Efficacy and side-effect profile of long-term bisphosphonate therapy in patients (pts) with multiple myeloma (MM): MRC myeloma IX study results.

Abstract

8015 Background: Bisphosphonates (BPs) are recommended in pts with osteolytic lesions from MM. However, data on the long-term efficacy and safety of BPs beyond 2 y is somewhat limited. The MRC Myeloma IX study has already revealed significant overall survival (OS) and progression-free survival (PFS) benefits for zoledronic acid (ZOL) over clodronate (CLO) in MM pts (N = 1960) initiating chemotherapy (Morgan GJ, et al. Lancet. 2010). We now report the efficacy and safety of BP therapy with long-term follow-up. Methods: Newly diagnosed MM pts were randomized to ZOL (4 mg IV q 21-28 days) or CLO (1600 mg/day PO) plus antimyeloma therapy. BPs continued at least until disease progression. PFS and OS were estimated using Kaplan-Meier methodology. Hazard ratios (HRs) were calculated using stratified Cox models. Adverse events (AEs) were monitored continuously and analyzed using cumulative incidence functions. Results: At a median follow-up of 5.8 y in 1960 evaluable pts, ZOL improved PFS (HR = 0.88; P = .01) and OS (HR = 0.88; P = .03) vs CLO. Both BPs were generally well tolerated, and acute renal failure events were similar between groups (ZOL 5.2% vs CLO 5.8% at 2 y, with incidence plateaued thereafter). Overall incidence of confirmed osteonecrosis of the jaw (ONJ) has remained low (ZOL 3.7% vs CLO 0.5%; P < .0001). ONJ incidence was lower among pts receiving thalidomide-containing regimens (1.4%) vs no thalidomide (2.76%; P = .041). Events were generally low-grade, most occurred between 8 and 30 mo (median time to ONJ = 23.7 mo), and cumulative incidence plateaued at ~36 mo. Ten pts had data on ONJ recovery: complete recovery in 4 pts, improvement in 2 pts, no change in 3 pts in the ZOL group; and no change in 1 CLO pt. Dental surgery or trauma preceded ONJ in 6 ZOL pts. Conclusions: ZOL provided sustained PFS and OS improvements vs CLO during long-term therapy in the MRC Myeloma IX study. Overall incidence of AEs was similar between groups, with no notable changes during long-term therapy. ONJ incidence remained low during long-term (> 2.5 y) therapy and was reduced in pts receiving thalidomide (possibly because of anticytokine effects of this agent).