DR LOVE: Again, getting back to these studies, the CASTOR and POLLUX studies, can you just, from 10,000 feet, talk about what those studies looked at and why, even though they’re completely separate studies, people are trying to compare them?

DR RAJE: Both of these studies are very important studies, wherein daratumumab now is being used earlier on. What we have right now is a label for quadruple-refractory myeloma where you can use single-agent daratumumab. Both of these studies — one is in combination with bortezomib, the other is in combination with lenalidomide. And, as we’ve been talking about, the lenalidomide combination obviously looks a lot better in terms of a sustained progression-free survival here.

And what this broadly tells us is that monoclonal antibodies are easy to combine with some of the backbone drugs we already have, so IMiD/dexamethasone combination, add on daratumumab. There’s no increased toxicity if you look at the data from the POLLUX study. Similarly, with the CASTOR study, you add on the daratumumab to bortezomib/dex. You are not compounding toxicity.

One thing to note is these studies, which were done earlier on, so 1 to 3 lines of therapy, they’re classic registration kind of studies. In practice, we tend to use these monoclonal antibodies later on. And the one thing I will absolutely highlight — and Rafael has mentioned this — is when you start combining daratumumab with the IMiDs, for example, in third-, fourth-, fifth-line treatment, you do have to be careful about myelotoxicity. Not just myelotoxicity. We do see hemoglobins go down as well.

And, therefore, your point about making sure you have a blood bank sample, making sure that there’s no cross-reactivity because of the daratumumab when you’re doing the typing there needs to happen, because these patients do need growth factor support. These patients do need dose adjustments, and they do need transfusions in later lines of therapy. But, overwhelmingly, all of this data has shown that it’s very efficacious. And the way these antibodies are going to be used in the future is combinations.

DR LOVE: Again, just taking one more shot at this indirect comparison thing. Is there anything about the designs or the pretreatment, the condition of these patients or anything else that might explain the differences, in your mind?

DR FONSECA: No. I think they’re very similar populations that are being studied and the combination of bortezomib/dexamethasone versus lenalidomide and dexamethasone. Practically speaking, while it can be done with the bortezomib, I think for the relapsed and refractory setting, we’re going to be talking more about the other agents. So I don’t think it will become that much of a critical decision point. I think maybe daratumumab will be combined with bortezomib for front-line therapy in additional future studies. But I don’t think in the setting of relapsed/refractory bortezomib will trump IMiD-based combinations.

DR RAJE: I will mention one difference though, Rafael. And the one difference here is the way the bortezomib trial — I believe that was the CASTOR trial — was, it was a specified duration of bortezomib treatment. And they had 8 cycles of treatment and nothing beyond. The way lenalidomide trials are designed, classically, is continue until progression. And with what we know about myeloma, continuing treatment does make a difference.

The other point, even though bortezomib was given subcutaneously in this trial, is it was given twice a week, so a little bit differently from how it’s routinely given by all of us. And that does impact your duration of treatment because bortezomib does have a dose-limiting toxicity where we end up stopping the drug. And that is largely neuropathy. Some of these other drugs, you can continue.

So, for example, if this study was done with ixazomib and continued on ixazomib, we may have seen different results.

DR FONSECA: Yes.

DR RAJE: It’s still a very positive study. It’s just that when you look at the control arm, you look at the bortezomib/dex arm, your median progression-free survival there is about 7.5 months. When you look at the len/dex control arm in the POLLUX study, it’s 18 months. That’s the difference. It’s not the addition of the dara which is the difference, it’s the inherent — either the bortezomib or the lenalidomide — difference, I think.

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Induction, consolidation and maintenance therapy for MM

Treatment of relapsed/refractory MM

Novel approaches under investigation for MM