Luciano Costa, MD, PhD
University of Alabama at Birmingham
Interview Date: April 16, 2018

Myeloma researchers are learning that the deeper our remissions, the better our outcomes (overall). Dr. Costa joins Myeloma Crowd Radio to share a key study for newly diagnosed multiple myeloma patients that includes four of the best myeloma therapies, a stem cell transplant and then variable maintenance based on the patient's depth of remission. This is one of the first studies ever run in myeloma to give risk-adapted treatment to patients. The study uses a powerful four-drug combination: daratumumab, carfilzomib, lenalidomide and dexamethasone and then stem cell transplant. Following the transplant, patients are tested with a highly sensitive test (MRD test) that can detect one myeloma cell in a million. If patients still have remaining disease, they are given more rounds of the same four-drug combination.

Thanks to our episode sponsor, Celgene Corporation.

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. I would like to thank our episode's sponsor, Celgene, for their support of Myeloma Crowd Radio. We've learned over the last few years that what patients do at the beginning of their treatment can really chart the course for their long-term outcome. And I learned about a study recently for newly diagnosed patients that I was so impressed with. On today's show, we'll be learning about this study. Not only does it use some of the best therapies in the myeloma arsenal today, it also looks at how patients respond to the therapy to know how long the maintenance or follow-up therapy should be. This is called risk-adapted therapy and it better personalizes myeloma care.

So with us today, we have the principal investigator on this clinical trial, Dr. Luciano Costa of the University of Alabama at Birmingham. Welcome, Dr. Costa.

Dr. Costa: Good morning. Thanks for having me here. It's a pleasure to talk to you and a privilege to share some more information about our study with your audience.

Jenny: Oh, yes, it's wonderful. We're looking forward to it. Let me introduce you before we get started into questions. Dr. Luciano Costa is Medical Director for the Blood and Marrow Transplantation program and Associate Professor of Medicine in the Division of Hematology, Oncology and Transplantation at the University of Alabama at Birmingham. Dr. Costa received his medical degree and PhD in Brazil, his home country. He is Associate Editor of Advances in Cell and Gene Therapy and has published over 100 articles, books and posters on stem cell transplant in multiple myeloma. Dr. Costa's research interests include strategies for stem cell transplant and population outcomes in blood cancers.
So again, we're so happy to have you. Why don't we start first with the general treatment landscape for newly diagnosed patients? When as things have evolved in treating myeloma, we have better drugs, we have more drugs. What are some common themes that patients may want to consider?

Dr. Costa: Absolutely. You're absolutely right that myeloma treatment has evolved substantially in the last 20 years and that has clearly affected the newly diagnosed setting. That's the one line of therapy that virtually every patient with myeloma goes through. However, just based on how new drugs are developed, it's usually that's where new drugs are less used. As a new drug has developed, it first gets its value proven in the relapsed setting and only subsequently in the newly diagnosed setting. So that is always a challenge because you can see new agents having very promising results in patients with relapsed myeloma and it takes sometimes five to ten years to see that new strategy or the new drug to help patients who are newly diagnosed.

But as you said, the current landscape of newly diagnosed patient is really dominated by a combination of immunomodulatory agents such as lenalidomide and proteasome inhibitors, particularly bortezomib. Patients who are not particularly old, and don have any significant cormobidity, do tend to integrate autologous transplant as part of the initial therapy. So I think if you do a survey throughout the country, the most commonly used strategy for newly diagnosed younger and fit patients tends to be the combination of bortezomib, lenalidomide and dexamethasone, followed by autologous transplant, followed by maintenance therapy.

Patients who are older or more frail, who are not considered candidates for high-dose chemotherapy and autologous transplant are often treated with triple therapy nowadays, the majority of patients. But instead of proceeding with autologous transplant, they do a finite number of cycles and then evolve with maintenance therapy. So this strategy you do far better results than you have 10 or 15 years ago, but there' are still some important shortfalls.
I would say, first and foremost, even though those strategies can have response rates that are in the neighborhood of 90%, many of those responses are partial responses. And even among the patients who do obtain a complete response, the majority will experience a relapse later on. So I would say, those treatments are better than they used to be, but they're still not sufficiently effective.

