Comprehensive Analysis of Serum Cytokines/Chemokines in Myeloma Patients for Pursuing the Abnormality in Microenvironment and Predicting the Prognosis
Authors: Cho Yukiko , Inada Katsushige , Okoshi Yasushi , Hori Mitsuo , Kojima Hiroshi 
Published: October 2019

Bone marrow microenvironment plays a crucial role for the development and progression of multiple myeloma (MM). To gain insights about the abnormality in microenvironment and to predict the prognosis, we comprehensively analyzed cytokines/chemokines in MM patients. Serum concentrations of 49 cytokines/chemokines were measured by using the suspension array system, Bio-Plex (Bio-Rad), and enzyme-linked immunosorbent assay (ELISA) kits. Serum samples were obtained from 35 MM patients including those with active disease (patients with newly diagnosed myeloma or exacerbated myeloma after more than 6 months of therapy-free period, n=26) and those with controlled disease (patients achieving ≥VGPR within 6 months of auto-PBSCT, n=9), 14 MGUS patients, and 32 healthy volunteers. Serum concentrations of 40 out of 49 assayed cytokines/chemokines were significantly increased or decreased in active disease MM patients in comparison with those of controls. As such a skewed cytokine/chemokine profile has never been observed in colorectal cancer (our unpublished data), we consider that this abnormality is a unique feature of MM. To extract cytokines/chemokines related to the disease progression, we compared serum concentrations of cytokines/chemokines between ISS stage I and II-III patients. Among the 40 cytokines/chemokines, 5 were selected as cytokines/chemokines whose concentrations became more deviated from the normal range as the disease progression. Indeed, serum concentrations of b-NGF (p=0.016), IL-2Ra (p=0.009), IL-12 (p40) (p=0.013), MIG (p=0.002), and SCF (p=0.003) increased significantly in stage II-III patients in comparison with stage I patients. Moreover, overall survival of patients with higher concentration of each of these 5 cytokines/chemokines was significantly worse in comparison with those with lower concentration (b-NGF: p=0.009; IL-2Ra: p=0.021; IL-12 (p40): p=0.007; MIG: p=0.006; and SCF: p=0.005). To our interest, concentrations of all of these 5 cytokines/chemokines were in normal range in MGUS patients. We thus consider that these 5 cytokines/chemokines are related to the development and progression of MM. We next analyzed whether such an abnormality in cytokines/chemokines is corrected by the disease control. For this purpose, we compared serum concentrations of cytokines/chemokines between MM patients with active disease and those with controlled disease. Contrary to our expectation, normalization of the serum concentration was observed only in MIG, and other 4 cytokines/chemokines remained in abnormal range even after achieving VGPR. It suggests that systemic changes of cytokine/chemokine profile in MM patients persist long even after an efficient treatment, which possibly contributes to the exacerbation. In summary, our findings suggest that extensive abnormality in internal environment does exist in MM patients and this abnormality is not corrected even after disease control. Future researches are warranted to elucidate the underlying mechanism of the abnormality in cytokines/chemokines in MM patients.

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Disclosures

No relevant conflicts of interest to declare.