Why is it important for a patient to know the cytogenetic abnormalities of their myeloma?

In this course, we'll take a deeper dive into these chromosomal abnormalities. What they are, why it's important to know them and what they mean for your risk level. 

Why is it important for a patient to know the genetic abnormalities of their myeloma? Why do chromosome testing or genetic testing in myeloma.

So a couple different reasons. So one of the biggest reasons is  we have a panel of known markers in myeloma or chromosome rearrangements or deletions that that we know portend a 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. So 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 and so forth. 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. Also the other there are other markers, like for example, the translocation 11;14 that can actually predict response to treatment for example, with venetoclax, a BCL2 inhibitor. Because the patients that have translocation of chromosome 11 and 14 typically have overexpression of BCL2 protein in their myeloma cells, and that renders them more susceptible to the effects of a drug called venetoclax. 

So myeloma is very different from a lot of what we call solid tumors diseases like breast cancer or lung cancer. So in solid tumors like breast cancer, prostate cancer, lung cancer, they're stage from stage one to stage four. Typically, but not always stage one solid tumors are simply removed either by surgery or radiation. Stage four typically we give chemotherapy and stage twos and threes or some combination of surgery or radiation or chemotherapy. Myeloma does not behave that way. In fact, myeloma has three different staging systems, but they all go 1 to 3. In general, that is not the better way that we describe patients, because we don't treat someone with stage one different from stage three. In our mind, we define myeloma as being standard risk or high risk. And in general, if you take a standard risk patient and a high risk patient, they tend to respond similarly to therapy. But the high risk patient will unfortunately relapse sooner. So part of our understanding of the disease and what's important to know is what type of cytogenetics abnormalities you have, because that helps us understand what type of myeloma you have.

Is it more high risk or more standard risk? 

When we speak about genetic abnormalities, they're not genetic abnormalities in the cells all over your body. They're just within the cancer cells themselves. And when we do those bone marrow tests, we specifically look for certain types of genetic abnormalities that we know make people higher risk or less high risk.

One of the big ones we typically think about is something called a 17p deletion. We all have 23 pairs of chromosomes, and each chromosome has a long arm and a short. On the short arm is p and the long arm is q. So when we say a 17p deletion, we mean some of the information on the short arm of the 17th chromosome is not there. And unfortunately, that's where something lives. It's called p53. It's this big tumor suppressor gene. And it's one of the mechanisms of our body to prevent cancer. And if you're missing that part on that chromosome, your myeloma tends to behave in a more high risk nature.

So it's important to know these things in terms of mapping out your long term outcomes and different therapy options. And as our technology gets better, understanding which genetic abnormalities we have help drive specific therapies. As in the case with Venetoclax, we know that people with an 11;14 translocation have a higher chance of responding to that drug.

So the whole idea here is myeloma genetics is complicated. That's why this is a hard disease to treat. We know that there's a variation in genetic events that occur between patients. We know that everybody's unique. We know that everybody's tumor is unique. They may have different chromosomal abnormalities, may have different mutations in genes. They may have different epigenetic events. They may have different levels of gene expression.

We now have the ability with the technologies to look at every one of those events and look at all that genetics information and try to make better decisions about predicting which are the really bad tumors, which are the tumors that are going to respond well, which tumors will respond to bortezomib, which tumors might respond to revlimid. All of those therapeutics now that are coming online now, give us the idea that maybe understanding the genetic background of every tumor is going to give us better information in how we treat it.

We know that genetics influence progression, influence response. And the other thing we now know, which makes it even more difficult to treat, is that even within one individual's tumor population, there can be individual cells that have different genetic events going on. What that means is that clonal evolution can occur. So that the therapy may treat most of the tumor, but some of those genetic events that occur in smaller populations may resist the therapy. And we got to think of a better therapy for those.

So the whole idea is genetics will give us better individualized understanding of every tumor, better individualized treatment. It's important to know what type of myeloma each person has, because we cannot treat everybody as if they're the same. We know that some people are more sensitive to treatment and have much longer survival, and other people have very aggressive and very resistant myeloma that despite chemotherapy, the disease tends to come back very quickly or does not respond well to treatment.

So if somebody has a diagnosis of multiple myeloma, that's not enough for us to be able to know what are the best ways of managing your treatment and to plan your treatment for the future. Even though the induction and the transplant portion of treatment tend to be the same, regardless of the cytogenetics, it is important to know the type of cytogenetics and if you're high risk or standard risk so that you can establish a proper maintenance.

So high risk cytogenetics at the beginning when somebody is diagnosed is important so that we can have an idea of not just the type of disease that you have, but is this a disease that's going to be hard to fight? Is this a disease that's going to be wanting to come back quicker and us have to be more cautious and surveil more frequently to look for relapses? Or is this a disease that is going to be more easy going and hopefully easier to treat, that by the time we put it in remission, there's a better chance that that person is going to stay in remission for a longer time.

So even though at the beginning it might not seem like a necessary thing for our patient because they say, well, why would I need to know my mutations and my cancer if the induction therapy is going to be the same and I'm still probably going to go to transplant after finishing induction, there are now some debates as to whether certain medicines should be used in high risk disease as part of the induction, and there are clinical trials currently comparing the use of carfilzomib instead of bortezomib in high risk disease patients, and if there is an added benefit or a better control of this disease.

When somebody has multiple myeloma, we want to know as many details as possible so we can have a better understanding of what we're dealing with, so we can have a better way of handling it, managing it, and at the same time have better information that we can provide to the patients so that they can have a better understanding of what to expect in the near future and how to plan their life accordingly.

What are the main genetic subgroups in myeloma?

The study of cell lines by cytogenetics, allowed the broad classification of myeloma into six subtypes. So the 4;14, the 14;16 14;20 11;14 and then cyclin D1 positive hyperdiploid and cyclin D2 positive hyperdiploid, which to six. So those groups are important because they behave very differently. The 4;14 has 50% of those cases can be really quite aggressive and needs specific treatment to respond well to proteasome inhibition. The 11;14 respond very well to anti apoptotic therapy with venetoclax. and would do very well with that when it becomes available, the cyclin D2 type tend to be more aggressive than the cyclin D1 type of hyperdiploid. And so there's a lot of nuances within the data that allows physicians really to try and personalize their therapeutic choices. 

Should patients know the type of myeloma they have? Where will they find this information?

I think it's an important part of the note. It's a very first thing I put in my note is to say what category a patient is. And so you might see the new doctors note. They might say hyperdiploid. They might say, you know, t(11;14) or t(4;14). It's typically somewhere in a summary where they summarize the the characteristics. In terms of treatment. we think that, the use of Velcade and Kyprolis, is particularly important in the patients with the 4;14. And we think IMiD work particularly well in the patients who are hyperdiploid. But of course, we use those drugs in all patients. And so it's perhaps more a matter of approach, where we think the patients that the high risk genetics require a more intensive approach. Understanding the genetics of your myeloma is crucial. Knowing your risk status can help guide your decisions about treatment and maintenance therapy, and it may also reveal a targetable mutation.

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