What are relapsed refractory myeloma? What is the difference between them?

So, when we're talking about multiple myeloma that a patient has had for however long, and they were treated originally for it and responded, and it went back away, when it first comes back, that's relapse disease. So basically, where you get to a point where there's less than where you started and it starts growing again, that's generally relapsed.

When you're talking about refractory disease, you're talking about a kind of myeloma that is either not responding to treatment, meaning that you just had your first relapse. You started on new treatment and your M-spike doesn't budge—that's refractory. Or technically, it's that it grows again within the first 60 days of starting treatment.

So, we're talking about a concept of myeloma growing back as relapse disease or refractory disease, meaning that the treatment just doesn't work.

Relapsed myeloma suggests that the disease is out of control. It's either getting worse off or on therapy.

Refractory disease, from usually a clinical trial standpoint, and the way myeloma physicians describe it, is myeloma that has not been responsive to therapy or started progressing within 60 days of stopping therapy.

Oftentimes, clinical trial eligibility says that a patient has to have relapsed disease and has to be refractory to the last line of therapy, meaning they progressed, or the disease became out of control, while on treatment or within 60 days of stopping treatment.

That way, it's trying to insert some sort of homogeneity into the type of patients described in a clinical trial so that we're not describing some patients who have lingered on without any treatment for years versus those patients who've gone from treatment to treatment to treatment, one right after the other.

So, when we look at the myeloma literature, when we see new information being presented, we often see a characterization of the population as being relapsed refractory, or relapsed or refractory to a certain drug. And that, over time, has generated a lot of confusion as we try to compare results of different trials.

So, there is a harmonization of nomenclature that was put together by the International Myeloma Working Group. And to make it very simple, a patient’s disease is considered refractory to a given drug if the myeloma progressed while the patient is on that drug or within 60 days of discontinuing the drug. The patient is considered relapsed if the disease evolves or comes back after that regimen or that drug has been discontinued for more than sixty days.

I think one typical example is, let's say, the patient receives therapy—a very typical scenario. Patients receive therapy with RVD, let's say, for a year. After the one year, the patient continues on lenalidomide (REVLIMID), and at some point, the myeloma progresses. I mean, the M-spike goes up by more than half a gram. Well, at that point, the patient is considered refractory to REVLIMID but is relapsing after Velcade, so the patient is not considered refractory to Velcade because Velcade was discontinued more than 60 days ago.

Those definitions are somewhat arbitrary but give us some guidance when it comes to managing patients, and particularly when it comes to interpreting data from clinical trials.

With relapsed diseases, does it grow back off treatment or on treatment?

It can be, in theory, either. I mean, more often than not, patients are not off treatment all that often. So that's why oftentimes we say relapsed/refractory because relapse can be on or off treatment. But when it's often on, that means they have become refractory to whatever treatment it grew on when it relapsed.

Are there any biomarkers that will identify that myeloma has relapsed?

So, there are different types of relapse disease, and we can define them a bit better going forward. But generally speaking, you need to have some degree of M-protein or biochemical lab results that basically signify that the disease has returned. So, that could be an M-protein value, generally that's more than 0.5 grams per deciliter in the blood. Then you have certain other parameters in the urine. Also, the serum free light chains could potentially be elevated, suggesting that the disease has returned.