What do I need to know about is translocation of (4;14) in multiple myeloma?

In a previous HealthTree University lesson, we explored how multiple myeloma can be classified into six distinct genetic subtypes.

Now it's time to take a closer look at myeloma that displays the translocation 4;14.

What is translocation 4;14?

So translocation 4;14 is when chromosome 14 and chromosome four merged together. So there's a translocation meaning a piece of chromosome four is now expressed on a piece of chromosome 14.

Chromosome 14 is where the heavy chain of an antibody is produced. So not surprisingly that's very highly expressed in myeloma patients because they're making lots of antibodies. So what else binds with chromosome 14 is oftentimes overexpressed in these patients.

So chromosome four, the specific translocation, is an FGFR3 and something called the myeloma SET protein. So those now get overexpressed in myeloma patients.

Whether or not this is high risk is somewhat controversial. Originally it was deemed to be a high risk criteria, and the IMW added it to the high risk criteria in 2014, and it still remains there. The IMWG has revised their definition of high-risk multiple myeloma.

Currently, t(4;14) is considered high-risk if it occurs in combination with a chromosome 1 abnormality.

This was before we had a lot of the types of treatments that we use commonly these days, and what we know is that the 4;14 patients actually respond quite well to proteasome inhibitors.

So previously we thought that 4;14, where we knew that 4;14 was associated with the worse prognosis, which is why it became a high risk criteria. But now with more commonly used proteasome inhibitors, that may not be as much of an issue as it used to be.

Should proteasome inhibitors be used as part of maintenance therapy in patients that have translocation 4;14?

With the 4;14 patients, they certainly do benefit from having a proteasome inhibitor as part of their induction. And likely as part of their maintenance should they go through transplant. So, I certainly would, would recommend a proteasome inhibitor at least, or a proteasome inhibitor plus an IMiD as a maintenance-based regimen post-transplant in these patients.

There are some trials that are currently looking at SET inhibitors in myeloma patients. And those are enriched for patients who have a 4;14 because, as I said earlier, the SET protein is expressed on chromosome four. So when patients have a 4;14, they get overexpression of MMSET. So there are some trials that are currently looking at specific inhibitors of that specific protein to see if that's going to be effective in myeloma patients.

So it's one of the common panels, the part of the common panel that's tested in almost all myeloma patients. It's present in about 15 to 20% of myeloma patients. So it's certainly one of the more common translocations that we'll see.

It appears to be something that is not what we would call a founder mutation. So it's not necessarily always present at the onset of someone's myeloma. If you look over time, patients with myeloma have higher levels of 4;14 than patients with smoldering myeloma. We have higher levels than patients with MGUS. So it seems to evolve over time.

And even in patients with myeloma, you would think that it would be more common in patients with high, more relapsed disease that have been through multiple lines of therapy than in patients who maybe are just newly diagnosed.

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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