番茄社区

Despite the rapidly changing landscape of treatments available for multiple myeloma, autologous stem cell transplant (ASCT) remains the standard of care among eligible patients. At December's American Society of Hematology (ASH) virtual meeting, a trial launched over a decade ago had a long-term follow-up analysis on , in light of the modern therapies we have today.

番茄社区 has brought together three expert leaders in their field: moderator , is joined by , and , for a virtual roundtable discussion; and this first of five exclusive episodes focuses on that very debate.

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

Episode four: FORTE Raises Question of Excessive Treatment in Myeloma

Episode five: CAR-T for Myeloma Excites at ASH, but Questions Remain

Following is a transcript of their remarks:

Vinay Prasad, MD: All right, I'm Dr. Vinay Prasad. I'm an associate professor and a practicing hematologist oncologist here at the University of California San Francisco. I'm joined via Zoom by two dear colleagues who are myeloma experts, Aaron Goodman, assistant professor at the University of California San Diego, an expert in bone marrow transplantation and hem malignancies, and Dr. Al-Ola Abdallah at the University of Kansas, also an expert in hematologic malignancies and bone marrow transplant. It's a pleasure to have you both here, sirs.

Well, let's get started. There is so much to talk about at this year's ASH annual meeting about myeloma. All our favorite drugs are there and some of the ones we don't like too much, and so let's get started.

Let's start by a randomized controlled trial that was launched now just over a decade ago by the French and DFCI investigators, a randomized controlled trial of autologous stem cell transplant in CR1. This is different than prior randomized controlled trials.

I hear people talk about prior randomized controlled trials in the age of melphalan, where all we had was melphalan and we didn't have anything better than melphalan, and those randomized controlled trials show a survival benefit from transplant. That's clear. But in the age of novel drugs, of proteasome inhibitors, of IMiDs, of CD38 antibodies, does transplant still have a survival benefit?

Aaron, I wonder if you might walk us through this study. This is the French study. What do you think about this study? How are you making sense of it? Is it affecting your practice?

Aaron Goodman, MD: Yeah, so it's a great study. They took a modern induction regimen that we are all using, at least it's my standard of care and still is, RVD, and as a transplanter myself, my go-to has been RVD induction, and for those eligible, recommending consolidation with high-dose melphalan followed by revlimid maintenance. This study took transplant-eligible patients and asked the question, is transplant still necessary in the era of these modern therapies? They randomized to upfront transplant or just going straight to a maintenance arm. What they showed was, as I think we can all expect, if you got transplant upfront, your progression-free survival was longer. Although you got more therapy, you had a longer progression-free survival.

But now with, I think you said it was 10-year follow-up, or a prolonged follow-up, the overall survival is still no different between the upfront transplant versus those who deferred transplant. Again, some of those patients who deferred transplant went on to receive transplant at relapse, while others did not.

For me, what this tells me, and it's very useful data when I discuss with my patients, I think I believe and I'm fairly confident that transplant is a very useful tool in the treatment of our patients with myeloma. If you get this transplant at some point during your disease course, it does offer a survival advantage. But whether you need it immediately upfront, especially in the era of COVID, or whether you can wait years, it doesn't seem to matter in the era of RVD-type therapy. I think it...

Another thing I tell my patients when I'm consenting them for this procedure is that I still think transplant is reasonable. There's a chance you might drop out later and not be eligible for transplant, but then the other side of that story is maybe in 5 years we won't be doing transplant, and thus by delaying transplant they are spared a transplant. Although relatively safe, it's still, for most patients, a few weeks in the hospital and not feeling too well. My standard of care is I still think transplant's useful in the treatment of the disease, but I do not think it's absolutely necessary upfront and that is what I discuss with my patients.

Prasad: As a transplanter, you can't say anything else. Abdallah, what are your thoughts on this study?

Al-Ola Abdallah, MD: I like this study a lot because actually it's just to compare well, do we really need transplant upfront or in delayed. But we really have to look at several points. Aaron is actually pointing out that the survival is similar for both groups, but let's look at the facts. One of the major facts here is that more than 78% of the patients in the RVD arm required transplant afterwards...

Prasad: They eventually get it.

Abdallah: They eventually get it, and that's a very important concern that we really don't know if the survival has been equal because they got transplant eventually. But also there is another point we also have to make. After 8 years of seeing these patients, 24% or 23% of the patients who got the RVD did not require transplant at all, and that's after 8 years, versus 38% of the patients who got the stem cell transplant they're still also in remission, so there was a 15% difference.

