P919: treatment of patients with multiple myeloma with zoledronic acid for four years instead of two years decreases risk of progressive bone disease without increasing risk of osteonecrosis of the jaw.

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Multiple Myeloma (MM) is a B-cell malignancy with proliferation of monoclonal plasma cells in the bone marrow. A common complication to MM is lytic bone destruction. At diagnosis 79% of MM patients have radiological bone disease, and bone pain is present in 58%. The condition is progressive and up to 90% of patients will during their course experience bone complications. Treatment with zoledronic acid (ZOL) inhibits progressive bone disease (PBD) in MM, increase quality of life (QoL), and increase survival, but is also associated to osteonecrosis of the jaw (BON). BON is a debilitating condition where maxillary or mandibular bone necrotize, often combined with infection. The risk of BON increases with potency and length of treatment with bisphosphonates and is often triggered by tooth extraction. Evidence on optimal treatment length with ZOL is limited. The original bisphosphonate studies continued for 21 and 24 months (1,2), respectively, and most guidelines therefore recommend 2 years of treatment, partly to reduce the risk of BON by continuing. The dilemma is whether discontinued treatment increases the risk of PBD. Aims: To investigate whether four years rather than two years treatment with ZOL decreases risk of PBD and whether the occurrence of BON is increased by continued treatment. Methods: 192 patients with newly diagnosed symptomatic MM consented to the study and were randomized after 2 years ZOL treatment to either two additional years of monthly ZOL treatment or observation. Patients were followed with monthly blood samples, bone imaging by low-dose whole body CT every 6 months and quality of life questionnaires (QoL) every 3 months. Moreover, bone imaging was performed when clinically indicated. Criteria for PBD were ≥25% increase in size of existing osteolytic lesions or new osteolytic lesions (both at least 10 mm increase/diameter), fractures, spontaneous fractures or lesions needing irradiation therapy or surgery. Results: Median follow up after randomization was 21.6 months. Progressive bone disease were observed in 26 patients, 8 in ZOL arm and 18 in the observational arm (Figure). Patients randomized to continue zoledronic acid had a significantly lower incidence of PBD (hazard ratio: 0.38; 95%CI (0.17-0.88), p = 0.024. The incidence of BON after randomization was overall low (3.6%) with no difference between the treatment groups. We found no difference between groups in overall survival. Summary/Conclusion: Continued monthly ZOL treatment after 2 years significantly reduce the risk of progressive bone disease. 1)Rosen, L.S., et al., Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer, 2003. 98(8): p. 1735-44. 6. 2)Berenson, J.R., et al., Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol, 1998. 16(2): p. 593-602.Keywords: Osteonecrosis, Zoledronate, Bone disease, Multiple myeloma