International staging system and metaphase cytogenetic abnormalities in the era of gene expression profiling data in multiple myeloma treated with total therapy 2 and 3 protocols.

Background: Myeloma survival varies markedly with International Staging System classification, presence of cytogenetic abnormalities, and, especially, gene expression profiling-based risk and delTP53 status, whose collective impact has not been examined in the context of specific therapies.

Methods: The authors examined overall survival (OS), event-free survival (EFS), and complete response duration (CRD) in Total Therapy 2 with randomization to a control or thalidomide arm and in Total Therapy 3 with added bortezomib. Among 612 patients with complete data sets, multivariate analyses were used to investigate the relative contributions to OS, EFS, and CRD of International Staging System stage, cytogenetic abnormalities, and gene expression profiling-derived risk and delTP53 status, in the context of the 3 Total Therapy regimens.

Results: Whereas gene expression profiling risk segregated outcomes within all 3 International Staging System stages, International Staging System 3 conferred inferior prognosis only in low-risk myeloma, whereas the grave prognosis of high-risk disease was International Staging System-independent. After adjusting for gene expression profiling-defined high risk and delTP53 in multivariate analysis, International Staging System 3 and cytogenetic abnormalities both retained independent adverse implications for OS, EFS, and CRD. Among the 86% with low-risk disease, cytogenetic abnormalities and delTP53 both affected all 3 endpoints negatively, whereas the International Staging System 3 effect was limited to OS. Total Therapy 3 improved survival outcomes beyond results obtained with Total Therapy 2.

Conclusions: In the genomic era, standard laboratory variables, such as International Staging System stage and presence of cytogenetic abnormalities, continue to impact survival after adjusting for gene expression profiling risk and delTP53 status, providing a basis for stratification in our current practice of gene expression profiling risk-based treatment assignment.