How does smoldering myeloma become active myeloma?

How does smoldering myeloma become active myeloma?

Patients often ask me two questions. So one, how does smoldering myeloma become active myeloma. And two is smoldering myeloma in and of itself dangerous. And so I'll answer both questions a bit by bit here.

So first how does smoldering myeloma become active myeloma. The idea is we often talk about this snowball analogy, a snowball rolling down the hill as this rush to gain control and roll down the hill again momentum and travels faster and faster and faster. If you imagine DNA mutations or mutations to the smoldering myeloma cells, that is probably what we're seeing, that the cells that having mutation that makes them grow faster, by definition, grow faster and outpace their peers. And then there's more of them. And then they pick up another mutation and grow faster and faster and faster. So that's typically what we see.

And sometimes we see mutations in genes that make the cells grow faster. Or we may see mutations in genes that make the cells other able to make them chew from the bone marrow into the bone around them more. Remember that that's the myeloid defining event. You may see mutations that make them, even if they're not growing more, they start spewing out their protein more, kappa or lambda more. And that can cause its own problems of kidney damage. And what we're starting to learn is that, you know, the immune system plays a very big role in this. And so patients with an altered immune system are at higher risk of smoldering myeloma becoming active myeloma, probably because your immune system is not able to keep things in check.

What's really interesting and there is work happening, you know, within the HealthTree collaboration of partners, where we shot month long, currently working off recognition of this work around a gut microbiome, for example. Many are, but she's one of them where the idea is that actually someone with smoldering myeloma, if you can keep their gut microbiome and make that means the bacteria that live in all of our gut, that colonize our guts, certain types of them play more friendly, cause less inflammation, and are able to keep your immune system on target. Both, you know, focusing and preventing smoldering myeloma from becoming active, myeloma and not causing more issues and more inflammation within the gut.

And so there's this theory actually, that maybe down the line we have to prove this, but it may be that for some people, smoldering myeloma, there are preventable things that we can do to kind of keep their immune system at top capacity to prevent this. smoldering coming into active myeloma, we're not there yet, but we might.

The second question then is, well, is smoldering myeloma a problem in and of itself? The answer is by the book. No. By definition, if it were causing a myeloma defining event, then we would call it active multiple myeloma. In real life, I will say it's a little bit trickier than that. It's obviously always more tricky than that. So two things I'll say. One, there are Perry myeloma conditions. So not myeloma but other conditions where the cells aren't the problem. The protein is a problem. For example, Al amyloidosis or POEMS syndrome or there are certainly there are other examples of monoclonal gammopathy of renal significance where basically instead of the kappa or the lambda or the m-spike protein just being a junk protein that goes from the myeloma cells, or in this case, smoldering myeloma cells into the blood and out, sorry into the blood, into the urine and out, I should say, in these conditions, the protein is causing problems. In amyloidosis, It causes clumps that form in various organs like the heart, the kidneys, the nerves. And POEMS syndrome. You produce this abnormal levels of this protein called VEGF that can cause its own complications later.

There are other examples like that. So in those particular patients, if someone has smoldering myeloma and a diagnosis of Al amyloidosis, I call them Al amyloidosis for intents and purposes thereafter. And I treat them. So in those particular patients smoldering myeloma is absolutely causing problems. And we manage them accordingly.

In terms of exploding myeloma cause problems within the bone marrow within the bone marrow microenvironment. It's very controversial whether patients with MGUS or smoldering myeloma are at higher risk of osteoporosis versus not. Studies have, you know, conflicting conclusions about this in terms of, you know, what kinds of patients they look that what kinds of precursor conditions they had MGUS versus smoldering versus not, and so forth.

In general, I say that the answer is no. The smoldering myeloma is not sufficiently modifying the bone marrow or the bones by itself to put someone to make someone osteoporotic. So, for example, if someone had osteoporosis in smoldering myeloma, I would not say, oh, this is active myeloma.

However, if someone already has high risk smoldering myeloma, I'll say this out loud and they have osteoporosis. I have had patients where I talk to them about the benefits and risks of treatment of high risk smoldering myeloma, and the fact that they already have weakened bones at baseline does, meaning that they're more theoretically predisposed, more at risk of getting a fracture if the smoldering becomes active myeloma. That does alter how they think.