Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS), a condition presenting with elevated blood levels of immunoglobulins. These conditions originate in the setting of chronic B cell activation, however the underlying triggers are not well understood. However, preliminary work by Madhav Dhodapkar, Richard Flavell, and Noah Palm suggest the intriguing possibility that certain commensal microbes may impact the growth of clonal plasma cells in MGUS, and that targeting these microbes for elimination may alter the clinical trajectory for those patients. The investigators hypothesize that these bacterial species directly engage with myeloma-encoded B cell receptors in part through the expression of a B cell “superantigen,” leading to chronic activation. Encouragingly, the team’s preclinical studies have inspired an ongoing pilot clinical trial, now demonstrating that treatment with a short course of a gut-selective antibiotic can lead to reduction in clonal immunoglobulin levels in some patients with MGUS.
To expand these findings with funding from this ASPIRE award, the researchers will combine their multi-disciplinary expertise in myeloma immunology, the gut microbiome, and sophisticated animal modeling. They will determine the full spectrum of human gut microbes that can potentially serve as antigenic triggers for human myeloma and evaluate the effect of manipulation of these microbes on B cells in germ-free humanized mice. They will also evaluate the impact of short-term gut microbial manipulation on inflammation-associated signatures in immune cells from MGUS patients. Addressing these questions may not only provide fundamental insights into the pathogenesis of human MGUS and MM, but also may provide clear direction for novel approaches to eliminate/reduce these bacteria that can be readily translated to improve prevention and therapy of these cancers.