Is transplant still needed in the age of novel therapies?

Is an upfront autologous stem cell transplant (ASCT) still needed in the age of novel therapies that lead to deep remissions?

Transplant is still a vital part of the way we approach myeloma. 10, 20, 30 years ago, we didn't have really great drugs, and we knew that transplant was better than the bad drugs we had back then. Nowadays, we have much better drugs. And it turns out there are probably some people who will do so well with induction therapy. They don't need transplant. That being said, we haven't exactly figured out who that specific patient is and does MRD exactly exclude you from leading that. Because if you're high risk, even if MRD negative, there still may be some benefit to transplanting.

Because remember, the deeper remission you get, the longer you stay in remission. So if you get into remission here, transplant can put you just a little bit further, there may be some advantage. You never do worse with transplant. Some patients just don't necessarily do better. So we just need more data to figure out who. Perhaps it's standard risk that gets MRD negative, may not really need the transplant upfront, but if you don't get MRD negative and you have high risk, maybe you need it more. Still trying to figure out all that granularity.

Clearly, in the old days, autologous stem cell transplant was a mainstay of treatment. It was a bridge to the next bridge. And I think what's important to recognize is it was a very valuable and important tool of old. The question is how does it apply now? And I think what's been very rewarding is to see that we could combine novel therapies with transplant and improve outcome.

But what then has happened is that these treatments have become so good. The question is how much does transplant add on? What we saw at this meeting was that antibodies added to three-drug platforms are revolutionizing the outcomes. At the same time, we have to be very honest with our patients. That mephalan in high dose is toxic. There are side effects of the transplant itself, both in the short and the long term. And so with that and with the impact that that has on quality of life, we have to really weigh its risks and benefits.

What we saw at this meeting was a fantastic presentation from doctor Francesca Gay and the Italian group, where they showed that, in fact, KRd, which is a triplet we use in the upfront setting, if you gave it for 12 cycles, it was just as good as KRd times, eight with a transplant. But what was interesting in her analysis was that in a subgroup of patients with higher risk, actually the transplant may be helpful.

Now, the important point to remember is in all of this data, it's very early. So it may be with longer follow-up that we see more of a benefit from transplant. We don't know. But the flip is also true that in those patients in whom were high-risk disease was defined, we don't know at this point how they were maintained. And so I think the conclusion she drew, which is one size doesn't fit all, is absolutely correct.

I think assuming just if you have high-risk disease that we must get a transplant is not necessarily true either yet. Because we don't know what they were maintained with. And as one of my colleagues pointed out to me, the playing fields completely changed yet again anyway, because of the antibodies. And so you may say, well, okay, well, if you've got nothing to lose, why not just do it anyway?

Oh, well, there's this thing. Because what we're realizing as our patients thankfully live longer, that the long-term consequences of melphalan exposure are real, and they revolve around myelodysplasia and secondary leukemia. Fortunately uncommon, arguably rare. But for those patients affected, absolutely devastating. So for that reason, we need to better understand who benefits from it and who doesn't protect those who don't need it.

And at the same time, optimize it for those patients who might derive significant benefit from it. We don't have definitive evidence yet. We still know that transplant provides a strong benefit in terms of progression-free survival, as seen in the IFM study that was reported in a couple of years ago. Showing the 14-month PFS benefit for those patients who received a transplant. There's no overall survival benefit yet, but the readouts are really the only a three-year readout.

And what we're seeing is the fact that we're seeing very effective drug combinations that allow for very good responses. So the Italian group just presented at the last as a results of their, Forte trial, which showed that KRd for eight cycles compared to KRd for four and transplant seemed to generate similar results early on. It's very exciting.

We also saw that the KCD was inferior, so we now know that, the carfilzomib lenalidomide, and dex for a prolonged period of time may be, a route for some patients, but then said it didn't do was divide up these high-risk standard risk. And we need to have that degree of granularity before we can recommend. Oh, you can just get chemotherapy and not have to get a transplant.

For some patients they just don't want to have a transplant. Right now there are issues etc.. But I do recommend for our patients they should have their stem cells collected if they are a transplant eligible patient, if they're not going to go on to a transplant early on because those patients, if they do delay and they get a lot of therapy, may have damaged marrow.

So I think that it's better off getting your stem cells collected early regardless, I still recommend it right now in the current age, because we don't have better data suggesting that, chemotherapy alone or chemotherapy and new drug approach is superior to transplant.

We are all thrilled, and we are all excited about all the new treatments that have come out, especially in the last 15 years or 15 to 20 years now, which was unleashed by the lenalidomide, and of course, followed by other immunomodulatory drugs and then proteasome inhibitors, and then followed by antibodies and now various immunotherapeutic agents. So that is great.

But, why is stem cell transplant still an important part of treatment? First, two very basic things. It is safe. Number two, it is effective. It is effective on its own, where before any other treatment, before any maintenance or consolidation, when you do a stem cell transplant patient would more than 90% would respond and their average progression-free survival or the duration of remission would be about 18 months to two years. So those were excellent results.

So since then a number of trials have been done. Some were done before the availability of these new, newer agents and several have been done now with the availability of novel drugs. And basically, all the studies show that when you combine stem cell transplant with conventional treatment, whether novel or the older ones, number one, we get deeper responses, which in this day and age includes minimal residual disease negative status.

Number two, we get more durable responses. So almost all the trials have shown that there is a longer progression-free survival when you combine stem cell transplant with novel agents. And in some of the studies there is an improvement in overall survival also. So given all these facts that again, since there is no single curative therapy available for myeloma, and the goal and the intent is to achieve the deepest and the most durable remission and to achieve that goal, I think stem cell transplant is one of the time-honored, safe, effective, and in this day of cost consciousness, which actually should have been there always, is a reasonably cost-effective treatment also.

So I think with all the evidence, we still feel that it is an integral part of myeloma treatment. So I think some of the biggest questions nowadays we get asked in clinic are whether someone should, should or should not do a stem cell transplant, especially in the at the time of first diagnosis. Certainly. Deferred transplantation approach has been validated, without compromising survival in our most recent, studies. But I think, again, kind of, honing in on that theme of individualized therapy, you know, don't feel that, particular, mode of therapy, is an absolute necessity for an individual. It's a discussion you should have with your doctors about pros and cons of therapy. There's plenty of patients we recommend a stem cell transplant for, but there's plenty that we do feel that can potentially keep it in reserve, at a later time. So this is an important, question that, hopefully continue to get more clarity as we get more tools about how to individualize therapy and choose a particular mode of therapy for, for a patient. So the way we look at transplant is in the age of new therapies, those new therapies can just make transplant more effective. So we've already made transplant extremely safe. In fact the risk score is the same as standard chemotherapy. Now what we do is and build upon that both the induction or the treatment before the transplant as well as the treatment after, whether it's consolidation or maintenance therapy.