers [bone-specific
· During the study period, only one patient developed a SRE (i.e. radiation to
presence of bisphosphonates, reduces RANKL and bone resorption and is associated with a
bone).
alkaline phosphatase (bALP) and osteocalcin (OC)].
very low incidence of SREs.
· As of July 2009, 8 of 32 patients have developed progressive disease. The
· However, bortezomib was not able to produce a significant anabolic effect on bones when
· Angiogenic cytokines such as vascular endothelial growth factor (VEGF), angiogenin
median TTP after ASCT was 27 months (CI 95% 16.3-37.6).
combined with TD even in these patients with low myeloma burden, while its effect on
(ANG), angiopoietin (Angp)-1 and -2, and basic fibroblast growth factor (bFGF) were also
angiogenic cytokines was modest.
studied on the same dates.
Printed by
The authors have nothing to disclose for this abstract.

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