Are there any targeted approaches for specific genetic subsets that patients should ask about?

Are there any targeted approaches for specific genetic subsets that patients should ask about?

So targeted therapy in myeloma, in fact, we just essentially have two

So, venetoclax targets the 11;14 translocation, particularly because those patients over express an anti-death protein, their myeloma expresses an anti-death protein called BCL two and venetoclax specifically targets that.

And the other one other targeted therapy that we have is actually for a mutation called BRAF.

It's more commonly much more commonly found in melanoma, not multiple myeloma, but some myelomas have it, it’s relatively small percentage and evidence suggests that you can use the BRAF inhibitors which have been developed for melanoma skin cancer to use in myeloma.

Now that's probably the only two that are really out there that are truly targeted therapy and there are opportunities that there may be other targetable mutations in myeloma.

RAS is one of them, MYC is another one, but those drugs aren't available.

And one of my my good friend Larry Boyce is down at Emory

Actually makes the point that if you look at what most of the vast majority of our myeloma drugs target, it's not the myeloma.

It's actually the normal biology of being a plasma cell, which is the normal cell that myeloma cells arise from our plasma cells.

And the vast majority of our chemotherapy actually targets the normal plasma cell biology. It doesn't target the cancer mutations.

Now, that doesn't mean that won't change. And again, the idea is that next generation sequencing will allow us to understand that better and perhaps define new targets that we can actually target.

But again, the challenge for targeted therapy is that not every myeloma clone in your body is going to have that mutation.

So you might kill off 80% of the myeloma, but 20% don't have that and they'll grow. So again, I think what we are really looking at in effective therapy against myeloma are overlapping and stacking treatments on top of each other that don't lut.

So if you have three different kinds of treatments that are killing the myeloma cells in very different ways, it's hard for a myeloma cell to evade that because it's being, you know, attacked from three different angles as opposed to, you know, this idea of a single drug.

All right, you're going to get rid of some myeloma, but a lot of it, you know, there's going to be stuff that's leftover that's just resistant to it so.

If you want to target a drug to a specific subset of patients, you obviously need a diagnostic test to find those variants.

So mutations that give rise to resistance to revlimid., thalidomide, pomalidomide are quite common at relapse.

Knowing if you have one of those can be important because maybe you should swap to a different class of drug or to use one of the more modern, more powerful drugs that target the proteins more efficiently. So that's one area I think is very important to know if you have an 11;14 translocation because those are the cases that will respond to venetoclax where the other ones don't respond as well and the drugs not indicated.

So very important.

You want to know if you have a RAS mutation or a BRAF mutation because there are specific therapies for those.

And I think we're going to start to exploit mutations in that pathway more in the next or the next years that that come up. So yeah, I kind of think there's a lot of information and even knowing if you have a P53 mutation, biological inactivation of p53, while not good prognosticly.

I think it's important to know if you have one of those mutations because it can allow you to choose the most appropriate approach to treatment for yourself and to avoid alkylating agents, which are unlikely to work in the context of those mutations.

What testing is used to help identify mutations unique to your myeloma.

So certainly for the 11;14, it will be either seen in cytogenetics or fish.

So these are the molecular tests that should be done on every myeloma, every myeloma patient's bone marrow from really at the time of diagnosis and the time of relapse, because new mutations will develop new new genetic changes.

So the 11;14 translocation is it can probably be most readily seen on this fluorescent in situ hybridization technique that again, everybody should have.

BRAF mutation’s a little bit harder that actually does require, for the most part, next generation sequencing or sequencing of the myeloma to actually look for those mutations in the myeloma cells.

If you don't have a particular mutation at diagnosis, can it pop up later on in the course of your disease?

so if you don't have a particular mutation at diagnosis, they can develop as you relapse. Because in more specific examples, the 11;14 translocation so they can develop as the patients progress, which is again why myelomas need to be looked at when patients relapse.

You can assume that the myeloma that happens when you relapse is exactly the same as the myeloma you had at the very beginning.

What clinical trials are looking at actionable mutations.

there are some clinical trials that are looking at actionable mutations like the my drug study within the Multiple Myeloma Research Foundation.

So if you have a myeloma research consortium member site close by, I think it would be a good idea to consult with them. You know, if you have been exposed to a PI an IMiD to see if one would qualify. I think the my drug trial specifically is focused on high risk patients who may be having a relapse for the first time.

So if your care team has identified you as high risk, it would be extremely important to kind of have that consultation. That would be the time to get that genomic analysis done.

There will be more trials coming in that are genomically focused. So just, you know, stay in touch with your Myeloma Center of Excellence and see if that may be an option for you.