Ola Landgren, MD, PhD: Let’s move into the second part of the discussion and focus a little more on the details of where we are heading in the future. That ties into what you are talking about here, Sundar. There are many trials that are being presented at meetings and communicated on the Internet these days. One of them is the FORTE trial. That is a randomized study from Italy using carfilzomib with lenalidomide.
On 1 arm, the duration is 12 months. The other arm has fewer cycles. I think it’s 8 cycles, and then there’s a transplant included. Then there is a third arm in which carfilzomib is given together with cyclophosphamide. From what we have heard from ASCO [American Society of Clinical Oncology Annual Meeting] 2019 and the EHA [European Hematology Association] meeting in Amsterdam, Netherlands, in 2019, the carfilzomib with Cytoxan [cyclophosphamide] is an inferior arm, in terms of depth of response and duration of the response with progression-free survival.
Then you have the 2 arms with a longer versus a slightly shorter duration of the combination therapy, where the shorter duration then has the added transplant. It’s interesting to see that although they have been shown to an audience at multiple meetings, the audience seems to interpret the data differently. The people who like transplant say transplant is still needed, and the people who say transplant may not be needed say this study shows that you don’t need transplant when they see the data. Then there are people attending the same presentation hearing 2 different things. What I see here is that the standard-risk patients seem to have a very similar outcome with a longer duration of combination therapy without transplants, versus a short duration with transplant, while the high-risk patients seem to have a better progression-free survival if they received a transplant. What is your interpretation of the data, Sundar?
Sundar Jagannath, MD: This is very interesting for me. I’ve been doing stem cell transplantation from Total Therapy 1 in 1989. We were doing tandem transplants in the ’90s. At that time, none of the new drugs were there, and we established that patients whose disease did very well had good risk, and patients whose disease came back quickly, were at high risk. High-dose therapy was not effective in the high-risk patient, as defined at that particular time.
Now we are coming into 2019, and we have a trial in which you give 4 cycles of KCd [carfilzomib, cyclophosphamide, dexamethasone] or KRd [carfilzomib, lenalidomide, dexamethasone], and then they all have their stem cells collected. Then there were 2 KRd [carfilzomib, lenalidomide, dexamethasone] arms. One goes through transplant, and another doesn’t. At the first phase, before they are randomized into transplant, you see that the KRd [carfilzomib, lenalidomide, dexamethasone] arm has a greater depth of response than the KCd [carfilzomib, cyclophosphamide, dexamethasone] arm. We had similar results with VCD [Velcade, cyclophosphamide, dexamethasone] versus VRd [bortezomib, lenalidomide, dexamethasone] and things like that. The alkylating agent is somewhat less efficient in the depth of response than the immunomodulatory molecule.
Then you had KCd [carfilzomib, cyclophosphamide, dexamethasone] going through transplant and KRd [carfilzomib, lenalidomide, dexamethasone] going through transplant, and all 3 went through consolidation. The arm that continued KRd [carfilzomib, lenalidomide, dexamethasone] for 4 cycles then got KRd [carfilzomib, lenalidomide, dexamethasone] again without transplant and KRd [carfilzomib, lenalidomide, dexamethasone] consolidation. Then before they went to maintenance, they looked at how many people were in what depth of response. We thought that maybe the KCd [carfilzomib, cyclophosphamide, dexamethasone] arm was not that great as the KRd [carfilzomib, lenalidomide, dexamethasone] during induction, but maybe the transplant would equalize it or something like that. It didn’t quite equalize it, because after consolidation, the KRd [carfilzomib, lenalidomide, dexamethasone] arm got a little more depth of response. What was amazing is that the KRd [carfilzomib, lenalidomide, dexamethasone]—transplant–KRd [carfilzomib, lenalidomide, dexamethasone] and KRd [carfilzomib, lenalidomide, dexamethasone]–KRd [carfilzomib, lenalidomide, dexamethasone] without the transplant arms were coming out fairly equal.
Ola Landgren, MD, PhD: Right.
Sundar Jagannath, MD: That was very intriguing. When you look at it, the transplant arm had a slightly better outcome, but in this particular study, surprisingly, they said the high-risk patient got the benefit.
Ola Landgren, MD, PhD: That’s almost what you would have guessed.
Sundar Jagannath, MD: That is important. I really have to say, first of all, this is a prognostic factor, not a predictive factor. The prognostic factor in myeloma is variable. We do know when you—and you did this study, especially in smoldering myeloma when you were at NIH [National Institute of Health]—you really dissected the patient at multiple times and did genome sequencing, RNA sequencing, exome sequencing, and whatever. You showed that, first of all, if you do that kind of thing and you compare it with FISH [fluorescence in situ hybridization] and cytogenetics, cytogenetics was terrible, because the myeloma cells don’t multiply. The FISH was not capturing all of it. The FISH was also not getting it, even when you did the enrichment. The genomics give you much more insight. That tells you right off the bat that how we classify patients with myeloma—high risk, poor risk—still needs work.
Ola Landgren, MD, PhD: Absolutely.
Sundar Jagannath, MD: All I would take up from here is that even after doing KRd [carfilzomib, lenalidomide, dexamethasone], there was a subset of patients who benefited. Until now, they have not seen who benefited from the high-dose alkylating therapy with the melphalan. You’ve caught some subset of patients who did better. In the future, once we dissect them with minimal residual disease and see what kind of patient they are, we will be able to determine which patient would have benefited from adding the high-dose therapy and stem cell transplant. Right now, this is a study, so it was rigid. Everybody got it, and then you tried to say this arm benefited from transplant. We will have to identify who gets the benefit from high-dose alkylating agents, and that will be a subpopulation which will be defined in the future, but it is not defined. That’s the way I look at it. There are also studies that have shown that if you are MRD negative and you have been a part of those trials published in JAMA Oncology, it doesn’t matter how you got to MRD negative.
Ola Landgren, MD, PhD: The treatment doesn’t matter. If you’re negative, you’re negative.
Sundar Jagannath, MD: You’re negative.
Ola Landgren, MD, PhD: To a degree, that’s true.
Sundar Jagannath, MD: The outcome is also equally good. I think that there are ways to look at it. Clinical trials have to have a fixed design so you can interpret them. But the knowledge we physicians gain can be applied differently at bedside.