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Published OnlineFirst June 23, 2014; DOI: 10.1158/1078-0432.CCR-14-0434
Clinical
Cancer
Research
Personalized Medicine and Imaging
Biomarkers of Bone Remodeling in Multiple Myeloma
Patients to Tailor Bisphosphonate Therapy
Chirayu G. Patel1, Andrew J. Yee1,3, Tyler A. Scullen1, Neeharika Nemani1,3, Loredana Santo1,3,
Paul G. Richardson2,3, Jacob P. Laubach2,3, Irene M. Ghobrial2,3, Robert L. Schlossman2,3, Nikhil C. Munshi2,3,
Kenneth C. Anderson2,3, and Noopur S. Raje1,3
Abstract
Background: Patients with multiple myeloma may be susceptible to osteonecrosis of the jaw (ONJ) and
stress fractures due to long-term aminobisphosphonate (aBP) therapy. However, it is unknown whether
urinary N-telopeptide (NTX) or other bone biomarkers are predictive of skeletal-related events (SRE) or the
impact of cessation of aBP therapy on bone remodeling.
Methods: We studied markers of bone turnover over a 6-month period after a single dose of zoledronic
acid in 29 patients with multiple myeloma in remission who previously received 8 to 12 doses of
pamidronate or zoledronate (NCT00577642). Our primary objective was to determine the duration
of time urinary NTX levels remain suppressed after a single dose of zoledronate. A secondary objective
was to identify and correlate other markers of bone remodeling with NTX changes. Thirty cytokines, based
on their possible role in bone remodeling, were tested using cytokine arrays. Candidates were confirmed by
ELISA.
Results: All patients had continued suppression of NTX levels, except 1 patient who had an increase in
NTX levels associated with an SRE. GDF-15 and decorin were found to decrease, whereas bone-specific
alkaline phosphatase (BSALP) increased. Although not significant in aggregate, osteopontin and osteoprotegerin levels increased in at least half of the patients.
Conclusion: Our data show that NTX levels continue to be suppressed after aBP therapy, and suggest that
suppressed NTX levels may be predictive of freedom from SRE in this patient population. Furthermore,
osteoblast suppression by aBP may be reversible in myeloma. These data provide the basis for less frequent
dosing of aBPs. Clin Cancer Res; 20(15); 3955–61. 2014 AACR.
Introduction
Aminobisphosphonates (aBP) such as zoledronate and
pamidronate are a mainstay of the treatment of multiple
myeloma and metastatic solid tumors to prevent bonerelated morbidity and mortality (1, 2). For multiple myeloma, most recent consensus guidelines recommend
monthly aBP treatment for a period of 2 years (3, 4).
However, it is unknown whether monthly dosing of aBPs
is optimal, as there are consequences of long-term aBP
therapy, such as osteonecrosis of the jaw (ONJ) and atypical
stress fractures (3–9). Bisphosphonate-related ONJ is char-
Authors' Affiliations: 1Massachusetts General Hospital Cancer Center;
2
LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for
Multiple Myeloma Research, Dana-Farber Cancer Institute; and 3Harvard
Medical School, Boston, Massachusetts
C.G. Patel and A.J. Yee contributed equally to this article.
Corresponding Author: Noopur S. Raje, Massachusetts General Hospital
Cancer Center, 55 Fruit Street, Boston, MA 02114. Phone: 617-726-0711;
Fax: 617-724-6801; E-mail: [email protected]
doi: 10.1158/1078-0432.CCR-14-0434
2014 American Association for Cancer Research.
acterized by bone that is necrotic and exposed, located in the
maxillofacial area, and present for at least 8 weeks in a
patient with history of bisphosphonate treatment, but no
history of prior radiation to that area (10). Although varying
incidences of ONJ between 0.94% to 18.6% have been
reported, in a longitudinal cohort study, patients with
multiple myeloma were more likely to develop ONJ than
patients with breast or prostate cancer (11). It is thought
that ONJ results from oversuppression of bone remodeling
by aBPs (12). As overall survival of patients with multiple
myeloma has improved, they are exposed to aBPs for longer
periods of time, making the issue of optimal aBP dosing
even more pertinent.
The pharmacodynamic and pharmacokinetic data of
aBPs is limited as these compounds incorporate directly
into the bone matrix, targeting osteoclast farnesyl pyrophosphate synthetase and inhibiting protein prenylation
(13). The half-life of aBPs in bone is long and on the order of
240 days with zoledronate (14). The activity of aBP can be
monitored via surrogates such as urinary N-telopeptide
(NTX). The monthly dosing of aBPs is based on the suppression of NTX for 4 to 8 weeks following a single dose of
aBP (15, 16). In the context of the bone-related sequelae of
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Patel et al.
