DR LOVE: Noopur, can you talk a little bit of the biology — of course, we’re talking about this in oncology all the time — of how checkpoint inhibitors work and what the thinking was in trying to bring it into myeloma therapy, particularly combining it with IMiDs?

DR RAJE: Sure. We’ve fallen behind a little bit, I will say, compared to some of our solid tumor colleagues. But I think we’re beginning to appreciate and understand the biology of how these PD-1/PD-L1 blockers work. And there’s data now, at least in the preclinical setting, to show that the ligand, the PD-L1, is present on your tumor cell. And we also know that PD-1 is expressed on T cells. We know that when you use some of these blockers, you can actually enhance the activity of drugs like IMiDs.

We have actually studied drugs like, I think it was nivolumab, which was studied as a single agent. And as a single agent, besides just stable disease, it did not do a whole lot.

What you saw at ASH was 2 studies: one with pembrolizumab, which is a PD-1 inhibitor, in combination with lenalidomide, and another study from the United States. Dr Badros presented the other study, wherein pomalidomide was combined with pembrolizumab.

And, to me, both of these are very striking studies because, at least in the lenalidomide data set, what we saw was about 50% of those patients included in that study were refractory to lenalidomide. And then you add on the checkpoint blocker, you’re seeing a restoration of sensitivity to an IMiD which was not working on its own, suggesting that you can kind of restore chemosensitivity by using checkpoint blockade.

So I think we just have to wait and watch this space, but I particularly am very excited because we are using IMiDs long-term. And if by adding checkpoint inhibitors we can, number 1, enhance the activity and, number 2, restore their sensitivity, I think it’s going to be amazing.

DR LOVE: It’s always tricky when you see adding on to something, people say it’s resistant — this happens all the time in oncology. Rafael, from what you’ve seen, are the case reports — I mean, I know some cases were presented, actually, when they presented these data — that have you convinced that this is a legitimate strategy that results in meaningful responses?

DR FONSECA: I would answer that twofold and both with a yes. The studies that we’re seeing, both — perhaps the most important one that Maria V Mateos presented last year — that show that even amongst patients who were refractory to lenalidomide, the addition of pembrolizumab resulted in a significant number of responses. And we’re seeing that now reported at the ASH meeting as well with pomalidomide. So I think there is clearly some ability to overcome this resistance. And that’s why I don’t call this resistance an all-or-nothing phenomenon. There’re degrees to which these cells can put pressure on the cells, to which, if you add on that, maybe you are able to overcome that tipping point for resistance.

The second one is I know of a number of colleagues, very good clinicians and people that I trust their clinical opinion, who have used particularly nivo in an off-label fashion with anecdotal but clear evidence of response despite failure of the IMiDs before.

DR LOVE: And I guess that leads into, again, a question, Noopur, we’re asking in almost every tumor type it seems like nowadays, which is, when you have drugs that are approved in another disease, when do you try to access it? And this comes up all the time with checkpoint inhibitors. Have you or would you attempt to treat a patient off study with a checkpoint inhibitor?

DR RAJE: The answer to that is I have actually used it. And the nivolumab has been made accessible to all of us. We all are in a situation where we have very relapsed/refractory patients, where nothing else works. And I have certainly seen, anecdotally, as Rafael has pointed out, when combined with an IMiD, we are seeing monoclonal proteins go down with the combination of the PD-1 blockers.

DR LOVE: Same question: Have you used it outside a trial?

DR FONSECA: I have personally not started, although I’ve been close to it. But I’ve seen patients referred to us from the community, because the community doctors are familiar now with PD-1-specific antibodies, right? So I think this has taken a very quick shortcut into the front-line thinking, for people thinking about relapsed myeloma.

DR RAJE: Yes. There are already trials, Neil, wherein pembro is being combined up front with lenalidomide in newly diagnosed myeloma. That’s an ongoing trial. It’s there in Clinicaltrials.gov. And in the relapsed setting, pembro is being combined with pomalidomide.

DR LOVE: Any particular toxicity/tolerability concerns with checkpoint inhibitors in myeloma? Obviously, as they say, anything that ends in “-itis,” you can see with it. Anything in particular about a myeloma patient that would have you concerned?

DR FONSECA: What I know second-hand through the studies, but from what I’ve read from the various presentations that have been made, I think it’s just similar to what — I don't know if you know of anything different —

DR RAJE: Nothing specifically different. I do think with the pom/PD-1 blocker studies, there is concern for pneumonitis and specific pulmonary toxicity. So that needs to be worked out a little bit. Dr Badros has done a lot of work around that for us to be able to learn. But it is also one of those “-itises” like you mentioned. It’s a pneumonitis which we don’t completely understand.

Diagnosis and management of smoldering myeloma

Induction, consolidation and maintenance therapy for MM

Treatment of relapsed/refractory MM

Novel approaches under investigation for MM