DR LOVE: Let’s get back to the nitty-gritty of clinical practice because I really want to start to get into this issue. I mean, it wasn’t that long ago that carfilzomib and pomalidomide entered practice. Now you’ve got 2 monoclonal antibodies. You’ve got ixazomib. And it’s just very confusing to figure out what to do, I think, for a lot of people in practice. So maybe we can get into this by pursuing a little more case discussion and see how you actually make these decisions.

DR RAJE: I have this young person, 45-year-old gentleman, who presented about 4 years back, so he was a lot younger. He got the standard triplet treatment. We gave him lenalidomide/bortezomib/dex. He got transplanted. He got lenalidomide maintenance, which he had for about 18 months and then progressed with bony disease. He had a T6 plasmacytoma with near cord compression but no neurological symptoms. He got treated at that time with a little bit of palliative radiation to T6, and then we put him on carfilzomib/pom/dex. And carfilzomib/pom/dex again got him into a VGPR.

DR LOVE: Now, how long ago was that?

DR RAJE: That was 18 months. So that was 2 years back. And then he continued the carfilzomib/pom/dex for close to 12 months.

DR LOVE: It’s interesting how patients are going through things as things change. And initially there was a lot of discussion before the daratumumab stuff and the elotuzumab stuff came out, Rafael, for example, about doublet versus triplet therapy, aggressiveness of treatment of first relapse. You have a young patient here. Then monoclonal antibodies came in and that was a whole other discussion. But what about this therapy that he got, the car/pom/dex? Where does that fit in right now in your relapsed algorithm? Is dara pushing that away?

DR FONSECA: Well, that’s one of the biggest questions right now: How are dara and carfilzomib going to play in that space of the early relapsed disease? I think this is obviously one of the best regimens we have, carfilzomib/pom/dex. And the way people are thinking, they’re thinking that front line, for now — and this could change 2 months from now — but the front line, for now, belongs to the bortezomib/len/dex. Then there’s a transplant, if the patient has a transplant. But early in the relapse, we’re thinking immediately of carfilzomib and pomalidomide. And the one that’s knocking on the door is of course daratumumab. And that’s one of the biggest questions. From what I understand, some of the newer guidelines for treatment of myeloma will bring daratumumab to this line for the early relapsed patient.

DR LOVE: And there always is the issue of regulatory issues and reimbursement issues. But what about this issue of early relapse? Would you have treated this patient the same at that point today?

DR RAJE: That’s a great point. And I think when you see the POLLUX data, when you see the CASTOR data, it’s going to be 1 to 3 lines of treatment. So this patient would have been able to get daratumumab.

The question is, patients are going to get this earlier and earlier in treatment. In trials, we are already bringing these monoclonal antibodies in the up-front setting, Neil. So we are going to be doing studies with drugs like daratumumab in combination early on. And I think the reality in the very near future is monoclonal antibodies are going to be incorporated pretty much throughout the process of treating a patient with myeloma.

DR LOVE: Would you really like to give dara/carfilzomib/pom/dex?

DR RAJE: Up front?

DR LOVE: No. At early relapse?

DR RAJE: Early relapse, aggressive relapse? Absolutely. And, in our practices, when patients are relapsing after 3 and 4 lines of treatment, we are beginning to resort to triplets with the monoclonal antibodies. I don't know if you do that, Rafael, but I have very sick patients where we are combining all of these drugs.

DR FONSECA: Yes.

DR LOVE: Well, what about this issue? Again, in the pre-antibody era, you were hearing people talking about this concept of trying to drive tumor burden down as much as possible in early relapse. We kind of got that up front. And we were talking about the SWOG study, for example. But what about in early relapse? In your mind, are you trying to quickly get the tumor burden down as much as possible?

DR FONSECA: Sure, and I think things change so fast. I think everyone agrees now that we go very intense, with a goal of an MRD-negative status after front-line therapy. Now, until recently, everyone thought, in the case of relapsing myeloma, it’s more the chronicity of therapy. And how do you align all of those therapies? And I think that’s a very important concept, particularly as we talk about elotuzumab.

But then there may be an in-between dose too. And that is, when you have regimens like the ASPIRE trial with KRd, you’re reaching 30% CR. I mean, you have trials like what was presented with the POLLUX. It has 43% CR.

DR LOVE: That’s len/dara.

DR FONSECA: Right, daratumumab/lenalidomide and dexamethasone. So we have 2 regimens that produce very high rates of response, as high as it used to be with what we got in the past with induction therapy. So I think we’re going to drill for that still in the first relapse, perhaps not for fifth- and sixth-line therapy.

DR RAJE: I think you have to be a little bit careful, also. In the relapsed setting, I think it’s important for us to appreciate that not all patients need all of this treatment. There is something known as a biochemical relapse. And it almost is analogous to what we’re thinking about in the smoldering myeloma space. Do we need to jump on the bandwagon and start treating all of those patients, or can I watch some of these patients a little bit before subjecting them to treatment? Those are harder questions to ask and harder questions to answer in terms of a clinical trial. But there are plenty of patients where you might have a monoclonal protein going up a little bit and who do well for years and do not need to go through the toxicity of all of these treatments.

DR LOVE: I want to find out what happened with this man and where he is right now. But just to keep with where we were, more practically, Rafael, at that situation of first relapse when this patient got carfilzomib/pom/dex, that was 2 years ago. Today, what’s your best guess in terms of what you think that patient would have gotten from you?

DR FONSECA: Probably I would have substituted the carfilzomib for daratumumab in this case. Another question would be whether you stick with pomalidomide or we go to lenalidomide. But I probably would just have substituted carfilzomib. So I would have done daratumumab/pomalidomide and dexamethasone. And this would be a pretty classic scenario right now, where I would think about that combination.

DR LOVE: Agree?

DR RAJE: I think he has a few options, really. The reason he went onto pomalidomide was because he was progressing on lenalidomide, and he was progressing aggressively. He was a young guy. He needed a triplet combination. So I would go with either carfilzomib/pom/dex or I would consider using daratumumab/pom/dex, either way. I would also consider pom/bortezomib/dex. Because he hasn’t seen a proteasome inhibitor now for about 18 months.

DR FONSECA: To make our lives a little bit more complicated, I don’t think a myeloma diagnosis means that if the patient is resistant to pomalidomide — or the cells of the patient are resistant to pomalidomide, better said — it doesn’t mean that 100% of the cells are resistant, number one. And it doesn’t mean that they’re resistant completely, zero to 100%. I think a lot of these drugs that affect normal plasma cell biology, they push to a point. Perhaps they don’t reach apoptosis. But then if you combine lenalidomide and dexamethasone, you can push those cells into apoptosis. If we combine lenalidomide and carfilzomib, then you can get those cells to go into apoptosis.

So I don’t think resistance is always an all-or-nothing phenomenon in myeloma. And that’s why a drug may not be working on its own but may be contributing significantly to a combination down the line. And we see that over and over from the clinical trials.

Diagnosis and management of smoldering myeloma

Induction, consolidation and maintenance therapy for MM

Treatment of relapsed/refractory MM

Novel approaches under investigation for MM