On the opposite side, you might have some patients who have an extremely sensitive disease and might obtain a very deep remission very early on. Some of those patients might be able to discontinue therapy without jeopardizing the outcome. The problem is we have for the longest time lacked adequate tools to measure depth of remission beyond what can be obtained with regular marrow exam or protein electrophoresis. So what results from that is that we tend to give a fixed treatment plan for all patients. And unless the patient becomes refractory and the disease progressed or the patient becomes intolerant, they tend to undergo the same number of cycles of therapy, the same transplant, and the same in depth with maintenance therapy.

And I think if you talk to patients as I do, what you hear from them is some patients are very dissatisfied with the fact that their responses are not complete. They are very dissatisfied with the fact that even though their disease at times may become undetectable, a relapse is eventually going to happen. And other patients are very unhappy with the idea that in order to have a somewhat normal life and get the most benefit in terms of disease control and survival, would have to be on therapy indefinitely.

I think those would be the main challenges for upfront therapy is to be able to adapt the intensity and the duration of therapy to the speed and depth of response and perhaps be able to identify patients who might have had that deep enough response, that they might be able to discontinue therapy altogether without jeopardizing their future.

Jenny: Right. And I think this is a really important point because as we know, all myeloma is not the same. So I have a friend who has had multiple relapses without transplant, but has been on multiple therapies and is still out 20 years. And I have friends who have done tandem autologous transplants and even an allo and now are out 20 years. So not everybody responds in the same way, not everybody has the same type of myeloma. And wouldn't it be great what you're saying?

Dr. Costa: Absolutely. Absolutely.

Jenny: So if you could figure out who should get how much therapy, that's really, really important.

Dr. Costa: I agree. Tremendous work has been done on recognizing some biological distinctions between patients who do very well from patients who do very poorly. While we haven't done yet so effective is to use that knowledge to translate into therapies that are adapted to a patient risk profile and to adapt to a patient speed and depth of response.

Jenny: It's very, very important. So this is great. In my opinion or in my understanding, this is one of the first studies to look at this type of risk adapted idea.

Dr. Costa: I believe so. So the study that we have started, we call it the MASTER and that stands for Monoclonal Antibody Sequential Therapy for Deep Remission Myeloma. It has really been developed for the last two years. We aggregate a group of somewhat ambitious myeloma investigators who also happened to be my good friends and colleagues. And what we saw in the near future was the emergence of new drugs that have a potential to be transformative in multiple myeloma, particularly monoclonal antibodies.

So we proposed to use daratumumab that as we know has made tremendous impact in the relapse setting. Along with carfilzomib that we now know has proven at least in the relapse setting as being as a more potent proteasome inhibitor than bortezomib, along with lenalidomide and dexamethasone. And we also sense the opportunity to utilize minimal residual disease assessment, not only as surrogate for outcome, no longer as an end point, but also as a decision-making tool.

So this trial, after multiple interactions and some pretty intense discussion and negotiation, the final product is a trial where outpatients received four cycles of this combination of carfilzomib, lenalidomide, dexamethasone and daratumumab. And patients are subsequently treated with an autologous transplant unless the patient is not eligible for some particular comorbidity or age. But we intend to proceed with transplant on all patients who are candidates recognizing that transplant has a proven role and induced deeper and durable remissions and is the best therapy or, I should say, the therapy with the best tracking record of clearing minimal residual disease.

And beyond the transplant, patients can receive up to two blocks of four cycles each of the same combination of KRd plus daratumumab. But the greater innovation, in our opinion, is not only bringing this combo to the upfront setting, which we have other reasons to believe is going to be a very effective combo, but also be able to tailor therapy to the depth and speed of MRD clearance. Even though we're collecting traditional response assessment, that's not the end point of the study. The primary point of the study is obtaining clearance of minimal residual disease. And the study design calls for complete interruption of therapy once you have two consecutive measurements with MRD below ten to minus five level of detection. Those patients will then discontinue therapy, be watched without maintenance therapy, but they will be monitored very closely by the traditional serum electrophoresis immunofixation, free light chain, urine electrophoresis immunofixation, but also by measurement of MRD in the bone marrow sample at fixed intervals to make sure that those patients who are now being watched with self-maintenance therapy do not see reemergence of the myeloma clone before even become symptomatic.

