DR LOVE: Your patient had resistance to IMiDs and still responded. What evidence do we have that by continuing an IMiD or adding an IMiD at that point, when they’ve been resistant — is it really a synergy with daratumumab, do you believe?

DR RAJE: That brings up the question which Rafael actually touched on earlier. All cells are not 100% refractory to that particular line of treatment. And in myeloma, specifically, we go back to the old drugs. We use them in different combinations. So even who you would define as refractory. And we’ve used these definitions for drug refractoriness more to try and understand what happens in the context of the clinical trials. It does not necessarily apply in the real world.

We go back to the IMiD. If they’ve been on an IMiD, on maintenance IMiD, we will still use an IMiD again, but maybe in a different combination. And we are able to restore sensitivity somewhat in these patients when they’re combined differently. And there’s — one can go into making it even more complicated — there are certain cells which are clonally selected, which may be resistant. And then they outgrow, and then they become sensitive again. And we can talk about clonal selection, clonal heterogeneity and all of that, but the bottom line is I do think you can go back to your old drugs again and try and use them in different combinations, if possible. Because if you do, you do see responses, as we did in this patient. He’s doing remarkably well.

Adding on the monoclonal antibody Rafael has talked about — some of the trials, which you mentioned, Neil, with bortezomib, with lenalidomide, and now data is coming out with pomalidomide as well — adding on a monoclonal antibody to whatever combination you have should work, and should work better, hopefully, if you have that target. So in this case, daratumumab targets CD38. If your myeloma cells are expressing CD38, there’s no reason why re-treating. Also we don’t have any data to that respect right now. But if you re-treat, if your myeloma cells are expressing CD38, you should be able to use the monoclonal antibody.

DR LOVE: What about the practical clinical issue of actually accessing pomalidomide to combine with daratumumab? Is that something a general oncologist should be able to do? Obviously, it’s out of indication.

DR FONSECA: Yes. And oftentimes it takes phone calls. And it takes peer-to-peer contact with insurance companies. In fact, it seemed to me like I spent quite a bit of time doing that this past week, just being with people and explaining why we’re doing that. And, so far, they have been receptive. I’m sure there’s going to be instances where that doesn’t happen. As this is built into the guidelines, I think that’s going to help people get approved for this.

DR LOVE: What about this issue of combining an IMiD with an antibody? Even in lymphoma, we’ve seen the R² regimen, rituximab with lenalidomide. And, obviously, we’re seeing a bunch of examples of that kind of strategy, elotuzumab/daratumumab, with myeloma. What’s going on biologically when you combine an antibody and IMiD, in your mind?

DR FONSECA: It’s very interesting because most of the regimens, even those without monoclonals now, have been based on lenalidomide/dex comparisons, right? There may be a reason why lenalidomide and dexamethasone works particularly well with immunotherapy. Whether they’re direct monoclonals or that evolves into some other vaccination, as Dr Raje was saying —

DR LOVE: Checkpoint inhibitors?

DR FONSECA: Yes, checkpoint inhibitors, the data with pembrolizumab, some people have looked at this, like Dr Dhodapkar from Yale. The study I was citing is the one from Ivan Borrello from Hopkins, where he compared response to vaccination. And they look at pneumococcal titers in patients with myeloma, those who were getting IMiDs versus those who were not. And, lo and behold, if you were on an IMiD, your response to the vaccine was much better.

DR LOVE: Wow! That's interesting.

DR FONSECA: So there is something to be said about IMiDs. You know how the story starts with this anti-angiogenesis. Probably most of us think that has nothing to do with myeloma now. But it’s such a pleiotropic set of drugs. And certainly immune enhancement appears to be one of the mechanisms.

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Induction, consolidation and maintenance therapy for MM

Treatment of relapsed/refractory MM

Novel approaches under investigation for MM