What do I need to know about translocation (14;20)?

What does translocation 14;20 mean for multiple myeloma patients?

In this HealthTree University lesson, we explain the rare but important chromosomal change known as translocation 14;20 in multiple myeloma. Translocation 14;20 only occurs in approximately 1 to 2% of myeloma cases. In this lesson, you will learn what it is, how it is found using modern diagnostics, and when it's considered a high risk genetic marker.

This lesson is ideal for patients, families and clinicians looking to better understand genetic risk factors in myeloma.

What is translocation 14;20? When we talk about high risk mutations and multiple myeloma, there are many, many changes within chromosomes that are considered that can be rendered as standard versus high risk. Now just to go back to the basics, chromosomes are condensed portions of DNA or deoxyribonucleic acid, which is a genetic information that all of us carry in each of us cells. The DNA is condensed into highly coiled structures called chromosomes. And normally humans are having 23 pairs of chromosomes, and they're supposed to exist in a certain way. Any deviation from it is called a mutation. So a deviation from the normal structure is typically called a mutation.

Now a translocation is when one portion of the chromosome breaks off. And for some reason it goes and attaches itself to another part of another chromosome. So that's what the translocation means. It's it can be considered a mutation, but ideally it's the breakage of one portion of the chromosome. And then there's an exchange. And then there's an attachment to another part of the chromosome. Again it's a deviation from what is supposed to be normal when that deviation happens.

What we have often seen in retrospective studies looking at patients who have had this mutations and also in clinical trials, is that there are certain translocations that render the patient at a higher risk for an earlier relapse. And that's what high risk means. So the question post was what is translocation 14;20 mean. That means a portion of the chromosome broke off from chromosome 14 and from chromosome 20. And it attached itself. And that abnormal pairing of 14 and 20 that's never supposed to pair 14 is so far away from 20 that abnormal pairing leads to a more somewhat a more of an aggressive form of myeloma, which tends to multiply a little bit more faster. Therefore, it can be less sensitive to treatments, which means that if a patient comes to me and I see that, okay, this patient is harboring translocation 14;20, I will be on my guard and expecting that the patient may relapse earlier than a patient of mine who does not have that translocation.

How is translocation 14;20 detected? Whenever we check a patient's bone marrow and we do that often at the time of initial diagnosis, it's kind of mandatory. We check a bone marrow biopsy. We send these cells for what is called as cytogenetics testing. Cytogenetics can either be karyotyping or a test called FISH. Karyotyping just arranges the chromosome in the order I mentioned chromosome 1 to 22 and then X and Y chromosomes. And we just look at it and see if there's any major abnormalities. FISH testing takes it one step above. FISH stands for fluorescent in situ hybridization. What we generally do is we send probes that can target these specific mutations, and that will light up under the microscope. And we can when we look at it, we can see that if it is lighting up, this person has that mutation.

So when we get the consolidated bone marrow report, the bone marrow report will show how much amount of cancer is present in the bone marrow, if cancer is present and how much is present. The second, if it's present, what is it characterized by? Are there abnormalities? Is the chromosome looking okay or are the mutations? And if there are mutations or translocations what are they. So the way I know that there is a translocation is by looking at the bone marrow biopsy, specifically the cytogenetics part of the bone marrow biopsy, which ideally should have a karyotype and a FISH testing that will give us these results.

To gain a deeper understanding of the genetic testing done in multiple myeloma, be sure to watch our course entitled Cytogenetic Testing in Myeloma.

Is translocation 14;20 considered a high risk mutation in and of itself? These are exciting times in which we are living. And a big change that is going to come in 2025, at which, as of the time of recording of this video is not published yet, is that the consideration that a standalone translocation 14;20 as a high risk may change, probably end of 2025, because there has been. The International Myeloma Working Group has met, and there has been a consensus that a standalone translocation 14;20 may not be enough to call it high risk anymore, and that the partnership with some chromosome one abnormalities may be needed.

However, this is, you know, as part of the discussion that happened at the International Myeloma Working Group, the paper should be out very shortly. So the definition is about to change. And so you know, just because you have translocation 14;20. And if you read online that this renders as high risk, it may not be true by the end of 2025. And please ask your provider what it means and how it changes your prognosis.

What other genetic abnormalities would translocation 14;20 need to be combined with to be considered high risk as defined by the new definition? So a lot of the translocations which earlier used to be considered as high risk, then you know, the translocation 4;14, 14;16, 14;20, they now most likely need to be combined with the chromosome one abnormality to be considered as high risk. But again, the one thing that is not changed from before, you know, the previous high risk definition to the new high risk definition is the fact that the presence of a deletion 17p or TP53, that's universally considered high risk. That has not changed from the previous high risk definition to the new high risk definition.

What is likely changing is that these chromosome 14 and its partner translocations may need an additional translocation to be considered high risk. To learn more about chromosomal one abnormalities. Make sure you watch the lesson on this topic in HealthTree University's chromosomal and gene abnormalities course.

Are translocations usually found at diagnosis? Can you acquire them later on? There are many timepoints in which we check bone marrow biopsies, usually at the time of diagnosis, at the time of suspected progression or relapse. And once we confirm ongoing remission, now there are time points in which we have seen that there is an evolution of the very nature of the myeloma. For example, if a patient had at the time of starting, they did not have any translocation. As the myeloma evolves and is exposed to a lot of chemotherapy, immunotherapy and treatments over the years, the clone that eventually survives tends to develop new mutations that are characteristic of myeloma.

So there is a very high possibility that way further along the line, these myeloma clones may develop new translocation, which is not present previously. So there can be an acquisition of deletion 17p. So for a patient who has been responding very well and has had a good response over years and was stable over the next few years, if you see that the myeloma is like relapse and really quickly, potentially you can see that it's an acquisition of new translocations, even deletion. 17p, TP53, translocation of chromosome 14, etc. and that renders the disease biology a little bit more aggressive.

So we often pay a close attention to every single time point in which new mutations that are acquired in the hope that we can treat them. And again in the future, there are any targeted therapies that ever will be developed against these. We keep an eye on it so that they can be eligible.

Are there any targeted therapies for translocation 14;20? So right now the only targeted therapy for any translocation which has been demonstrated to have any kind of effect has been a translocation 11;14 and that is with the BCL-2 inhibitors, Venetoclax and new drugs are being studied called sonrotoclax. Typically we have seen that there are some translocations with chromosome 14, especially 4;14, that may have somewhat more of a sensitivity to proteasome inhibitors. But then there hasn't been any clinical trial demonstrating a clear benefit for chromosome 14 translocations with any particular drug.

However, when we see that a patient does harbor these kind of translocations, we keep an extra eye out to see, you know, we keep a very close eye. This patient can have a shortened remission period and may be at risk for relapse very soon. And this is a patient that I would keep a very close eye on MRD testing. Like for example, if they're MRD negative, are they converting to a MRD positivity at some point. And if they did convert my MRD positivity, do they exhibit any signs of progression? So these are some things that I would keep in mind.

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