What is conditioning chemotherapy used in myeloma prior to transplant? What is the dose?

What conditioning chemotherapy is used in myeloma prior to transplant?

What is the dose?

Condition in regimen, a standard of care is Melphalan.

It is a very high dose Melphalan we give it out of 140 to 200 milligrams per meter square of the patient's body mass.

And it depends on the patient's kidney function, age.

We decide which one would be more appropriate.

So that's the standard.

Also, we have this regime of Busulfan plus Melphalan that can be used for high-risk patients.

And we can just talk about it based on the phase three clinical trials.

In stem cell transplant is a drug called Melphalan, which is a very old drug, which is related to a wartime chemical, which is used to actually kill people called nitrogen mustard.

And this agent basically attacks the DNA of the myeloma molecule, myeloma cells or the plasma cells, and makes the DNA molecules that are two strands. They form cross-linkages between the strands, which basically destroys the function of the DNA and leads to cell death.

And this drug turns out to be one of the most effective drugs in myeloma. Even when we have all these new therapies, it still remains a very effective drug.

In myeloma, the concept is that everything that is effective has to be used at some point during the person's lifetime with myeloma.

So if you miss out on a drug, you missed out on the benefit from that drug, which could sometimes be measured in years, for example.

So Melphalan is the drug of choice for transplants in myeloma.

When we look at the CIBMTR data, we find that 98% of transplants in America are done with this one drug as a single agent.

In the old days, we also used to do whole-body radiation along with Melphalan, but it turned out that that was not necessary because Melphalan alone was good enough, and whole-body radiation had a whole host of side effects, which is not acceptable.

For the most part, we have had high-dose Melphalan as the primary chemotherapy that we give before a stem cell transplant.

And in fact, the term transplant is kind of a misnomer. What we're really trying to do when we give the transplant in myeloma is give high doses of Melphalan, because Melphalan is one of the most effective drugs we have against myeloma.

But as a consequence of giving high-dose Melphalan, patients develop myelosuppression, so their blood counts can go really low and stay there because the stem cells get killed and damaged with high-dose Melphalan.

So collecting stem cells and giving them back is a way of countering that effect of Melphalan.

Why is conditioning treatment used?

I would say they started doing that just because we want to wipe out the bone marrow completely and replace it with the stem cells that we already collected ahead of time.

So when we give them Melphalan, it wipes out the whole bone marrow, but if we don't replace it with these stem cells, then the whole blood factory or the bone marrow are going to shut down.

So the patient is going to die from the toxicity of the Melphalan.

So that's why we collected the stem cells. We give them Melphalan, we wipe out the bone marrow, and then we give the stem cell back within 1 to 2 days after the Melphalan, just giving the time for the washout for the acute toxicity after Melphalan could just go up by the poison, goes away from the body, and then we give them stem cells back and then we give the patient time for recovery, basically we reset the factory.

And like whenever you have a computer and just reset the computer and it takes a couple of minutes to come out. Exactly, we do that when we're rebooting the patient's bone marrow or blood factory and will let them time for two or three weeks until like stem cells start working in the cells, making their own new stem cells that replace the previous ones.

How is Melphalan administered?

So Melphalan is administered to the IV or intravenously and usually takes 30 to 45 minutes for administration. Before getting the Melphalan, the patient has the ice chip to kind of decrease the chance of getting some kind of complication of Melphalan, such as mucositis or inflammation of sore in the mouth and the G.I. system.

And so we do it 1 to 2 days before the patient gets the actual stem cells.

And this one-day or two-day washout, usually it's based on the kidney function.

So how long does it take for this Melphalan to get away from the kidney?

And if a kidney is not as good as the normal kidneys at that poison, it's going to stay in the body a little bit longer.

So that's why we just kind of give a two-day washout, because we don't want that poison affecting the stem cells going into the body.

How many days will Melphalan be administered?

So between one or two days, it depends on a trial. Historically, people were divided into two days, and some chemotherapy treatments that we have not one of myeloma before others that they give them Melphalan, they give the lower dose in two different days.

But routinely right now, it's a one day.

So if they decide to just give it in two days, they're going to just make it half. For example, if the patient is supposed to receive 200 milligrams per meter square, so 100 of it’s going to be day one and the other 100 is going to be on day two.

If you increase the intensity of the conditioning therapy, will remissions be longer?

A number of regimens have been tried because of course, with any new drug or even older drugs, we come up with these rationale combinations that if we combine Melphalan with this other agent, are we going to get better results?

But Melphalan over decades has actually shown that there is no better alternative than Melphalan 200 milligrams per meter square for most patients.

And of course, in some patients, depending on the age and other medical issues, you can decrease the dose. So that's the gold standard for myeloma.

So we actually did a phase three trial where our hypothesis, based on the work of our colleagues in the lab, in the pharmacology lab, was that when you combine busulfan, another DNA damaging agent that has activity in a number of blood cancers and is used as part of transplant conditioning regimen, if we combine your busulfan with Melphalan, we may potentially get better myeloma cell killed, which may translate into a more durable remission.

So we conducted a clinical trial. It was a phase three trial.

So half the patients received the two-drug combination. These were all newly diagnosed myeloma patients.

They all received a fixed number of induction cycles with whatever the regimen of choice for the treating doctor was, which in most patients is a triplet of a proteasome inhibitor, an immunomodulatory drug, and steroids.

And then we collected their stem cells, and they got a single transplant. So about 100 patients received Melphalan only and the other 100 patients received Busulfan plus Melphalan.

And we treated 204 patients. And then with a follow-up for that median follow-up, extending to almost three years, what we saw was that patients in Busulfan plus Melphalan are now at about a 20-month longer progression-free survival.

So again, this is and we were pleasantly surprised with that.

So again, when you use a drug regimen, of course, you do see more side effects. They were all reversible, but patients had more mucositis, which is basically inflammation of the mouth and throat, which can be quite painful.

But it was fully reversible. We saw more neutropenic fever in patients who got the two-drug regimen, which was also expected, and some liver enzyme changes, which were also reversible.

We did not see any increase in toxicity based on the follow-up that we have. We did not see any increase in second primary malignancies, but we definitely saw fewer progressions in the two-drug regimen.

So these are very encouraging results. We are very excited.

Again, in myeloma, it's hard to show an improvement in overall survival with the median follow-up going only three years. But we'll see. More importantly, there were about a third of patients in each arm who had high-risk chromosomal abnormalities.

And those patients particularly benefited from the two-drug regimen. And we saw a significant improvement in progression-free survival in those patients as well.

So this is the summary of this regimen.

And again, this was the first such trial and one can make the argument that, well, we still saw more side effects and we still haven't seen an improvement in overall survival.

And perhaps another group or a cooperative group may want to take up this regimen and do another study. And if they can reproduce the studies, if they can reproduce the result, perhaps this could become the standard at that time.

But I think those questions need to be answered before we go there. But this is a very encouraging finding.

And we were, of course, very excited to see this.

There have been other clinical trials that have combined proteasome inhibitors like Bortezomib and Carfilzomib, as well as old-fashioned chemotherapy drugs like busulfan.

With Melphalan to show that there is an increased depth of response. And there is a suggestion that compared to historic data, those kinds of preparation regimen strategies may actually result in better progression-free survival for patients.

In fact, MD Anderson did a randomized trial comparing Melphalan with Bu-Melphalan and myeloma patients, both frontline newly diagnosed patients, as well as patients who are in the relapse setting, showing that the Bu-Mel regimen actually does increase progression-free survival benefit for myeloma patients. So those are some of the options.

If a patient walks into the clinic today, what would be the standard of care regimen?

It would still be the Melphalan.