CD38-Targeted Monoclonal Antibodies in Myeloma

Transcript: Paul Richardson, MD: I now want to ask Nina to sort of think about the antibodies. To me, certainly, with the advent of antibodies, it’s sort of become R-CHOP/rituxan [cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab], hasn’t it?

Nina Shah, MD: Exactly.

Paul Richardson, MD: In the induction setting. With that in mind, if you can walk us through…some of the data around daratumumab, which are looking so promising.

Nina Shah, MD: We used to think of daratumumab as a relapsed/refractory drug, even 3 years ago. Now we have 4 different trials showing us that, in fact, it is a drug that you can move up front. The first data that we had were the data presented several years ago at the American Society of Hematology showing improvement in PFS [progression-free survival] for VMP/DARA [melphalan, prednisone, and daratumumab] versus VMP [melphalan and prednisone]. It was good, because we knew that a quad was better than triple, but not useful for us in the US [United States] because we don’t use that. Subsequently to that, we had the DRd [daratumumab, lenalidomide, and dexamethasone] versus Rd [lenalidomide and dexamethasone] data for transplant-ineligible patients showing increased PFS. Again, something for transplant-ineligible patients. For us, I think, now we have more data with the trial, which looked at DARA/VTd [daratumumab, bortezomib, thalidomide, and dexamethasone] versus VTd [bortezomib, thalidomide, and dexamethasone], showing an improvement in PFS. There was a second randomization. We don’t have those data yet, and that now led to an approval for the quad in the up-front setting for transplant-eligible patients, which I think is closer to what our practices are more commonly, as we just heard.

Now, data which were updated at this past ASH [American Society of Hematology] Annual Meeting, and basically have been updated every single conference since last ASH, it’s like the abstract that has many lives. It is showing very nice overall response rate, very nice CR [complete response] rates and as we’re talking about it, MRD [minimal residual disease]-negativity rates after 4 cycles of DARA/RVd [daratumumab, lenalidomide, bortezomib, and dexamethasone], transplant and 2 cycles of consolidation, so before maintenance. This really now brings us to this point of what are we going to do, are we going to incorporate DARA [daratumumab] up front? I do want to also point out that ALCYONE has updated for an overall survival improvement, so we know that adding DARA up front, at least in 1 incidence, has improved that end point. I don’t know what’s going to happen for the GRIFFIN study and CASSIOPEIA study.

What does this mean for us? I have trouble with it, because I think DARA/RVd is a great regimen. It’s pretty well tolerated. Sure, there were some cytopenias, but that was manageable. I don’t know that it’s better than KRd [Kyprolis, lenalidomide, and dexamethasone]. I know we’re talking about DARA/KRd in the future, but let’s just talk about what we think about now, KRd versus DARA/RVd. That comparison hasn’t been done. I think there’s some talk about doing that comparison. It will be very difficult to get end points on it if they’re not MRD. I think for now, and slowly but surely, DARA is coming to the front. As my colleague Dr Tom Martin always says, “You want to put LeBron James in first.” You don’t want to wait till the end to put your best drug in, and I think that’s what’s happening.

Paul Richardson, MD: Yes. Thank you, Nina. That’s excellent. Other comments, if I may?

Amrita Krishnan, MD: Are you impressed enough with the ALCYONE overall survival benefit that was presented now to say that it convinces me that moving DARA up front will confer an overall survival with every other regimen?

Nina Shah, MD: No, we just don’t know because I don’t think that VMP [bortezomib, melphalan, and prednisone] is the same thing as RVd and transplant. For me that was just okay, but it’s another.

Amrita Krishnan, MD: But CASSIOPEIA study doesn’t have any maintenance in one arm, so we already know that that’s going to.

Nina Shah, MD: That’s why I think the GRIFFIN study is, for me, the outcome data.

Sagar Lonial, MD, FACP: The challenge is that in the newly diagnosed setting, or even in the smoldering setting, you have so many treatment options down the road that I’m not sure OS [overall survival] is the right end point.

Amrita Krishnan, MD: Wow, I can’t believe you are saying that now.

Sagar Lonial, MD, FACP: I’m a PFS, and I worry that some of these trials in the older, frailer patient where OS is a primary end point; it’s about access as opposed to actually does that treatment deliver a sustained survival benefit? And that’s a messy question.

Ajai Chari, MD: I think the purpose of the ALCYONE trial to me wasn’t so much to look for OS as an improvement. I actually wouldn’t have cared if it didn’t. I think there’s a question that a lot of people have is this: using your LeBron James early, what are you going to compromise downstream? Are the relapses worse? Are you going to compromise PFS2 [Progression after the next line of therapy]? To me the message is from ALCYONE that if PFS2 is not compromised, the OS was not compromised.

Paul Richardson, MD: Exactly. Well said, Ajai.

Transcript Edited for Clarity