Transcript: Paul Richardson, MD: I really wanted to move into, in the last half an hour, to our relapsed/refractory discussion because I think this is obviously critically important, despite the success of our upfront regimens, despite the impact of maintenance, which is so profound. What happens when patients relapse? Amrita, I wondered if you could begin this for us and talk to us a little bit about our outcomes for the treatment of relapsed disease and what we’ve learned from this meeting and how you think about your patients in that context.

Amrita Krishnan, MD: Well, I think the fact that we still have so many trials in the relapsed space, and that we’re all filling those trials, we have waiting lists, speaks to the tremendous need still for our patients. Looking at when we start therapy, I think we all do the same things, we look at prior disease to help us, we look at a cytogenetic risk profile, molecular risk. I think there is that group of biochemical relapses where we’re willing to wait. But I think more and more, most of us tend to intervene earlier, in part because we have better drugs now.

Paul G. Richardson, MD: Yes, good point.

Amrita Krishnan, MD: And hopefully less toxicity with those drugs to help us when we do intervene. If I may make the comment in terms of the CAR [chimeric antigen receptor] T-cell therapy trials, even though I have Dr CAR T sitting here, is I think they show incredible promise. We heard Deepu Madduri, MD’s, CAR T 100% response. Those are different patients. As we know, getting a patient to CAR T, those are not the cases exploding before your eyes, right? It’s a much slower progressor.

Paul G. Richardson, MD: Excellent. Other thoughts on this particular aspect of how you think about relapsed disease, very similar to what Amrita I think summarized beautifully?

Sagar Lonial, MD, FACP: Well, I think relapsed disease is the new newly diagnosed, in the sense that it’s not sufficient to say, “Well, I’m going to throw a few drugs and see what happens.” I think we really expect very long durations of remission even in the context of first relapse. Some of the trials that we’ve seen for the triplets versus doublets suggest that your second PFS [progression-free survival] may actually be longer than your first, depending upon what you got and how you got it. I think that’s important.

Paul Richardson, MD: I agree and in that spirit, Sagar, perhaps you can talk to us a little bit about molecular risk status because you were saying think about it as newly diagnosed, reassess molecular risk. Perhaps you can touch on that.

Sagar Lonial, MD, FACP: One tool that we probably can walk away from this meeting with is the idea that for translocation 11;14 certainly, we do have a precision medicine-based approach. Whether it’s VEN/DEX [venetoclax, dexamethasone], or whether it’s VEN/DEX/DARA [venetoclax, dexamethasone, daratumumab], or whether it’s even venetoclax, dexamethasone, and bortezomib in the subset analysis from the BELLINI trial, I think it’s clear that 11;14 is a slightly different subset of myeloma. It has not benefitted as much from the proteasome inhibitor and IMiD [immunomodulatory drug] era as the other subsets of myeloma have. I think venetoclax offers them a unique option that most other subsets don’t have. There may be a broader group of patients beyond venetoclax, whether it’s the BCL-2 [B-cell lymphoma 2 protein]—high or the CD20 expression, all those kinds of things may identify a smaller percentage that may benefit as well. But it’s not quite ready, I think, and as clear as 11;14 is.

Kenneth H. Shain, MD, PhD: I was going to say the same thing; 11;14 is an obvious place to go. A hazard ratio of 0.9, you can’t get a whole lot better.

Paul G. Richardson, MD: Oh no, you can’t. The venetoclax data are striking.

Kenneth H. Shain, MD, PhD: That’s the group you want to stick with. We all use venetoclax. We’ve been on the studies. This is a very powerful drug in that patient population.

Paul G. Richardson, MD: Nina, your practice with venetoclax, how do you typically embrace it and do you use it off protocol?

Nina Shah, MD: Well, we did use it off protocol for so long. We actually did an analysis and we found the same thing, that the 11;14s did way better. This solidified the BELLINI analysis from this meeting, data from Jonathan Kaufman, MD, and Nizar Bahlis, MD. All this solidifies that it’s an active drug in 11;14, and like we’re saying, it’s an easy thing to know. Like BCL-2—high, it’s going to be hard for us to figure that out, especially with the community bone marrows, etcetera. I think this is an easy thing to fix, and actually the next time I have somebody with 11;14 progress, and maybe in the third line, so after the daratumumab, depending on what they got, I’m going to go for venetoclax. Luciano Costa, MD, PhD’s data were pretty good there, so maybe something like that depending on what they got.

Paul G. Richardson, MD: Yes. I agree.

Amrita Y. Krishnan, MD: I think we were in the session, I can’t remember if it was Nizar or Jonathan’s, the non-11;14 group actually had a decent response.

Nina Shah, MD: With the proteasome inhibitor, yes.

Amrita Y. Krishnan, MD: Yes.

Paul G. Richardson, MD: Thoughts on that, Ajai?

Ajai Chari, MD: I think it’s been said well. It’s the first personalized medicine we probably have in myeloma instead of treating everybody the same. I would actually probably move it even into, based on Nizar’s data with daratumumab, I think if somebody has not gotten daratumumab in the front line, I would feel pretty comfortable using it in second line because I think the key concern from BELLINI was the toxicity, but really it only applied to high risk, low BCL-2, non-11;14. I think I would feel comfortable.

Nina Shah, MD: We know this now. His data showed pretty good toxicity outcome because if you know it and you’re preemptive about it, I think you can mitigate a lot of it.

Amrita Y. Krishnan, MD: Nizar made some very important points that they did a lot of supportive care, they used...prophylaxis. They gave IVIg [intravenous immunoglobulin].

Nina Shah, MD: That’s important.

Paul G. Richardson, MD: I think what’s also very interesting to note though is the fascinating observation that those patients who are non-11;14 positive and low BCL-2 expressors in the high-risk group, actually when they relapsed, died quickly. It’s almost as if a Pandora’s box was released by some interaction that obviously we’re trying to figure out. That was a very important observation.

Ajai Chari, MD: We had a very interesting presentation from Israel that was looking at patients who were primary refractory to bortezomib-based induction. They did DARA/KRd [daratumumab and carfilzomib, lenalidomide, dexamethasone]. Maybe as important, if not more was they did single-cell sequencing of those patients and found that, for example, XBP1 protein unfolded pathways were being aberrantly regulated. I think going back to my movie analogy, we can predict all we want at baseline, but way more important is what happens. If you have an early relapser, particularly on maintained therapy, we know that lenalidomide refractory, which is a big part of relapsed disease management, those patients don’t do well, and we need to understand the why so that we can then start addressing that

Transcript Edited for Clarity