Translational Relevance
Aminobisphosphonates (aBP), such as zoledronate or
pamidronate, are highly effective in preventing skeletalrelated events in patients with multiple myeloma and
solid tumors with bone metastases. aBPs are dosed
monthly based on the suppression of urinary N-telopeptide (NTX), a marker of bone resorption correlated with
bone-related morbidity and mortality in patients with
cancer. NTX levels are suppressed for 4 to 8 weeks
following a single dose of aBP. However, the long-term
use of aBPs has highlighted osteonecrosis of the jaw and
stress fractures as possible consequences of aBP-related
oversuppression of bone remodeling. Our study found
that NTX levels remained stable in the 6 months following cessation of aBPs in 28 of 29 patients with multiple
myeloma previously treated with aBPs for at least 8 to 12
doses, suggesting that less frequent dosing of aBPs is
feasible.
long-term aBP therapy, we sought to examine bone remodeling after cessation of long-term aBP therapy for a period
of 6 months in patients with multiple myeloma in complete
or partial remission with 8 to 12 prior doses of aBPs. A 6month duration of follow-up was chosen as it is reasonably
greater than the current monthly aBP dosing interval to be
able to document the clinical effects of aBP cessation, yet
short enough to minimize the previously uncertain risk of
aBP cessation to enrolled patients. We also evaluated whether NTX or other potential surrogate markers of aBP activity
are predictive of skeletal-related events (SRE) in these
patients.
Materials and Methods
Patients and study design
Patients were enrolled at Massachusetts General
Hospital and Dana-Farber Cancer Institute after study
approval by the Institutional Review Board and informed
consent. This trial is registered at www.clinicaltrials.gov as
NCT00577642. The inclusion criteria were age at least 18
years, confirmed diagnosis of multiple myeloma by International Myeloma Working Group (IMWG) criteria,
intravenous bisphosphonate therapy with either pamidronate or zoledronate for 8 to 12 months, complete
response or partial response by European Blood and
Marrow Transplantation (EBMT) criteria, and Eastern Cooperative Oncology Group (ECOG) performance status 2.
Patients were excluded if they were on active anti–multiple
myeloma therapy, renal dysfunction with serum creatinine
>2 mg/dL and/or creatinine clearance <30 mL/min; or had
relapsed, refractory, or progressive disease. Maintenance
therapy for multiple myeloma was allowed on study.
At entry into study, patients underwent measurement of
urinary NTX (Quest Diagnostics), banking of serum, bone
marrow aspiration and core biopsy, and skeletal survey.
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Clin Cancer Res; 20(15) August 1, 2014
Patients were then given a single dose of zoledronate 4 mg
or adjusted according to institutional guidelines of creatinine clearance, and then followed over a period of 6
months. No further aBP therapy was allowed during the
study. Each month, urinary NTX was followed and serum
was banked. In our study, if NTX surpassed a threshold of 50
nmol/mmol Cr, or there was disease progression or an SRE,
patients were removed from the study. At the end of the
study, the testing done at entry was repeated.
Assay methods
Antibody-based cytokine arrays were used to evaluate
serum samples as per the manufacturer’s protocol (RayBiotech, Inc.). Thirty cytokines were curated from the
literature as being most relevant to the bone microenvironment for inclusion on the array. For bone biomarkers
not available on the array, ELISA was used: C-terminal
telopeptide of type I collagen (CTX1), amino-terminal
propeptide of type I collagen (P1NP), sclerostin, soluble
receptor activator of NF-kB ligand (sRANKL), and bonespecific alkaline phosphatase (BSALP). ELISAs were
performed according to the manufacturer’s protocols
supplied with the kits: CTX1 and P1NP (TSZ ELISA),
sclerostin (ALPCO), sRANKL (Antigenix America), decorin (RayBiotech, Inc.), BSALP (Quidel), and activin A
and GDF-15 (R&D Systems).
Statistical analysis methods
Paired t tests were used to compare differences of cytokine
levels at study entry versus end-of-study. For antibodybased cytokine array, fluorescence intensities were computed by normalization of fluorescence values using software
from the array manufacturer and then log transformed.
Fluorescence intensities without log transformation are
reported. GDF-15, decorin, and activin A were selected for
validation by ELISA.
