Author(s): G. Morgan, F. Davies, W. Gregory, S. E. Bell, A. Szubert, N. Navarro Coy, M. Drayson, R. G. Owen, G. H. Jackson, J. A. Child

ABSTRACT:

Background: Bisphosphonates (BPs) are standard of care for reducing the risk of skeletal-related events (SREs) in pts with bone metastases from solid tumours or bone lesions from MM. Several BPs have also demonstrated anticancer activity in preclinical models. With the highest level of activity among approved BPs, ZOL has shown anticancer activity in preclinical and clinical studies in various cancer types, including MM. Of note, in pts with early breast cancer, ZOL improved disease-free survival by 36% (P = 0.01) vs endocrine therapy alone (Gnant, et al. NEJM. 2009). Among other endpoints, the MRC Myeloma IX Study investigated effects of ZOL vs clodronate (CLO) on SREs, progression-free survival (PFS), and OS in MM pts.

Methods: Newly diagnosed MM pts were randomised to ZOL (4 mg q 21-28 days) or CLO (1,600 mg q day) plus antimyeloma therapy. Treatment continued at least until disease progression.

Results: Of 1,970 pts randomised, 1,960 were evaluable, with a median follow-up of 3.7 yrs. To date, approximately 75% of pts have stayed on treatment until disease progression. The median time on treatment for the 25% of discontinued pts was 156 days (CLO) and 270 days (ZOL). ZOL reduced the proportion of pts with an SRE vs CLO (27.0% vs 35.3%, respectively; P = 0.0004). ZOL-treated pts showed 5.5 months' prolonged OS (50 vs 44.5 months, respectively; P= 0.0118) and 2 months greater PFS (19.5 vs 17.5 months, respectively; P= 0.0179) versus CLO. Of note, the OS benefit with ZOL was maintained after adjustment for potential effects of SREs on survival. After time to first SRE was included as a time-dependent covariate in a Cox model, ZOL maintained OS benefits (P= 0.0178). Both BPs were generally well-tolerated, and deterioration in renal function was similar between treatment groups. The incidence of confirmed osteonecrosis of the jaw was also low (ZOL, 3.5%; CLO, 0.3%).

Conclusions: The results demonstrate a beneficial effect of ZOL on survival, in addition to superior SRE prevention versus CLO, in pts with MM. Moreover, survival benefits associated with ZOL seem to be independent of SRE prevention, suggesting that ZOL may improve survival through anticancer activity.