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4245 Prospective Observational Study of 110 Multiple Myeloma (MM) Patients On Monthly Versus 3 Monthly Infusion of Zoledronic Acid

Program: Oral and Poster Abstracts
Session: 901. Health Services and Outcomes Research: Poster III
Monday, December 10, 2012, 6:00 PM-8:00 PM
Hall B1-B2, Level 1, Building B (Georgia World Congress Center)

Ashraf Z. Badros, MD1, Sunita Philip2*, Patricia Lesho3*, Dianna Weikel4*, Olga Goloubeva3*, Mariola Sadowska5*, Rena Lapidus, PhD5*, Lisa Hester6*, Todd Milliron7* and Timothy Meiller8*

1M & S Greenebaum Cancer Center, University of Maryland, Baltimore, MD
2M & S Greenebaum Cancer Center, Univeristy of Maryland, Baltimore, MD
3M & S Greenebaum Cancer Center, University of Maryland, Baltimore
4Dental School, University of Maryland, Baltimore
5Translational Core Laboratory, Univeristy of Maryland, Baltimore
6Cytokine Core Laboratory, Univeristy of Maryland, Baltimore
7M & S Greenebaum Cancer Center, Univeristy of Maryland, Baltimore
8Dental School, Univeristy of Maryland, Baltimore

Introduction: Osteonecrosis of the jaw (ONJ) is a recognized risk of bisphosphonate infusion; the incidence, etiology, risk factors and pathophysiology remains largely undefined. In this prospective study we evaluated patients on long-term zoledronic acid infusions; the aims of the study were to provide a comprehensive clinical, oral/dental assessment of patients prospectively and sequentially measure changes in zoledronic acid PKs, cytokines, microbial signatures and bone turnover markers in saliva and serum in correlation with 2 major clinical end points development of ONJ and myeloma relapse. 

Methods and patients: Over 6 months 110 patients were enrolled and followed for 18 months. Patients were on zoledronic acid infusions: monthly (n=75) for patients with significant bone disease (relapsed or newly diagnosed) or every 3 months (n=35) for those in stable remission > 3years. During the study follow up therapy was changed to pamidronate (n=4) due to renal insufficiency or denosumab (n=1). Patients had clinical and oral evaluations and saliva and blood samples collected at baseline and every 3 months up to 18 months; saliva samples were obtained before and after (5 and 15 minutes) zoledronic acid infusions.

Results: Median time from MM diagnosis was 3.7 years (range: 1.5-13) for 100 patients; 10 newly diagnosed patients were enrolled as control with a median of 7 months (range: 1-9). Median age was 60 yrs (range: 32-82); 60 were Caucasians, 49 African American, one Asian; 68 were males. At study entry 79% of the patients were in remission: CR (n=35, 32%) of them 15 were in CR for > 7 years, PR (n=52, 47%) and PD (n=23, 21%). Twenty-four patients were not receiving any MM therapy; most were on maintenance with lenalidomide (n=52) or thalidomide (n=11) and the rest on other regimens (n=23). Fifty patients progressed during the 18 month study period; they continued the study with various salvage therapies that included: bortezomib (n=14), carfilzomib (n=14), lenalidomide (n=6) and clinical trails (n=16). Thirteen patients had died: 9 from complications of relapsed MM and 4 from other causes. Eighteen patients withdrew consent for sample collection and dental evaluations but were followed clinically. Most patients had prior-to-study entry dental procedures (extractions, n=80). The prevalent oral pathology detected on dental evaluations included: gingivitis (n=41), moderate/severe periodontal disease (n=35) and gross dental caries (n=15). During the 18 months of observation; 13 patients developed ONJ. Median time from MM diagnosis to ONJ was 5.7 years (range: 1.9-12 years). Risk factors for ONJ were relapsed disease (n=11), monthly zoledronic acid (n=8), dental extractions (n=8), severe periodontal disease (n=9), older age [median age was 62 yrs] and prior ONJ (n=3). ONJ treatment was conservative with antibiotics and holding BP therapy: 9 patients had complete healing of the site of ONJ and 4 had persistent non-healing ONJ lesions.  Sequential saliva and serum samples were assessed for various cytokines involved in immune/inflammatory process (IL-1β, IL-6, IL-17, TNF-α, IFN-α, TGF-β, MIP-1 α β, MMP-9); bone turnover (Osteopontin, ostiocalcin, RANKL, Osteoprotregerin) and angiogenesis factors (VEGF and EGF) in 42 patients with ONJ (n=13), severe periodontal disease (n=10) and normal control (n=19), the later included 10 patients in remission and 9 with relapsed MM.

In conclusion: In this longitudinal observational study, the ONJ incidence was 11%, 70% eventually healed. Our cytokine analysis suggest that saliva may accurately detect changes reflective of mucosal inflammation as well as bone turnover markers; data correlating these changes with ONJ and MM status will be presented.

Supported by NIH grant DE019509-01

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH