Yogesh Jethava, MD
University of Iowa, Holden Cancer Center 
Interview Date: April 18, 2019

Most myeloma patients are familiar with how the chemotherapy melphalan is used during stem cell transplant. It is typically used in high doses and remains the single most effective drug to kill myeloma, but has significant side effects. Dr. Yogesh Jethava of the University of Iowa joins us to share how his open clinical trial for relapsed or refractory myeloma patients (those who have failed proteasome inhibitors, immunomodulators or daratumumab) can use low doses of melphalan combined with high dose IV Vitamin C. Dr. Jethava shares two more upcoming studies (smoldering myeloma and older patients who are currently transplant ineligible) that will open soon. Learn more about this fascinating use of existing drugs in combination. 

Thanks to our episode sponsor

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, Takeda Oncology, for their support of Myeloma Crowd Radio.

Before we get started with today's show, I'd like to give you a brief update. As many of you know, we've launched a tool last year for myeloma patients called HealthTree. We created HealthTree because myeloma is a very complicated cancer to have and to treat. Knowing how to treat patients individually is a big challenge.

What if we could share each of our myeloma stories to identify which treatment have the best outcome for specific types of patients or groups of patients? That's really what I wanted to see when I was diagnosed and it didn't exist. We thought other companies could do it like tech companies or research companies, but it turns out they couldn't. It didn't exist. We built it because over 80% of patients are being treated by general oncologists. It's a challenge because the data shows from both the Mayo Clinic and the University of North Carolina that if you see a specialist, the Mayo Clinic study says you can live two plus years longer and the University of North Carolina says that if you have a myeloma specialist on your team in the first year of diagnosis, you'll live 39% longer. That's a big difference. If a drug was giving us that type of better outcome, we would probably all be taking it.

Now, we built HealthTree in collaboration with many myeloma experts. Our goal is to help you meet with them to have intelligent conversations about your care. Going to a specialist is critical. Now, with HealthTree, you can find a myeloma specialist in the directory. You can also see treatment options that are personally relevant to you based on your myeloma genetics, your health status, your fitness status, and your prior therapies. You can keep everything about your disease in a single place to better understand what tests are relevant. You can track your labs. You can also see clinical trials you're eligible to join. We have other features in development that are coming soon. It was very exciting because we were recently featured on the Today Show in New York City sharing this idea about Health Tree that we can learn more about the right treatment for the right patient, the right time when patients are actually involved and helping lead the charge to give the research community access to the data that they need to help come to newer conclusions and new hypothesis. We're almost at 4,000 patients using HealthTree and we are so excited about the growth and the opportunities that it provides to patients.

Now onto today’s show. We've been hearing a lot about new treatments in myeloma. There seems to be really a robust set of options especially in immunotherapies. But what about drugs that have worked well in the past? Could it be combined with other things to really make an impact on patient outcomes? Today, we are joined by Dr. Yogesh Jethava of the University of Iowa who is opening a study using low dose melphalan and high dose IV Vitamin C, also called ascorbic acid. Dr. Jethava, thank you so much for joining us on the program.

Dr. Jethava: Thank you very much for having me, Jenny.

Jenny: Well, let me give a quick introduction for you before we get started. Dr. Jethava is Associate Professor and Director of the Multiple Myeloma program as well as Associate Director of the Blood and Marrow Transplant Program at the University of Iowa. Before this appointment, he was director of the Bone Marrow and Stem Cell Transplant Services Division of Hematology and Oncology at the Winthrop Rockefeller Cancer Institute at UAMS or University of Arkansas where he received an award there for establishing a fully functional allo transplant unit.

Dr. Jethava is an International Myeloma Working Group member. He is also part of the EBMT chronic malignancy working group in the plasma cell section and a member of the Experimental Therapeutics and Protocol Review Committees at Holden Comprehensive Cancer Center at the University of Iowa. He is a regular reviewer of abstracts for publications like Blood, Leukemia and Blood Cancer Journal in addition to many others. He is joining us today to talk about this study that involves high dose Vitamin C especially in myeloma. We're excited to talk to you and learn more about this today.

Dr. Jethava: I am excited to share this new -- well, I won't call it new because Vitamin C and the role of Vitamin C in cancer has been there. People have tried to understand how to make Vitamin C work for the past 60 years. It's not in the real sense new but I would call it old wine in a new bottle. I'm also excited to share the initial laboratory experiments and what we have planned with Vitamin C with the audience today.

Jenny: Great. Well, we have a lot of callers who have joined us, so we’re excited to hear about it. Maybe you want to give us a little bit of background. Where did the idea for IV Vitamin C come from in the treatment of cancer?

Dr. Jethava: The idea of Vitamin C in treatment of cancer was propagated by Linus Pauling who was a Nobel Prize laureate. He basically propagated this idea in 1960s and 1970s. As of our group, why we got interested in Vitamin C is because we all know that myeloma has a tendency to relapse. One of the things which we see in relapsed myeloma patient is that drugs become ineffective. What we see is that the same combination which worked before, it becomes ineffective subsequently or even if it is effective, the effect doesn't last longer.

To be honest with you, drug resistance is a major problem for myeloma patients. That is the reason why in subsequent stages of the disease, in latter part of the disease, the responses are shorter lived. Then eventually, patient succumbs to this disease. So our whole idea was to find out what is leading the myeloma cells to become resistant to the treatment, why it is getting resistant to bortezomib or why it is getting resistant to Revlimid.

My colleague, the laboratory colleague who is himself a well-established, internationally recognized researcher, Dr. Zhan, showed that myeloma cells, the malignant plasma cells, when treated with high dose ascorbic acid or Vitamin C at pharmacological doses, they become sensitive to the drugs which they were resistant to before.

Before I go any step further, I just want to explain one thing about high dose Vitamin C. What do we mean by high dose Vitamin C? It means that we want to achieve certain concentrations of Vitamin C in the blood. We want to achieve at least ten micromole concentration of Vitamin C in the blood when Vitamin C is given intravenously. For that, we have to really give high doses, meaning to say 90 grams or about 50 grams by IV. To give you a simple comparison, one glass of orange juice will contain probably 100 milligrams of Vitamin C. Here, we are talking about more than 50 grams of Vitamin C. You can just imagine it's a big dose.

What Dr. Zhan found in the laboratory, in the animal mouse model experiments was that these are mice where they have resistant or relapsed myeloma. When we treat them with high dose ascorbic acid to achieve certain concentration in the blood, the plasma cells become sensitive. Suppose for example, if the plasma cells were resistant to, say, Revlimid or Kyprolis, when you treat them with high dose Vitamin C, they are easier to kill. That was the beginning of this whole research and this whole concept.

We have actually published this information way back three, four years ago in the EBioMedicinejournal. That led to the subsequent steps. We thought we should try to get this whole concept into clinics because as we all know, there are multiple drugs. There are many companies which are working on relapsed refractory myeloma area and trying to develop drugs. That is one aspect of furthering or advancing the care of myeloma patient. The other aspect is to identify why the existing drugs are not working as well as we would want. That's where our group's focus has been. Sorry for the longwinded answer, but that's the background of Vitamin C.

Jenny: Oh, no, it's perfect.

Dr. Jethava: That's the background of Vitamin C. That is how we have tried to develop this whole concept now.

Jenny: Yeah, I love it. It seemed like the University of Iowa had unique and specific experience using this.

Dr. Jethava: That is absolutely true. The University of Iowa, is one of the few institutes which have a Free Radical Biology group. Our Free Radical Biology group has been working on Vitamin C for the past several years or exactly ten years. We have pioneered the use of Vitamin C in pancreatic cancer in glioblastoma multiforme which is a terminal brain cancer and also in lung cancer. At present, we received a $20 million grant from the National Cancer Institute which is called as PO1 grant for studying Vitamin C in pancreatic cancer, which I'm sure many of the viewers know that it's quite a bad cancer actually. It's almost like a death sentence. We do have a lot of experience. Our Free Radical Biology group has a lot of experience in using Vitamin C and understanding the disease biology.

Jenny: That's really amazing. I'm going to follow-up later with you on the glioblastoma because I have a friend whose mother just had that diagnosed yesterday. Why don't you explain how you're combining it? Because melphalan is this typical drug that you use at high doses in a stem cell transplant and you're really looking at the combination between melphalan and IV Vitamin C combined. Vitamin C doesn't necessarily kill the myeloma cells directly, but what you're saying is it makes the plasma cells more sensitive so when you give the other standard myeloma drugs that they are more effective, right? Regardless, I mean -- or is it just the melphalan?

Dr. Jethava: Right now, we are just testing it with melphalan because it's one of the most potent anti-plasma cell drugs. It's one drug which has been there for the past 50 years. It still is used for autologous stem cell transplants in myeloma. If we just go by the history of drugs, it has proved to be one of the most effective drugs for plasma cell, for destroying the plasma cell. That's why we started with melphalan. Now, eventually, we want to test Vitamin C in combination with lenalidomide or, say, pomalidomide. It does not work well with Velcade. We know that from our animal experiments so we are not going to try that with Velcade. But our further aim is to try it with other immunomodulator agent.

Now, coming to your question, what are we doing exactly with Vitamin C and melphalan? We have proposed two trials. Out of which, the first trial is up and running right now. I will describe both the trials. The first trial is basically a Phase I trial where we are testing patients who have relapsed refractory disease after -- if they have relapsed after daratumumab. Basically, end of the road patients who have no other options, we are testing them with high dose Vitamin C at three different doses. We will have one cohort with 50 grams, second cohort with 75 grams Vitamin C. These are given in six doses, so Vitamin C, 50 grams, six doses; 75 grams, six doses; and 90 grams, six doses. We will be giving them one oral dose of melphalan, only one dose of melphalan. The overall aim will be to see what will be their disease response, what is their day 30 response, what will be the rate of MRD negativity, how many patients can achieve MRD negativity and essentially, what will be the toxicities. Because whenever we start any new combination or any new drug, when we want to use in a disease space, the first thing FDA asks us is to do is to establish toxicity. We don't want to create a regimen which is excessively toxic for the patients. This was what FDA suggested to us, that, “You want to start using Vitamin C in myeloma patients? Fine. But just let -- prove that it is not excessively toxic and will cause harm to patients.”

So that's where we started this trial. We got the internal funding from our cancer institute. We got a small grant. Our Phase I trial of Vitamin C testing at three different doses with melphalan is up and running. We are hoping to enroll first patient who has failed essentially every possible line of treatment. Unfortunately, we couldn't get CAR T-cells because of the stringent criteria surrounding the CAR T-cell trials.

That is our first trial.

Jenny: Oh, wait. Before we move onto that one, can I ask you a few questions about this one?

Dr. Jethava: Sure. Sure. Go on.

Jenny: Okay. For people who might not know, if you've used daratumumab and you’re relapsed or refractory, it means you've probably gone through the proteasome inhibitors and the immunomodulatory drugs like Revlimid or Pomalyst and things like that. I just want to clarify that for people who might not be that familiar with the drug names.

Dr. Jethava: Okay.

Jenny: Then what is the dose of melphalan? How much melphalan are you giving? Because usually, it's used in transplant. It's very high doses. You lose your hair and all that. I think people might want to know what's the dose of the melphalan.

Dr. Jethava: You pointed at a very important aspect of treatment. Yes, this trial is for those patients who have failed immunomodulatory agents such as thalidomide, Revlimid, pomalidomide and have failed proteasome inhibitors such as Velcade, Kyprolis and also have failed daratumumab and also have failed or relapsed after autologous transplant. Essentially, all lines of currently available treatment patients have failed and then they will be eligible for this trial.

