Comprehensive analysis of serum cytokines in patients with multiple myeloma before and after lenalidomide and dexamethasone

Abstract

Multiple myeloma (MM) is an incurable B-cell malignancy often accompanied by profound immunodeficiency. Lenalidomide (Len) is an immunomodulatory drug that exerts promising therapeutic effects on MM through the immune system. However, predictive markers related to the effects of Len treatment are not fully understood. This study aimed to identify candidate biomarkers for predicting the clinical efficacy of Len and dexamethasone (Ld) therapy through a comprehensive analysis of serum cytokines. The levels of 48 cytokines in the serum of patients with MM just before Ld therapy (n = 77), at the time of best response (n = 56), and at disease progression (n = 49) were measured and evaluated. Patients with high IL-18 and M-CSF levels showed significantly shorter progression-free survival and overall survival (OS). In contrast, patients with high PDGF-BB levels had longer survival. Moreover, low levels of G-CSF, IL-7, IL-8, and SDF-1α were associated with shorter OS after Ld therapy. During Ld therapy, pro-inflammatory cytokines such as IL-2Rα, IL-18, and TNF-α were decreased, while IFN-γ was increased. IL-4 and IL-6 levels increased during disease progression. In conclusion, this study provides a better understanding of the association between cytokines and the efficacy of Ld therapy as well as the unique changes in cytokines related to inflammatory and immune responses during Ld therapy.

Keywords: IL‐18; M‐CSF; PDGF‐BB; lenalidomide; multiple myeloma.

FIGURE 1

Association between pre‐Ld cytokine levels and best response after Ld therapy. Patients were classified as good responders (complete response [CR] + very good partial response [VGPR] + partial response [PR]) or poor responders (minimal response [MR] + stable disease [SD] + progressive disease [PD]). The horizontal red bars represented the median values of the levels of each group. (A, B) The expression levels of IL‐18 and M‐CSF were significantly higher in poor responders to Ld therapy. (C) The concentration of PDGF‐BB was significantly lower in poor responders.

FIGURE 2

Association between pre‐Ld cytokine levels and survival after Ld therapy. (A, B) PFS and OS were significantly shorter in the group with high IL‐18 and M‐CSF levels. (C) No significant differences were observed in PDGF‐BB, but PFS and OS were shorter in the group with low PDGF‐BB levels.

FIGURE 3

Association between pre‐Ld cytokine levels and overall survival after Ld therapy. (A–D) OS was significantly shorter in the group with low G‐CSF, IL‐7, IL‐8, and SDF‐1α levels.

FIGURE 4

Comparison of serum cytokine levels in patients with MM treated with Ld therapy at different disease stages. (A–F) Levels of each cytokine at different disease stages (i.e. pre‐Ld therapy (pre‐Ld), at the best response (BR), and progressive disease (PD)) were shown.