Sequencing Therapies in Multiple Myeloma

Transcript:Keith Stewart, MB, ChB: You pushed the envelope in clinical trials in the United Kingdom (UK) with a 4-drug regimen. Tell us about that, Gareth, if you don’t mind?

Gareth Morgan, MD, PhD: We introduced carfilzomib, Revlimid, cyclophosphamide, and dexamethasone as one of the major induction arms, and I think there are about 1,000 patients in that. It was well tolerated. There was no cardiotoxicity. There were excellent responses and everybody was able to go on from that to the transplant. I think there is some merit in 4-drug regimens, especially in younger, fitter patients.

Keith Stewart, MB, ChB: Panobinostat—you were telling me earlier that you use this in the third-line setting?

Sagar Lonial, MD: Yes. The challenge with panobinostat is that there is some gastrointestinal (GI) toxicity, so you have to figure out the right schedule, and then you have to figure out the right partner. I’ll be honest, I don’t think bortezomib is the right partner. I think there’s just too much overlapping GI toxicity. We’ve been able to use carfilzomib as the partner, and then the 1 week on, 1 week off schedule of panobinostat.

Keith Stewart, MB, ChB: What dose of panobinostat?

Sagar Lonial, MD: 20 mg 3 times a week.

Keith Stewart, MB, ChB: Is anybody else using panobinostat?

Saad Z. Usmani, MD: Yes. So, I’ve utilized the combination in third- and fourth-line relapses, and I agree that the Monday, Wednesday, Friday 20 mg schedule appears to be well tolerated and increases the efficacy, too.

Keith Stewart, MB, ChB: What about second transplant, Ivan? Are you still in favor or against those if people have done well with the first transplant?

Ivan M. Borrello, MD: We have transplanted people a second time, but, in general, it would be for people who have achieved at least 5 years or more from their first transplant. Those are the people that we would recommend a second transplant to.

Keith Stewart, MB, ChB: Is this the same all over? Are people doing second transplants, Tom?

Thomas G. Martin, MD: It’s pretty interesting. We collect enough stem cells up front for 2 transplants—essentially for everybody. And if we look at our database, and review how many really got a second transplant, it’s less than 5% of patients.

Keith Stewart, MB, ChB: Yes. We would transplant 10%, which is shocking, really. You would think it would be much higher.

Thomas G. Martin, MD: Right.

Keith Stewart, MB, ChB: Why is that? Is it because we have better drugs, or we’re just not doing it?

Thomas G. Martin, MD: I do think that we have better drugs—drugs that are less toxic than a second transplant. It’s a last-ditch effort, in my mind. For patients who have had all these drugs and now have cytopenias and you have some stem cells sitting in the bank, I think it’s a great time to give them a melphalan-based therapy. Then, give them back stem cells so they can get their counts back up and become eligible for clinical trials again, etc.

Sagar Lonial, MD: That’s our most common indication.

Saad Z. Usmani, MD: Agreed. I think that is probably the most common salvage indication. You’re not going full dose melphalan with those patients.

Gareth Morgan, MD, PhD: I may be a bit of an outlier, yet again, in that I think there’s quite a lot of efficacy to be had for transplant at relapse, especially if you haven’t seen therapy for a while or you’ve been on non-alkylating agents. You can adjust the dose and support the toxicity using stem cells that are stored at presentation. I think it offers a way of shaking up the composition of the tumor, and then, as long as you have some form of maintenance strategy afterwards, I think it’s more than a reasonable approach.

Sagar Lonial, MD: What’s your time cutoff?

Gareth Morgan, MD, PhD: We were using an 18-month cutoff in the UK. I produced the set of data that’s published that says they benefit from a second transplant compared to people who didn’t. And I think 5 years is a bit long, but times have changed and if you add on maintenance for 2 or 3 years, or 5 years, maybe, from presentation...

Saad Z. Usmani, MD: Maybe we can compromise at 3 years. How about that?

Sagar Lonial, MD: 18 months. To be fair to your study, they didn’t have access to all the stuff.

Gareth Morgan, MD, PhD: Yes, it was historical.

Sagar Lonial, MD: Yes. It’s hard to extrapolate.

Keith Stewart, MB, ChB: We still use second transplants. I was actually surprised it was only 10%. It feels like more than that. Let’s talk about sequencing. We started off talking about induction therapy. Do you think monoclonal antibodies are going to move into the frontline setting?

Ivan M. Borrello, MD: Some of the data in the relapsed setting look very promising—certainly, with daratumumab, it does. There are early studies being presented here at the 2017 ASCO Annual Meeting that are looking at daratumumab combinations that we discussed earlier—still, in the phase I setting. But, I think it’s only a matter of time before that data matures and we do the sort of definitive studies in the upfront setting.

Keith Stewart, MB, ChB: What’s going to happen with sequencing of therapy when that takes place—this transition to 2 or 3 drugs plus an antibody in the newly diagnosed setting? Do you think we’ll be re-treating with the monoclonal antibodies, or are we going to be switching to newer drugs? What do you think?

Ivan M. Borrello, MD: I think we’ll have another panel discussion asking the same question. I think it’s going to be driven, in large part, by the data, and I think it’s going to be driven by what new agents are on the market. It’s also going to be driven by biology.

The one thing that we’re learning more and more, like with Arkansas molecular profiling, is that myeloma is not 1 disease. There may be some patients that are more likely to respond to proteasomes, whereas others may respond to monoclonal antibodies, and others, yet, to different forms of immunotherapy. We are going to have more precision medicine guided by biology, as opposed to empiricism that we’re currently doing.

Keith Stewart, MB, ChB: It’s very hard to be prescriptive, these days, when you’re asked how you treat relapses. It’s almost as if you need to treat every single patient differently. Would you agree, Saad?

Ivan M. Borrello, MD: Absolutely.

Saad Z. Usmani, MD: I agree with you. I think that there are so many factors involved—disease biology, to begin with, and the disease biology that you’re dealing with at the time of relapse; how patients have been treated; and what kind of toxicity they had. All of that factors in to what therapy to give.

Keith Stewart, MB, ChB: Are there any other thoughts on treating relapse that we haven’t covered?

Gareth Morgan, MD, PhD: I think I’d like to develop that point that Saad just hit on. In some level, people don’t think about molecularly reassessing patients at relapse. I think we have to. We have to know if they have p53 mutations, what molecular subtype they are, and the nature of their relapse. It is becoming a field where we tacitly use precision medicine, or personalized medicine, whichever way you wish to describe it.

Transcript Edited for Clarity