Coming to the dose of melphalan, it's just going to be 25 milligrams. To give you some background, for autologous transplant, the typical dose of melphalan is 200 milligrams per meter square. Now, if we consider average body mass index of a person, it's, say, close to 1.8 or 1.9. Then when you multiply that by 200, it comes out to around 380 or say 400 milligrams of melphalan. That is a pretty high dose. On the contrary, we will be giving only 25 milligrams. That's it, oral, so very less toxicity, GI toxicity, very less -- I mean virtually non-hair loss.

We also believe that this much dose is sufficient to kill the plasma cells because the Vitamin C that we will give intravenously, that will sensitize the plasma cells. This 25 milligrams of melphalan will be enough to kill the plasma cells. We wouldn't have to give too much melphalan which also can cause toxicity.

Jenny: Right. I know. If anybody has sat in the chair and chewed the ice for stem cell transplant, they know what to expect with melphalan. The issues that you talked about are there but it doesn't sound like it at this dose, so that's fantastic.

Dr. Jethava: I mean I'm very hopeful. We have started the clinical trial. As I mentioned earlier, we have one patient who we will be enrolling probably next week. I'm very hopeful that the toxicity will be less, but that is the aim of this trial, to make sure that there is not excessive toxicity. But considering the amount of melphalan we are giving, it's very minimum. When we look at the historical regimens for myeloma care, I don't know but someone might remember there used to be a regimen called Velcade, melphalan, prednisone, VMP, or VTMP, Velcade, thalidomide, melphalan, prednisone. Even in those regimens, the dose of melphalan used to be much higher than what we are proposing. That was all oral melphalan. We are also giving oral melphalan. What I'm trying to say that in comparison, we are giving very little melphalan as compared to the established standard of care.

Jenny: Like I said before, the IV Vitamin C doesn't have any myeloma killing properties by itself, does it? It's just a sensitizing agent, right?

Dr. Jethava: That's a very good question. We will be studying that as well. I mean we believe that high dose Vitamin C on its own can kill myeloma cells. I mean it can function both ways. We do feel that it might have some cytotoxic properties for plasma cells. The reason I say that is because in -- and I'm going to discuss a little bit of disease biology here. Interrupt me if I'm talking in too many medical jargons.

Jenny: Oh, it's okay.

Dr. Jethava: What we have found in our research is that myeloma cells accumulate a lot of iron over a period of time. Because of this excessive iron within the plasma cells or myeloma cells, that is what makes the myeloma cells resistant to the treatment. Now, when we give Vitamin C, this iron which is accumulated in the plasma cells is exported out. That helps in getting the cells sensitized, plus it might help in cell killing. I was going to discuss it in the next question but I can share right now.

We have proposed two more trials. One is in smoldering myeloma because we feel that this will be the ideal treatment for smoldering myeloma. We all know that smoldering myeloma progresses to myeloma. We all know that it happens in certain patients quickly. In certain patients, it happens at later stages. Nowadays, smoldering myeloma patients are divided into high risk smoldering myeloma and low risk smoldering myeloma. There are certain trials out there for high risk smoldering myeloma. These trials use conventional chemotherapeutic drugs or chemo immunotherapeutic drugs such, say, Revlimid or daratumumab. At the end of the day, it's a chemotherapy or chemo immunotherapy. Why not use something as benign as Vitamin C for smoldering myeloma? If we can use it and get rid of the clonal plasma cells, there we have a perfectly good effective treatment without any side effects. So that's our trial in pipeline.

Jenny: Okay. That's the second trial that you were talking about, one for smoldering myeloma patients. Do they have to be high risk or is it just any smoldering myeloma patient could join? Because really, it sounds like you're going after maybe even the low risk smoldering myeloma patients.

Dr. Jethava: Right.

Jenny: Or does that not makes sense because some of those patients might not ever proceed to myeloma?

