Irene Ghobrial

M.D.

Dana-Farber Cancer Institute

Professor of Medicine

PLCO (Learn more about this study)

2019-1020

Apr 29, 2020

Studying the role of Clonal Hematopoiesis of Indeterminate Potential in disease progression from Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma

Multiple Myeloma (MM) is the second most common hematological malignancy and, despite significant advances in MM therapeutics, it remains fatal. MM is almost always preceded by the subclinical precursor condition of Monoclonal Gammopathy of Undetermined Significance (MGUS). Progression risk is quite heterogeneous in patients with MGUS, with certain patients progressing quickly, while others never do. In a recent study by our group, we discovered that 24% of MM patients at the time of autologous stem cell transplantation have evidence of Clonal Hematopoiesis of Indeterminate Potential (CHIP). CHIP encompasses somatic mutations specific to the myeloid and/or lymphoid lineage that accrue in hematopoietic stem cells and their progeny with age, and as we demonstrated, can have an adverse impact on progression-free survival in patients that do not receive lenalidomide maintenance following transplantation. It is known today that patients with CHIP exhibit altered inflammation that can affect biological processes, however its effect on disease progression in MM has not been studied.
Here, we propose to profile the somatic mutational repertoire of peripheral blood mononuclear cells (PBMCs) in patients with MGUS and assess its role in disease progression. For this purpose, we will first apply ultra-low-pass whole-genome sequencing of PBMC DNA derived from patients with MGUS at time of diagnosis, in order to detect potential contamination with circulating tumor cell DNA, and perform whole-exome sequencing and deep targeted sequencing to detect somatic mutations in the patients’ immune cells. We will perform this analysis on the 187 non-IgM and light chain MGUS PLCO cases that progressed to MM over time and compare them to a matched cohort of individuals with non-IgM and light chain MGUS that did not progress to overt disease. We will also assay a sample of healthy individuals, with no evidence of cancer or other disease, to control for technical noise related to sample processing/storage, library preparation and sequencing. Cytokine profiling of matched serum samples will be performed and coupled with mutation calling for functional evidence of altered immune response.
This study will be the first to characterize the somatic mutational repertoire of immune cells in patients with MGUS and assess its role and functional importance in disease progression. Our work is positioned to help better define and understand risk of progression in patients with MGUS and inform clinical practice for improved patient outcomes.