I understand we don't like transplant for a reason because there is that three months of that patient who is severely neutropenic, mucositis, and having old GI symptoms, and so old treatment, which we agree with that. But there is a question about that 15% margin of differences that makes these patients staying in remission longer comparing to those who don't do the transplant.

I agree with Aaron about maybe in 5 years we will not need transplant because we have new immunotherapies coming out and evolving. But until that time comes, we still consider transmitted as a potential treatment.

To be honest with you, I still use the newer treatments upfront to get patients at least a partial response, which sometimes is difficult. Once I get them to transplant, immediately they respond very fast, and they go to a complete remission, so transplant will still be considered as initial therapy.

In the COVID-19 era, I think it's a great idea to consider waiting for a transplant, for these patients to have a delayed transplant. I totally agree with Aaron. We should not jump into the conclusion that we have to do early transplant for these patients, but also let's look at the facts about this study.

These patients who got the RVD transplant, let's say they got about 4 cycles followed by transplant and then maintenance therapy with the revlimid. The other arm, they got 8 cycles of RVD followed by maintenance therapy, but eventually they needed a transplant. Patients have to be aware that they're going to get more RVD, more cycles of therapy, eventually, comparing to the transplant arm.

I usually tell the patients that 78% of them might need transplant eventually and they will make that decision. If they decide, "No, I would prefer to do the early transplant than waiting late," that's their decision, which I prefer because eventually, based on this study, we will see them require a transplant.

Another thing also that was a major concern, don't forget this is a clinical trial for our patients. Clinical trials have one thing distinguished from real-world patients. In clinical trials, we can follow these patients. We can make sure that eventually these patients might have the best option of getting a transplant. But in the real world, we might miss these patients, and again, we don't know if there is really a survival benefit or no survival benefit with a delayed transplant. Again, that's a very important thing because...

Prasad: That's a tough one, yeah.

Abdallah: ...it's a tough one.

Prasad: I guess I would say a spirited debate, gentleman, a spirited debate. I think that there are a couple of interesting things I pull out of this conversation. One interesting thing is we all agree that this study, in the era of RVD induction therapy, there is no clear survival benefit at 8-year follow-up and I think different people will interpret that differently.

I admit my bias is to say that it's a justification to wait if you want to wait and I think there are a couple of things I've heard. Some people argued that by doing transplant in CR1 you buy longer time until relapse, where potentially there are more efficacious drugs available. But the flipside is, as Aaron articulates, by not doing transplant in CR1 you may buy time until transplant is no longer a de facto standard of care and something else is available.

This trial, although it included many of the drugs that all of us use in our practice, doesn't have all of the drugs all of us use in our practice. Rates of daratumumab were quite low. Carfilzomib were a little bit lower than we might expect.

It's difficult to know what a study would really look like in sort of a U.S.-based setting with all the drugs we have available, whether or not transplant in CR1 one has a survival benefit, whether or not CR2 is necessary to do transplant, or whether or not at some point in the future you need to do transplant and when. There is a lot of open questions here, so a spirited debate.

I guess that because auto transplant put so much food on the table of academic medical centers, and we've been hit so hard in this year of COVID, that for the near future transplant will continue in the near future. A lot of enthusiasm at transplant centers. When you have a transplant center, you've got to do a transplant, that's what I always say.

Aaron, last thoughts?

Goodman: My only last thought is there is something, too, being said, I think the patients, if they want to consolidate their treatment and get the biggest bang for their buck -- and possibly have a very durable remission, even some with a decade -- then a transplant's still a very viable option to do upfront, although reassured if you wait there's no effect on your overall survival.

Prasad: And last word, Abdallah?

Abdallah: Yeah. Well, again, you're not wrong in any way about if you want to delay the transplant. I still think like we still have to give all this information. The IFM study is very great, very thorough. We have a longer duration that we actually followed these patients for about 8 years. We just have to translate that to the patients and make them decide about that. Because don't forget, patients also talk to other patients. You know, like a patient who got a transplant let's say 10 years ago, and say, "I'm still in remission. I didn't relapse. Why your doctor never offered you transplant?" They have the right to actually know about that, about the longer duration. They have to look at the pros and cons of the transplant, what can it cause as side effects and toxicity short-term and long-term as well.

If we kind of give that update for the patients and make them make the final decision, I think eventually we're in the right situation. In terms of like survival, there is no survival benefit using transplant earlier versus delayed, but there is a progression-free survival benefit eventually that we can see with early transplant.

Prasad: Like all great questions, shared decision-making will rule supreme here, so thank you both for this provocative conversation.

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