Can ASCT be delayed? Should I get transplant upfront or delay?

Can autologous stem cell transplant be delayed?

How do you decide to do transplant upfront or delay?

Does a patient need one at all?

Stem cell transplant can absolutely be delayed and it's a viable option in many of our patients.

So the whole idea is if you think about everything in myeloma, at the end of the day, one of the most important things is marrow health.

When you're diagnosed, your marrow is unhealthy. It's filled with myeloma.

So we give medicine to clear out the bad stuff, improve the health.

But over time, that medicine may affect our ability to collect stem cells.

So usually after around 4 to 6 cycles of induction, we will stop and collect stem cells and we can put them in the freezer and we can keep in the freezer forever.

I've actually used stem cells on patients that were collected more than a decade prior.

So for some patients we do upfront transplant. It's part of their treatment approach based off of their response, their age, their co-morbidities, their risk stratification.

But for some patients they say, I don't want to do a transplant. Now, maybe the end of induction. You have a big family event, kids are graduating or something very important where it's just not part of what you want to do now or you and your care team have decided we don't need it at the moment.

Those cells can be stored for later and at some point in the future, if your labs start ticking up, the best part about it is they're ready to go.

They're sitting in a freezer, ready to go at a moment's notice.

So I recommend collecting on everyone. And we have a discussion should we do a transplant now? Should we do it later?

I often like to do it in the beginning because your myeloma will never be as naive as it is as it is in the beginning.

You kind of want to kick it when it's down.

But that being said, I've had wonderful responses in patients where we chose not to do it upfront, but we did it later on in the disease course at first relapse or second relapse and still get amazing responses.

So the incorporation of stem cell transplant into the therapy of patients with myeloma has certainly evolved over recent years.

Ten plus years ago, anyone who was really eligible was sent for a stem cell transplant.

Options were a little bit more limited then in terms of medications and stem cell transplant was and remains a very effective therapy for multiple myeloma.

However, it's a very strong therapy. It involves time in the hospital and involves temporary hair loss, time away from work.

So it's a decision that isn't made casually or flippantly.

We certainly have known over recent years, data has shown us that delaying a stem cell transplant and doing it upon relapse offers the exact same results at doing it upfront.

So for patients that are interested in what we call a harvest and hold approach, where stem cells are stored and available for the future, that's become a very reasonable patient.

Preference plays a role too. We know that stem cell transplant offers a prolongation of what we call progression free survival, meaning time until the myeloma starts to act up again.

So for patients for whom that's a major priority to, quote unquote, do anything they can to delay a myeloma recurrence and are willing to undergo the stem cell transplant, it remains very reasonable for upfront.

But for those who would like to try to avoid it, a harvest and hold has become equally reasonable for many patients.

The next question is do you have to go forward to transplant?

And the transplant community, of course, will always say yes, because that's what the transplant community does.

But if we very critically look at the data, I think you could argue yes, because it is a very well-established therapy.

It really works. You can reduce the amount of disease we transplant and is very well implemented. It's been around for 40 years.

It was developed in 1983.

So this year we are accelerating 40 year anniversary mail following chemotherapy.

But there are also recent trials that have looked into it and most recently the Dana-Farber Clinic.

They showed in a randomized determination study that the addition of transplant versus not in a setting of a three drug combination with VRD had no survival difference at six years of follow up.

So patients who did or did not transplant, there was no benefit in survival.

And this was the second study showing the same thing as has been shown before by the French group in 2017.

They do the same exact study design for the combination and transplant or not, and show that eight years of follow up there is no survival difference.

So a fact on the table is that two large randomized trials showed there was no survival benefit to the defense of transplant.

If you look at how long the disease stays away, there is clearly a benefit in these two studies.

I mention the transplant makes the disease stay away longer.

In the French study, it was about one and a half year and in the determination study it was 21 months.

So I think in favor of the transplant, you could say that.

Why would you not like the disease to stay away longer?

And if you want that transplant shows in two studies that that is the case.

