Renal safety evaluation of zoledronic acid and thalidomide when used as post-stem cell transplant maintenance therapy in multiple myeloma

Abstract

6655 Background: Anecdotal reports suggest that combination therapy with zoledronic acid (ZA) and thalidomide (T) in multiple myeloma (MM) patients may increase the risk of renal dysfunction compared to ZA alone. As part of a multicentre Phase III trial of post autologous stem cell transplant (ASCT) T maintenance therapy we have compared renal function in MM patients receiving ZA with or without concomitant T. Methods: A multicentre, open label, randomised trial of T 200mg p.o daily for 12 months post-ASCT in patients with non-progressive MM. All patients also received ZA 4mg IV over 15 minutes every 28 days and alternate day prednisolone 50mg. A subset of patients underwent ZA Cmax and AUC (0–48) determinations for the first two ZA doses. Univariate analysis was conducted using student t-tests and chi-square tests for equal proportion. Multivariate analysis was conducted using a repeat measures analysis of variance. Differences in creatinine (Cr) between arms over time were determined by fitting an interaction between dose and arm, with dose and arm treated as linear predictors. Results: To-date 83 patients have commenced maintenance therapy (T=40), received a median of 9 (T) or 8 (no T) ZA doses and 15 patients have completed the PK study (T=8). The arms were well matched for gender, age, pre-ASCT B2microglobulin and baseline Cr. Four patients have had ZA withheld because of a rise in Cr (T = 1, no T=3). No ZA-related serious adverse events have occurred. Multivariate analysis demonstrated that higher Cr levels were associated with male gender and pre-ASCT B2M >4mg/L (both p<0.001). The relationship between Cr and cumulative ZA dose demonstrated no significant difference between the two arms (p =.12, for T vs no T). Peak drug concentrations (Cmax) and overall drug exposure (AUC 0–48) were similar between the two arms, both at day 1 and day 29 (p = ns, student t-test), and there was no suggestion of accumulation or changed PK profile after the second ZA dose. Conclusions: There is no evidence for a PK interaction by T on ZA. ZA was found to be safe in this previously treated MM population irrespective of concomitant T administration. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals; Novartis Pharmaceuticals Australia Pty Ltd. Novartis Pharmaceuticals Novartis Pharmaceuticals Pharmion Pty Ltd. Novartis Pharma; Amgen Australia Pty Ltd.; Pharmion Pty Ltd.