How does cytogenetic testing help determine risk and treatment protocols?

Cytogenetics testing takes a close look at your chromosomes, the carriers of your genetic information, to spot any abnormalities. But you might be wondering, why does this kind of testing matter? Does it really make a difference? The answer is a resounding yes. In this lesson, we'll explore how understanding the specific type of myeloma you have, based on your chromosomal changes, can be a game changer. This isn't just about science, it's about personalizing your treatment and improving your care. Let's dive into why this knowledge is so powerful.

Why is it important to have myeloma cytogenetic testing done? So we often talk about different types of myeloma. And the reason we're interested in different types of myeloma is that we recognize myeloma is different in different people, and we want to have better ideas of how to group the type of myeloma one individual has versus the type of myeloma another individual has. I'm a geneticist, so I look at the world through the lens of genetics. And part of the reason that I look at the world of myeloma through genetics is that I recognized that there are different genetic variations, different genetic abnormalities, different genetic mutations that might define one particular group of myelomas.

So there may be a group of myelomas that have a deleted chromosome 13, or there may be a group of myelomas, ones that have what's called a translocation where two chromosomes get together like chromosome 14 and 12. So these all are genetic definitions. And we've become more aware that some of these genetic definitions now give us some groupings of different types of myeloma, and some of these genetic variations that occur are associated with either more or less aggressive myeloma.

So in my mind, when I look at the genetics of myeloma, I'm looking at genetic tests and genetic results that distinguish low risk, high risk disease, for example, as genetic markers.

What testing is used to determine chromosome mutations? Currently, we use the method most widely used to assess what type of myeloma a patient might have is to get a test called FISH, which stands for fluorescent in situ hybridization and is a test where we take a bone marrow sample from a patient and collect their myeloma cells and use some fluorescent markers to stain for chromosomes. And so that we have a good idea of what types of chromosomes are present in the myeloma cells of a given patient.

We found that there are some patterns of chromosome abnormalities, where certain patients' myeloma cells might have extra chromosomes, or they might have missing chromosomes, or that maybe they've had a fusion between chromosomes that are not normally fused. For example, a common finding is the translocation between chromosome 11 and chromosome 14. The translocation 11;14 fusion, which puts genes from chromosome 11 next to genes on chromosome 14, has some biologic relevance for certain types of patients’ myeloma cells.

So this has been the most widely used test and is available generally nationally to try to get information about a certain type of myeloma patient, what type of information is available. This is how this is most commonly done. There are additional tests that could be developed in the future, sort of like genetic testing, that might provide more information beyond just the FISH testing. Some centers are doing this, but this is not yet kind of widely available. But to understand what genes might be mutated in the myeloma cells could provide some information about what the risk is for a certain myeloma patient.

Why is it important to know your genetic markers? How does risk markers guide treatment in myeloma? Why do chromosome testing or genetic testing in myeloma? So, a couple of different reasons. One of the biggest reasons is, we have a panel of known markers in myeloma or chromosome rearrangements or deletions that we know portend different prognosis. So, for example, some patients have particular chromosome rearrangements or changes that indicate they have a high risk for early relapse.

So we call those high risk markers. For example, the 4;14 translocation or deletion 17p, and especially if they have more than one of those or double hit, those patients have even more risk of early relapse with treatment. Just knowing that you have high risk chromosome changes means that we want to be particularly aggressive with the treatment, and also probably with the maintenance therapy, and not just do the standard all run-of-the-mill treatment that might lead to earlier relapse.

There are other markers, like for example, the translocation 11;14 that can actually predict response to treatment, for example, with venetoclax, a BCL-2 inhibitor. Because the patients that have translocation of chromosome 11;14 typically have overexpression of BCL-2 protein in their myeloma cells, and that renders them more susceptible to the effects of a drug called venetoclax.

Initial therapy right now is really like starting the decision to start initial therapy. Right now, it's not based on the risk status. Right now it's based on whether or not you have symptoms. Or in the case of smoldering myeloma, sometimes, usually in clinical trials, if you have lots of risk factors for developing symptoms in the very near future, those are the scenarios where we start treatments.

The way that it does affect selection of therapy mostly right now is when we're thinking about maintenance therapy in the first line setting. Standard maintenance is usually a single drug, usually the most common being lenalidomide, but there's data about other drugs. There’s data about daratumumab and isatuximab and actually about carfilzomib as maintenance therapy. Lots of different drugs have been studied as maintenance, but the most commonly used one is lenalidomide all by itself. It's a pill, more convenient to take than IV chemotherapy, for instance. But we also don't think it's quite enough in patients who are high risk, and so it is very usual to add a second drug, or at least a second drug, to somebody who's high risk. So knowing that is important when selecting sort of the long-term management of these patients.

The other way that it's helpful for the treating physician, in terms of decision making, is there are some myeloma subtypes for which certain therapies may be uniquely beneficial. The most common one is probably the patients whose bone marrow plasma cells have t(11;14) translocation. That's when pieces of chromosome 11 and 14 flip-flop; they trade pieces, and when that happens, that creates a situation within the cell where their myeloma may be more susceptible to the effects of drugs which suppress a protein called BCL-2.

Venetoclax and sonrotoclax are the BCL-2 inhibitors. Venetoclax is not FDA approved for myeloma, and sonrotoclax is currently in clinical trials. Other patients who don't have that translocation—it's not that they can never respond to those drugs, but they're way less likely to. And so when you're thinking about what might be a reasonable treatment option for a patient who's had a bunch of prior therapies, you might think about drugs in that class of drugs, but only for the patients who have that specific molecular subset.

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