Monday, April 29, 2024
4/29/2024
Project Summary Although effective therapies exist in many cancers, an initial response to therapy is often followed by relapse. An extreme example is multiple myeloma, a plasma cell malignancy in the bone marrow, which responds to treatment in almost all patients, but which cannot be cured. Myeloma patients therefore receive many different lines of therapy during the course of their disease. Repeated bone marrow biopsies are crucial for monitoring of treatment response and for informing the optimal choice of treatment and are therefore currently recommended with any change in treatment. However, the excessive number of biopsies over time creates an enormous burden for patients, and these tissue biopsies are often not performed beyond initial diagnosis. In addition, bone marrow biopsies only capture myeloma cells from a single site, and therefore do not provide a complete representation of the heterogeneity and ongoing evolution of this multifocal disease that is characterized by patchy bone marrow involvement. It is therefore imperative to develop novel approaches that allow to frequently assess myeloma evolution during therapy and choose those treatments that are most efficacious. We are proposing to use novel “liquid biopsy” approaches to replace bone marrow biopsy by interrogating circulating myeloma cells and cell-free DNA in myeloma patients, obtained from a simple blood draw. We hypothesize that liquid biopsy provides more comprehensive and clinically relevant insights into the molecular dynamics and genomic evolution of myeloma than can be obtained through single-site bone marrow biopsies. To accomplish this task, we have pioneered technologies for highly sensitive isolation and deep molecular and genomic characterization of circulating multiple myeloma cells (CMMCs) with single cell resolution, as well as whole genome and targeted sequencing of cell-free DNA (cfDNA). We will leverage these technologies to inform clinical decision-making in a way that is impossible with the current practice of using bone marrow biopsies as standard-of-care. Specifically, we will demonstrate that: 1) Liquid biopsy is a better predictor of survival than parameters currently used in clinical routine, 2) Liquid biopsy has greater sensitivity and specificity to detect established prognostic and predictive genetic disease variants than bone marrow biopsy, the current gold-standard, 3) Liquid biopsy provides a therapeutically more relevant representation of the clonal composition and actionable treatment targets of myeloma than bone marrow biopsy, 4) Liquid biopsy outperforms bone marrow biopsy in determining minimal residual disease (MRD) status. Importantly, replacing repeated invasive biopsies with liquid biopsy from a simple blood draw will dramatically reduce risk and discomfort for patients. We expect that the concepts we are investigating will be practice-changing for the care of myeloma patients and will be broadly relevant across many different cancers and produce important new opportunities for therapies.
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