OA-10: Four years treatment with Zoledronic Acid is superior to two years in protection against progressive bone disease in Multiple Myeloma

Introduction: Bone destruction is a common complication in multiple myeloma. Radiological bone disease at diagnosis is present in 79% of multiple myeloma (MM) patients and 59% experience bone pain. Even more patients will experience bone complications at some time point in their course of disease.
Progression of bone disease can be inhibited by treating MM patients with Zoledronic acid (ZOL). ZOL has been shown to increase quality of life and overall survival in myeloma patients, however ZOL is also associated to osteonecrosis of the jaw (BON). BON is a debilitating condition where maxillary and/or mandibular bone necrotize, often with infection. The risk of BON increases with potency and length of treatment with bisphosphonates. BON can be triggered by tooth extraction and a number of precautions have been suggested including treating tooth problems before initiating ZOL, to pause ZOL treatment before procedures, and to give prophylactic perioperative antibiotics at procedures.
The optimal length of treatment with ZOL is yet uncertain, as evidence is limited. The original bisphosphonate studies followed myeloma patients for 21 and 24 months, respectively, and considering possible increased risk of BON most guidelines currently recommends two years treatment.
As the average lifetime of myeloma patients increase, the question arises whether longer treatment is better for optimal protection of progressive bone disease, and if this can be achieved without unacceptable high risk of BON.

Methods: Patients with newly diagnosed symptomatic MM were included and randomized after 2 years ZOL treatment to either two additional years of monthly IV ZOL treatment or observation. Patients with progressive bone disease (PBD) just prior to randomization did not proceed to randomization but remained on ZOL treatment. Patients were followed with monthly visits and blood samples. Bone imaging by low-dose whole body CT was performed every 6 months and quality of life questionnaire data were sampled 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), new fractures, or lesions needing irradiation therapy or surgery.

Results: A total of 192 patients with myeloma were randomized, median follow up after randomization was 21.6 months. In total, 8 cases of PBD were found in the ZOL arm and 18 cases were found in the observational arm. Risk of PBD was significantly lower in the ZOL arm (hazard ratio: 0.38, 95% CI (0.17-0.88), p = 0.024). The incidence of BON after 2 years was 3.6% and not different between the two groups. We found no difference in overall survival between the ZOL arm and the observational arm

Conclusions: Four years of monthly zoledronic acid are superior to two years treatment in protection against progressive bone disease in multiple myeloma.