Immunotherapy for Myeloma & Final Thoughts on Myeloma Research at ASH 2016

Transcript:Keith Stewart, MB, CHB: I want to close with our most exciting new area in cancer therapy in general and hematologic malignancies—immunotherapies above and beyond monoclonal antibodies, CD38, CS1 (SLAMF7). Particularly let’s talk about, first of all, checkpoint inhibition. Saad, what’s happening with respect to myeloma and checkpoint inhibitors?

Saad Usmani, MD: I think we’re seeing some data with pembrolizumab in combination with immunomodulatory drugs (IMiDs). The one abstract that I’m particularly struck by from the 2016 ASH Annual Meeting is Dr. Ashraf Badros’ experience with pomalidomide and dexamethasone in a fairly advanced patient population that is refractory, showing responses above and beyond what we would expect with pomalidomide/dexamethasone—about 60-odd %. So, that is quite remarkable.

Keith Stewart, MB, CHB: Are you convinced that, that’s better than what we would get with pomalidomide/dexamethasone alone, Paul?

Paul Richardson, MD: I think so, and I think that the whole construct of immuno-oncology in myeloma is, obviously we’ve been doing it for years, perhaps unbeknownst, promising with the IMiDs. At the same time, to see this sort of synergy is incredibly encouraging.

Sagar Lonial, MD: Keith, the response rate is always how we traditionally measure these things, but one of the benefits of PD-1 inhibition may not be response rate. Instead, it may be durability of response.

Paul Richardson, MD: Exactly. I agree.

Sagar Lonial, MD: And what we see from Dr. Ashraf Badros’ data are that the progression free survival actually looks almost as good, if not perhaps better, than pomalidomide/daratumumab in terms of PFS.

Saad Usmani, MD: I agree.

Sagar Lonial, MD: So, that, I think, is the real interesting theme.

Saad Usmani, MD: The PFS is going on to 14 months, which, historically, you would expect a PFS of maybe 4 to 5 months at best. So, that was extremely striking.

Keith Stewart, MB, CHB: I didn’t fully appreciate that, so that’s good to hear because I was a bit nervous.

Sagar Lonial, MD: Yes, and I think it’s a single study, so it’s always hard to make huge conclusions. But, it wasn’t the response rate that really drew my attention to that abstract. It was the PFS that really struck me.

Paul Richardson, MD: I agree.

Keith Stewart, MB, CHB: Were there other studies of checkpoint inhibitors with lenalidomide or other drugs, Amrita?

Amrita Krishnan, MD: I think there was one about nivolumab in high-risk smoldering disease that also, again, is interesting in combination with lenalidomide.

Keith Stewart, MB, CHB: There are a lot of undergoing trials of these drugs. For now, is anybody using these off-label?

Amrita Krishnan, MD: Should I hide under the table and say yes? Yes. I think, again, we certainly have been struck by the pembrolizumab data.

Keith Stewart, MB, CHB: I guess I haven’t, yet. I’m not totally convinced, but we’ll see as time goes on. There’s certainly some updates on checkpoint inhibitors. What about cellular therapies? That’s a really hot topic. Sagar, tell us what’s new?

Sagar Lonial, MD: We are seeing the data on B-cell maturation antigen (BCMA) as a target for chimeric antigen receptors (CAR)-T cells, and the data that was presented last year from the NIH Group was very provocative and interesting. Between additional studies looking at BCMA that have been presented either at the 2016 ASH Annual Meeting or in press releases, it’s looking increasingly like BCMA is probably the better target for a cellular-based therapy for myeloma. I think, in my view, there’s still questions about the broad applicability of that approach. But, certainly, the proof of concept is quite clear.

Keith Stewart, MB, CHB: Thoughts?

Amrita Krishnan, MD: I agree with Sagar in terms of the data with BCMA as a target. Data at another meeting, also, I think is striking. I’d like to bring up 2 things in terms of CAR-T cell therapy. Someone said it last night. Don’t try this at home yet because we do need to appreciate, for example, in the University of Pennsylvania data regarding the toxicity. At least 3 of those patients had severe cytokine release syndrome which, speaking from experience, is challenging to manage. So, I think that’s one thing to note.

