BETA What are myeloma clones, how are they identified, why are they important?

Myeloma is not a single cancer, but a collection of different types of cancer sub-clones that compete for resources within the bone marrow. In this video, we break down the key concepts of tumor evolution in myeloma, learn how scientists identify and track these clones over time using genomic technologies, and why understanding clonal dynamics is critical for developing personalized treatment strategies. Whether you're a patient, medical student, researcher, or just curious about precision oncology, this is your go-to guide. Like, comment, and subscribe for more Precision Medicine Insights. What is a founding clone? We often talk about a clone. You think about a clone, you think, well, I'm going to clone a person so I have an identical person. That's a type of cloning. But in the field of malignancy and oncology, we often talk about a clone being the cell of origin. It was the cell that originally went bad. It's the cell that had the mutations. It had the chromosomal translocations. It deregulated events so that it proliferated and went to the marrow. An original cell clone now divides and gives progeny that have all the same traits as the original bad acting cell. So it's the clonal origin of the tumor that now all subsequent proliferating cells were derived from. When we talk about clones, we're talking about the malignant cells. So we all have plasma cells, which are normal cells. They're part of our immune system. What happens in multiple myeloma is some of these plasma cells go rogue and become malignant or cancerous, and that's what leads to myeloma. Now over the last 25 or so years, there's been a lot of work done to identify what are the phenotypes or characteristics of these clones, if you will. Many people, including my colleagues here, have worked on delineating when do these initial genetic alterations happen that lead the normal plasma cells to become abnormal. So a founding clone really refers to that very initial event that happens, often many years before the patient develops any symptoms of multiple myeloma, that leads one or more of these plasma cells to become malignant. So that is the founder clone. So work done by Dr. Mora here at MSK, by Dr. Gobrial at Boston, and their groups have shown that often these kinds of genetic alterations that lead to malignant transformation can precede the diagnosis of multiple myeloma by many years, sometimes many decades. So that initial founding clone is founded several years before clinical symptoms. Over a period of time, that founding clone can acquire additional mutations, genetic alterations that eventually will lead to the development of multiple myeloma, with clinical symptoms of multiple myeloma. What are subclones? What is a dominant clone? Over time, random mutations in the DNA of the tumor cells can occur, and these mutations can give a survival advantage to one cell that then becomes more proliferative, meaning it grows more rapidly and starts to take over the population. We call these subclones because they originated from the original founder clone. They can dominate the population of tumor cells, and this happens regularly during treatment. So treatment can actually spur a cell to become different because it's trying to resist the treatment, and if it is effective, it will dominate the population, and the cells that were susceptible to the treatment will die off. And so this process regularly happens as new treatment is introduced, making it really challenging to treat the disease. How are myeloma subclones identified and tracked over time? From a clinical perspective, for now, finding how many clones a patient has and what is a founding clone does not influence our treatments. We would still give patients the effective treatments we have available, whether that's newly diagnosed myeloma or relapsed myeloma. So currently, clonal heterogeneity, if you will, i.e. those kinds of pretty pictures you're referring to, which is how these clones develop and what mutations lead to different clones, they're very, very important scientifically, but they have not reached a level where we would use to make clinical decisions yet. The technologies we use for identifying these clones are quite similar to the technologies that have been used for many years now, which would be a whole genome sequencing, which would sequence the entire genome. And then you would use bioinformatic pipelines, statistical pipelines, to outline these different the frequency of those mutations to say how many, on average, how many clones does a given patient have, which one is the dominant clone or clones, and which are the subclones that have developed over a period of time. But this is not a test that's clinically available currently for patients with multiple myeloma because there's not yet a clinical application quite for this testing. What is the purpose of identifying myeloma clones and subclones and tracking them over time? There isn't a test that we do clinically, meaning you wouldn't go to your doctor and request a phylogenetic tumor analysis. Rather, it's something we do in the research laboratory, and the purpose is to try and understand how disease becomes resistant to therapy and how it changes over time, which as you can imagine is super important to try and cure the disease. We need to understand how it's changing so that we can alter our treatments to affect that change. For example, we might identify that if a common mutation is occurring for some specific treatment A, but that same subclone is susceptible to treatment B, then maybe doing combination therapy A and B at the same time to prevent a new subclone from arising that would cause resistance would be the strategy. So again, a DNA sequencing analysis of the tumor cells to determine their phylogenetic relationship is really in the research phase, but we hope that the information we get from that will translate over to the clinic. When an individual is diagnosed with myeloma, on average, how many different myeloma subclones will that individual display? That depends on the technology we use to detect these clones. Whole exome sequencing, which looks at parts of the genome, whole genome sequencing, which looks at the entire genome. It depends also on how we would define subclones and clones, but I would say it's quite common for patients to have multiple clones at the time of diagnosis, anywhere from five to twenty different clones potentially. Some of these clones could be dominant, some of these could be subclones that have developed over a period of time. Can a dominant clone reemerge after it has disappeared? How does this impact treatment decisions? So absolutely it's possible that when you introduce new treatment, the old clones that were resistant now emerge again because they are no longer resistant to the current treatment. And it's possible you can go back in time and try a different therapy. So I try and tell patients, even at the end of trying all the available treatment options, there is a chance we can go back and use one of the old treatments because it's likely that the clones that were resistant to that treatment have been eliminated. 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