The Microbiome: A New Variable in Multiple Myeloma Disease Progression

Microbiota and host have co-evolved into a complex ecosystem, the intricate relationships of which benefit the host in many ways.^1,2  However, these close interactions carry risks for development of disease, including cancer.^3,4  Multiple myeloma (MM) is characterized by the accumulation of clonal plasma cells within the bone marrow (BM).⁵  MM is consistently preceded by the precursor states of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), an asymptomatic phase of increased tumor burden that may progress to full-blown MM.⁶  Although genetic, epigenetic, and microenvironmental alterations have been implicated in disease progression,^7-9  significant interpatient variability remains to be accounted for.

Although the role of the microbiome in MM disease progression has not been extensively studied, gastrointestinal tract commensal bacteria are known to drive the development of Th17 cells, which in turn regulate autoimmune inflammation by producing cytokines including IL-17.¹⁰  Interestingly, IL-17–producing lymphocytes were reported to drive bone lytic lesions in advanced MM, while the Th17 T-cell phenotype tightly correlated with the extent of bone disease in patients.¹¹  Additionally, IL-17 was shown to promote tumor growth via the IL-6-STAT3 signaling pathway, which is critical for plasma cell growth.¹²  Taken together, these findings indicate a potential role for gut microbiota, Th17 cells, and IL-17, in regulating MM disease progression.

Given the lack of data on the role of IL-17–producing cells in the early, asymptomatic phases of MM, Dr. Adriana Calcinotto and colleagues recently used the Vk*MYC mouse model to assess the potential link between gut microbiota, IL-17, and the progression from SMM to overt disease.¹³  In their study, the authors showed that gut microbiota only exert their effect on mice whose plasma cells already carry driver genetic alterations such as overactivation of MYC, but they are not sufficient to induce MM development in healthy mice with spontaneous MGUS. Specifically, while transformed B cells carrying genetic mutations acquire the characteristics of malignant plasma cells and migrate from the germinal center to the BM, gut microbiota locally favor the expansion and subsequent migration of Th17 cells to distant BM niches. The co-accumulation of tumor plasma cells and Th17 cells in the BM microenvironment triggers an intricate signaling network whereby eosinophils are activated by Th17-produced IL-17 and subsequently secrete proinflammatory cytokines such as IL-6 and TNF-α — a favorable cytokine milieu for tumor growth. These results by Dr. Calcinotto and colleagues seem to suggest a role for the microbiome in compounding disease progression in MM, which might help explain residual variability in progression risk, after genetic and epigenetic variables are accounted for.

Hypothesizing that the Vk*MYC model faithfully recapitulates disease progression in patients with SMM, Dr. Calcinotto and colleagues went on to measure BM IL-17 levels in a cohort of patients that rapidly progressed to active MM in less than three years, and compared them to data obtained from a cohort of patients with SMM that did not progress to MM in that same time frame. At the time of SMM diagnosis, progressors already had much higher BM IL-17 levels compared to nonprogressors, suggesting that IL-17 levels in the BM sera of patients with SMM could be a predictive marker of progression to symptomatic disease. Although these results are promising, the study’s sample size was small, and a much larger cohort is needed to assess whether IL-17 is truly a predictor of progression to MM.