Transcript:Keith Stewart, MB, CHB: Are there other regimens used for elderly patients, before we move on to the younger patient? Some people use cyclophosphamide in this situation, or is there anybody you wouldn't give lenalidomide or bortezomib to?

Sagar Lonial, MD: I think that the real question is going to be, when you use the lenalidomide/dexamethasone platform with an antibody, does that sort of give you a longer PFS and OS that may eliminate the need for adding one?

Keith Stewart, MB, CHB: I do, I promise I'm going to come to the new drugs. But cyclophosphamide, anybody using that now with these patients?

Ajai Chari, MD: I think there are some roles for cyclophosphamide still. So, for example, with renal failure or somebody with poor performance status, so you're worried about a thrombotic risk with an IMiD. Somebody who's potentially inpatient or…

Keith Stewart, MB, CHB: Took anticoagulants maybe.

Ajai Chari, MD: Exactly. Sometimes people feel like it's an either/or, it doesn't have to be. You could start with bortezomib-cyclophosphamide-dexamethasone. And when some of those concerns have improved, switch to oral therapy.

Paul G. Richardson, MD: Yes. Well I think that's very, very well said. And the other point I'd make, Keith, is that really building on Sagar's work, we are also very comfortable in our maintenance strategies with higher risk older patients, offering bortezomib every couple of weeks subcutaneously.

Ajai Chari, MD: Yes.

Paul G. Richardson, MD: Because we do think that in those patients particularly, with adverse cytogenetics, that there may be benefit to that approach, particularly if it's well tolerated.

Keith Stewart, MB, CHB: And so for this older patient, does it matter to you if their genetics are high risk or low risk, or just is everybody going to get VRD? Maybe any change in therapy, any point in measuring it?

Jatin J. Shah, MD: Well I think there is a risk. There is a role for bortezomib-based therapy for high-risk patients. I think the other important thing, coming back to the Cytoxan, is a different issue with the fact of cost. So a good cheap drug that's effective. So I think we have to keep that in mind as well for patients.

Paul G. Richardson, MD: To Ajai's point, yes.

Sagar Lonial, MD: I guess the flip side of that is there is data being presented at the meeting where VTD is superior to VCD. And again, it's anecdotal data. I know you probably have the world's largest collection of VCD, but the cyclophosphamide in the context of high-risk disease is not a benign thing.

Jatin J. Shah, MD: I agree, not in high risk.

Keith Stewart, MB, CHB: Yes. But it depends. The devil is in the details; how you give the drugs.

Sagar Lonial, MD: Yes, understood.

Keith Stewart, MB, CHB: So you've been dying to get to the new drugs. Tell us all about what's exciting and what's coming. Obviously none of these drugs are approved in the front-line setting yet, and we're going to talk a lot about them in relapse. But just very briefly, what do you think is going to change? We're talking elderly patients still. What will get you excited with the new drugs? You start it Paul.

Paul G. Richardson, MD: Well if I may, I think that the availability of ixazomib up front as an oral weekly drug is a well tolerated proteasome inhibitor.

Keith Stewart, MB, CHB: Just to be clear, it's not available yet.

Paul G. Richardson, MD: Not yet. It's in the relapse setting. But I mean that will be coming because we will have the results hopefully from TOURMALINE and support its use up front. But it's a well tolerated drug, once-a-week, part of an oral regimen; complements lenalidomide-based therapy, in my experience, very well. I think that will be a major advance for older, frailer patients. It simply doesn't have the neurotoxicity of bortezomib.

The cutaneous issues with it are relevant, but very manageable. It has minimal GI toxicity once you get very comfortable with its use. And it doesn't also have some of the more rare, but worrisome side effects that we sometimes see with carfilzomib, mainly the cardiovascular-vascular thrombotic risk. That's not seen in either case. So for older patients, this I think would be an excellent proteasome inhibitor in the future.

Keith Stewart, MB, CHB: I'm going to guess what you're going to say, but go ahead and say it.

Sagar Lonial, MD: I think it's the antibodies.

Keith Stewart, MB, CHB: Any one in particular?

Sagar Lonial, MD: Well, I think there's certainly encouraging data with both elotuzumab and daratumumab.

Keith Stewart, MB, CHB: Yes, I agree.

Sagar Lonial, MD: In the newly-diagnosed myeloma setting in combination with lenalidomide. I think the question is for the truly frail patient, is it going to be an antibody IMiD, or is it going to be a proteasome IMiD? And I don't know the answer to that. But, the antibodies are just so well tolerated.

Keith Stewart, MB, CHB: Not that require intravenous delivery every week or two?

Sagar Lonial, MD: It depends on where you are in therapy. In the beginning, more frequent visits, but once you get beyond that, the frequency does drop.

Ajai Chari, MD: I think, to expound on that a little bit, the two patient groups that are probably bringing down the median overall survival for myeloma now, because we've made a lot of strides, are elderly and high risk. And those are populations where these monoclonal antibodies should do really well because of the excellent tolerance, and they're genomically agnostic. So I think we have a real exciting future improving with our median overall survival for all patients.

Paul G. Richardson, MD: Yes, but to the point of clonal heterogeneity and to the point of what, I love the way Sagar's framed this. You've got plasma cell biology that you drive with inhibiting protein degradation and the immunomodulatory effects of our IMiDs. I do think it's not necessarily going to be a zero-sum game. I think what we're going to have is an immunomodulator, a proteasome inhibitor that's well tolerated, and an antibody as sort of our mainframe going forward. And I think that will provide us with really dramatic duration, and duration of clinical benefit that will be transformative, I hope.

Keith Stewart, MB, CHB: Okay, so what I think we heard for the elderly patient is that most people are framing their lenalidomide, bortezomib, dexamethasone attenuated doses as a therapy of choice. Perhaps lenalidomide, dexamethasone for people who are very frail, alone. For those who can't take lenalidomide-dexamethasone, perhaps a cyclophosphamide-bortezomib combination. And the future, there's obviously oral proteasome inhibitors and antibodies.

Transcript Edited for Clarity