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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 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on August 12, 2017. © 2014 American Association for Cancer Research. 3955 Published OnlineFirst June 23, 2014; DOI: 10.1158/1078-0432.CCR-14-0434 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. 3956 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 Downloaded from clincancerres.aacrjournals.org on August 12, 2017. © 2014 American Association for Cancer Research. 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 www.aacrjournals.org Clin Cancer Res; 20(15) August 1, 2014 Downloaded from clincancerres.aacrjournals.org on August 12, 2017. © 2014 American Association for Cancer Research. 3957 Published OnlineFirst June 23, 2014; DOI: 10.1158/1078-0432.CCR-14-0434 Patel et al. 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, 3958 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 Clinical Cancer Research Downloaded from clincancerres.aacrjournals.org on August 12, 2017. © 2014 American Association for Cancer Research. Published OnlineFirst June 23, 2014; DOI: 10.1158/1078-0432.CCR-14-0434 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 www.aacrjournals.org 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. Clin Cancer Res; 20(15) August 1, 2014 Downloaded from clincancerres.aacrjournals.org on August 12, 2017. © 2014 American Association for Cancer Research. 3959 Published OnlineFirst June 23, 2014; DOI: 10.1158/1078-0432.CCR-14-0434 Patel et al. 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. References 1. 2. 3. 4. 5. 6. 7. 3960 Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. 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Clin Cancer Res; 20(15) August 1, 2014 Downloaded from clincancerres.aacrjournals.org on August 12, 2017. © 2014 American Association for Cancer Research. 3961 Published OnlineFirst June 23, 2014; DOI: 10.1158/1078-0432.CCR-14-0434 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. Updated version Cited articles E-mail alerts Reprints and Subscriptions Permissions Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-14-0434 This article cites 31 articles, 14 of which you can access for free at: http://clincancerres.aacrjournals.org/content/20/15/3955.full#ref-list-1 Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected]. Downloaded from clincancerres.aacrjournals.org on August 12, 2017. © 2014 American Association for Cancer Research.