Dr Mithraprabhu Discusses Liquid Biopsy to Define Genomic Characteristics of Patients With MM

Dr Sridurga Mithraprabhu, Research Fellow, Myeloma Research Group, Monash Univerity’s Australian Center for Blood Diseases, Melbourne, Australia, discusses liquid biopsy, which can be utilized to define the genomic characteristics of a patient with multiple myeloma (MM).

Transcript

Hello, everyone. My name is Dr. Sridurga Mithraprabhu. I'm a research fellow at the Myeloma Research Group based at Monash University's Australian Center for Blood Diseases in Melbourne, Australia.

Our group works on a bone marrow cancer called multiple myeloma that results due to the clonal proliferation of plasma cells. These are the antibody-producing cells in the bone marrow. It is a genetically complex disease, and it manifests at several sites within the bone marrow.

Traditionally, bone marrow biopsy is performed to understand the genomics of the disease so better therapies can be designed for patients who are treatment-resistant.

However, due to the genetically complex nature of the disease, each site within the bone marrow of an individual patient could have a different mutation. This is called spatial genetic heterogeneity, and it is a hallmark of multiple myeloma.

Therefore, a single-site bone marrow biopsy does not capture the spatial genetic heterogeneity of this disease as it is too site-specific. Consequently, better methodologies are required.

Our group focuses on developing an alternative methodology called liquid biopsy. Cancer cells shed small amounts of genetic material into the bloodstream. Therefore, liquid biopsy or blood test can enable us to capture bits of DNA floating around in the bloodstream.

These bits of DNA are potentially sourced from all bone marrow sites within the patient, so it is representative of the disease as a whole and can be utilized to define the genomic characteristics of the myeloma patient.

We were one of the first groups to establish that the bloodstream of myeloma patients contains mutations that are representative of the genomic characteristics of the disease. This was published in the Leukemia Journal in 2017.

We have since followed up with a number of publications that demonstrate the utility of liquid biopsy for specific aspects of multiple myeloma research. I'm going to go through 3 key findings.

First was our analysis of circulating bloodstream-derived DNA has shown a number of mutations identified were not actually present in the bone marrow analysis, indicating that these mutations were sourced from sites that were distinct to the bone marrow biopsy site, and that liquid biopsy can actually address spatial genetic heterogeneity of myeloma.

The second key finding is that we demonstrated that the number and the amount of mutations in the bloodstream are predictive of how a patient responds to therapy.

Third, we observed that patients with the TP53 gene mutation in their circulating DNA had a higher chance of relapsing on therapy.

One of the first things that we were surprised about was the fact that we could identify so many mutations in the bloodstream that we couldn't detect with the traditional bone marrow analysis. This sets up the foundation for a number of studies that we have done in the last few years.

We could potentially use circulating tumor DNA analysis or liquid biopsy for 2 aspects of myeloma therapy. Our analysis has demonstrated that circulating tumor DNA levels could be a predictor of response to therapy as early as 5 days after treatment.

This analysis can be utilized in real-time as a dynamic early marker of response to therapy. This could allow us to intervene early for non-responsive patients, for example.

The second aspect that we can possibly use it for is that we can utilize circulating tumor DNA to determine the mutational spectrum of patients who are resistant to standard therapy or at a higher risk of progression. Once we determine these mutations that are specific to certain subsets of patients, we could then design personalized therapies for patients harboring these mutations.

This is something we have initiated recently wherein myeloma patients who have failed multiple therapies will be assessed for mutations in 3 genes, KRAS, NRAS, and BRAF. These are genes that are known to be mutated in myeloma.

We'll look for these gene mutations in circulating tumor DNA. Any patients with these mutations will be then enrolled onto an investigator-initiated clinical trial that utilizes a drug that specifically targets these mutations. This is an example of how we can move from basic research to the clinical setting.

We have currently several ongoing projects that I've spoken about, and we will continue to work on these aspects. One of them is the identification of mutational spectrum of patients who are resistant to front-line therapy using liquid biopsy analysis.

The other major project area that we are starting to establish is to determine what risk factors contribute to the development of multiple myeloma. This will be analyzed in a subset of patients who have the precursor conditions. These precursor conditions are asymptomatic and benign. They're called either monoclonal gammopathy of undetermined significance, MGUS, or smoldering myeloma. We have an ongoing collection of liquid biopsy samples from a national blood bank that aims to collect 2,000 liquid biopsy samples from MGUS, smoldering myeloma, and newly-diagnosed myeloma patients.

We hope to identify any biomarkers, all through liquid biopsy analysis, that can predict which MGUS patients go on to develop multiple myeloma. Hopefully, this will provide us with some clues about what risk factors these patients harbor that eventually leads them to go to develop multiple myeloma.

While I have spoken about conducting DNA analysis from the bloodstream today, our lab also focuses on other genetic information available in the blood in the form of RNA, proteins, and extracellular vesicles or exosomes.

We have parallel studies ongoing for all subsets of myeloma that I spoke about today from all of these sources as well. It's a comprehensive liquid biopsy analysis and a number of projects that are ongoing in our lab.