What testing should be done to confirm a SMM diagnosis?

What testing should be done to confirm a smoldering multiple myeloma diagnosis?

So if you're diagnosed with smoldering multiple myeloma, by definition, you should have had all the testing that had been done if you were diagnosed with active multiple myeloma. Because we need to prove that you have multiple myeloma that is not hurting your body.

So you should have had bloodwork, urine, you should have had a bone marrow biopsy. And you should have had imaging of your bones. And it's not just x-rays. The X-ray is not enough; by the time you have something appear on an X-ray, 40% of your bone has to be destroyed by a tumor or lesion. So that it's a little too late. It's not sensitive enough.

So if you do have an X-ray and it's negative, then you have to have at least a whole MRI, preferably a whole body MRI, but it could be an MRI of your entire spine and pelvis looking for hidden lesions. Because if you have at least two small lesions, you should be treated as active multiple myeloma. If that is negative, then you potentially are a smoldering myeloma patient.

So you should have all that testing done to prove that you have smoldering multiple myeloma and not active multiple myeloma.

In terms of smoldering myeloma, smoldering myeloma is a tricky diagnosis. We have very clear diagnostic pathways and diagnostic definitions for MGUS (monoclonal gammopathy of uncertain or undetermined significance) and active multiple myeloma, which often has what we call CRAB criteria or slim CRAB criteria. And smoldering myeloma by definition is the absence of those two.

So in brief, to say for sure that someone has smoldering myeloma, I have to be sure that today I have MGUS and then most importantly, they do not have active myeloma. The difference being, in real life, smoldering myeloma and active myeloma exist along a continuum, and some patients with smoldering myeloma will go on to get active myeloma. The question is, when do the benefits of treatment outweigh the risks?

And traditionally speaking, that has been when there have been symptoms, for example, spots in the bones, bone pain, anemia causing fatigue, kidney damage.

We've changed the continuum just slightly. So for example, someone who has spots on an MRI in the bone marrow, even if the bones that are outside the bone marrow are untouched, if the bone marrow itself shows any abnormal spots, we now call that active myeloma.

If the ratio of kappa to lambda or lambda to kappa, which is the free light chain that many of you have heard of, if that ratio is wildly off—over 100 to 1 in either direction—we call that active myeloma because we say, look, even if there's no CRAB criteria, no kidney damage, it may be happening soon and we should intervene.

Similarly, if we do a bone marrow biopsy and more than 60% of the cells are plasma cells, meaning that the bone marrow itself is functioning at less than 40% capacity, if a normal bone (like a hip bone that's presumably unaffected) has 60% or more plasma cells, the other sign is that there's going to be a spot chewing into the bone marrow around it soon, and we choose to intervene.

So with that prelude in mind, smoldering myeloma is by definition not MGUS. So the difference here would be, for example, if the M-spike was more than three for US units (3.0), or if there were more than 10% plasma cells, I would say, look, this is probably not MGUS. There's a little bit more than I would expect in the bone marrow, so I would call that smoldering.

The key question for me when I see someone with presumed smoldering myeloma is, I do have M-spike over three, or they have something about their light chain ratio or something about their presentation that makes me say that this patient probably has more than 10% bone marrow plasma cells, and probably a smoldering myeloma and not MGUS.

I do a bone marrow biopsy to look. There are risk prediction tools that we can use. One is from the Mayo group and one is from Iceland called iStopMM to help us say who doesn't have MGUS and who has smoldering myeloma.

Once they get to that point, so they have smoldering myeloma, now the big question in my mind is, how do I make sure that they do not have active myeloma?

Some of the tests in my head are pretty easy. So the traditional CRAB criteria that many of you may have heard of are pretty straightforward. C is high blood calcium. If they have high blood calcium, we should talk. We should look. R is renal. So if they have any type of renal insufficiency or kidney damage, or if the creatinine is off, there's a test we can use to figure out what's causing that—whether it's myeloma versus not. If they are anemic and I cannot figure out why the hemoglobin or hematocrit are low under complete blood count, and I can't figure out why, that may be the active myeloma. And B as in bones—if there are spots in the bones on an X-ray, on a CT scan, or on a PET CT, that is myeloma, like no negotiating with that, because those bones can fracture if something has chewed out of the bone marrow and into the bone around it. We need to move very quickly on those particular patients.

The other part, a little bit more controversial, but I think it's very established as part of myeloma-defining criteria, is more than 50% plasma cells. If someone's gotten a bone marrow biopsy, I already know that answer. If the light chain ratio is more than 100 to 1 in either direction, even if they have no CRAB criteria, I call them active myeloma. That should be readily available.

So the one last one I had to say for the end—this is the one that I think people sometimes forget to check—is an MRI. Remember again that an X-ray is not a very good test at all, but a CT scan or a PET CT scan can pick out the bones in very good detail. If something's chewing into the bones, the PET scan or a whole body CT scan will identify that. An MRI can go a step further because it can look inside the bone marrow. It's actually not very good for the bones; it's good for the bone marrow that's inside every bone, including the hip bone, which is where bone marrow biopsies occur.

So I would say if someone has multiple myeloma, to be sure that they do not have an M and CRAB slim as a myeloma-defining event, you need to do an MRI. Ideally, there should be an MRI of the bone marrow, also called a whole body MRI. Or if that's not possible, a lot of centers don't know how to do that, and the radiologists haven't been trained to put that into their protocols. An MRI of the skull, the spine, and the hips is often sufficient.

Some patients cannot get MRIs because of logistical issues, metal, or claustrophobia. That's okay. We can just keep a close eye on them and do serial imaging. But I will say that if someone can get an MRI to confirm the diagnosis of smoldering myeloma and not active myeloma, it's worth it.