Trial Data in Newly Diagnosed Transplant-Eligible Myeloma
Panelists: Sagar Lonial, MD, FACP, Winship Cancer Institute of Emory University; Amrita Y. Krishnan, MD, City of Hope Comprehensive Cancer Center; Thomas G. Martin, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Krina K. Patel, MD, MSc, University of Texas MD Anderson Cancer Center; Saad Z. Usmani, MD, FACP, Levine Cancer Institute
Sagar Lonial, MD, FACP: Let’s let Saad get us caught up because everybody may not know those trials. So let’s talk about that FORTE, and let’s do the CASSIOPEIA as well, just in a little bit of a nutshell.
Saad Z. Usmani, MD, FACP: The FORTE trial was actually updated data only on response. The FORTE was a 3-arm randomized phase III trial with roughly 470 patients. Patients got either KRd [carfilzomib, lenalidomide, dexamethasone] continuously for 12 months or K [carfilzomib] with cyclophosphamide-dex [dexamethasone] as induction for 4 cycles, transplant, and then 4 cycles of consolidation or KRd [carfilzomib, lenalidomide, dexamethasone] for 4 cycles of induction, transplant, and 4 cycles of consolidation with KRd [carfilzomib, lenalidomide, dexamethasone]. I think that the key message for me from this trial when I first heard it at ASH [the American Society of Hematology Annual Meeting & Exposition] was that the PI [proteasome inhibitor] IMiD-dexa [immunomodulatory-dexamethasone] combination is probably the better combination. Many of us actually have always thought like that, but we actually have data to support it in terms of depth of response that patients get.
The other message, I agree with Amrita, was sustained MRD [minimal residual disease] negativity or sustained depth of response is what you get with addition of autologous stem cell transplant, and that’s what we saw with the data being presented. The other study, CASSIOPEIA, was a phenomenal effort by our European colleagues enrolling over 1000 myeloma patients within 2 years and then reading it out and presenting it to us in record time. So this was a trial that randomized patients to VTD [bortezomib-thalidomide-dexamethasone] induction with or without daratumumab, followed by a similar consolidation before maintenance, post transplantation, showing the addition of daratumumab led to improved depth of response in patients. In fact, the paper just came out in Lancet. One thing that surprised me about this trial was the comment about stem cell mobilization. Because we did not see that in GRIFFIN. I’m not sure whether it is the lack of experience in mobilizing with just growth factors. But I’m not sure because we don’t see that signal when we use dara [daratumumab] with RVd [lenalidomide-bortezomib-dexamethasone] in clinical trial settings.
Sagar Lonial, MD, FACP: Yes, I think at least 1 take-home message for me—and you may want to comment a little bit more on MRD—is that while we always talk about MRD, MRD, MRD, the reality is 10-5 is not 10-6. And PFS [progression-free survival] doesn’t always match what the MRD data tell you. And so I think the transplant still continues to have an important role. I think about it as the response is dependent on induction and PFS is dependent on maintenance. And that’s really an important issue with CASSIOPEIA, that it was dara [daratumumab] versus nothing in the maintenance phase.
Saad Z. Usmani, MD, FACP: Right, right.
Sagar Lonial, MD, FACP: And no matter how you look at the randomization, the curves start to separate at about 9 months after diagnosis, which is around the time that you could get randomized to dara [daratumumab] or nothing. So I really wonder about the importance of some form of maintenance. I don’t know what you all think.
Saad Z. Usmani, MD, FACP: I agree with you on that. I think that’s a similar pattern to what we see with GRIFFIN as well. The response data that Peter Ward presented at ASH.
Sagar Lonial, MD, FACP: All 16 patients.
Saad Z. Usmani, MD, FACP: All 16 patients. Interestingly, the depth of response actually improved post transplant. I didn’t see any differences between the responses we get with RVd [lenalidomide-bortezomib-dexamethasone] compared with dara-RVd [daratumumab-lenalidomide-bortezomib-dexamethasone] just with the induction piece of that whole regimen.
Thomas G. Martin, MD: This transplant, this preparative, or this therapy for transplant—I think 1 advantage to this is we are going to see what happens with maintenance or no maintenance, right? We don’t really know where monoclonal antibody will have its biggest splash: as part of induction, as part of consolidation, or as part of maintenance. This is the only trial that will tell us as part of maintenance because it’s against nothing.
Sagar Lonial, MD, FACP: In CASSIOPEIA.
Thomas G. Martin, MD: Yes, CASSIOPEIA.
Amrita Y. Krishnan, MD: I don’t think that’s fair because you’re still going to get dara [daratumumab] in your induction arm, though.
Thomas G. Martin, MD: Well, people will get dara [daratumumab] induction.
Amrita Y. Krishnan, MD: But don’t get it as maintenance.
Thomas G. Martin, MD: Correct, exactly.
Saad Z. Usmani, MD, FACP: There will eventually be 4 subgroups of patients.
Thomas G. Martin, MD: Yes. It will be interesting to see. I think we all believe that lenalidomide maintenance is a very important part of the post-transplant effect, especially even the immune effect that we’ve been talking about. This therapy we wouldn’t be giving to patients I think in the United States. But, that said, this is going to provide some very important data for us.
Amrita Y. Krishnan, MD: I think the PERSEUS trial is going to be the 1 that really moves our curve because that trial is RVd [lenalidomide-bortezomib-dexamethasone] plus or minus dara [daratumumab], which is obviously very reflective of the United States, and then randomization to dara [daratumumab]-lenalidomide versus lenalidomide alone, so very reflective of our practice. So I think the question I would ask everyone, is everyone ready to immediately jump to dara-RVd [daratumumab-lenalidomide-bortezomib-dexamethasone] based on CASSIOPEIA?
Thomas G. Martin, MD: I don’t think we can. I don’t think we’re going to be able to do that, but I do like PERSEUS because there is an adaptive design at the maintenance. If they achieve MRD negativity, then they’re going to be able to stop the daratumumab, continue lenalidomide. And that will be great, because then maybe when they relapse, then you can put back on the CD38.
Amrita Y. Krishnan, MD: Can I put a plug in, then, at the risk of sounding like The Tonight Show, that we’re going to have that option in the United States too, with the SWOG [Southwest Oncology Group Cancer Research Network] trial that’s going to open in July, which is also going to be any induction, transplant, and then randomization to dara [daratumumab]-lenalidomide or lenalidomide for 2 years and then second randomization based on MRD. So hopefully we can, in fact, accrue quicker than our European colleagues this time and answer that.
Saad Z. Usmani, MD, FACP: I’m happy to jump on adding the DARA to a triplet bandwagon for standard-risk patients. I’m still on the fence about the high-risk patients in the frontline setting. If you look at those prespecified PFS subgroup analyses on MAIA and ALCYONE, even in CASSIOPEIA, the high-risk patients aren’t really benefiting from the addition of daratumumab. And maybe that will happen over time. Maybe that will happen with the subsequent longer follow-ups. But at this point in time, I’m a little on the fence about the high-risk patients specifically.