Emerging Therapies for Myeloma

Transcript:Keith Stewart, MB, CHB: Let’s move on to emerging therapies. There is some very interesting, new data from the 2016 ASH Annual Meeting about different combination therapies. We’ve talked about some of them already (ie, ixazomib/pomalidomide/dexamethasone). In the realm of new drugs, what’s got you excited, Saad?

Saad Usmani, MD: I think the most exciting drug, and perhaps the first targeted, biomarker-driven targeted therapy we are going to get is venetoclax, which is a BCL-2 inhibitor that appears to have striking activity in translocation t(11;14) patients. I believe the data were presented in the monotherapy setting by Dr. Shaji Kumar.

Keith Stewart, MB, CHB: What was the response rate in this population for this audience? Was it 40% for the t(11;14)s?

Saad Usmani, MD: I’d say about 40% for relapsed/refractory patients with t(11;14), which is pretty striking and is higher than what we’ve seen with other therapies in this similar setting. So, I think that’s probably exciting.

Keith Stewart, MB, CHB: Let’s stick with venetoclax for a minute. We participated in that study, and the interesting thing is that the overall response rate to all the patients is about 20%. But, it was just an observation that the t(11;14)s seemed to be really responding well. And if you just look at those, it’s almost double that at 40%. Clearly, as an oral single-agent pill, it’s already FDA-approved in chronic lymphocytic leukemia. This is quite exciting stuff! What do you think about it, Paul?

Paul Richardson, MD: I’m very impressed by it, and I applaud Dr. Shaji Kumar for his work here. Essentially, as you’ve pointed out, Keith, it’s oral, it’s well tolerated, and there’s t(11;14)s subset benefit. The other piece of it, of course, is the addition to bortezomib, which Dr. Philippe Moreau presented on. I think that that combination is very striking.

Keith Stewart, MB, CHB: And there is some mechanism of action rationale for that, isn’t there, with downregulation of Mcl-1 by Velcade? It facilitates in venetoclax’s function, I think?

Paul Richardson, MD: Absolutely. And that rationale seems to have really panned out in terms of the results.

Keith Stewart, MB, CHB: Sagar and Amrita, tell us, do you have any experience with this? You’ve been involved in the studies, for sure, so tell us about them.

Sagar Lonial, MD: Yes. I think we’ve been struck not just about t(11;14) as an enrichment factor, but Vikas Gupta has data suggesting that CD20 actually may be even a better enrichment factor than t(11;14). If you look at venetoclax not just as a single agent, which is what’s reported, but the addition of a little bit of dexamethasone, which actually may make cells more dependent on BCL-2, the response rate may be even higher in that subset of patients. We’ve been really struck by advanced patients having almost a tumor lysis-like syndrome with either a single agent or combination with dexamethasone.

Keith Stewart, MB, CHB: Thoughts?

Sagar Lonial, MD: I would echo what everyone said. I’ve been using it in the context of patients who’ve literally failed everything (including antibody) and have been astounded by some of the responses we’ve had.

Keith Stewart, MB, CHB: Yes, I’ve had the same experience. So, that’s a very exciting one to watch for, and trials are ongoing. I think there is a compassionate use program. We can sometimes obtain it, even today, from the company. Were there other drugs that caught your attention at the 2016 ASH Annual Conference, Sagar?

Sagar Lonial, MD: As a new target, I think selinexor represents an interesting concept of targeting this idea of nuclear transport export inhibitors. What I think we’ve all been struck by is that it does appear to have single agent activity, but there were some toxicities associated with the current formulation of the compound.

Keith Stewart, MB, CHB: What kind of toxicities have been seen with selinexor?

Sagar Lonial, MD: Mostly gastrointestinal—so nausea, diarrhea, anorexia. Weight loss and a lot of fatigue was seen with the single agent.

Keith Stewart, MB, CHB: What did the trial do, and what did it show?

Sagar Lonial, MD: The data that have been presented really looked at single-agent therapy or the addition of dexamethasone with selinexor. The response rate was somewhere in the 20% to 25% range, but some of these patients, again, were very, very advanced. Some of the responses have been quite durable.

Keith Stewart, MB, CHB: As I recall, this study was called the STORM study. It enrolled patients who were refractory to bortezomib, lenalidomide, pomalidomide, and carfilzomib, or were refractory to all 4 of those drugs and daratumumab—so penta-refractory. And the response rate was about 20% in those patients. Does that impress you?

Sagar Lonial, MD: I think, certainly, it suggests that there’s a very significant signal here. And again, we’ve been struck by the kinds of responses we’ve seen in those penta-refractory patients that are usually quite beat up.

Keith Stewart, MB, CHB: Anybody else have any experience with selinexor that you’d like to share?

Paul Richardson, MD: I just think the penta-refractory data are very striking. I agree with Sagar. And I think that to see patients in whom all those drug classes have failed them and then benefit is remarkable. What’s also worth mentioning is the combination with bortezomib has been very favorable in terms of tolerability, which I think was quite unexpected, but, nonetheless, very encouraging.

Sagar Lonial, MD: It appears, at least from the data with bortezomib and carfilzomib, that the best way to prevent the gastrointestinal toxicity we were talking about is to use a proteasome inhibitor because of the safety profile.

Keith Stewart, MB, CHB: How does that work? I heard somebody say that. I’m struggling with that.

Sagar Lonial, MD: I’m not sure I can understand or explain the mechanism. I can tell you that in other diseases like acute myeloid leukemia, for instance, the adverse events profile for the single agent is the same as we’ve seen in myeloma. But the combination with, say 7 and 3, does the same thing. It seems to somehow reduce the gastrointestinal events and the fatigue that is seen with single agent selinexor.

Keith Stewart, MB, CHB: Selinexor was also presented at the 2016 ASH Annual Meeting in combination with carfilzomib. I’ve heard that’s been quite successful. So, this is a new drug, with a new mechanism of action, and an impressive response rate. We are going to have to learn how to manage the toxicities to make this part of our routine practice. But, I think you’re right—in addition to venetoclax, this is the second new drug that we’re quite excited about.

Transcript Edited for Clarity