How can MRD negativity be used as an endpoint in clinical trials?

Every clinical trial has to have a primary endpoint. Otherwise, you would not know if the study is successful or not. When a protocol is written, it goes to a scientific review committee. It will go to the IRB, the Ethics Review Board, and it will go to the FDA.

All these different instances will always look for what the primary endpoint is. It could be overall survival, it could be progression-free survival, it could be response to therapy, or things like that. Also, studies have secondary endpoints, but the primary endpoint is what determines whether the study is successful or not. For a registrational clinical trial that's developed to take a drug to full approval or for accelerated approval to the FDA, the primary endpoint is what determines if the drug will be approved or not. MRD negativity is not yet endorsed by the FDA as a primary endpoint for myeloma trials. If you look at all the clinical trials currently ongoing in the world that are registrational for the newly diagnosed patient population, all of them include MRD negativity as a secondary endpoint.

The primary endpoint for now is progression-free survival, and this is because the FDA has not yet endorsed MRD negativity. There are some new studies that are ongoing that just have been started that have put MRD negativity as the primary endpoint. If the FDA were to approve that, that means that the drugs could be evaluated for the primary endpoint. Let's say after only a year. So you have the randomized study of the experimental drug and the control arm. And instead of waiting for six years or seven years to have the progression-free data available and mature for the FDA to review, let's say you look after one year and if you pick up MRD information after one year and there is a higher MRD negativity rate in the new drug, the FDA in this scenario could give approval many years earlier.

This is where the field has to go in this direction, and there is no other way for the field to move. This will give patients access to new drugs much faster, and drugs that don't deliver in those trials could be stopped, and patients don't have to be on those trials that are not really giving patients any benefit. This is an area where there is a lot of investigation right now.

Sometimes there is a discussion whether MRD negativity is not an appropriate endpoint for drug approval, and sometimes people could say that maybe that could be a dangerous endpoint.

I think that type of argumentation you could use for any endpoint. And if you look a little bit back and forth, so a long time ago, overall survival was the regulatory endpoint for drugs in myeloma. This was at a time when there were very few treatment options. So if a drug could really extend survival for patients, that would make sense to give such a drug approval.

Today, drugs are so good and we have so many options. Even a trial comparing one drug with the other. If the patient unfortunately relapses on either of the two arms, there will be so many other alternative medicines to use after the trial is done. And you could do other options and other options and other options. So they will dilute any difference that the trial test in the very beginning.

Overall survival is almost impossible to prove, at least in the United States. Outside the United States, when you don't have access to drugs, maybe you could still see it. But it's hard to do here. And importantly, it could take ten or twenty years to prove it. And no one has the patience to wait that long. The FDA has realized this too. Therefore, they have given progression-free survival as an okay endpoint for the newly diagnosed patients, and for patients in the relapsed setting, they have allowed accelerated approval based on the response to the therapy. So if a patient has a partial response, 50% of the abnormal serum protein, that would be a partial response, 50% or better would be counted as an overall response.

The current precedence for the currently approved drugs seems to be by the FDA that if about 20% or more of the patients do respond to a drug in the relapse setting in patients who have gone through many prior lines of therapy, that that would still be okay to get the drug approved. As it is right now.

What we are seeing right now is that the drugs are getting better and better and better. And MRD is now on the table. The FDA is being asked, can this be used to give drugs the okay and be approved to enter the market and become available to patients? I don't think that is any different from any other endpoint that I have mentioned.

You could have the same criticism that it is or takes too long, or it may not be correlated with other endpoints and so forth, but I think that there are very few other alternatives right now. PFS is not perfect. MRD is not perfect, but I think we could at least agree that it's not worse than any of the existing ones.

The major benefit is that the time it takes to collect MRD data is much, much shorter. You could collect it within the year and PFS could take five, six, seven or more years to collect. So patients will get access to the drugs faster. This is the direction the field is moving. The FDA will have to make a decision in favor of MRD, and it's just a matter of time.

Yeah. So the question, can we use MRD testing as a surrogate marker for the activity of a new combination or new drug or a new therapy? And I think for many years now, the FDA has approved many drugs based on how long it takes for the patient to relapse with certain therapy. We call that progression-free survival. It may not be the best outcome and may be hard to achieve that in a short period of time, because sometimes it takes two or three years to see that signal.

So the question is, can we find a better way to say this regimen is very effective? I think the depth of the response, getting rid of more myeloma, is a good thing. So the more myeloma we get rid of, I think the better the outcome will be. So achieving MRD-negative results with a new novel combination in a high percentage of patients should indicate that this combination, this regimen, this new treatment, is actually worthy of maybe approval or accelerated approval pending confirmatory studies.

But I think that should become a good mark. I mean, I think, you know, nobody's going to be cured with a partial response. I think if we're going to cure patients, they need to achieve MRD-negative status and an MRD-negative status that is lasting. So I think it does make sense to consider MRD negativity as a new surrogate marker for the activity of a new combination or new drug.