So I think you are absolutely right, this is one of the first trials to use MRD as an end point of therapy. And I suspect it might be the first trial, at least the first trial that I'm aware of, in the newly diagnosed setting to use MRD-based response adapted therapy to myeloma.

Jenny: That's fantastic. So as you described the study, you give the four cycles of daratumumab and KRd before the transplant, and then everyone goes to transplant, and then when you're deciding who to -- and you said you have two consecutive measurements of MRD negativity, which means you can't find any myeloma cells at a really deep level, and we'll talk about this later. But for patients who don't know what MRD negative means, it just means that you're looking at a very detailed level of disease detection. And if you find nothing in two consecutive measurements, then you can stop that therapy and for people who still have remaining disease you keep going.

Dr. Costa: That's correct.

Jenny: So my question is, how far apart are these two different measurements? Right after transplant, when are you doing that?

Dr. Costa: Very good question. So the very first measurement is at the end of induction, even before the patient goes to transplant. The second management is after transplant and the subsequent measurements will be after each block of four more cycles of KRd dara. So with this design, the earliest patient would stop therapy would be after induction in transplant. And the latest the patient would stop therapy would be after induction transplant and eight more cycles of KRd dara. And for patients, and I'm sure there will be some, that go through the whole treatment plan and are still MRD positive, then we recommend that they continue on maintenance therapy with lenalidomide because that is considered standard of care.
So this has the potential to be a longer therapy for some patients who are slow at clearing MRD, or who do not clear MRD, where they could receive four cycles transplant and eight more cycle. But it also could be a shorter therapy for patients who have a more responsive disease where they would receive four cycles of KRd transplant and no consolidation, no maintenance therapy.

Jenny: So you would do two blocks potentially and then after the two blocks, you would go to lenalidomide maintenance? Is that right, two blocks of four cycles - is that what you said? Did I get that right?

Dr. Costa: After transplant?

Jenny: Yes.

Dr. Costa: Yes. So you're absolutely right. So let's say a patient who turns out does not clear MRD, then would have first cycles of induction transplant up to eight cycles of consolidation and then lenalidomide maintenance.

Jenny: That makes a lot of sense. So let's talk about why you're including daratumumab, because I know when they talk about standard of care before a stem cell transplant, you may have Velcade, Revlimid, dex or you may have carfilzomib, Revlimid, dex as two different induction options before stem cell transplant. But in this situation, daratumumab has been such a powerhouse, it seems like, that you're bringing it to the first line setting. And for patients who don't understand clinical trials, what you were saying in the beginning of the show, when you say these new therapies that come out, they're always tested in the relapsed setting and it take years to come to the newly diagnosed setting. This is one of the few instances where you're using daratumumab when someone's first diagnosed in a setting, which is I think we should just call that out as an important thing about this study.

Dr. Costa: Correct.

Jenny: So maybe you want to just describe why you're adding daratumumab.

Dr. Costa: Sure. So for your audience that might not be so familiar, daratumumab is a monoclonal antibody that targets CD-38, which is a protein that is expressed in the surface of all plasma cells and that includes multiple myeloma cells. So it's an antibody that has been produced and engineered to be specific to that particular marker in the surface of CD-38. And once infused, it binds almost exclusively to plasma cells and engages the individual immune system in more than one way, actually three or four different ways, and leads ultimately to the killing of the cancer cells. So that is a fascinating concept.

But one that turns out is not new into oncology, we have had monoclonal antibodies using breast cancer, lymphoma, just to mention a few, for exactly 20 years. But only recently we have had monoclonal antibodies in multiple myeloma, elotuzumab being the first one and daratumumab, a not distant second. The clinical data has really been quite impressive for daratumumab. Initially tested in patients, we have had multiple relapses. We saw about 30% response rate with the daratumumab alone.

We have seen two large Phase III clinical trials in patients with relapsed myeloma comparing Revlimid, dexamethasone versus daratumumab, Revlimid and dexamethasone in one study that they called the POLLUX Study. And on another study called the CASTOR Study, we saw bortezomib, dexamethasone versus daratumumab, bortezomib and dexamethasone. And what we saw in those studies is two things. One, daratumumab plays well with others. So it's not a drug in the same family of the same nature than a proteasome inhibitor or an IMiD or an alkylator. The side effect profile is quite different and for the most part does not overlap in terms of side effects with either bortezomib or lenalidomide. So it plays well with others. There's little in terms of added toxicity. But what we saw was a very strong signal in terms of better efficacy.

