Impact of denosumab (DMB) compared with zoledronic acid (ZA) on renal function in the treatment of myeloma bone disease.

Abstract

8005 Background: Osteolytic bone disease and renal dysfunction are complications of multiple myeloma. ZA, used for the prevention and treatment of bone complications, can be nephrotoxic. DMB inhibits RANKL and thereby osteoclast function, and is not renally cleared. This international, phase III, randomized, double blind study evaluates the efficacy and safety of DMB compared with ZA in newly diagnosed myeloma patients (pts). Methods: Eligible pts were randomized 1:1 to DMB 120mg SC Q4W or ZA 4mg (renally adjusted) IV Q4W along with anti-myeloma therapy. Pts with baseline CrCl<30mL/min were excluded due to ZA dosing restrictions. The primary endpoint was non-inferiority of DMB to ZA with respect to time to first on-study SRE. Overall survival (OS) was a secondary endpoint; progression-free survival (PFS) was an exploratory endpoint. Renal toxicity and safety were assessed. Results: 1718 pts were randomized, 859 to each arm. Baseline renal insufficiency (CrCl ≤ 60mL/min) was reported in 26.7% of pts. DMB was non-inferior to ZA ( P = 0.01) in delaying time to first on-study SRE. Fewer AEs potentially related to renal toxicity were reported with DMB compared to ZA overall (10.0% vs 17.1%, P < 0.001) in those with baseline CrCl > 60mL/min (8.8% vs 14.2%) and particularly in those with baseline CrCl ≤ 60mL/min (12.9% vs 26.4%). 12.5% of pts on DMB experienced an increase in creatinine, compared to 20.8% of those on ZA. Median cumulative exposure (Q1, Q3) to DMB was 15.75 months (8.18, 25.79) compared to 14.78 months (7.46, 24.87) for ZA. PFS yielded a HR (95%CI) of 0.82 (0.68, 0.99); descriptive P = 0.036. OS HR (95%CI) between DMB and ZA was 0.9 ([0.70, 1.16]; P = 0.41), with fewer deaths in DMB (121 [14.1%]) than in ZA (129 [15.0%]). Conclusions: DMB achieved the primary endpoint of non-inferiority to ZA in delaying time to first on study SRE in pts with newly diagnosed MM. Pts on DMB had a significantly lower rate of renal AEs compared to ZA; more importantly this rate was 2-fold lower in pts with renal insufficiency (CrCl≤60mL/min). The bone specific benefits in combination with the renal function results and possible prolongation of PFS with DMB therapy is promising. Clinical trial information: NCT01345019.