Dr. Jethava: Yes, yes. That's interesting because a lot of the time, low risk smoldering myeloma patients, they almost behave like MGUS. They can be smoldering for several years before they actually start progressing. The question is that what time we start treating them because it's a long-term commitment. Someone, say we have a 40-year old who has low risk smoldering myeloma. Do we really want to start treating them? Then, what is the endpoint? All of those questions come up. That's why I am more keen on using high dose Vitamin C for high risk smoldering myeloma to begin with. Now, if it delays the progression, well, we have something to look forward to. Then at some point, maybe even low risk smoldering myeloma. What can be done? I mean how low of a dose can be given? What can be done with the overall preparation? I mean there's so many other questions to think about. Coming to your question, we'll be mostly focusing on high risk smoldering myeloma with this Vitamin C eventually.

Jenny: Okay. When do you anticipate opening that study?

Dr. Jethava: That I anticipate opening in 2020, in the fall of 2020.

Jenny: That's so interesting. Okay. Well, you'll probably use some of the results if you identify the appropriate dose in this Phase I study that you have for relapsed/refractory patients, can you move that over to the second study or do you have to go through that process again?

Dr. Jethava: I'm hoping that we can move over that dose.

Jenny: Yeah, because then, you'll know what's the optimal dose.

Dr. Jethava: Optimal dose, yes.

Jenny: You might have even a little bit of data by then.

Dr. Jethava: Yes. I want to point out one more study which we are planning with Vitamin C. The first study is for relapsed refractory patient. The second study is smoldering. Then the third study which we are planning is for upfront autologous transplant in elderly patients using Vitamin C and melphalan combination.

Let me give you a little background here. Myeloma, we know that autologous transplant really helps in achieving disease control. It also leads to MRD negativity in many patients. The majority of the patients achieve MRD negativity after autologous stem cell transplant but then there is always a debate as to what is transplant eligibility. If I have a patient who is 70 years old, am I going to transplant them? Probably not because the transplant might have its own adverse effects, say, chemo toxicity and toxicity of the melphalan.

Now, in our animal experiments, what we have found is that we can reduce the dose of melphalan by one-fourth and with high dose Vitamin C, we can achieve the same amount of efficacy. To give you an example, if we are using 200 milligram per meter square dose for autologous transplant as conditioning, with high dose Vitamin C, if we combine melphalan and high dose vitamin, then the melphalan needed is only 50 milligram per meter square. 

Jenny: Oh, wow. I would like to do a transplant like that.

Dr. Jethava: The efficacy is exactly the same in animal models. So I'm very excited about it because this changes the whole paradigm of autologous transplant. I mean you imagine a 70-year-old patient who has achieved, say, VGPR or PR after three, four rounds of conventional standard of care treatment and they go to a transplant center hoping that they won't get transplant. Well, they would get a transplant but then because of certain comorbidiity risks, they are denied autologous transplant.

Here, we are changing that completely. We are going to reduce the dose of melphalan by one-fourth and combine it with high dose Vitamin C and the same efficacy, extremely less toxicity. So we will be essentially be able to provide transplant up to 75 or even beyond that, even beyond that for physically fit patients. That's the third trial. We have this umbrella concept of Vitamin C under which we are planning these three trials.

Jenny: Okay. A follow-up question about that, when you do a stem cell transplant, I think the term they call it is “myeloablation” where you're basically wiping out the bone marrow. Can you wipe out the bone marrow with just 50 milligrams of melphalan with high dose Vitamin C? It sounds like you're saying, "Yes, you can." So it's like a traditional transplant, right?

Dr. Jethava: That's what we're trying with the mice models. We haven't done this one study so we don't know the answer there but that's exactly what we saw in mice studies that combined with high dose Vitamin C, one-fourth dose of melphalan was enough to cause myeloablation.

Jenny: Wow. That's crazy. That's amazing. I think it's a great positioning for that study because these are patients who might want a transplant but because of age or physical fitness status might not be able to get it. You would open up a whole another realm of treatment options for people who are older. That's amazing.

Dr. Jethava: Yes.

Jenny: Then you can replicate that, right, to the younger patients? I mean if you told me as a younger patient that I was going to get the same efficacy with a lower dose of melphalan and high dose Vitamin C, I would choose that because that's not a very fun process.