In both those trials, the addition of daratumuamb reduced the risk of progression of myeloma in about two-thirds as compared to either lenalidomide alone or bortezomib alone. So that makes a very compelling case to go up to the next level, which would be to test this myeloma agent up front. So studies are being done and have been done, testing in a proper large Phase III setting treatment template versus that same template plus daratumumab. And one of those studies was performed in Europe in older non-transplant eligible patients using a template that is not very popular in this country, which is bortezomib, melphalan, prednisone versus bortezomib, melphalan, prednisone plus daratumumab. And again, a very dramatic effect in terms of reduction and risk of progression was seen. So to us, it seems pretty evident that adding daratumumab to other more mainstream agents would be ultimately beneficial.

But the other thing that was also seen is since daratumumab helps regular agents or establish agents to become more effective, we also see a higher level of elimination of minimal residual disease, even in the relapsed setting, which further supports the case for using daratumumab up front in a regimen that intends to eradicate MRD. Other studies have used daratumumab in combination with VRD, which is a more established upfront regimen. We did intend, however, to use KRd for a couple of reasons. One is in the relapsed setting, carfilzomib has been proven to be more potent than bortezomib. In prior trials, using KRd in the upfront setting with transplant have shown that this combination is not only safe but also highly active and can induce elimination of MRD in a high proportion of patients.

So we really felt that this combination with four agents would probably be the one that, among the available agents in myeloma, would give us the highest likelihood of clearing MRD in the highest proportion of patients.

Jenny: Well, I think it's a great approach just because if you can take some of the best drugs and apply them before the myeloma has had a chance to get more complicated on you, then the better. So maybe we should talk about the importance of this first line of therapy because I know I've talked to a lot of different experts at our meetings and things and they always stress, what you choose for the beginning of your treatment can really impact your long-term outcomes and how your disease behaves over time. Do you want to speak to that point at all?

Dr. Costa: Absolutely. And that's an excellent point and I cannot emphasize that enough. Oftentimes, we hear the criticism of that. Well, if you're going to use your best agents up front, so what are you going to do when the myeloma comes back and the patient has already been treated with your best regimens? Well, saving the best for last, as we say, is not a good strategy, has never been proven to be beneficial in essentially any cancer. And the same is certainly not the case in multiple myeloma. I think a few things to pursue there is the greatest remission, the longest remission that patients with myeloma will ever have tends to be the first remission. And it has been very well shown that a strategy that leads to better PFS, better progression free survival,  in the upfront setting will translate into best survival in the long run.

Another aspect that oftentimes goes unrecognized is as patients progress and go through second and third and fourth line of therapy, their fitness changes and their ability to receive subsequent of line of therapy does change. Every time the myeloma becomes active again, there is morbidity and mortality associated with that recurrence. That might not be the case for the patient with a more indolent myeloma where we have the chance to slowly observe some biochemical progression for weeks or months before the disease becomes clinically evident. But it's certainly the case for some patients with more aggressive disease, where no matter how close you monitor their disease, it might progress with new fracture, renal failure and changing performance status. So there is even a mortality associated with every episode of recurrence.

The other more practical aspect is as people age and the myeloma takes additional hits on their health, they may not become eligible for a clinical trial or candidates for standard of care therapy with those novel agents up front or later on. So I think that on itself makes a very compelling case for using your drugs earlier. But if you want to take this up one notch and look at a more ambitious way, what I hope will soon become the case is that if you have the right agents and treat the right patients and have the proper tools to monitor and tailor your therapy, we really have the hope that the first therapy might become a definitive therapy. And if you are effective enough with your first line therapy, you might not have to ever worry about treating a recurrence at least in a subset of patients.

This is a very, of course, ambitious goal and is not a goal for one investigator or a group of investigators. It's a goal for a community of myeloma physicians, myeloma investigators, and myeloma patients. But I think that's where we need to keep our focus on, on developing therapies up front that are effective enough that we won't even have to worry about a progression.

