The gut microbiome refers to the bacteria, viruses, fungi, and other microscopic living things such as microorganisms, or microbes, that live in your intestine. There is growing evidence for the relationship between the microbiome and human cancers, including plasma cell dyscrasias.
Recently, immunotherapies such as bispecific antibodies and chimeric antigen receptor T cells (CAR T cells) have shown impressive results in multiple myeloma. However, there is an urgent need to identify mechanisms to predict and enhance responses to immunotherapy.
Though data is limited, there is evidence for a role of the gut microbiome in disease progression and response to immunotherapy. We are currently studying the role of the gut microbiome in patients with smoldering myeloma and relapsed, refractory multiple myeloma undergoing immunotherapy. We hypothesize that specific microbiota are regulators of response to immunotherapy, including bispecific antibodies and CAR T-cells.
Our current study includes 40 patients with smoldering myeloma and 40 patients with relapsed, refractory multiple myeloma receiving B cell maturation antigen (BCMA)-directed bispecific antibody (teclistamab) and BCMA-directed CAR T cells (idecabtagene-vicleucel, ciltacabtagene-autoleucel). We are characterizing the gut microbiome of patients with MM and SMM receiving immunotherapies in an effort to define specific microbiota present in responders versus non-responders.
In addition to characterizing the gut microbiome, we are comprehensively characterizing changes in the abundance, expression profile, repertoire, and spatial localization of T cells in the bone marrow of patients with smoldering myeloma and MM based on their responses to immunotherapy and specific diversity of microbiota. We are performing single-cell RNA sequencing of immune cells, along with T-cell repertoire (TCR) sequencing of the peripheral blood and bone marrow samples from multiple myeloma patients treated with immunotherapies, and comparing it to the microbiome taxonomy data to identify bacteria that specifically regulate the immune composition in this patient population.
This study offers a unique examination of the changing microbiome and immunologic milieu in smoldering myeloma and multiple myeloma, and how disease response can be intercepted by harnessing the immune system. The gut microbiome represents a potentially modifiable factor to affect response. The information gained from this trial can be used to guide therapy selection and to inform future investigations of dietary interventions, fecal transplant, or targeted probiotics which may enhance the response to immune therapy. Further, with the advent of technologies such as single-cell RNA sequencing coupled with T-cell receptor sequencing along with microbiome sequencing, we may then identify interactions between the gut microbiome and changes in immune cell composition, expression profiles, T-cell repertoire diversity, and the proximity of T cells to tumor cells or other immune/non-immune cells that are affected by the microbiota diversity and can affect response to immunotherapy.
Our goal is to identify mechanisms that may be modified through lifestyle or microbiome-targeting interventions that can enhance response to immunotherapy and improve outcomes for patients with plasma cell disorders.