Dr. Jethava: Well, that's our aim but we'll see what happens. I mean there are so many variables here that -- and plus, we have to really prove that it is not a toxic combination. From what I have seen with the lung cancer and with pancreatic cancer -- currently, the lung cancer and the pancreatic cancer studies and the glioblastoma which is a brain cancer study at U Iowa, Vitamin C is combined with chemotherapeutic agents. So for lung, high dose Vitamin C, the dose is 90 grams. It's combined with gemcitabine. In pancreatic cancer, again, it's combined with gemcitabine and cisplatin and other things. We haven't seen that bad toxicity, I mean. I'm also very hopeful. I mean if I just use that example and consider that analogy, I think we should be fine but I think it's just the time. Time will show. Time will prove more.

Jenny: Yes. Right. You just need to see the data after it. Well, those sound like three really great approaches for this treatment combination. Melphalan has been around forever so you know exactly what you're dealing with. I have a question. How is the Vitamin C produced? Then how expensive is it? Because I know there are some alternative clinics and things that will do vitamin infusions and things like that. I think patients might be wondering about that. These doses that you're talking about are very high. You might not want to consider adding anything on your own but only in the context of a clinical trial to whatever treatment regimen you're currently on. That would be my concern in talking just in general about IV Vitamin C.

Dr. Jethava: Yeah. This Vitamin C is produced or provided by a pharmaceutical company. There is only one pharmaceutical company based out of California which is currently making pharmacologically dosed – or meeting the FDA guidelines for pharmacologically dosed Vitamin C. I don't remember the name of that company. I mean it's interesting. I dealt with the company for the past one year to get the Vitamin C and I'm not remembering it right now. But there is just only one company.

Jenny: That’s okay.

Dr. Jethava: The other thing is that how much it costs. Per vial is the cost. Per vial, it comes in strengths like 15 grams or 25 grams. The cost depends on the strength of the vial. I think it can be anywhere from $85 to $135 per vial.

Jenny: My question is about relative cost. I mean when you're thinking about being on traditional myeloma therapy, it tends to be pretty expensive. So relative to those types of treatments, this might be one that might be less costly. I guess it’s what I'm asking.

Dr. Jethava: Yeah. I agree with you. I mean this might be a very effective -- if it works out, it will be effective treatment but it will also be not as costly as the, say, three drug combination or four drug combination. Now, my only worry is that the moment we see that it's working, the prices of per vial will go up significantly. That's my concern. 

Jenny: Yes. Well, maybe there needs to be at least two companies producing those. You talked about the different treatment strategies. You mentioned MRD status. Let's talk a little bit about minimal residual disease or MRD testing. Because you mentioned earlier in the show that if you get to a MRD negative state, then that's typically better. How are you relating the MRD status to this particular treatment?

Dr. Jethava: We are checking MRD as a part of our study. In the first study, we'll be checking MRD at day 30 and then at three months and then at six months and then at a year time point. Most of the studies now have MRD as important endpoint because the depth of remission – sorry, the depth of response and the remission all correlates with better progression-free survival. MRD is becoming important. We are doing MRD by next generation flow cytometry here. It's a EuroFlow Next-Generation Flow Cytometry where we analyze at least a million cells. We analyze at least five million bone marrow cells. Then we try to identify when one malignant clonal plasma cell is within those five million bone marrow cells.

We have extremely sensitive techniques for MRD detection. We also are planning to do functional imaging for just PET scan or MRI, myeloma MRI sequence at one month, then at six months and then at a year. Now, it is clear to me and as well as there is ample evidence out there. Most recent was last year from Dr. Gareth Morgan's group in Arkansas. To achieve long term remission and possibly cure, we must achieve MRD negativity which means the bone marrow negativity as well as the PET negativity because there can be different clones in a different part of the body. When we do a bone marrow test, there might be a different clone. Then the PET scan shows a focal lesion in a different area. That might be a completely different clone. So far, long term remission and possibly cure, it is essential to achieve bone marrow MRD negativity as well as PET scan MRD – or PET scan negativity. The PET scan should be FDG negative. There is where my stand on MRD is. We have included both imaging as well as bone marrow as a part of our study.