Jenny: That would be amazing. And sometimes, our strategy is just get you out as far as possible. And if you're getting a five, seven, nine, ten-year remission versus a two, three, four-year remission, then the likelihood of having more curative therapies, even if you do relapse, is just so much higher.

Dr. Costa: Absolutely. Absolutely. So I think a strategy of using the best therapy up front, it pays itself off even on a static system where there's no innovation. But in myeloma, the case is even more compelling because as you very well know, there are novel therapies being developed on a yearly basis. I have some myeloma colleagues I'm sure can give the same testimony. I have  patients who are now 18 years, 19 years free of disease, and when they were diagnosed all that was available was VAD and transplant. And essentially, they have been on multiple lines of therapy, they are doing well, and they have benefit from the innovations that came along the way. So I think if you can buy your patient a very long upfront remission and this is not only on itself a noble and available outcome but also bridge that patient to a possibility of benefiting from future therapies that can be transformational.

Jenny:  I totally agree. So care goal at the beginning and longer outcome goal as a secondary if your myeloma is not behaving in the right way that you want. I have a question for you.

Dr. Costa: Sure.

Jenny: You mentioned that sometimes different patients respond in different ways, I know. And when I was going through treatment -- but this was a very long time ago -- sometimes my doctor said, "Sometimes I see patients who respond really quickly, but their myeloma relapses more quickly. And sometimes patients who take more time to get into remission respond more longer term." That was before all this MRD testing and you could even detect to that level. But have you seen similar things in your practice or can you speak to that?

Dr. Costa: Absolutely. Anecdotally, you're absolutely right. I have patients who have never obtained more than a partial remission, who have opted not to be on maintenance and are off therapy for six years doing well with no signs or symptoms of myeloma even though the myeloma is present. And we also have seen patients who have very quick remissions but then have very quick progressions. I think that speaks to the heterogeneity of multiple myeloma. This is different on every patient. We don't fully understand why it behaves that way. Some patients have a myeloma with a more MGUS-like phenotype. And eventually, you have an additional biological step and becomes multiple myeloma and you can treat that myeloma component, but MGUS component remains stable, which may account for that long-term persistence of the malignant clone without features of multiple myeloma.

But the patients who have cytogenetic high risk in a patient with 17p or translocation (4;14), they are the ones who tend to have quick responses and quick progressions. And we know now that in part, I'm not saying in totality but in part, this is due to the fact that that clearance of disease, that the initial eradication of disease is not complete, even though some of those patients might reach a complete remission, meaning the myeloma is not promptly noted in the bone marrow exam and the immunofixation electrophoresis are negative, they still harbor disease at a very low level. We hope that if we can treat them up to the next level, which would be eradication of that minimal amount of disease, we might be able to break that cycle and break that paradigm and create a possibility that those deep or those quick remissions can also be definitive remissions.

This has long been an aspiration, but I think we're starting to see data to support that. The French group at the last ASH meeting show data from IFM 2009, which were patients treated with RVd and some received transplants, some did not. But what was shown for the first time is, at least a subset of patients, attainment of minimal residual disease negative status at the end of therapy might trump the prognostic impact of poor risk chromosomes. So in other words, if you take those patients who are high risk of recurrence based on chromosome analysis and you can't treat their disease down to undetectable by very state-of-the-art molecular technology, they might not recur at all. And that's really an eye opener and really sets a wind of opportunity that we should pursue further.

Jenny: That's wonderful. Wonderful. Now, this study, I understand, is called a single-arm study where no patients are getting randomized to different protocols. So maybe you want to explain that for patients who don't understand sometimes how studies are created and why this might be important for participating newly diagnosed patients.

Dr. Costa: Absolutely. So randomization, there's nothing intrinsically wrong with randomization. For the scientific standpoint, the only way you can definitively conclude that treatment A is better than treatment B is when you do a large study where some patients are randomly assigned to other patients around you assigned to be. And at the end, you show the one is superior to the other for a given meaningful end point. Those studies are very important. They take hundreds of patients and oftentimes many years to be completed. They are considered definitive evidence of the benefit of a new therapy or a new diagnostic test. But there are, of course, many other types of studies that have a different design and a different goal.

