Extramedullary disease portends poor prognosis in multiple myeloma and is overrepresented in high risk disease even in era of novel agents.

Abstract

Background. Extramedullary disease is an uncommon manifestation in multiple myeloma and can either accompany newly diagnosed disease or can develop with disease progression or relapse. We evaluated the impact of this disease feature on patient outcome in the context of novel agents. Design and Methods. We analyzed clinical and biological features of extramedullary disease in 936 patients with multiple myeloma enrolled in Total Therapy protocols, 240 patients in non-Total Therapy protocols, and 789 non-protocol patients, all of whom had baseline PET scans to document extramedullary disease at diagnosis and its subsequent development at the time of disease progression or relapse.Results. The most common sites for extramedullary disease at diagnosis were skin and soft tissue whereas liver involvement was the striking feature in extramedullary disease at disease relapse or progression. Regardless of therapy, extramedullary disease was associated with shorter progression-free and overall survival, as well presence of anemia, thrombocytopenia, elevated serum LDH, cytogenetic abnormalities, and high-risk features in 70- and 80-gene risk models in univariate analysis. Multivariate analysis with logistic regression revealed that this disease feature was more prevalent in patients with elevated centrosome index by gene expression profiling, as well as myeloma molecular subtypes that are more prone for relapse. These include MF subtype (also called MAF subtype, associated with over expression of MAF gene seen with chromosome translocation 14;16 or translocation 14;20, respectively) and PR subtype (also called "Proliferation" subtype, associated with overexpression of pro-proliferative genes). Conclusions. These data show that extramedullary disease is more prevalent in genomically defined high risk multiple myeloma and is associated with a shorter progression free survival and overall survival, even in the era of novel agents.All clinical trials included in the analyses were registered with www.clinicaltrials.gov.