Inflammatory fingerprints reveal how multiple myeloma turns aggressive

Multiple myeloma has long been described as a disease of rogue plasma cells, but a growing body of evidence points to an equally important accomplice: chronic inflammation. In a new study published in GeroScience, researchers at the University of Pécs in Hungary have mapped, in unusual detail, how the circulating cytokine network and a protective neuropeptide called PACAP-38 change across the course of the disease, and how those shifts track with the most feared form of the illness, extramedullary disease. Their findings suggest that a simple blood test measuring inflammatory signals could one day help clinicians identify patients whose myeloma is quietly turning aggressive, long before conventional staging systems sound the alarm.

Multiple myeloma remains incurable, accounting for roughly 1.8 percent of all cancers and between 10 and 18 percent of hematological malignancies. The disease begins as a clonal expansion of plasma cells tucked into specialized niches of the bone marrow, evolving slowly through precursor states such as monoclonal gammopathy of undetermined significance and smoldering myeloma. In some patients, however, malignant plasma cells eventually break their dependence on the marrow and disseminate to soft tissues and organs, a phenomenon known as extramedullary disease. This high-risk variant carries a grim prognosis, with median survival measured in little more than a year, and its biology remains incompletely understood despite rapid advances in myeloma therapy.

The Hungarian team, led by Tünde Tóth and Andrea Tamás, set out to test whether the inflammatory milieu of the blood could serve as a window onto these microenvironmental changes. They enrolled 48 patients with multiple myeloma, including 15 with extramedullary involvement, along with 10 healthy controls of comparable age. Using an enzyme-linked immunosorbent assay for PACAP-38 and a high-sensitivity Luminex multiplex platform for 13 cytokines and chemokines, including interferon-gamma, interleukin-1 beta, IL-2, IL-3, IL-6, IL-8, IL-9, IL-10, IL-17A, MCP-1, MIP-1 alpha, TGF-alpha and TNF-alpha, they quantified each molecule in plasma and then asked how the resulting profiles related to disease activity, extramedullary spread and progression-free survival.

The results reveal a distinctive inflammatory signature in myeloma. Compared with healthy controls, patients showed significantly elevated levels of interferon-gamma, the immunosuppressive cytokine IL-10 and the monocyte-recruiting chemokine MCP-1, alongside reduced levels of IL-17A and TGF-alpha. When the investigators applied a stringent correction for multiple testing, only IL-10, IL-17A and MCP-1 retained statistical significance, marking them as the most robust biomarker candidates to emerge from the comparison. Receiver operating characteristic analysis indicated that IL-10, IL-17A and MCP-1 offered excellent discrimination between patients and controls, while TGF-alpha performed acceptably, suggesting these molecules could potentially serve as accessible diagnostic indicators of myeloma biology.

Disease activity left an even clearer fingerprint. Patients with active myeloma, whether newly diagnosed, relapsed or refractory, had markedly higher IL-10 and TNF-alpha than patients in remission, and their interferon-gamma, IL-10 and MCP-1 levels were all significantly elevated relative to controls. After multiple-testing correction, IL-10 alone remained significant, but its consistency across every comparison in the study impressed the authors. IL-10 is a paradoxical cytokine in cancer: it dampens antigen presentation, fosters regulatory T cell expansion and supports angiogenesis, collectively helping malignant cells escape immune surveillance. Its co-elevation with interferon-gamma, normally an antitumor cytokine, points to a dysfunctional immune state in which chronic stimulation paradoxically drives immune exhaustion rather than tumor rejection.

The extramedullary subgroup told an even more striking story. Patients whose myeloma had escaped the bone marrow showed sharply increased interferon-gamma, IL-10, MCP-1 and, unexpectedly, PACAP-38, together with a pronounced drop in TGF-alpha. Only IL-10 survived correction for multiple testing in this comparison, but the overall pattern suggests that extramedullary disease represents a genuinely distinct inflammatory phenotype rather than simply a more advanced version of marrow-bound myeloma. Mechanistically, this fits with what is known about how myeloma cells disseminate: hypoxia stabilizes HIF-1 alpha, upregulating the chemokine receptor CXCR4 and promoting an epithelial-mesenchymal transition-like program that loosens the cells’ adhesion to the marrow and licenses migration to distant sites.