Results
Baseline characteristics are shown in Table 1. Twentynine patients were enrolled in the study. Median age at entry
into the study was 60 years (range, 46–85 years). Most
patients had received a combination of drugs including
bortezomib and lenalidomide (14 patients) or bortezomib
in combination with other drugs (10 patients). Five patients
received regimens that did not include bortezomib. Ten of
29 patients in the trial were on maintenance therapy (lenalidomide, 5; thalidomide, 4; bortezomib, 1). The mean time
between diagnosis and enrollment on the trial was 13
months. The majority of patients had more than three lytic
lesions. No patients had appreciable increase in bone
lesions over the course of the study.
The mean urine NTX level was 22.2 nmol/mmol Cr at
baseline (Fig. 1). All patients had an NTX level at baseline
less than 50 nmol/mmol Cr except for 1 patient, whose
baseline was 82 nmol/mmol Cr. A paired t test comparing
NTX levels at earliest and latest available time points in the
study for each patient showed a mean increase of only 1.5
Clinical Cancer Research
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Published OnlineFirst June 23, 2014; DOI: 10.1158/1078-0432.CCR-14-0434
Biomarkers of Bone Remodeling to Tailor Bisphosphonates
Given that NTX levels did not significantly change during
the 6-month duration, we studied cytokine levels at baseline
and end-of-study using ELISA and antibody-based cytokine
arrays. CTX1, P1NP, sclerostin, and sRANKL had no significant differences between baseline and end-of-study when
tested by ELISA. BSALP had a mean increase of 2.26 U/L (P ¼
0.003) from baseline to end of study.
The results of the antibody-based cytokine array are
shown in Table 2. Although osteopontin and osteoprotegerin were not significant in aggregate, at least half of
patients had an increase in these cytokines. On the basis
of the cytokine array results and potential biologic relevance, we selected GDF15, decorin, and activin A for validation by ELISA. Activin A showed no significant difference
(P ¼ 0.980), whereas mean GDF15 level decreased by 231
pg/mL (P ¼ 0.00053) and mean decorin level decreased by
701 pg/mL (P ¼ 0.00025). Waterfall plots for the three
significant cytokines measured by ELISA, GDF15, decorin,
and BSALP, are shown in Fig. 2.
Table 1. Baseline characteristics of enrolled
patients with multiple myeloma
Characteristics
Number
Age, y
65
<65
Gender
Male
Female
ISS stage
I
II
III
Therapy
Bortezomib þ lenalidomide
Bortezomib þ other
Other
Autologous transplant
Yes
No
Bone lesions
>3
3
10
19
16
13
11
9
9
14
10
5
13
16
Discussion
The impact of aBP cessation among patients with multiple myeloma who have achieved a clinical response on
urine NTX, the key marker that was used to originally dose
aBPs, heretofore has not been studied. In a study of more
than 1,800 patients with metastatic cancer treated with
aBPs, patients with urinary NTX greater than 99 nmol/
mmol Cr or 50 to 99 nmol/mmol Cr have 4 to 6 and 2
to 4 times increased risk of SRE, respectively, as compared
with patients with NTX less than 50 nmol/mmol Cr (17).
However, it is unclear what happens to the association
between NTX and SREs with cessation of aBP therapy.
Our study reveals that urine NTX remains suppressed in
patients who had a complete or partial response to multiple
myeloma therapy and who had suppressed NTX at baseline
(<50 nmol/mmol Cr). This observation extends on previous studies showing that patients who respond to antimyeloma therapy have significant reduction in bone resorption
markers (18–20). In a recent study of patients who were
20
9
Abbreviation: ISS, International Staging System.
80
60
40
20
Figure 1. Urine NTX levels by
month. Urine NTX levels were
measured monthly. There was no
significant change in NTX
throughout the study. Gray bars,
mean measurements. One patient
(gray circle) had elevated urine NTX
at baseline and later developed
hypercalcemia, which was
classified as an SRE.
Urine NTX nmol/mmol Cr
nmol/mmol Cr that was not significant (P ¼ 0.38). There
was no difference in change in NTX levels in patients on
maintenance treatment versus patients on observation
alone. The 1 patient with baseline NTX level of 82 nmol/
mmol Cr remained on the study until month 3, as NTX first
decreased to 32 nmol/mmol Cr before climbing to 90
nmol/mmol Cr. This patient developed hypercalcemia,
which was categorized as an SRE. Another patient showed
evidence of disease progression by increasing monoclonal
protein, without elevated NTX level or SRE. This patient was
removed from study at month 5.
