Transcript:Keith Stewart, MB, CHB: I want to move on now to transplant-eligible patients, the younger population, and I think we'll all agree that this is not an age-dependent phenomena, it's at least up to the age of 75 or so, it's more to do with physical performance status. So that said, let's do the same thing. Let's ask each of you to say what you do today and what you'd like to do maybe if insurance wasn't a barrier. So, Jatin, what do you do today for the younger transplant-eligible patient induction therapy?

Jatin J. Shah, MD: Good question. So I think there's a couple of key principles here. One, the depth of response matters. And so I think that the deeper the response going into the transplant, the better these patients do, the better product you collect, and so I think that's important. And number two, I think that we're going to be giving a short course of therapy, and so the goal is in a short time frame to get the best response we can.

So for us, we use a three-drug combination off protocol with either VRD or carfilzomib with Revlimid/dexamethasone. But I think more importantly we have a clinical trial now. We're going into four drugs, as Paul mentioned earlier, and so we have a nice trial with RVD plus panobinostat. So looking at incorporating HDAC inhibitors in earlier lines of therapy.

Keith Stewart, MB, CHB: But you would use RVD or KRD and we'll ask you why if you would use one or the other in a minute. But do you think the future is histone deacetylase inhibitors in combination or others?

Jatin J. Shah, MD: I think we're going to go to four-drug combinations in the future. I think there's certainly going to be a role for HDAC inhibitors based on their initial experience about how well tolerated they are in combination, and the depth of responses that we're seeing is amazing.

Keith Stewart, MB, CHB: I'm going to ask Paul this. I'm dying to know the answer. KRD or VRD, if you had your choice?

Paul G. Richardson, MD: I think one size does certainly not fit all. And I think that I would tailor. I think that, I'm very impressed that KRD is very active. I do think, however, that there's this rare, but real issue of some of the vascular toxicity that comes with it, and I think we need to better understand who's going to be affected by it and why, and fence them off to some extent.

But having said that, I'm very impressed by how deep and pronounced and prolonged the responses are. And, again, in discussions with people who've led in this field in the upfront setting such as Andrzej Jakubowiak, you know I'm struck by the durability of responses that he's reporting. Although as I participated in a clinical trial with him, I realized the patients are very carefully selected and I think one has to be careful about extrapolating from early phase 2 data.

I'm very impressed by the work being led by actually Shaji Kumar in the ECOG group comparing KRD to RVD, and I can share, as we all participate in group trials, there have been some surprising toxicity signals from that trial that surprisingly have been against KRD.

So I think we have to be careful. Having said that, I think a proteasome inhibitor, IMiD platform for induction, to Jatin's point, is clearly established. I think what's really interesting, Keith, as we go forward, is the field is moving so fast. As Sagar said, the monoclonal antibodies are going to be in this space very soon, already are. And I think that's going to, again, make us have to rethink what we do in the transplant-eligible population.

Ajai Chari, MD: I would just add that, yet again, it doesn't have to be either/or. You can start with RVD because the convenience of the subcutaneous bortezomib, and not having to come two days back-to-back is great. And if somebody does not have a dramatic response, let's say, you aren't even getting a VGPR or PR, you could switch after one or two cycles to KRD. It doesn't have to be an either/or outside of the clinical trial.

Keith Stewart, MB, CHB: All things being equal and a patient walked in tomorrow, what do you use?

Ajai Chari, MD: I think for the vast majority, RVD. But if somebody has very high risk or aggressive disease, I would start with KRD.

Keith Stewart, MB, CHB: So that's an interesting concept. You would choose the carfilzomib option for a high-risk patient? And why would that be?

Ajai Chari, MD: We're accumulating data from several studies that when you compare head-to-head carfilzomib with bortezomib, I think that carfilzomib has a more potent activity both pre-clinically, as well as clinically.

Jatin J. Shah, MD: So if you're supposed to use your best therapies upfront though, why would you limit the KRD if you think that's better for high risk?

Ajai Chari, MD: Well I think two things. One is, again, sometimes it can be cost convenience, particularly for the practicing community doctor. We have used it in academic centers and I think we get away with a lot more, but for the community practicing doctor, that's an important consideration. And the second thing is if you have a VGPR after one cycle with RVD, do you really need the KRD?

Keith Stewart, MB, CHB: Do you want neuropathy or not?

Ajai Chari, MD: But I think the rates of neuropathy with subcutaneous bortezomib are low, and to Paul's point, there's definitely some cardiopulmonary signal and it's not very high, but it's hard to predict who's going to get it.

Keith Stewart, MB, CHB: Right.

Ajai Chari, MD: But we also have to be very mindful that all the carfilzomib studies are very selected populations, and that may not be what's happening.

Keith Stewart, MB, CHB: Sure. Sagar, did you already go?

Sagar Lonial, MD: No.

Keith Stewart, MB, CHB: You published the definitive so far until this randomized trial VRD with transplant.

Sagar Lonial, MD: I think VRD is easy, it's convenient. I think if you're going to talk about potency issues, you're going to 56 mg per meter squared of carfilzomib, which is not the dose we use with KRD upfront. So I think RVD is the current standard and the ECOG trial will tell us whether that's right or wrong.