Jenny: I know that in general, that trend is true that MRD negativity status is like what you were saying: it extends progression-free survival and overall survival numbers. I've heard some of the myeloma specialists also talk about how some of their patients go back into this MGUS like state. They still have detectable disease but it stays low for long period time. Then they don't have new focal lesions on the PET scans. What percentage of patients are those or how does that correlate? Because you're not necessarily MRD negative but some patients stay in remission for a really long time.

Dr. Jethava: That's a very good question. This information comes from the gene expression profiling. To give you a little background about this whole thing, this MGUS like thing and what exactly it means is that there are two ways to risk stratify newly diagnosed myeloma patient. One is conventional cytogenetics and FISH. We all know that on FISH, there is a standard risk and high risk. The high risk features are the  4;14, translocation 14;16, 1qgain, 17p and others. Then there are standard risks of FISH.

Then the other way of risk stratify newly diagnosed myeloma is by gene expression profiling. According to gene expression profiling, myeloma is sub-classified into six -- sorry, seven risk groups. One of the risk groups is called as “MS”, molecular subtype. Now, all data comes from Arkansas, from Dr. Barlogie who initially pioneered this gene expression profiling technique. What they found was this particular group patient, they never went into MRD negativity. If anything, they just reverted back to a low-grade disease like MGUS.

What is the clinical implication of this? Say, if I have a patient in my clinic and if I offered them stem cell transplant, then after that (if they are still MRD positive) am I going to beat them up with more chemo? Well, the ideal would be that I would like to do that gene expression profiling and find out whether this is this particular subgroup which might go back into MGUS-like stage and stay in MGUS stage for several years. That would be the best way to move forward. But suppose if I don't have the facility to do gene expression profiling, what would be my strategy for such patients? 

After autologous transplant, those patients who are MRD positive, we definitely start them on maintenance. We just observe the disease. I mean suppose if they have progressive disease, definitely, it speaks for itself that this is a different kind of subtype. Then you need to treat them more aggressively. Offer them salvage treatment, salvage transplant, what have you. But suppose if it stayed without any problems, the same lower range of M protein, then that again says that this is something we are dealing like MGUS-like situation. That's how we decide in clinical practice.

Jenny: You said you were going to be using MRD testing at one month, six months, one year and day 30, three months and six months and one year for some of those trials. I think I'd like you to cover why myeloma specialists and especially researchers like yourselves are looking to MRD as a new endpoint? Because now that patients are living so much longer, then it's hard to run a clinical trial where you don't get results for five or eight years. You can't do your research very fast. Do you want to talk about why the researcher community is looking to MRD to maybe become this new endpoint of the study that you're talking about?

Dr. Jethava: The question is that why are we so much fixated on MRD, right? Why do we really want to achieve MRD negativity? First of all, we all know that myeloma is clonally heterogeneous disease. At any given time, in a newly diagnosed patient, there will be at least four to five different myeloma clones and then the different clones of plasma cells. What does it mean? It means that if you treat them with two drug or simple -- even three drug combination, we will never be able to wipe out all the clones. Then there will be subsequent relapses where newer clones will come up which will be resistant to the previous treatment. That's just the vicious cycle which feeds and eventually patients develop extremely refractory disease. So the whole concept of autologous stem cell transplant in myeloma has originated from the fact that we want to wipe out all these clones upfront immediately. Are we able to successfully do that? Maybe yes because autologous transplant and maintenance is the only treatment which has shown overall survival benefit in myeloma. It says that when we do autologous transplant, we are wiping out all the existing clones of plasma cells.

Now again, we must remember that we can never ever be confident about it. Current MRD testing, the guideline, the EuroFlow guideline mentions about a one million event, so ten to the minus five. If we have more sensitive machines, we can go down up to ten is to minus six or minus seven and we might still find some malignant clonal plasma cells in the bone marrow. What I'm trying to say is that the concept of autologous transplant is mainly to wipe out all the clones which will eventually give a better outcome for the patient.