0
1
2
3
4
5
6
Month
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Table 2. Cytokine array: change at end-of-study relative to baseline
Cytokine
Activin A
BDNF
BMP7
Decorin
DKK1
GDF15
HGF
ICAM1
IGFI
IGFBP3
IL3
IL1a
IL1b
IL6
IL7
IL8
MCSF
MIP1a
MMP9
Osteopontin
Osteoprotegerin
Procalcitonin
TGFb1
VCAM1
VEGF
VEGFC
VEGFD
Baseline
End-of-study
% Change
96 17
605 88
440 33
4,113 240
451 33
3,928 427
313 132
2,522 1,359
152 10
336 34
435 30
1,049 82
215 15
1,103 85
1,076 77
1,190 235
207 18
175 17
10,346 2,171
1,466 238
142 10
443 45
1,079 67
2,389 189
216 22
352 39
196 11
135 36
684 81
471 24
3,669 239
430 32
3,127 322
304 84
2,224 981
157 7
318 25
478 27
1,038 77
236 16
1,098 83
1,124 71
1,036 70
191 14
188 20
8,644 2,525
1,507 157
157 12
384 35
1,185 83
2,562 179
201 14
302 23
179 12
41.2
13
6.9
10.8
4.7
20.4
3.1
11.8
3.6
5.4
10
1.1
9.6
0.5
4.5
13
8
7.4
16.5
2.8
10.9
13.3
9.8
7.3
7
14.2
8.6
P
0.0384
0.184
0.0791
0.276
0.382
0.00183
0.109
0.074
0.483
0.889
0.136
0.799
0.12
0.862
0.238
0.963
0.547
0.643
0.403
0.267
0.193
0.0254
0.173
0.24
0.742
0.185
0.182
FDR
0.345
0.402
0.402
0.439
0.573
0.0493
0.402
0.402
0.653
0.923
0.402
0.899
0.402
0.923
0.431
0.963
0.703
0.789
0.573
0.439
0.402
0.343
0.402
0.431
0.871
0.402
0.402
NOTE: Values reported are mean relative fluorescence units SE in 21 out of 28 patients.
P values are from paired t tests of log-transformed measurements. BMP4, MIP3a, and SDF1a are not reported; measurements were not
above baseline.
Of note, comparisons of cytokine measurements may not necessarily be directly possible from this platform.
consolidated with bortezomib, thalidomide, and dexamethasone and who did not receive subsequent bisphosphonate therapy, SREs were uncommon (21). In our study,
almost a third of patients in our study were on maintenance
therapy, and this may have played a part in suppression of
NTX. The 1 patient who had elevated NTX at baseline later
went on to have an SRE. Suppressed NTX may, therefore, be
predictive of freedom from SRE in patients who are in
remission, but not necessarily freedom from multiple myeloma disease progression, as 1 patient with suppressed NTX
was removed from the study for disease progression based
on monoclonal protein elevation. Although our findings
are based on a small sample size, they suggest that the effects
of long-term aBP therapy last well beyond 1 month, the
current aBP dosing interval.
Of note, the Z-MARK study in patients with multiple
myeloma previously treated with 1 to 2 years of aBPs found
that changing the dosing interval of zoledronate from 1 to 3
months based on suppressed NTX levels appeared to be safe
for patients, and only 3.3% of patients experienced an SRE,
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Clin Cancer Res; 20(15) August 1, 2014
indicating that SRE risk was not any greater than reported
previously in the literature (22). Patients who remained in
the 3-month interval dosing group throughout the study
were less likely to discontinue aBP treatment and less likely
to experience a serious adverse event.
Given that numerous cytokines have been postulated to
be involved in the bone marrow microenvironment, we
wished to see whether a select number of these changed
from baseline to end-of-study and if any of these may be
suitable surrogates for aBP activity, in addition to urine
NTX. BSALP has been shown to increase in patients treated
with bortezomib-containing regimens (23, 24), although
the effect may be temporary (25). It has been thought that
such rise of BSALP may signal possible osteoblast activity
with concomitant bone healing (25). In this study, 64% of
patients (18 of 28) had an increase in BSALP, indicating that
osteoblast recovery may be possible with cessation of longterm aBP therapy. There is some evidence that there is
increase in osteopontin and osteoprotegerin, which
increased in about half of patients, although the results
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Biomarkers of Bone Remodeling to Tailor Bisphosphonates
Decorin
P = 0.000531
−500
−2,500 −2,000 −1,500 −1,000
pg/mL
−200
−800
−600
−400
pg/mL
0
0
200
500
400
1,000
GDF15
P = 0.000253
4
−2
0
2
U/L
6
8
10
BSALP
P = 0.00304
Figure 2. Change at end-of-study compared with baseline for selected biomarkers. Selected biomarkers were measured by ELISA at baseline and end-ofstudy. Data for GDF15, decorin, and BSALP are shown as waterfall plots. Horizontal line, mean difference from baseline to end-of-study. P values are from
paired t tests.
were not significant. Osteoblasts secrete osteoprotegerin, a
member of the tumor necrosis receptor superfamily, which
acts as a negative regulator of osteoclast differentiation by
serving as a decoy receptor for RANKL (26). On the other
hand, osteopontin, a ligand for endothelial cell aVb3
integrin, is secreted by osteoclasts and may enhance endothelial cell–mediated osteoclastic bone resorption and
angiogenesis (27).
