Defining the biological subgroup of multiple myeloma patients which benefits maximally from the overall survival (OS) benefit associated with treatment with zoledronic acid (ZOL).

8083 Background: Myeloma IX examined thalidomide-based induction and maintenance in patients (pts) with multiple myeloma (MM) treated in intensive or non-intensive pathways and SRE reduction with bisphosphonates (BPs; IV ZOL vs oral clodronate [CLO]). In 1960 evaluable pts, ZOL improved OS by 5.5 mo (P = .04) and significantly reduced SRE risk vs CLO (Morgan et al. Lancet. 2010). A biologic basis for this benefit has not been reported. Methods: Here we discuss subgroup analyses (demographics and biologic disease characteristics) that can inform our understanding of how ZOL OS benefit is derived. Baseline bone disease (BD+ or BD−) was screened using axial skeletal surveys. FISH analysis of CD138-selected plasma cells was performed using standard methodology on a subset (n = ~1000); gene expression was assessed using the Affymatrix system. Results: In subgroup analyses, ZOL OS benefit vs CLO was not affected by gender, ISS stage, or specific myeloma genotypes. BD rates at presentation varied between genotypes (higher with hyperdiploidy and t[11:14], lower with t[4;14]). Integration of FISH and ISS data to better delineate high- and low-risk myeloma biology was performed, and evaluation of effects on ZOL’s OS benefits is underway. Previously, among BD− pts (~30% of total), ZOL significantly decreased SRE risk (~30%) vs CLO. For the first time, we report that OS was significantly shorter in BD+ (median 45.5 mo, n = 1401) vs BD− pts (median 51.6 mo, n = 540; P =.009). OS benefit with ZOL vs CLO was apparently most profound in BD+ pts, with no significant OS difference between BPs in BD− pts. Differences in gene expression profiles and myeloma-bone interactions in BD+ and BD– pts may explain the varying OS benefit despite similar SRE prevention with ZOL. Conclusions: ZOL OS benefits vs CLO are independent of demographic and baseline disease characteristics evaluated except for BD. ZOL more effectively reduced SREs than CLO in both BD+ and BD− pts, but OS benefits were restricted to BD+ pts. Further investigations of gene expression profiles are ongoing and may provide further insight into differential interactions between these BPs and myeloma in bone marrow.