Paul G. Richardson, MD: One just additional point Keith. I think there is a point for community oncologists. Just be a little bit careful, in my experience now, because we've used it as part of clinical trials too, KRD upfront in renal dysfunction. That's one thing that I think is worth sharing with community docs because, whilst I don't think in any way carfilzomib is nephrotoxic, I've definitely seen an interaction in patients who have had some degree of renal dysfunction. And correct me if I'm wrong, but the trials were careful to exclude patients with significant renal disease.

Ajai Chari, MD: To that point, it may be worth also reminding people that the hydration, pre and post, does not need to be continued indefinitely.

Paul G. Richardson, MD: Right, that's a good point.

Ajai Chari, MD: If the patient can tolerate cycle one.

Keith Stewart, MB, CHB: So I'm taken by the tone of the group here that VRD remains the standard. But I'll tell you, I've been in other groups in the last few weeks where asked to vote, the whole room of myeloma doctors have said KRD would be their choice. So I'm just coming back to that and saying that there seems a little bit of discrepancy with what I'm hearing here today.

Jatin J. Shah, MD: So I mean I think that on a trial, as I mentioned, there's going to be some other options as we go down the road, but I think that there's still a role for KRD. And so, in our practice, there's I think a mix between VRD and KRD up front.

Keith Stewart, MB, CHB: Well, personally I would use KRD if I had the choice, but sometimes insurance coverage concerns, we've gone with VRD. I often, frankly, as an academic center, the patients come to us already on VRD. What about depth of response? Does everybody agree that that's important, we need deep responses before transplant?

Sagar Lonial, MD: So I think you want to give the treatment that has the highest likelihood of achieving a deep response, but if you don't get the deep response, I don't think you should change therapy, assuming you achieve a PR.

Keith Stewart, MB, CHB: I think everybody's in agreement with that. Is everybody transplanting every patient who's eligible?

Jatin J. Shah, MD: I’d actually emphasize that point again, because I think that sometimes that gets lost where people want to continue on to a CR in the community, and that happens quite frequently, actually. So I think we take that as a given, but I think actually that's important to reemphasize that if you just got to a PR, you don't need to go for 10 more cycles to try and drive towards a CR. If you're going to go for transplant, go for transplant.

Keith Stewart, MB, CHB: And one of the reasons for that is sometimes it gets a little hard to collect stem cells if you take too much lenalidomide. Jatin J. Shah, MD: You just have more toxicity at that point in time.

Paul G. Richardson, MD: I think different groups have different approaches to this though. Because I will show you that certainly based on our data from the IFMD of Sci Collaboration, the quality of response, prior to transplant, really does predict for whom is going to do what when. But I take your point Jatin, you have a dynamic of a response.

To your question Keith, do we transplant everyone? No, we do not. Well, we see our randomized trial remains our top priority, for good reason I think. At the end of the day, we firmly remain of the view within our center that, again, one size does not fit all, and that the younger patients clearly, overall, benefit from transplant as an option.

The issue of timing is a great and important issue that obviously we're addressing in our randomized trial. But at the same time, I'm struck that there's a subgroup of patients who we may not benefit from high-dose alkylation. There is the majority who probably are, but there is a subgroup in who we may do less, and I think we need to better understand who they are. Hopefully our perspective trials will dissect those people.

Ajai Chari, MD: And since you had the lead of the study, what do you think of the IFM data that are coming out?

Keith Stewart, MB, CHB: That's exactly what I was going to ask.

Paul G. Richardson, MD: Well I think they're very helpful.

Keith Stewart, MB, CHB: Can you explain it to our audience?

Paul G. Richardson, MD: Of course. Well there are two parallel studies and the US trial is the so-called Determination Study, CTN1304 and it's now Alliance-endorsed, so it's a true intergroup study. And in this regard, the trial looks at RVD followed by stem cell collection after high-dose cyclophosphamide and GCSF. And then patients are either assigned to early transplantation followed by RVD consolidation, and then R maintenance continuously on the US trial. Or, if they're randomized to the transplant-delayed group, essentially they keep transplant in reserve. They get a further five cycles of RVD, R maintenance, and then at first sign of progression get salvaged and then transplanted. So it's really early versus late transplant.

Keith Stewart, MB, CHB: So, Paul, the French Myeloma Group is reporting that with their version of the same trial—which the only difference is really that lenalidomide only goes for one year—A major benefit in progression-free survival to transplant. So how do you react to that?

Paul G. Richardson, MD: Oh very favorably and the following. You say the only difference is lenalidomide maintenance for one year. I think that's enormous. And I think the important point to know from the French data is the following. The progression-free survival benefit is eight months. There is no survival benefit Arm A versus Arm B. No, Arm A currently is 83% survival at four years. Arm B is 80%, that's the transplant arm. Now, you're right, it's not yet, but the continuous therapy may be vital to that equation.

Keith Stewart, MB, CHB: That's a good point.

Paul G. Richardson, MD: And I think the point is that although the data is not there yet in terms of the aggregate of the trial, the events start when the lenalidomide stops. And interestingly in our trial, we don't have enough events, which I think is really interesting. Obviously, we're behind in terms of enrollment, but we're almost there, we're at 540 actually with another 120 to go. Once we've accrued, I think we'll be able to really inform our physician colleagues…

Ajai Chari, MD: No, wait. The difference between French and American studies, it kind of approximates the first study. Do you do RD18 and stop or do you do RD to progression.

Paul G. Richardson, MD: Excellent point.

Transcript Edited for Clarity