GDF15, a member of the TGFb superfamily, has been
shown to increase during progression of a number of solid
malignancies, but there is also evidence that GDF15 is
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upregulated by a number of tumor-suppressor pathways
(28). In multiple myeloma, GDF15 appears to be secreted
from bone marrow mesenchymal stem cells (29). Patients
with multiple myeloma with higher levels of GDF15 have
worse event-free survival compared with patients with lower
levels of GDF15 (30). The exact physiologic role of GDF15
in myeloma is yet to be defined. The cessation of long-term
aBP therapy led to a decrease in GDF15 in this study,
potentially conferring a better prognosis, but further
research is needed to elucidate the role of GDF15 in this
context.
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Decorin, a small leucine-rich proteoglycan secreted by
mesenchymal stem cells and osteoblasts, seems to inhibit
angiogenesis and osteoclastogenesis (31). Knockdown of
decorin has been shown to increase primary myeloma cell
survival (31). In monoclonal gammopathy of unknown
significance (MGUS) and patients with multiple myeloma,
decorin has been shown to be downregulated as compared
with healthy volunteers (32). Thus, given that decorin
seems to reduce survival of myeloma cells, the decrease in
decorin at the end of the study warrants further study. Our
group is currently investigating the change in decorin
expression with differentiation of osteoblasts and the effect
of recombinant decorin on both osteoblasts and primary
myeloma cells. These data further underscore the continued
use of aBPs, although less frequent dosing is potentially
feasible.
While involving a small number of patients, our study
suggests that suppressed NTX levels may be predictive of
freedom from SRE among patients in response to multiple
myeloma therapy, over a period of 6 months. Furthermore,
osteoblast suppression by aBPs is reversible in myeloma, as
indicated by the significant increase in BSALP. Importantly,
the role of other surrogates such as decorin and GDF15 need
further validation and are the subject of ongoing studies.
Taken together, these findings may provide a rationale for
less frequent aBP dosing in patients with multiple myeloma
with at least a partial response to primary myeloma therapy
to help lower the incidence of long-term toxicities such as
ONJ and stress fractures, by allowing limited recovery of
bone remodeling without adverse effects on multiple myeloma progression.
Disclosure of Potential Conflicts of Interest
P.G. Richardson is a consultant/advisory board member for Celgene,
Millennium Pharmaceuticals, and Johnson & Johnson. R.L. Schlossman is a
consultant/advisory board member for Millennium Pharmaceuticals. No
potential conflicts of interest were disclosed by the other authors.
Authors' Contributions
Conception and design: C.G. Patel, N.C. Munshi, K.C. Anderson, N.S. Raje
Development of methodology: C.G. Patel, I.M. Ghobrial, K.C. Anderson,
N.S. Raje
Acquisition of data (provided animals, acquired and managed patients,
provided facilities, etc.): T.A. Scullen, N. Nemani, L. Santo, R.L. Schlossman, K.C. Anderson, N.S. Raje
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): C.G. Patel, A.J. Yee, T.A. Scullen, P.G.
Richardson, I.M. Ghobrial, N.C. Munshi, K.C. Anderson, N.S. Raje
Writing, review, and/or revision of the manuscript: C.G. Patel, A.J. Yee,
P.G. Richardson, J.P. Laubach, I.M. Ghobrial, R.L. Schlossman, N.C. Munshi,
K.C. Anderson, N.S. Raje
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): C.G. Patel
Study supervision: N.S. Raje
Acknowledgments
The authors thank the patients and their families, the coinvestigators, and
the nursing and research staff involved in the trial.
Grant Support
N.S. Raje was funded by the ASCO Career Development Award. C. G. Patel
was funded by an ASH Research Trainee Award.
The costs of publication of this article were defrayed in part by the payment
of page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received February 20, 2014; revised May 9, 2014; accepted May 23, 2014;
published OnlineFirst June 23, 2014.
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Biomarkers of Bone Remodeling in Multiple Myeloma Patients to
Tailor Bisphosphonate Therapy
Chirayu G. Patel, Andrew J. Yee, Tyler A. Scullen, et al.
Clin Cancer Res 2014;20:3955-3961. Published OnlineFirst June 23, 2014.
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