Coming back to the counterargument against us is that in both the French and the determination study, they looked in patients who were not transplant said and they looked at patients who were transported and they looked to see if patients could achieve amour de negativity.

And what they found is that there are more patients being more negative after transplant than in you see in the non transplanted group.

And that is why the progression free survival is superior.

But when they looked at those patients who were M.D. negative after transplant compared to those who were multi negative without transplant, their progression free survival was identical.

So now we have a very complicated situation where you can give a therapy and you are not going to live longer with or without the therapy, but on average it's going to last longer.

But if you actually have a deep response and you cannot find the disease with just the drugs, it doesn't add anything to it.

And I also think it's important to think about toxicity.

So the determination study showed that there were ten patients of the most recent update having developed myelodysplastic syndrome and acute myeloid leukemia, MDS and AML, and they were all in the group that had received a transplant.

We know that the absolute risk is not very high, but if you want to minimize all the risks, you could argue that that would go against.

I think it's a great question. I mean I go through this with all my patients all the time with newly diagnosed myeloma. I think to answer your questions shortly, then can it be delayed?

The answer is yes in most cases.

And I think the most important determinant of that is based on how well patients do or how well the tumors respond to the initial combination therapy.

So in my practice, all patients received, usually regimen like CRT-D or daratumumab with VRD.

And after about four cycles, most of the patients will send to get their stem cells harvested and temporarily or maybe more permanently stored.

So our my by default is delayed.

But after four cycles, I feel like everyone should get their stem cells harvested.

I think it's low hanging fruit in my opinion.

Then the patients continue with their combination therapy and somewhere between 8 to 10 cycles.

I would say we really look at how deep the response therapy was and in patients who attained medi negativity and as you know, there's different definitions and you have to be really careful. You really have to look at the level of sensitivity on the actual pathology report.

But if it meets I am WG criteria, which is at least ten to the minus five.

So if you can rule out one bad cell out of 100,000 good cells, then that's considered a margin negative.

And I actually recommend to my patients to forego transplant, immediate transplant.

I usually have them again receive somewhere between 8 to 10 if we have to consolidate.

It kind of depends on another things, how well they did. You know, with the combination side effect, etc.

And usually I transition them to maintenance, therapy and most patients to do really well.

And then and then if and when the time comes, if the myeloma picks its head again if need be transplant is there as an option, as is potentially other therapies?

I always practice this way. I felt this way based on the data that was available.

But I think what was really icing on the cake and crystallizing this in my mind was the determination study that was presented by Dr. Richardson at Dana-Farber really showed in patients who are who attain Martin negativity that neither do the does it that it's equal if you get transplant or not in terms of how long it takes for the myeloma to come back or how long patients live.

So so it's easy when you're imagining.

But what if what if patients don't attain emerging negativity?

I think then it's again, it's a conversation, I think, again, based on the same, you know, phase three randomized study by Dr. Richardson, it shows that if you don't reach emerging negativity, that it takes longer for the myeloma to come back.

If you do receive the high dose multiple and with the stem cell support, i.e. the transplant.

But there's no difference in survival.

And then so I kind of narrow down on whether you get transplant or not, but then I narrowed down to the benefit and progression free survival, which is the the technical term.

When I say, you know, how long it takes for the myeloma to come back, and although it's significantly longer, the progression free survival in patients who received the high dose chemotherapy, the question is they just got high dose chemotherapy to get that longer progression free survival.

Is that important for the patient or is the patient more content potentially not to get that high dose chemotherapy up front?

If that's an option, I always think patients should at least get their stem cells harvested so that they have that potential future option.

And I think the great thing is, the way I do it is that you really allow patients to get their highest efficacy upfront because you're treating the myeloma at its weakest point. The response is deep, and you can often with that deep response avoid the need to get stem cell transplant or high dose chemotherapy at the beginning.

At the same time, if you know if the patient needs it, the option is still there.

So that's kind of how I approached it.