New Treatment Paradigms in Multiple Myeloma - Episode 13
Keith Stewart, MB, CHB: So I have a question about the FDA-approved labels here in this country for elotuzumab and ixazomib. If I recall rightly, both said you only had to receive one prior therapy.
Paul G. Richardson, MD: Yes, correct.
Keith Stewart, MB, CHB: What does that mean to you? Does that mean you wait for first relapse or does that mean if you're not tolerating your up-front therapy, you can switch or add? So you have any thoughts on that Sagar?
Sagar Lonial, MD: Yeah, I actually hadn't thought about it that way. I mean, I think about it typically.
Keith Stewart, MB, CHB: Well, what good are you? I'm going to ask Ajai.
Ajai Chari, MD: Well, in some prior labels, the FDA has come down and defined what a line of therapy is, which as you know, induction→transplant→maintenance is all considered one line of therapy. But I think we have to be cognizant of the fact that sometimes people may progress on combination bortezomib-lenalidomide/dexamethasone, and that's in some ways worse than having had a long, “one” line of therapy.
Keith Stewart, MB, CHB: Yes. Interestingly enough, I think here they don't talk about lines of therapy, they just talk about prior therapy.
Jatin J. Shah, MD: I think that's an interesting thing. I mean, I think the data support in one to three lines of relapsed myeloma, but the label actually says after one prior therapy. So you technically don't need to relapse after first-line therapy.
Keith Stewart, MB, CHB: So, would you use it in maintenance?
Jatin J. Shah, MD: So that's, I think, a nuance. I would in high-risk patients, potentially. We have a trial with lenalidomide plus ixazomib as maintenance therapy post transplant, 64 patients that we'll present here. And so I think it's safe, it's very well tolerated. We might need more phase 3 data and more data to support that combination. And maybe in high-risk patients, I think it plays a role there.
Keith Stewart, MB, CHB: All right. So…
Jatin J. Shah, MD: Could I just add one quick comment?
Keith Stewart, MB, CHB: Yes, please.
Jatin J. Shah, MD: So, I mean, I think we talked about pomalidomide and a lot of the partner drugs in that relapse space with elotuzumab and daratumumab and carfilzomib. But then panobinostat I think still plays a role.
Keith Stewart, MB, CHB: Yes, we haven't talked about the one that was approved first, which was panobinostat. Talk about the Panorama trial. Paul was the Principal Investigator so let's let him tell us about the Panorama trial.
Paul G. Richardson, MD: No, no, I mean Jatin was very kind to say that. I think that the bottom line with panobinostat is the addition of panobinostat to the bortezomib-dexamethasone platform.
Keith Stewart, MB, CHB: Maybe just as panobinostat.
Paul G. Richardson, MD: Yes, of course. Panobinostat is obviously a completely novel mechanism of action. It's in the histone deacetylase inhibitor class, and it builds on the early work done with vorinostat, which unfortunately didn't translate into something considered meaningful enough to go forward with approval. But very importantly, panobinostat followed up on it and has actually shown clinical benefit in the randomized setting. And that clinical benefit was a solid 4 1/2 months, which is very similar to what we've obviously seen in other settings, as well.
And what was particularly impressive and led to the accelerated approval was the subgroup of patients in whom the biggest benefit was seen. And actually the PFS benefit in the bortezomib-exposed, lenalidomide-resistant, bortezomib-resistant patients was no less than seven months.
So I think that, just to be clear, it's lenalidomide-resistant, because to be in the trial, you had to be bortezomib-sensitive. But my point is that in those refractory patients, the PFS difference was very impressive. So I think that it supports clearly the accelerated approval. I think the challenge with panobinostat in Panorama-1 was the way we built the trial at the time was with intravenous bortezomib twice a week. There was a registration study, so changing in midstream is not feasible. And so a lot of the toxicities we encountered we can actually get around with subcutaneous bortezomib on the one hand, weekly on the other. And the reality, too, that in our experience anyway, HDAC inhibitors actually combined very favorably with IMiDs. And I think that's a whole new direction that's being explored.
Keith Stewart, MB, CHB: And I seem to recall there was a carfilzomib trial also that was quite well tolerated, as well.
Jatin J. Shah, MD: I think there are two important trials actually. So carfilzomib plus panobinostat, and there was a trial that Dr. Lonial did with his team—Dr. Kaufman, as well as MD Anderson—where we looked at carfilzomib and panobinostat, and really shown that's actually a rather well-tolerated regimen. We don't see the same GI toxicities that we saw in the Panorama-1 study with less than 5% and very active combination. Dr. Chari also did a trial with lenalidomide and panobinostat, which I thought was very compelling data with…
Keith Stewart, MB, CHB: I feel left out again.
Jatin J. Shah, MD: Sorry.
Keith Stewart, MB, CHB: I'm having déjà vu because we were all at the FDA together talking about this.
Jatin J. Shah, MD: Yes. But that's very compelling data that you can comment on. But I think that there's still a role for panobinostat with different partner drugs, including, potentially, pomalidomide. So that's why I just wanted to bring that up, that it's important in these early lines of therapy.
Keith Stewart, MB, CHB: So novel mechanisms of action…
Jatin J. Shah, MD: Yup.
Keith Stewart, MB, CHB: Better tolerability with subcutaneous, weekly Velcade.
Jatin J. Shah, MD: Carfilzomib.
Keith Stewart, MB, CHB: Or with some of the newer combinations that you've all worked on with carfilzomib. And so, certainly, what kind of patient would you treat? I do want to spend some time here on daratumumab, but just very briefly. What kind of patients would you give panobinostat to?
Ajai Chari, MD: Just to speak to the study that Jatin was referring to: it was panobinostat-lenalidomide/dexamethasone—where the panobinostat was given week one and week three, week two was off—and standard lenalidomide/dexamethasone. And even in a very lenalidomide-refractory population, almost 90%, the response rates were about 40%, PFS with about 6 1/2 months, even in that population. So I think this is a completely oral regimen and it's very well tolerated. And importantly, we had no GI issues. Not one person had to have dose modification for GI problems.
Sagar Lonial, MD: Yes.
Ajai Chari, MD: Mean complications were cytopenias, which is expected and manageable.
Keith Stewart, MB, CHB: Did they require antiemetics or Imodium or anything?
Ajai Chari, MD: No, excellent tolerability. So I think the key is the partner that you give it with. I think we have a lot of options now, and you can partner with any of these agents.
Paul G. Richardson, MD: Yeah, and if I may, Ajai, I would agree with you. And I think the other thing to share here is that obviously this was such an important approval in my view because it opened the door to the HDAC class, which had been closed previously. And at this meeting there's some very nice data that Sagar and I am both involved in with the HDAC6 selective inhibitor, AC1215. And now the new one, AC241, where this concept of the IMiD partner is really validated. Because with pomalidomide, for example, it's an excellent platform.
Transcript Edited for Clarity