What is a Biochemical vs Clinical Relapse?

What is the difference between clinical relapse and biochemical relapse?

Biochemical progression is different from clinical relapse. So when we say biochemical progression, it means that your M spike or your myeloma has been treated to a point where the number hits something nice and low, preferably zero, let's say. As we notice that your myeloma starts growing back and your M spike starts rising again, we can trend that number and see that the spike goes from zero to 0.2 to 0.5 or whatever that may be.

The concept of the number rising before it has actually caused any problem in your body, that CRAB criteria we talk about, is true biochemical progression, as opposed to clinical relapse, which means that the myeloma has started to grow to a point now where it's affected your body in some way. So new plasma cytomas, new bone damage, new anemia, new hypercalcemia, and new kidney dysfunction. That is true clinical relapse.

And what we're really just trying to hope to avoid as best as we can.

So first of all, we need to talk about relapse. There are two kinds of relapse. You have biochemical relapse, and you have symptomatic relapse. The biochemical relapse is the myeloma protein is going up, the light chain is going up. The symptomatic relapse, you have anemia, you have bone disease, you have kidney failure, you have extramedullary disease, the tumor growing outside the bone marrow, forming little tumors.

That is different than biochemical relapse. Sometimes we don't treat biochemical relapse. We see what is the tempo of the relapse. So if the myeloma protein was zero and now 0.5, we may not do anything. We will wait another month or two.

And if staying around 0.5 and the patient’s asymptomatic, we kind of wait a little longer. There is some argument about that because people say, you know, the pros will say, yeah, 25% of the patients will stay with that progression for a long time. But then some people will say some of these people start relapsing in six months and having symptomatic disease.

Why wait?

But all clinical trials are actually based on biochemical relapse, you know. So what we learn about the outcome of patient is based on biochemical relapse, but you don't have to jump the gun with biochemical relapse.

So basically, when you're dealing with biochemical relapse, you're saying, and you're trying to communicate, on average the numbers are going the wrong way and usually doubled.

And usually have an absolute increase. So there's 500 milligrams increase in the monoclonal protein in the blood, 200 milligrams increase in the monoclonal protein in the urine, and 100 milligrams per liter increase in the serum free light chain or essentially doubling from where they were. 25% increase from their lowest level is usually thought to be a biochemical relapse, and that's there.

When you have a clinical relapse, it is tucked together, meaning that whether they had those numbers or not that led to a biochemical relapse, they have worsening myeloma.

So you can have a very slight increase in your monoclonal protein. But if you have a new lytic lesion, if you have a new spot and your PET scan or you become hypocalcemia can start to be related to your plasma cell disorder, that's clinical relapse. So it's a clinical sign or symptom that leads you to begin treatment almost immediately.

Do you change treatment immediately at biochemical relapse?

There's two answers to that. If only it was that easy. So as a part of it is understanding how quickly is your myeloma growing?

Because much of what we do with myeloma is trying to kick the can down the road, and we want to make sure we're intervening on changing or growing myeloma at the right time before it causes any effect on your body.

So if we see that your myeloma and your first M spike check is up just a smidge, we want to check it again to see how much more of a smidge it's increased.

If we find that two data points in a row are changing where it's growing, the first question is, how quickly is that happening? Is it doubling?

Is it tripling? Is it quadrupling? Or is it really just having a very slow, steady rate of rise?

The patients who are growing quickly and the patients for whom which have known higher risk disease are the patients we need to intervene upon quickly because we don't want that to take off faster then and cause organ disease. For patients who do not have high risk disease and have a slowly changing or rising M spike, we may be able to watch them because those patients may not budge or change all that much over the course of the next many months.

And maybe we don't need to introduce new medicines and therefore side effects, etc. So everyone relapses differently. It's a matter of trying to intervene before any damage is done.

So treatment for relapsed disease generally is pretty quick. Usually you don't have a lot of time to think about it, but that's for clinical relapse. For biochemical relapse, you sometimes have some time to think about it. In fact, you can have quite a long time to think about it, and what you want to do as a myeloma physician is try to basically not treat the patient for a number.

You want to treat the patient when clinical symptoms are coming down the track. You can see them coming, and you need to treat the patient to get them off the track so they don't get run over. You don't want to have the patient have fractures, anemia, or kidney failure. You want to treat the patient to prevent those complications, but you don't want to treat them if their monoclonal protein goes from 100 to 200 to 300 to 400 over a space of 12 months, and the patient is asymptomatic. Their life is not going to get better with treatment for a number.

So you need to be able to have some confidence that you can see clinical relapse coming down the track and that's when you treat them.

People will often ask me, okay, Craig, my myeloma is here.

At what point, what monoclonal protein level do I need treatment? And I never say there's a particular level.

What I need is slope of the curve. When their change of their monoclonal protein, their light chain, whatever we're using to best describe the status of the disease, when that starts changing, the slope of the curve starts changing. That's why we need to treat them.