S1604 EFFECTIVENESS OF DENOSUMAB COMPARED TO ZOLEDRONIC ACID IN BONE DISEASE TREATMENT OF MULTIPLE MYELOMA (MM): A META‐ANALYSIS
Authors: J.A. Malala, G.W. Ng, L. Osias, C. Rosales
Journal: HemaSphere (2019)

Background: About 80% of multiple myeloma patients at diagnosis presents myeloma bone disease (MBD) leading to bone pain and pathological fractures, significantly affecting patients’ quality of life. Bisphosphonates are the treatment of choice for myeloma bone disease. Several studies clarified the mechanisms involved in MM‐induced osteoclast formation and activation, leading to the identification of new possible targets and the development of better bone‐directed therapies. Aims: The aim of this study was to meta‐analyze currently available data comparing zoledronic acid to denosumab for the prevention of skeletal‐related events in patients diagnosed with multiple myeloma. Also, to assess the survival benefit and gauge which is more prone to most common and dreaded adverse events. Methods: A literature search until April 2018 for randomized, controlled trials comparing zoledronic acid to denosumab among patients diagnosed with multiple myeloma revealed two published studies. Statistical analysis was performed using fixed effects model meta‐analysis. This review was registered with PROSPERO (CRD42018095190) Available from: http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018095190 Results: Time to first SRE favors the denosumab group with statistically significant effect size compared to zoledronic acid (MD −1.22; 95% CI −1.93, −0.55; z = 3.36, p = 0.0008). Overall survival at 24 months was not statistically different between patients receiving denosumab and zoledronic acid (RR 0.99; 95% CI 0.87, 1.13; z = 3.36; p = 0.87). For adverse events, hypocalcemia was lower in patients treated with zoledronic acid (RR 1.35; 95% CI 1.08, 1.69). Jaw osteonecrosis was noted to lean more into the denosumab arm (RR 1.51; 95% CI 0.93, 2.46). Summary/Conclusion: Our analysis supports the use of zoledronic acid as the mainstay first line treatment of MBD with statistically significant longer time to first SRE. However, while patients on zoledronic acid do experience longer time to first SRE as compared to denosumab which may make their life more comfortable, less incidence of pain and pathologic fractures, these agents clearly have no survival benefit. image One of the strengths of our meta‐analysis is the high rate of agreement between studies for the adverse events. This is a factor many hematologists take into account when recommending bone‐targeted agent – the potential for adverse events such as the most common hypocalcemia and the dreaded complication of jaw osteonecrosis. Our study has limitations, including key differences in the two studies. We believe that the paucity of information addressing the relative risks &amp; benefits of these two drugs and the difference in conclusions drawn from the results of each study makes this pooled analysis worthwhile. In conclusion, our analysis still supports the use of zoledronic acid as a first line bone‐targeted agent for MBD based on longer time to first SRE &amp; lesser rates of the most common &amp; dreaded complications such as hypocalcemia and jaw osteonecrosis, respectively. In addition, since denosumab doesn’t require renal function for use, our findings suggest that denosumab is an effective second‐line agent for patients who has contraindications with zoledronic acid use due to renal dysfunction. Lastly, treatment of myeloma bone disease whichever agent doesn’t change the overall survival of multiple myeloma patients.