Effects of Denosumab Therapy on Renal Function in Multiple Myeloma Patients: A Single Center Retrospective Analysis

Background: Bone antiresorptive agents are standard of care for patients with multiple myeloma (MM) to reduce the risk of pathologic fractures, hypercalcemia and to prevent other sequelae of myeloma bone disease. However, chronic kidney disease (CKD) is common in this population, and is a limiting factor in the use of antiresorptive agents such as bisphosphonates. Denosumab is considered a safer option in patients with CKD. Here, we investigated denosumab efficacy and effects on renal function and bone-mineral metabolism in MM patients ineligible for bisphosphates and/or with pre-existing renal disease. Methods:We performed a single center, retrospective review of adults with MM who received denosumab at our institution from January 1, 2016 to January 1, 2023. Cockroft-Gault creatinine clearance (CrCl), albumin-adjusted serum calcium level (sCa), and serum alkaline phosphatase (sAP) were measured before the first administration of denosumab and after treatment. Incidence of hypocalcemia, fractures, or osteonecrosis of the jaw (ONJ) at any point during denosumab treatment was recorded. Changes in renal function were correlated with baseline CrCl prior to starting denosumab and with relapsed myeloma. Statistical significance was obtained by paired t-test and Chi-square test. Results: Data for 97 patients were collected. Median age was 67 years (range 42-96); 47% were men. Twenty-six were newly diagnosed and on first-line MM therapy, 21 patients were on salvage therapy, and 50 had stable disease, most of whom were on maintenance therapy. Sixty-two patients had received prior bisphosphonates (zoledronic acid). Baseline CrCl before starting denosumab was ≥ 60 ml/min in 51 patients, ≥ 30-60 ml/min in 27 patients, and < 30 ml/min in 19 patients including 9 on hemodialysis. Patients received denosumab at a dose of 120 mg monthly (n = 63), every 3 months (n=14), every 6 months (n = 3), and the remainder received treatment less frequently. There was a significant decrease in CrCl after denosumab treatment (5.59 ml/min; p = 0.0086), especially in patients with baseline CrCl ≥ 30 ml/min (7.56 ml/min; p = 0.0028) and in patients receiving denosumab monthly (4.79 ml/min; p = 0.036). When stratified by progression status, MM with stable disease had a mean decrease in CrCl of 9.15 ml/min (p = 0.0002), whereas those with relapsed MM did not have a statistically significant change (1.95 ml/min; p = 0.76). Overall, 53% of the patients experienced hypocalcemia, correlating with decreased CrCl (χ2 = 13.58, p = 0.019) and most frequently in patients on hemodialysis (89%). No statistically significant associations were seen with hypocalcemia and denosumab dosing frequency (χ2 = 2.96, p = 0.23). There was no significant change in sAP level with denosumab (mean = 3.72 IU/L, p = 0.62). Four patients developed ONJ, of which 3 patients had prior treatment with zoledronic acid. Fifteen patients had skeletal-related events: atypical femoral fractures (n = 3); compression fractures (n = 7), and traumatic fractures (n = 5) Conclusions: Our findings suggest that denosumab is safe in regard to renal function for MM patients with severe CKD (baseline CrCl < 30 ml/min). Hypocalcemia is a concern, especially for those with severe CKD or on hemodialysis, and needs careful monitoring and replacement therapy. Lower pretreatment sCa level was a reason to hold therapy so the impact of denosumab is not clear. The cause of decline in CrCl seen in patient with CrCl ≥ 30 ml/min is unclear, and of uncertain clinical consequences. Further prospective studies with larger cohorts and longer follow up are needed to confirm the safety of denosumab and possibly explore lower dosing and infrequent schedule in MM patients with various degrees of renal insufficiency to better define treatment guidelines.