What I would like to talk to you about today is the concept of endpoints for clinical trials in multiple myeloma. Now, clinical trials as you all know is a very important component of how we learn about how to treat patients with various cancers and not just cancer, all kinds of illnesses. In the setting of multiple myeloma, there have been several endpoints that have been used in the clinical trials that we have done in the past. Now, it is very important how these clinical trial endpoints are defined because that is how we interpret what we are going to learn from a particular clinical trial. Now, I will go over a few of the most commonly used endpoints for the clinical trials, not just in myeloma, these are the endpoints that are used in a variety of different cancers as well as other conditions. In the setting of multiple myeloma, one of the most frequently used endpoints, and that is true for that whether it be phase I, phase II, or phase III clinical trials and also, one of the endpoints that we are able to see the quickest of the initiation of therapy is the response rate. The response rate in multiple myeloma is for most part related to how much of the M-protein or the monoclonal protein decrease can be seen with these therapies. Now, the responses are assessed using the International Myeloma Working Group consensus response criteria that have been developed several years ago now. Broadly, patients are grouped into either having a complete response, which means we do not have any of the monoclonal protein detectable in the blood or in the urine, or any significant amount of bone marrow plasma cells, or a very good partial response where you have a 90% decrease in the monoclonal protein in the blood and a significant decrease in the urine as well, and a partial response which reflects a 50% decrease in the protein in the blood, and a minor response which is a 25% decrease. And all these are accompanied by very detailed criteria in terms of how much the reduction has to be in the blood and that has to be accompanied by a reduction in the urine. Over the past few years the response criteria has been revised to include an additional set of testing which is the serum-free light chain. On the basis of the serum-free light chain assay as well as some of the more sophisticated flow cytometry-based testing of the bone marrow, a separate group of responses have been identified which are called the stringent complete responses. We believe that this represents another layer of response which we think are probably deeper than the complete response that we have traditionally used. So, the response rates are the closest in terms of the endpoints that we can achieve on a clinical trial. We can read them out very rapidly. After a few cycles of therapy, we know whether the patients are responding or not. Now, in the longer term, we want to get a sense of how long do these responses last when they do occur. There are several endpoints that are used to capture the duration of response. The easiest thing is obviously the duration of response, but however, that is only applied to patients who already have gotten a response. Now we know that there are patients who may not quite get a response as defined by these criteria, but their disease might stay stable for a while and then their disease will progress. So there is a different endpoint that we use which is called a progression-free survival which is often a combination of the time it takes for the myeloma to start going back up again, as well as the time taken or the time to the patient’s dying because of either complications of the treatment or complications of the illness. So it is a composite endpoint which captures both the time to death as well as the time to the disease progression.
Now, there is another endpoint that we often see in the clinical trial descriptions, which is called a time to progression. The main difference between the time to progression and the progression-free survival is that the time to progression only looks at the time that it takes for the myeloma to come back. So, if someone dies of the complications of the treatment or if the patient dies of something else, they are all treated equally, but the only thing we are concerned here is the myeloma coming back. Now finally, there is another endpoint that we often use in these studies which is the overall survival. That is often considered a gold standard for determining if a particular therapy is better than the other because that captures multiple facets of the therapy. One, is the therapy effective? Two, is the therapy too toxic? And three, how long does the therapy last? And then finally, when the therapy stops working, are there other therapies which can actually make the patients live even longer? So they all have different functions in terms of what information they provide and they are all critical. So, if you look at any of the clinical trials we are doing right now, especially the phase II clinical trials, the main endpoint we are looking at is the response rate and the duration of response, and often the time to progression. Whereas if you are looking at the phase III clinical trials, you are going to be incorporating almost all of these endpoints trying to compare the two different or three different therapies that are included in the study. So we will compare the response rates, the progression-free survival, the time to progression, as well as the overall survival based on whichever therapy they are getting. Now as the treatment of myeloma has significantly improved over the past decade, we are starting to look at other endpoints which are likely to be quite meaningful in this patient population. The one aspect that is clearly changing is that with the new therapies, patients are getting deeper responses. With the older therapies we used to have may be at the most half of the patients who would get a complete response which included transplant as well. However, with the new therapies, especially in the context of stem cell transplant, we are looking at 70% or 80% of the patients managing to get a complete response. Now, it is in that context the stringent complete response have allowed us to carve out a group of patients who have a deeper response. However, that still does not quite get to the point where we can identify patients who have very, very small amount of myeloma left behind, if any, and that is where this whole aspect of minimal residual decease assessment has come in, and increasingly what is happening is in the clinical trials we are starting to incorporate this minimal residual disease assessment. The two main methods we are using right now for assessing the minimal residual disease is 1) the flow cytometry-based methods and 2) the PCR-based methods. Both have their own advantages and disadvantages, but they are increasingly being incorporated into the clinical trials, and we will see the future clinical trials giving out numbers as to what proportion of patients actually were able to get to a minimal residual disease negative state. So clearly, the field is moving forward, but I think the gold standard for the endpoints for clinical trial still continues to be the overall survival and the progression-free survival, which really gives us a best estimate as to what is the value of a particular therapy.
Reviewed on January 17, 2017 for clinical relevance.