The other thing is persistence of these modified T cells. We still struggle with whether it is a loss of BCMA-expression that causes relapse. We need to sort of modify it. We need to make a better generation of CAR-T cells, and I think that’s what we’re also going to see in the future—safer and better constructs.

Keith Stewart, MB, CHB: Precision medicine has gotten a lot of attention, and we haven’t talked much about that today. There are clinical trials underway trying to match drugs to genomics. Is there anything from the 2016 ASH Annual Meeting that struck you with respect to genomics and precision therapies? Paul Richardson, MD: Well, the venetoclax story itself sort of speaks volumes to targeted therapy.

Keith Stewart, MB, CHB: I guess that was the best example.

Paul Richardson, MD: And I think it is the best example. But, I think at the same time, it’s interesting because it’s a great question, Keith. You’re seeing this sort of dichotomy. On the one hand, you’re seeing the antibody and immunotherapy data, which just throws a big net around the disease and shuts it down regardless of what the mutational thrust may be. And, on the other hand, there are these more targeted approaches. Again, I think there’s space for both, but I think the venetoclax story is the most powerful in reminding us that targeted approaches can really matter.

Sagar Lonial, MD: I think the challenge with the precision medicine piece really relates to the fact that because even in a single patient the clone can be so heterogeneous, it’s hard to know whether that precision approach will actually get you where you want to be.

Paul Richardson, MD: I agree.

Keith Stewart, MB, CHB: This has been an extremely informative discussion. Before we end, I’d like to get final thoughts from each of our panelists—maybe a take-home message. At the 2016 ASH Annual Meeting, what was new that you enjoyed? What is your message for the community oncologists who might be watching? We’ll start with Dr. Krishnan, ladies first.

Amrita Krishnan, MD: I think what I enjoyed is obviously, there is so much in terms of new drugs and old drugs inventing themselves. I did want to speak to that point, and to nelfinavir, which I actually was struck by. I admit that I was skeptical when I saw the early data—that a drug used for something completely different, for HIV, can have responses in bortezomib-refractory patients. I think I’m struck by new combinations—old agents used in new ways. And I think venetoclax speaks to that as well.

Keith Stewart, MB, CHB: Sagar, what is your favorite take-home message from ASH 2016?

Sagar Lonial, MD: We’ve been involved with the venetoclax story, from the laboratory aspect, for a long time. That really is quite a striking story, and I think it speaks against what many of us have said—which is that combination therapy is the answer to get to minimal residual disease-negativity and cure. If you can find a vulnerability like this, it may actually be more important than 4-drug, 3-drug, or 5-drug combinations (if you can find the right cell).

Keith Stewart, MB, CHB: Excellent point. Paul?

Paul Richardson, MD: I just think that there are some really exciting new agents as well. I’m very impressed, frankly, by the selinexor story. It’s a testament to the investigators that sticking at it, managing the side effects, and seeing a signal but not giving up is very important for everyone to share. And certainly, my takeaway from ASH 2016 in myeloma is that we need all these drugs. It isn’t one versus the other. And I think that as we think about daratumumab, for example, there’s a sense of, “Well, now you’ve got daratumumab—game over.” No, absolutely not. We’ve still got plenty of work to do.

Keith Stewart, MB, CHB: I would totally agree with that. Saad, what was your favorite moment?

Saad Usmani, MD: I share everyone’s sentiments. Even though we’re overwhelmed with these nice stories, specifically selinexor and venetoclax. The other challenge that faces us, moving forward, is how do we tease out which agents to use at what period of time? And then, in what combinations? I think that’s the bigger challenge that we have ahead of us.

Keith Stewart, MB, CHB: I think the highlight is the CAR-T cell story, particularly the BCMA CAR-Ts, which we need to learn how to use, when to use, and how to manage. Those are really incredible stories even though some are anecdotal right now. This has been a very enjoyable discussion. There was a lot of impressive data at the 2016 ASH Annual Meeting. I’d like to thank all of you for your contributions to this discussion. On behalf of our panel, we thank you for joining us and we hope you found this Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity