The FORTE study, presented at the recent American Society of Hematology (ASH) virtual meeting, compared giving 12 months of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) plus transplant to KRd alone in patients with newly diagnosed multiple myeloma.
MedPage Today has brought together three expert leaders in the field: moderator Vinay Prasad, MD, is joined by Aaron Goodman, MD, and Al-Ola Abdallah, MD, for a virtual roundtable discussion to discuss whether positive results should mean adding more potentially toxic and expensive treatments to standard of care, in this third of five exclusive roundtable episodes.
Episode one: Early Transplant or Delayed? Multiple Myeloma Experts Debate
Episode two: Selinexor OK’d for Myeloma, But Does That Make It a Good Drug?
Episode three: Many Questions Surround GRIFFIN Study
Following is a transcript of their remarks:
Vinay Prasad, MD: I’m back with Dr. Aaron Goodman and Dr. Al-Ola Abdallah and we’re talking about ASH and multiple myeloma. We have an exciting study to discuss, the FORTE study. This is a three-arm study that looks at carfilzomib-containing regimens, which, to my knowledge, is not the official standard of care in multiple myeloma in the frontline setting, although some believe it plays a role, and they ask a very provocative question about the role of transplant and maintenance.
Dr. Goodman, I wonder if you might summarize the FORTE study. What is going on in FORTE, what are we finding, and what should we be thinking about?
Aaron Goodman, MD: Well, the FORTE study, where they gave KRd upfront, which is not my practice. We have a randomized study showing that KRd was no better than RVd [lenalidomide, [Velcade], dexamethasone] that was recently published. Basically KRd was given for a long time, and then they gave close to a year of Kd-maintenance therapy, and they were able to show that progression-free survival looks amazing. These patients can have very durable remissions, but it doesn’t affect my practice yet. I’m interested to see how my colleagues, what they believe in this.
If you give a lot of KRd, and then give Kd basically indefinitely, you’re going to have very long progression-free survivals, at the expense of cost and toxicity, and these patients are on an indefinite therapy.
And Kyprolis has some — it’s manageable — but it can have some serious toxicities. Again, these patients are going to be burned out of Kyprolis by the end of this, and that will have no role for any of these patients at relapse. Again, unless you can show me a strategy with indefinite Kyprolis, basically continuous for years, will make patients live longer and feel better, I don’t see much of a role for it in my practice.
Prasad: Dr. Abdallah, what are your thoughts on FORTE?
Al-Ola Abdallah, MD: We have to look at the positive and the negative thing. I agree with Aaron about saying about that Kyprolis just to kind of give information. We have the ENDURANCE trial that compared the Kyprolis versus Velcade. It’s over. We just realized that the Velcade and Kyprolis are similar. The only time I’m going to use Kyprolis in myeloma, newly diagnosed myeloma patients, is if they have peripheral neuropathy. I will save it for relapsed myeloma. That’s where I will use it.
This study, actually, was designed, I think, based on some thoughts that Kyprolis is a good treatment for newly diagnosed myeloma, so they did the study, and I think it was a good study, in my opinion, being three arms.
Using carfilzomib/Cytoxan/dex with carfilzomib/Revlimid/dex with transplant was a good idea to see exactly, also, the benefit of Revlimid, because there was a lot of debate about what is the benefit of Revlimid upfront. This study really actually showed why the STAMINA trial that was in the United States — different from a European study that showed that there was a benefit of two transplants — while here in the United States one transplant was more than enough. And it was the Revlimid upfront therapy that we use comparing to Europe — they don’t use it upfront — that made really a big difference. I think this study actually confirmed all the things about that Revlimid upfront therapy is a great treatment. That’s the only major thing I thought about that helps me.
It didn’t actually answer any question about the transplant so far, except that we know that transplant has a better progression-free survival. I agree with Aaron about like, is it right now? Comparing the second randomization which they’re conveying maintenance therapy, carfilzomib-Revlimid versus Revlimid. It’s another way to ask the question, can carfilzomib onto progression be added to the Revlimid? Can it actually impact the progression-free survival and maybe overall survival? We don’t have any answer yet. There is a small increase in the MRD [minimal residual disease] negativity and we don’t have median progression-free survival in order to make that final thoughts about that.
The only thing I get from this is that, of course, early transplant is good in these myeloma patients, but also Revlimid is really an important treatment upfront therapy. Like you have to really try to get these patients, give them Revlimid upfront prior to whether you want to do transplant. Or if you’re opting not to give transplant, at least give it for, in some studies like IFM, for about eight cycles. Or like in this study, if you want to follow the FORTE trial, it’s going to be about 12 cycles.
But my opinion, I think we should not actually jump to the conclusion that maintenance therapy, adding more drugs makes it better. We need these randomized trials. We need the mature results of these trials before we make these decisions, not based on MRD testing.
Prasad: Yeah. I think that’s right. I think you make a good point about Revlimid. It is an important drug, particularly in the induction phase of VRd [bortezomib, lenalidomide, dexamethasone]. It’s, as based on the ENDURANCE study, still the de facto standard of care and it’s the regimen that needs to be beat before we switch our standard-of-care regimens.
I think if one were to stand on a mountaintop and look at the landscape of myeloma drugs, it’s hard not to see the following. At every instance, individuals are trying to move forward triplets and quadruplet therapies. We’re talking about treating high-risk smoldering multiple myeloma today, despite the fact that the SWOG study did not show an overall survival benefit and the investigators have crossed everyone over, so it will never be able to answer that question.
People cite the Jesús San-Miguel study in the smoldering setting, but that is an underpowered phase II study that we talked [about] in another video. When those find benefits for non-primary endpoints like survival, they are often exaggerated, sometimes even false positives. I don’t put a lot of stock in that Jesús San-Miguel/Maria Mateos study because also the regimens they get on progression myeloma are not consistent with the United States regimens, so that doesn’t tell us a lot about treating smoldering. But we can have a big push in the myeloma field to take our drugs — triplet regimens, quadruplet regimens — move it to smoldering.
We also have a push to add in the maintenance setting. Instead of Revlimid only, here in FORTE people are arguing you can give Kyprolis and Revlimid, so now two drugs in the maintenance setting.
It’s hard to escape the conclusion that the entire multiple myeloma research landscape is about giving more drugs sooner, indefinitely, forever, to everyone, which is certainly going to increase the cost of care, the cost of therapy, and in fact many of the funders of the studies might benefit from an increasing cost of care. It’s certainly going to increase the therapeutic burden to patients, giving even more toxicity.
But the real question is, do people live longer or live better as a result of all of these interventions? The truth is almost none of these clinical studies are able to reliably answer the question about whether or not this improves overall survival or health-related quality of life over the course of someone’s myeloma journey. Dr. Goodman, any thoughts on this broad-picture view of myeloma? Is it too cynical?
Goodman: No. Unless the investigators are going to show us that by combining all these therapies and doing prolonged periods cures patients, which we don’t know yet, or makes them live longer, for me it’s pretty simple. If we’re going to take someone who is asymptomatic, whether it be a high-risk smoldering myeloma or in the maintenance setting… in the maintenance setting, they’ve gone through all their treatment, including, perhaps, a transplant, and are finally in remission and should be feeling better.
If we’re going to recommend aggressive therapies, whether it be the addition of Kyprolis or treating early high-risk smoldering myeloma, we really can only settle for overall survival as an endpoint. At least, that’s all I can settle for, and I’m surprised that many people are so quick to say, “Oh, well. It keeps them in a remission longer.”
We don’t… in all of the other… like treating lymphomas, acute leukemias. There’s no rush to do this in any of the other diseases, but in myeloma there appears to be that feeling that we need to treat more, sooner, with more therapies, without the knowledge that they were actually helping these patients live longer.
Prasad: Yeah. It seems like folks won’t be satisfied until we have a regimen that’s over half a million dollars a year that we use continuously in patients. Dr. Abdallah, last thoughts on this question?
Abdallah: I agree with you all. I think everybody who thinks that their drug has a 20% response rate, they want to just move it up front. They believe it’s going to be better. It might be better, it might not be better, but why are we actually increasing the number of the drugs?
Again, I agree with Aaron. If it’s going to cure myeloma, then let’s do it. But if it’s not going to cure myeloma and it’s just going to improve the progression-free survival, and we’re eventually going to need other treatments, what’s the whole purpose of doing it?
I think that now we’re talking about four-drug regimen and tomorrow we’re going to talk about five-drug regimen. I don’t know if the six-drug regimen is going to come out later on. But any new drug that will be available and applicable, they’re just going to say let’s move it upfront.
That’s exactly what we’re seeing. Because everybody believed that since the drug is working somehow in the relapsed/refractory myeloma, they will work much better in the newly diagnosed myeloma, because in anybody’s opinion new is always better. But we always look at that.
We saw it with a transplant. Melphalan has been there since 1950s. We have been doing transplant for a long time. So far, let’s admit it, nobody, no treatment so far, had beaten a stem cell transplant. Nobody actually beat a stem cell transplant. That’s a fact. None of the new drugs. A matter of fact, I don’t think any clinical trial will go head-to-head against transplant anymore because it’s just a waste of time. Either they will do it with transplant or they will omit transplant at all.
It’s an old drug. It doesn’t mean like if it’s an old drug it doesn’t mean it can’t work. We just have to have that mentality of just stopping thinking about since it’s new, it has some efficacy, it’s going to be better than any other treatment.
Prasad: Yeah. Absolutely.
Abdallah: We have to have really focus on these randomized clinical trials. Let’s really go focus on do we need to cure myeloma or do we just need to improve the progression-free survival? That’s the biggest answer that we have to have and a question for that.
Prasad: Absolutely. We have a generation of myeloma doctors that I think has confused two things, activity and efficacy. Activity, of course, means you give a drug to somebody and the plasma cell burden and the burden of M protein and light chains goes down.
Lots of things have activity in life. In cancer, lots of things have long had activity, but the efficacy question is, in what combinations and in what order do you give people therapies to maximize the duration of life or the quality of life, and give them the least amount of therapy for the least amount of time? That used to be the goal of oncology, but we’ve forgotten that entirely and now it’s all the drugs early. It’s going to be five drugs upfront for smoldering myeloma. Who knows? Maybe someday we’ll take MGUS [monoclonal gammopathy of undetermined significance] patients and start treating them too. But we’re going to give all the drugs early, follow it off with a transplant, and then some CAR-T to boot. On that note, let’s turn to our next topic.