MRD Testing and Relapsed/Refractory Multiple Myeloma Treatment Options

Rafael Fonseca, MD: MRD testing has gained significant prominence as a diagnostic test at this meeting and previous ones. Obviously ,this refers to the determination of minimal residual disease status, positive or negative. And there’s a quantifiable aspect to this. More and more clinical trials are incorporating this. It’s still not a regulatory approved end point. However, as I mentioned in some of the comments regarding the transplant eligible patients, this is really becoming the goal for induction regimen, and I think from the get-go one is going to start thinking, “Let’s give this patient the regimen that has the greatest possibility of inducing that MRD negative status.”

Now, where do we use it? Clinically, it can be done by flow; it can be done by next-generation sequencing. In our institution I’ve done next-generation sequencing, and we use it at day 100 to determine status post stem cell transplant. And we share that information with our patients as we discuss the depth of their response.

We’ve used it also for patients who have sustained complete responses. Sometimes these patients may be on chronic therapy and chronic maintenance, and they may be experiencing some adverse effects and perhaps they’re considering discontinuation of therapy. It’s not like this is the “go” and “no go” signal. It’s just 1 bit more of information that is used for counseling of patients.

So in that setting, you have patients who have such toxicity or intolerance that no matter what, they’re going to have to stop that maintenance. You may have patients that are doing well enough and don’t have toxicity and who may be not wanting dose continued therapy, so you know we don’t have data to say they have to stop. But there’s an in between that’s quite large, and that’s how we have brought it.

To finalize with the MRD, this is how I’m thinking about it conceptually: There are 2 dimensions to myeloma therapy right now. The vertical dimension is how deep you go with your responses, and I think that boundary will be defined by MRD. And the second one is, for how long do you treat? And if you’re able to discontinue therapy, that means that boundary will be defined by MRD. So MRD is defining the boundaries of what we do.

In the treatment of patients who are experiencing a relapse, we have a plethora of options. But as we are getting back data from the various phase III clinical trials, I think things have been simplified. For most patients who are treated in the United States and go through induction therapy, and whether they have a transplant or not, most patients still keep some maintenance schedule. When they experience a relapse, there are 2 big choices right now. One is a daratumumab-based combination—I’ll explain in a second how we choose those partners—or a carfilzomib-based combination.

Now, given that the majority of patients will be placed on lenalidomide maintenance, if not more, the question comes up: Should we escalate the dose of lenalidomide, or should we switch agents altogether to something like pomalidomide? Practically speaking, most of us are switching to pomalidomide. So the 2 go-to regimens, if you may, for that first relapse are going to be DARA with PD [daratumumab with pomalidomide] or KPD [carfilzomib/pomalidomide/dexamethasone].

The selection of either one of those 2 regimens will depend on comorbidities and prior exposure. Now, this is going to get awfully complicated, because what you’re seeing at meetings like this is that it’s quite possible DARA will become frontline therapy for multiple myeloma, and it’s quite possible that K [carfilzomib] will become frontline therapy. So then we’re going to have think, OK, how do we go about treating that first relapse?

There are other agents that are being explored. Of course 1 of them is elotuzumab. Elotuzumab recently had a publication in the New England Journal of Medicine, a combination with pomalidomide and dexamethasone. In that particular clinical trial there was just a very small subset of patients who had prior DARA exposure, and that’s really an important clinical question. Now there are some trials that have looked at the combination of pomalidomide with cyclophosphamide. And then it’s not farfetched to think, well, maybe for some patients in relapse, one potentially could consider ELOS/CYCLO/POM/DEX [elotuzumab/cyclophosphamide/pomalidomide/dexamethasone] combination—so, 4 drugs.

Now, what about the dynamics of that relapse? You know for patients who are experiencing a slow biochemical relapse, I think we have time, so one could also and should consider things like ixazomib. Ixazomib has very good data based on the TOURMALINE study, in that case combined with lenalidomide and DEX. But, once more, we would do the switch to pomalidomide and dexamethasone, so that would be something else to consider in that scenario. And sometimes you’ll switch to a single agent, but most people are really embracing the concept of at least a triplet.

We presented some data at this meeting, that once myeloma goes out of control it becomes hard to control. And there’s a high rate of attrition between the different lines of therapy. So if you can’t control myeloma in the first treatment, don’t do it in the second-line. There are a set of patients going to be able to get a third- or a fourth-line diminution. In this meeting, our data were for nontransplant candidates, and we showed a 50% attrition rate per line of therapy. So one has to be mindful of those things.