So our studies are Phase II non-randomized studies, which means how the patients enroll receive the same treatment plan. And the objective of the study is not to definitively prove that this approach is better than any other approach but to generate data that is compelling enough, that might support a more definitive Phase III study that could eventually change the standard of care. So oftentimes, how new treatments are developed, you first do Phase II and use a more short-term end point. If you can obtain at any point on a compelling proportion of patients, that's your pass to proceed into a large Phase III study.

So in this study, our patients receive the experimental regimen. There is no comparison against another group of patients treated at the same time. We're comparing the results of this therapy with the results that are of what is obtainable with other more traditional regimens. So it can be considered a proof of principle essentially. We're trying to demonstrate that 1), you can use those four drugs in newly diagnosed patients on a safe and effective way, 2), you can obtain MRD negatively in the large proportion of patients, 3) that the majority of those patients can discontinue therapy without seeing recurrence of disease, and 4) and perhaps just as important is that it's feasible to operate a treatment program where you use MRD for real-time guidance of therapy. So those are the things that we hope to accomplish with this single-arm study.

Jenny: Well, let's talk about MRD or minimal residual disease for a minute, because I think this is a really important thing. Now that we have more myeloma drugs and better myeloma drugs and more combinations, as an investigator, when you're trying to run these studies, people can be living eight, ten years. So you're really not getting your data back until many, many, many years later after you try these different combinations. So being able to test or detect disease at a much deeper, more sensitive level for these MRD tests might help you understand who's responding, who's not, and be able to come from some conclusions for us as patients earlier without waiting eight or ten years because we don't really want to wait to know which might be the best option for us.

Dr. Costa: Right. So you're absolutely right. So just to explain a little bit about minimal residual disease, so traditionally how we assess response in multiple myeloma, it's by using morphology under bone marrow and using a serum and urine test to look for the paraprotein that the myeloma produced. And based on those tests, a set of criteria for response has been set up and validated by international myeloma working group. That really has to do with the elimination of the protein and elimination of visible abnormal plasma cells in the bone marrow.

Those tests are very helpful. Those are still the bread and butter of myeloma response assessment, but those are tests that go back many, many decades. And for the longest time, we did not need anything better because most patients were not obtained even a complete remission. They're obtaining no response at all or a partial response or a very good partial response. So it has really for the longest time, not being that crucial to have a test that can see it better because still the majority of patients were left with a large number of plasma cells that produced an abnormal protein in the blood and in the urine.
As the treatments got better, we start seeing more patients reaching what's called complete remission, which can be quite misleading. Complete remission means I cannot detect the protein in the blood or in the urine. And if I do a bone marrow, and have less than 5% of plasma cells. But we know patients can still have a lot of myeloma cells in their body and still be considered in complete remission. And the most definitive proof of that is that most patients who reach complete remission, they're still going to have a relapse later on.

As the treatments become better, the traditional methods of evaluating disease response becomes greatly inadequate. So just keep that in perspective. When you say complete remission by traditional methods, that means the patient can have one in 100 to even five in 100 myeloma cells in their bone marrow, which is a lot of myeloma. But we're talking now about technologies that can detect one cell in 100,000, even one cell in a million, and that's what we call minimal residual disease. There has been essentially two methods to minimal residual disease. They are both being developed. There are some groups that are more aligned with one method, the other group are more aligned with other method. They all have their pros and cons, but we foresee a future where both are going to be utilized and both are going to be helpful.

One of those methods is flow cytometry which essentially makes the cells from the sample, typically a bone marrow sample. Those cells are treated with antibodies that detect different markers and those cells go through a machine called flow cytometry that detects the aberrant expression of some markers that identify those cells are being malignant. This test can detect a one cell in 10,000. The European group, particularly the Spanish group, has developed what's called Euroflow that can detect one cell in 100,000, and they're trying to improve this even further.

Another technology that's a completely DNA-based technology using what's called next generation sequencing and that essentially consist  the patients on bone marrow sample from the time of diagnose, when there was an abundance of malignant cells. It identifies one or more specific what we call clonogenic sequences, which are DNA sequence that are unique to the patient's multiple myeloma. And then once the disease is treated, you take a post-treatment sample and look for that sequence or sequences in the new sample. And that technology can detect one cell in 100,000 and one cell in a million.
So what can be shown is that MRD presence, and the level of MRD is clearly link to outcomes. So this has been shown with more than ten years follow up from the Spanish group using particularly a flow methodology. And there had been shown more recently by the French group on the IFM 2009 study where patients who had less than ten to minus six did better than patients that had ten to minus five to ten to minus six, which did better than patients who had ten to minus four to ten to minus five, that did better than patients who have more than ten to minus four. So there's clearly a gradient effect and there might be a level that's low enough if the patients can clear the disease beyond their level, recurrence simply does not happen. And that would be eventually a wonderful thing.

