Biomarkers of Bone Remodeling in Multiple Myeloma Patients to Tailor Bisphosphonate Therapy

Abstract 3965 Background: Aminobisphosphonates (aBP) are standard of care for myeloma-related bone disease and are recommended every 3–4 weeks. Multiple myeloma patients may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures secondary to altered bone remodeling due to long-term aBP therapy. Monthly dosing of aBP is based on early studies that documented the suppression of N-telopeptide (NTX), a marker of bone resorption, for 4–8 weeks following a single dose of aBP. However, it is unclear whether NTX or other bone biomarkers are predictive of skeletal related events (SRE) or what the impact of cessation of aBP therapy has on bone remodeling. Methods: We studied markers of bone turnover after a single dose of zoledronic acid in myeloma patients in remission (NCT00577642). All patients had received 8–12 doses of aBP (pamidronate/zoledronic acid) prior to study inclusion. Patients were not receiving active anti-myeloma therapy besides maintenance therapy. Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronic acid on study. A secondary objective was the identification and correlation of other markers of bone remodeling with NTX changes. High throughput cytokine arrays of validated and potential surrogate markers of bone remodeling were performed. Bone marrow biopsies at start and end of protocol during which time aBPs were not administered were performed. Patients were removed from study if NTX crossed a threshold value (50 nMol), based on correlation of NTX levels with bone-related morbidity and mortality. Results: Twenty-nine patients were enrolled in a 6-month period. Cytokine array data is available in 28 patients. All patients had suppressed NTX levels, except one patient who had an increase in NTX levels associated with a SRE and disease progression. To identify other surrogate as yet unexplored cytokines that may serve as better markers in addition to NTX to monitor aBP activity, thirty cytokines were curated from the literature based on their possible role in bone remodeling and tested using custom designed cytokine arrays. Positive hits were confirmed by ELISA. GDF-15, which correlates with poor prognosis in myeloma and is thought to be produced by bone marrow mesenchymal stem cells, decreased in 24 of 28 patients (two-sided paired T test, p Conclusion: Our data suggest that suppressed NTX levels are predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP is reversible in myeloma. Importantly, the role of other surrogates such as decorin and GDF-15 need further validation and are the subject of ongoing studies. Taken together, this evidence may provide rationale for less frequent aBP dosing in multiple myeloma patients 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. Disclosures: Richardson: Novartis: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Millennium: Membership on an entity9s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity9s Board of Directors or advisory committees. Ghobrial: Bristol Myers Squibb: Advisory Board, Advisory Board Other; Millennium: Advisory Board, Advisory Board Other; Onyx: Advisory Board, Advisory Board Other; Novartis: Advisory Board Other. Schlossman: Celgene: Membership on an entity9s Board of Directors or advisory committees. Anderson: Onyx: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Millennium: Membership on an entity9s Board of Directors or advisory committees. Raje: Onyx: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding.