What is smoldering (asymptomatic) multiple myeloma?

What is smoldering multiple myeloma?

Smoldering myeloma is defined as having 10% plasma cells or cancer cells in the bone marrow. Now, that's a very arbitrary definition because I can do a bone marrow biopsy and one side has 5%, the other side has 30%. So suddenly I'm MGUS on one side and I'm smoldering on the other side. That doesn't make sense. And we know that even two pathologists can look at the same pathology slide and see, Oh, this looks like a 5 to 10. And then another person would say, No, this looks like a 10 to 15. So suddenly you changed as a patient from MGUS with a 1% chance of progression per year to smoldering, which is 10% chance of progression per year. So just as we think about it, a patient is not divided into MGUS and smoldering. It's a continuum. And we put those arbitrary definitions. We put those numbers just for us to talk to each other. But that does not mean that a patient suddenly changed between MGUS and smoldering. It's really a continuous disease and we need to treat it that way.

Is smoldering myeloma considered cancer?

Smoldering myeloma is a very heterogeneous area. It's basically a bucket of a lot of people, a bucket of people who may be more like MGUS and may never develop myeloma and a bucket of people who are very active disease, almost myeloma. And it's just waiting to have the first fracture or the first anemia or the first kidney problem. And we put all of that into 10% plasma cells or more and no CRAB criteria. Well, that's very hard because you have a lot of people who are behaving very differently. So the first thing we need to do is trying to redefine smoldering myeloma correctly. And we're doing now a lot of next-generation sequencing where we're truly defining who is at risk of progressing and not just by using the M spike or the light chain, but using genomics, using the biology, using the immune microenvironment to dissect truly who is that patient who would progress in two years. These are the patients we need to treat. And who are the patients who may never progress? Let's leave them alone and observe them carefully, and that needs to be redefined. So I would say smoldering myeloma needs to be redefined.

What are symptoms of smoldering myeloma?

Smoldering myeloma should have no active symptoms of myeloma, so we don't have the hypocalcemia, the anemia, the little lesions, the renal failure, and we don't have other markers to 60% plasma cells. Having said that, patients do have symptoms. We just don't capture it because we don't have a database of all of the other symptoms. I see patients with neuropathy, I see patients with fatigue, I see patients having rheumatologic-like things. There are symptoms related to it. We just don't capture it correctly. And it's very hard to capture fatigue and other things that are not very objective.

How long can you have smoldering myeloma?

In general, The rate of progression of smoldering myeloma is 10% per year, but that doesn't mean anything. There is a chance every year that you have myeloma and a chance that you would never have myeloma, 90% chance that you would not have myeloma. And within the first five years, that's the highest rate of progression of 10% per year, 50% in five years. However, people confuse those curves later on and say, well, if I've already had five years, then I'm actually fine. I'm not going to develop myeloma. That's not true. What we know from that large cohort of data is because it was so heterogeneous, the ones who looked more like myeloma, the high risk was the ultra-high-risk ones, all developed myeloma very fast within those first five years. So the ones left over are the ones who have a better prognostic markers are the ones who likely are the MGUS like, and they can still develop myeloma, but the risk of progression is much lower because all of the ones who are going to have bad disease already had the disease happening.

When does smoldering myeloma become active myeloma?

When we have certain criteria, then we call this active myeloma. So the difference between smoldering myeloma and active myeloma is just presenting with end organ damage, meaning you've damaged enough organs that we have to treat you. And I would say let's step back and say any other cancer, you never do that. You never wait for someone to have a fracture or anemia or kidney failure, and then you treat them. So by definition, two words active myeloma versus smoldering myeloma is a misnomer. Everyone has myeloma, and it's a question of do they need treatment or not, and what are the criteria of treatment? We've already moved the bar from CRAB criteria alone into let's add a few more, which was what we call SLiM CRAB. And hopefully in the future we will add a few more to make sure that we treat at the right time. What we don't want to do is over treat certain patients who will never progress to myeloma. And that's the gray area. This is where we don't know who are those patients we should treat. And we have an opportunity now to do it in the right way, to do it scientifically, rather than just putting one marker and treating everyone.

Anything else about smoldering myeloma?

I think in general, smoldering myeloma needs to be redefined. But there may be an entity still that's called smoldering myeloma. They're not MGUS. They're not the high-risk group. There is that intermediate group, and it just needs to be defined correctly with the understanding of the biology underlying these patients. But I'm not saying that we will remove smoldering myeloma. There is an intermediate between MGUS and myeloma. We just need to redefine it correctly.