So what we have so far is this test being use as a prognosticator. If you end the initial phase of your therapy and your MRD is down to a certain level, let's say ten to minus six, you know you're better off and your chances of recurrence are less than if it was, for example, ten to minus four. So it's a good surrogate of long-term end points. What we're trying to do is help take to the next level, make that a meaningful end point for clinical trials and more important, stratify therapy. In other words, be a deciding factor of who should receive more therapy versus who should receive less therapy.

Jenny: Right. And when you say ten to the minus six, that is one cell in a million, right?

Dr. Costa: Yes, one cell in a million.

Jenny: And ten to the minus five is one cell in 100,000.

Dr. Costa: One cell in 100,000.

Jenny: And then ten to the minus four, that's not as very sensitive when you're just looking at one in 10,000, right?

Dr. Costa: Yes. One to minus four would be one 10,000, which is -- you're absolutely right, it doesn't seem so sensitive, but still far better than just morphology in protein electrophoresis, which can miss a much higher burden of the disease.

Jenny: Well, wonderful that these new tests are coming out. And I think the test you're using is the Adaptive clonoSEQ test, right?

Dr. Costa: That's correct. The test that we use in this protocol is the clonoSEQ test that is based on next generation sequencing.

Jenny: Okay. Wonderful. So just a little bit of information, do you want to review just details about the study, like where is it being run and how many patients are you looking for, how do patients join?

Dr. Costa: Absolutely.

Jenny: Maybe the cost. Because I think what was unique about this is that carfilzomib and daratumumab are being given for free from Amgen and from Janssen, right?

Dr. Costa: Absolutely. This study is a investigator-initiated study, which means, yes, as the investigator, we hold the primary responsibility over the study. They study receives financial support and drug from both Amgen and Janssen that provide carfilzomib and daratumumab respectively. The trial intends to accrue 82 patients in seven different myeloma centers because we are the principal investigators and UAB is the coordinating site. The trial started here. We had our first patient treated for the mid-March, and we have close to ten patients already identified and four patients who have started therapy. Eventually, the trial would open at six other sites. We are fortunate to have the support and collaboration of my colleagues from Medical College of Wisconsin, Vanderbilt University, University of Wisconsin, Oregon Health Science University, Duke University and Emory University. We really expect the initial projection was to accrue this trial in two years, but I suspect we're going to be accruing in just one year based on the interest and the success we have had in those early days of the study.

As you highlighted, the study, like any other clinical trials, that our components are considered standard of care and they are charged to the patient or to the insurance. For example, the costs of seeing the doctor, the cost of doing the main test for a traditional disease assessment, the cost of stem cell transplant, but there are components that are considered experimental and are covered by the study, in this case, the daratumumab, the carfilzomib and the MRD testing by itself. We're very fortunate to have had input from patient advocates on the design of this study and our mutual friend, Jim Omel, was very instrumental in making sure that we had a design that will answer scientific questions and it was also appealing for patients.

This trial is different from many other trials for newly diagnosed patients. It does not have an age gap. We recognize that patients who are older than perhaps 75 might not be adequate transplant candidates, but as long as they fit the other eligibility for the study, they can be treated and patients who are not going to pursue transplant, they receive four additional cycles of care, via daratumumab.

There are patients newly diagnosed. Oftentimes patients are diagnosed in renal failure or in the hospital setting with a new fracture, which makes it difficult for them to meet criteria such as performance status or even renal function. So this trial accepts patients who have had minimal therapy up to four weeks of therapy with bortezomib, cyclophosphamide and dexamethasone to work themselves out of a crisis, for example, acute pain or hypercalcemia or renal dysfunction and they can still qualify for the study. And patients who are interested on this trial should feel free -- at this point, UAB is the only site accruing, but of course, we have information posted in the clinicaltrials.gov where we have my contact information and our coordinator contact information. I'll be more than happy to talk to patients who might be interested. As new sites get activated, we're going to make sure that information is up to date in clinicaltrials.gov so patients can look for a site in their area.

