Targeting CD38 in Relapsed/Refractory Multiple Myeloma - Episode 7

Emerging Therapies to Treat RRMM

December 24, 2019

Paul G. Richardson, MD:In the spirit of being comprehensive about relapsed/refractory options, I do want to mention 2 very exciting new approaches that are on the horizon. We’ve heard a lot at this meeting about CAR [chimeric antigen receptor] T therapy. I do want to emphasize the excitement around bispecific T-cell engagers, and in particular, a platform that’s been developed, so-called 269 [CD269] that appears to have the convenience of being that much easier to deploy in the real-world setting. But there were other bispecific T-cell engagers that look very promising, in my opinion.

As I mentioned, the CAR T data were remarkable, particularly with some durability of response seen with certain CAR T platforms. In the same construct of immune therapy, I did also want to mention iberdomide, CC-220; and of course there are very early data on CC-480. CC-220 data have been presented and show, very importantly, a solid 30%, 34% response rate overall in highly resistant patients, just as an oral therapy with dexamethasone. But what’s so important is that this signal is seen in the penta-refractory patients as well. And just to share, this particular group of drugs does appear to be particularly promising going forward.

As we think about other exciting new agents that are emerging in the context of relapsed/refractory disease, another very important BCMA [B-cell maturation antigen]-targeting approach that may be very important after CD38 failure—I should stress, in patients for whom CD38-targeting approaches have failed them—we obviously have very exciting data regarding the antibody drug conjugates. And at this meeting, there was a lot of correlative science presented around the excitement that we’re seeing with the so-called antibody drug conjugate GSK'916, which is named belantamab mafodotin.

This is an antibody drug conjugate that integrates auristatin, and we’ve had very interesting data from the first study, DREAMM-1, which was published and showed around a 60% response rate in highly refractory patients; and importantly, in the daratumumab-refractory subgroup, around 35% to 40%. So that’s the true sort of penta-refractory group of patients.

In DREAMM-2, we were able to announce that the primary end point of the study had been met. This was in truly penta-refractory patients. A late-breaking abstract that had been submitted unfortunately was not accepted because of the large phase III CANDOR study, but we will be making results from DREAMM-2 fully available soon.

The message for community oncologists is this is a once-every-3-week infusion of an antibody drug conjugate. There is corneal toxicity, but it is generally very manageable. We’re learning more about it, and are making it that much less of an issue than it had been concerned to be in the past. And we’re very pleased by the promise of this new approach.

In the relapsed/refractory space, we’ve had a lot of exciting data at this meeting. We focused in our discussion on antibody-based approaches. I do want to emphasize that beyond antibodies, there are lots of exciting small molecules in development. This includes selinexor, which is already FDA approved. There was tremendous data at the meeting looking at selinexor combined with pomalidomide, and there are excellent outcomes in the relapsed/refractory setting. Fascinatingly, there was data for patients who responded to selinexor when CAR T had failed them.

Similarly, there is a very exciting novel targeted cytotoxic called melflufen, which is aminopeptidase-activated, and that demonstrated really nice data in terms of activity seen in very advanced patients with extramedullary disease. We were reporting, at this meeting, on a number of outcomes and related studies to that.

My point of illustrating these is to simply show that beyond the antibody approaches, there are multiple others available. I think the other point to share is that the options that exist in relapsed/refractory myeloma also include already approved drugs like panobinostat. And in combination, these agents can be used to salvage patients after some of these antibody and cellular therapy approaches have unfortunately not worked or run out of benefit. I think that’s the incredibly important message: That in the relapsed/refractory space, there are multiple options. I’ve only shared a few examples to illustrate this.

We touched earlier on the importance of venetoclax, and I think that just illustrates, in a snapshot, the numerous available treatment options that our patients have. So my concluding comment would really be that relapsed/refractory myeloma is becoming almost more like newly diagnosed myeloma was before, but with the caution that obviously relapsed disease is 1 thing, but relapsed/refractory disease remains particularly challenging. Nonetheless, I think we’re making continuous progress in improving outcomes, and that’s obviously very good news for our patients.

Transcript edited for clarity.