Transplant Patients' Options, CoMMpass Study, and Doublet Versus Triplet Therapy

Rafael Fonseca, MD: The NCCN [National Comprehensive Cancer Network] guidelines, as our audience knows, provide some guidance for clinicians as to what choices might be used in the treatment of patients with myeloma. Now, these guidelines tend to be heavily focused on evidence-based medicine. So they really look at the regimens very carefully, and then they provide some weight behind the recommendations that they make for the treatment of patients. Unfortunately, because of that, they tend to be pretty broad. So it’s hard to completely know, for someone, say, in practice, how to go about selecting agents just from those guidelines. They obviously provide a very important framework for reimbursements for medications. But more and more we’re moving towards a more simplified approach to the recommendations for treatment when, in fact, as a group we have participated in the development of some of those guidelines. And the reality and the beauty of this is those guidelines are so dynamic, they have to be changing almost with every single meeting.

For instance, let’s talk about the transplant candidates. Across the United States, the vast majority of patients are treated, and rightfully so, with a combination of bortezomib, lenalidomide and dexamethasone, the regimen VRD. So, a large fraction of patients are treated that way. Some patients are still treated with the regimens that include cyclophosphamide instead of an IMiD [immunomodulatory imide drug], CyBorD [cyclophosphamide/bortezomib/dexamethasone]; however, that’s on its way out, and less and less people are being treated with that.

But the question that’s really pressing upon us now is, what about KRD [carfilzomib/lenalidomide/dexamethasone]? So, KRD is a highly effective regimen, and there are a number of studies addressing this. I think most importantly we have an ongoing national study, E1E11, that will do a head-to-head comparison of KRD versus VRD.

Now, as we get there, there are all sorts of bits of information that are doing a very thorough assessment of KRD. In my opinion, one of the best abstracts that was presented at this meeting was a study by Dr Francesca Gay, MD, PhD, from Italy. It was a 3-arm study. One of the arms got KRD, followed by a transplant, followed by 4 more cycles of KRD. And then there will be subsequent maintenance randomization; she’ll present that later. The second arm was KRD for 12 cycles. And the third arm was CyBorD like approach with KCD [carfilzomib/cyclophosphamide/dexamethasone] transplant followed by more KCD. The results are absolutely spectacular.

They were able to show 58% MRD [minimal residual disease]­—negative, post stem cell transplant in that arm that had stem cell transplant. So, number 1, very deep responses. Number 2, the responses were quite similar in those that didn’t get a transplant with 12 cycles. Now, we’re not quite ready to say transplant is dispensable, but that was a great study.

Dr. Ola Landgren MD, PhD made an analysis of the CoMMpass study that you referred to. It’s a retrospective study, so it has some limitations, but let’s call it exploratory. It does some comparisons between VRD and KRD. And his conclusion was, at least from what we know there, that the indicators might be for superiority of care for KRD. We clearly don’t know this, and we won’t have the answer until we complete studies like E1E11, but this is a fundamental question because of the results I had discussed previously.

Now, the NCCN guidelines also provide recommendations for the nontransplant candidates, and that will change after this meeting. So this meeting was marked by the presentation of 1 of the key studies, which was just presented this morning, the MAIA study, that looked at the combination of daratumumab, RD [lenalidomide/dexamethasone] versus RD alone. The study was, frankly, positive and overwhelmingly positive for the triplet versus a doublet. And this is a lesson we’ve learned in other settings. We learned that with the SWOG [Southwest Oncology Group] study S0777 that compared VRD to RD.

Now, the advantage that was seen with the daratumumab is quite striking. The median PFS [progression-free survival] has now been reached. Now these patients can stay on therapy. We learned that obviously patients are treated more chronically with this. Surprisingly, the control arm did very well. PFS, I believe, was around 31 months. So this is really going to take us back to the drawing board and say, for the elderly, even though we have to be very mindful about doses and toxicities, steroids are a big part of that. If the person can do it, I think that the lesson is there to go for the triplet instead of the doublet. And maybe the selection will depend on comorbidities, tolerance, etc. But you know if someone is 73, that person could have a life expectancy of 10 more years, and cutting back on effective treatment may not be in their best interest.