Jenny: Wonderful. And also, we link with a clinical trial finder called SparkCures that we find to be a lot easier to use than clinicaltrials.gov. So I know that this trial is in there, and we'll include a link with the final show so people can find it also. They can help navigate at each of the different centers as well. (see link above)

Dr. Costa: Thank you, appreciate it.

Jenny:  I have more questions and the time is going too fast, but I do want to open it up for caller questions just in case somebody wants to ask a question. So if you have a question for Dr. Costa, you can call 347-637-2631 and press 1 on your keypad.So go ahead with your question.

Caller: Hi, Dr. Costa. First, thank you so much. This has been so great. I just have a quick question. So I was wondering, why would a newly diagnosed patient want to consider joining this study over the standard of care treatments?

Dr. Costa: Absolutely. And the reason for it is it's out of hope that a new therapy could be better. There is no proof that a new therapy is better, otherwise would be no need for the clinical trial. But I think the reason a patient would join this study, just like the patient would join any study, is for the possibility of having access to a treatment that might be better it would not be assessed otherwise. So that should be always the primary reason for a patient to join a clinical trial.

Now, there are other potential advantages of being in a clinical trial and they include -- there is an extra level of oversight in reassurance that the treatment goals follow a pre-specified plan that has been approved by multiple layers of oversight, including the FDA, the investigational review board and local scientific review committee. Patients on clinical trials end up receiving an extra patient in addition to the regular clinical staff. There's a resource of staff that make sure that toxicity is properly evaluated, degraded, and the necessary corrections are made.
And the last, and sometimes we don't present that as being a motive for patients, but I'm sure many patients feel good about this is at the end, you also contributing to generate knowledge and pave the way for future patients.

Caller: Well, it sounds like a great study, so thank you so much for everything you've shared.

Dr. Costa: Absolutely. Thank you so much.

Jenny: Okay. Thank you. And one last question for you before we end. Because this is in the newly diagnosed setting and so most of the time, patients will have gone to their doctor and they might have gone to a local community center or something, and someone may have started them on any kind of treatment. Does it make them ineligible for participation in this study if they've already received some kind of prior therapy?

Dr. Costa: That's a good question. And most studies for newly diagnosed patients, if you have received one dose of anything, you are excluded. This study is not like that. We wrote the eligibility in that way essentially to capture those patients that you described. So patients have received up to four doses of bortezomib, or they have received of up to four doses of cyclophosphamide, or they have received up to four doses of dexamethasone within four weeks period of time, they are still eligible for the study as long as information that details the disease’s stage and the level of the paraprotein at the time of diagnosis is available. So patients who have received minimal therapy, they still can be enrolled.

Jenny: Right. Because when you start a therapy, of course, hopefully, your myeloma is going to go down and then you're not using a good baseline of disease burden, right?

Dr. Costa: Absolutely.

Jenny: So you can't measure it or detect and try to figure out what's working better.
Well, amazing. Well, we are so thankful that you have shared the study with us and it's been just so valuable to learn more about it. And again, I was diagnosed in 2010 and there weren't these types of options, but this is a study that I would have really seriously considered and tried to learn more about because I just think it takes some of the best available treatments and then gives you just one of the best options for long-term remissions. So thank you for putting this study together and all your work. I can’t imagine how difficult it was to try to put four different drugs together into a study.

Dr. Costa: Thank you. Thank you so much for the opportunity. And you're absolutely right, there still has been quite a bit of effort to align two different companies, the FDA who has some very specific criteria to allow us to use MRD for decision making and the endorsement of the patient community is extremely meaningful and really gives purpose for the work we do. And we're very excited to have the opportunity, the privilege to run a study like this, and hopefully that that would translate into better outcomes for our patients. And thank you very much for the opportunity.

Jenny: Oh, thank you. And I believe it will, I really do. So thank you so much for joining us and thank you for our listeners for tuning into Myeloma Crowd Radio. And we hope you tune in next time to learn more about the latest in myeloma research and what it means for you.