The behavior of PACAP-38, an anti-inflammatory and cytoprotective neuropeptide, added a further layer of complexity. Previous work by the same group had shown that PACAP-38 levels are lower in myeloma patients than in healthy individuals, with reductions linked to poorer prognosis, particularly in older patients. In the new cohort, however, PACAP-38 was paradoxically elevated in patients with extramedullary disease. The authors propose that this rise may represent a compensatory response to extreme systemic stress, since hypoxia and oxidative stress are known inducers of PACAP expression, though they are careful to frame this as a hypothesis-generating interpretation rather than a demonstrated mechanism. Notably, PACAP-38 correlated positively with IL-10 and negatively with the pro-inflammatory chemokines MCP-1 and MIP-1 alpha, consistent with a role in counter-regulating inflammation and protecting the marrow microenvironment.

Survival analyses reinforced the prognostic relevance of the cytokine network. Progression-free survival correlated negatively with IL-6, IL-10 and TGF-alpha across the myeloma cohort, and in the extramedullary subgroup with IL-6 and IL-9, while IL-17A showed a positive association with survival. Exploratory Kaplan-Meier analyses, splitting patients at the median concentration of each cytokine, confirmed that IL-6, IL-9 and IL-10 distinguished patients with different progression-free survival, although the small number of progression events meant that multivariable adjustment was not feasible. After correction for multiple testing, IL-9 was the only survival-associated variable to remain significant, underscoring the exploratory nature of these findings and the need for larger validation cohorts.

The study arrives at a moment when myeloma treatment is being transformed by chimeric antigen receptor T cell therapy, bispecific antibodies and increasingly sensitive monitoring technologies, yet current staging systems still lean heavily on tumor burden and cytogenetic risk while largely ignoring the inflammatory microenvironment. The Hungarian authors argue that biomarkers such as IL-10 could complement, rather than replace, existing frameworks by capturing biological features that clinical variables miss, from identifying biologically aggressive disease to flagging patients at risk of extramedullary progression or relapse. They also suggest that inflammatory pathways, including IL-6 and MCP-1 signaling, warrant attention as therapeutic targets, and that restoring PACAP-38-mediated neuroimmune regulation might one day offer a complementary strategy, potentially in combination with immune-based therapies.

The researchers are candid about their study’s limitations. It was a single-center investigation with a modest sample size, particularly in the control and extramedullary subgroups, and cytokines were measured in peripheral blood rather than bone marrow, which may not fully reflect the local milieu. Treatment effects, detectable only for IL-10 in this cohort, cannot be entirely excluded, and the cross-sectional design precludes causal inference. Several cytokines, including IL-1 beta, IL-2 and IL-3, fell below detection limits in many samples. Even so, the strengths are real: a simultaneous assessment of a broad cytokine panel together with PACAP-38, careful characterization of extramedullary patients, and rigorous false-discovery-rate correction that sharpened rather than diluted the central message. What emerges is a coherent picture of multiple myeloma as an inflammation-driven malignancy in which IL-10 stands out as the most promising blood-based biomarker, and in which the ebb and flow of a protective neuropeptide may help explain why some patients’ disease stays confined while others break free. Larger, multicenter, longitudinal studies will now be needed to determine whether these inflammatory fingerprints can earn a place in the clinic.

Subject of Research: Inflammatory cytokine and PACAP-38 alterations and their prognostic value in multiple myeloma

Article Title: The relationship between inflammation and multiple myeloma: insights into alterations and prognostic value

Article References: Tóth, T., Alizadeh, H., Polgár, B., Csalódi, R., Kemény, Á., Reglődi, D., Faludi, P., Pethő, B., & Tamás, A. (2026). The relationship between inflammation and multiple myeloma: insights into alterations and prognostic value. GeroScience. https://doi.org/10.1007/s11357-026-02494-3

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02494-3

Keywords: multiple myeloma, extramedullary disease, cytokines, IL-10, PACAP-38, inflammation, bone marrow microenvironment, prognosis, biomarkers, MCP-1, interferon-gamma, GeroScience