Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under lendex: A longitudinal analysis

Abstract

There is significant interest in immunotherapy for the treatment of high-risk smoldering multiplemyeloma (SMM), butnoavailabledataontheimmunestatusof this particular disease stage. Such information is important to understand the interplay between immunosurveillance and disease transformation, but also to define whether patients with high-risk SMM might benefit from immunotherapy. Here, we have characterized T lymphocytes (including CD4, CD8, T-cell receptor gd, and regulatory T cells), natural killer (NK) cells, and dendritic cells from 31 high-risk SMM patients included in the treatment arm of the QUIREDEX trial, and with longitudinal peripheral bloodsamples atbaselineandafter 3 and 9 cycles of lenalidomide plus low-dose dexamethasone (LenDex). High-risk SMM patients showed at baseline decreased expression of activation-(CD25/CD28/CD54), type 1 T helper-(CD195/interferon-g/tumor necrosis factor-a/interleukin-2), and proliferation-related markers (CD119/CD120b) as compared with age-matched healthy individuals. However, LenDex was able to restore the normal expression levels for thosemarkers and induced amarked shift in T-lymphocyte and NK-cell phenotype. Accordingly, high-risk SMM patients treated with LenDex showed higher numbers of functionally active T lymphocytes. Together, our results indicate that high-risk SMM patients have an impaired immune system that could be reactivated by the immunomodulatory effects of lenalidomide, even when combined with low-dose dexamethasone, and support the value of therapeutic immunomodulation to delay the progression to multiple myeloma. The QUIREDEX trial was registered to www.clinicaltrials.gov as #NCT00480363.