(PA-162) Cytokine Dysregulation in Multiple Myeloma: A Comprehensive, Comparative Analysis of Blood and Bone Marrow Profiles

In multiple myeloma (MM), the bone marrow (BM) microenvironment fosters immune dysfunction through cytokine-driven signaling that promotes tumor survival and progression. Cytokines have direct effects on both MM cells and immune cells, including those mediating responses to immunotherapy such as NK cells. Previous studies quantifying cytokine levels in MM patients frequently examined small numbers of cytokines; and often examined only blood levels, without direct comparison to BM levels, clouding interpretation. Comparison of cytokine levels between MM and controls generally uses blood samples, as bone marrow from controls is not routinely available. Gaining a more comprehensive understanding of the cytokine milieu in MM will inform the development of novel therapeutic strategies. To address existing knowledge gaps, we quantitated and compared the levels of a panel of cytokines in the blood and BM of MM patients and the blood of control subjects.

Methods:   

We analyzed cytokine expression in 62 blood and 34 BM plasma samples obtained from MM patients at diagnosis or in various phases of follow-up, alongside 15 age-matched control blood samples. Using a Bio-Rad Bio-Plex 200 system, we quantified 23 cytokines. Selection prioritized cytokines implicated in immune surveillance and NK cell function as well as those known to directly impact MM cells. Data analysis involved standard curve calibration, quality control measures, and replicate assessments. Among the samples, 25 pairs of blood and BM specimens were obtained simultaneously from the same patients, allowing for matched analysis.

Results:   

MM patients exhibited significantly (p< 0.05) increased expression of several cytokines in blood compared to controls, notably TGF-β1, IL-8, IL-16, IL-12p70, G-CSF, IL1 β and IFN-γ. IL-18 was higher in controls (p< 0.05). BM samples showed significantly (p< 0.05) higher levels of 15 cytokines compared to blood, including IL-8, IL-10, TNF-a, IL-7, TGF-β isoforms, and RANTES. In paired matched samples, 11 cytokines were significantly elevated in BM, highlighting its role as an immunosuppressive environment. Cytokine levels in MM blood and BM were highly correlated, validating the comparison between MM and control blood samples. There were no significant correlations seen between cytokine profiles and disease or treatment characteristics in this small study.

Conclusions:   

This study is the first to our knowledge to quantify >20 relevant cytokines in both MM blood and BM as well as in control BL. Our analysis characterizes an environment that, based on the known functions of these cytokines, could potentially enable immune evasion and therapy resistance and promote MM cell survival. These results suggest possible new avenues for therapeutic cytokine modulation in MM in conjunction with other immunotherapies and warrant further translational exploration.