Abstract
Despite improved outcomes in multiple myeloma (MM), a cure remains elusive. However, even before the current therapeutic era, 5% of patients survived >10 years and we propose that immune factors contribute to this longer survival. We identified patients attending our clinic, who had survived >10 years (n=20) and analysed their blood for the presence of T-cell clones, T-regulatory cells (Tregs) and T helper 17 (Th17) cells. These results were compared with MM patients with shorter follow-up and age-matched healthy control donors. The frequency of cytotoxic T-cell clonal expansions in patients with <10 years follow-up (MM patients) was 54% (n=144), whereas it was 100% (n=19/19) in the long-survivors (LTS-MM). T-cell clones from MM patients proliferated poorly in vitro, whereas those from LTS-MM patients proliferated readily (median proliferations 6.1% and 61.5%, respectively (P<0.0001)). In addition, we found significantly higher Th17 cells and lower Tregs in the LTS-MM group when compared with the MM group. These results indicate that long-term survival in MM is associated with a distinct immunological profile, which is consistent with decreased immune suppression.
Highlights
Before the introduction of immunomodulatory agents and proteasome inhibitors, less than 5% of patients with multiple myeloma (MM) survived for longer than 10 years
We hypothesised that patients with myeloma who are long-term survivors (LTS-MM) have greater immunocompetence and that a study of immune biomarkers in these LTS-MM patients might provide a novel approach to understanding the mechanisms of immune dysfunction in MM
The T-regulatory cells (Tregs)/T helper 17 (Th17) ratio may be the best discriminator of immunoregulatory control, as it indicates the balance of suppressive and pro-inflammatory regulatory cells
Summary
Before the introduction of immunomodulatory agents and proteasome inhibitors, less than 5% of patients with multiple myeloma (MM) survived for longer than 10 years. We analysed the number of cytotoxic T-cell clones and their ability to proliferate and secrete cytokines, as well as the balance between suppressive Tregs and pro-inflammatory Th17 cells. These immune biomarkers were determined in LTS-MM patients, MM patients with shorter follow-up and a group of age-matched controls. The frequency of clonal T-cell expansions was compared with patients tested in the context of a clinical trial (n 1⁄4 120), with a similar median age and International Staging System (ISS) risk group at diagnosis,[10,26] and a large local cohort of MM patients as previously published (n 1⁄4 144).[9] As all LTS-MM patients were diagnosed 410 years ago, there is little fluorescence in situ hybridization data available, and treatment was predominantly with multi-agent chemotherapy as novel
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