Now, why are we interested in MRD negativity? Because we know that the faster and the earliest we wipe out all these clones, there will be less disease plus less resistant clones eventually. That will lead to better PFS and better OS. We are just making sure that we don't want to see any plasma cell clones. That is where MRD comes into picture because it tells us, “Are there any plasma cells left anywhere in the bone marrow?” which is to say malignant plasma cells, because even if one plasma cell is left or say two plasma cells are left, there is possibility that these are the resistant clones. That's why we all in the field now agree on at least the fact, this one thing. It’s that we want to achieve MRD negativity which will mean that we will be getting rid of most of the clones -- of existing clones. That's why it has become an important endpoint for many studies now.

The second thing is also when to stop treatment.

Jenny: Go ahead.

Dr. Jethava: Another important thing is when to stop treatment. If we look at the European data, the Europeans stopped the treatment. European countries stop treatment (i.e. Revlimid for 2 years as maintenance for example). Then when we look at the GRIFFIN study in America, here, the Revlimid was given until disease progression. Then when we look at the Arkansas data, the total therapy data, Dr. Barlogie used three drug combination for three years and then stopped all the treatment. There are now studies being conducted or they are in the pipeline where we are looking at achieving MRD negativity and then treating patients for probably two years after MRD negativity and then stopping all the treatment because, again, the purpose of chemotherapy shouldn’t be lifelong chemotherapy. I mean I think it's just against the principles of treatment where you continue treatment forever for the rest of their life.

Again, MRD comes into picture there because the studies are in the pipeline where we are thinking of doing MRD? Then if patient achieves MRD negativity, then treat for a year or two years and then stop it because that will mean it's a deep response. The patient has achieved deep sustained remission. In both scenarios, MRD is becoming important.

Jenny: Right. How widely do you think MRD testing is being done now?

Dr. Jethava: I can't say about other centers but I can -- well, I can tell you about a few centers which I know personally where they are doing MRD. We are doing MRD. We have one of the most sensitive techniques which I mentioned earlier, five million count, bone marrow count, cell count. Then we can identify one cell out of the five million cells. Then Arkansas, UAMS, the Myeloma Center at Arkansas is doing MRD detection. Then Sloan Kettering does MRD and they do by sequencing. I don't know about other centers. Those centers don't have an in-house facility. I believe they are also doing it at regular time intervals. We can afford to do it more frequently because we have in-house facility here.

Jenny: Well, I'm glad you're doing the MRD testing. I think it'll give you a lot more information because it's just more sensitive. Well, my final question before I open it up for caller questions will be how the strategy that we talked today relates towards a cure and what you see happening in terms of curative treatment strategies coming to the myeloma clinic?

Dr. Jethava: That's a million dollar question. I think you have opened up a Pandora's Box because if you ask ten doctors who treat myeloma, everyone will have their own opinion about curability of myeloma. I personally believe that there is a subset of myeloma patients who are curable, I mean, absolutely and that we know from Total Therapy I and Total Therapy II trials. These are the pioneering studies done by Dr. Barlogie, started in 1993, Total Therapy I. Then in 2000 or 1999, it was Total Therapy II. There are around 20 patients who are alive without disease until now from 1993. It is evident that some patients, group of patients achieve sustained deep remission for long duration. I mean that is what curability is. We want to achieve sustained deep remission for longest possible time.

Now, what treatment strategies we can use for that? In my opinion, the best treatment strategies are to use all the drugs upfront because we know that there are at least five different clonal plasma cells present at the time of diagnosis. I mean it's there. Why do we want to use treatment combinations? I personally believe that a four or five drug upfront combination, let me say maybe four or five months' worth of treatment and then autologous transplant and then, again, defined endpoint of achieving MRD negativity and then continuing treatment with appropriate combination for another year or two years after they achieve MRD negativity and stopping the treatment, that is probably the way to go forward to achieving cure in subset of myeloma patients. 

Jenny: Thank you for sharing your perspective on that because when I was diagnosed, no one was willing to say the word cure. It's really nice to hear that some patients potentially are cured and that a cure is possible for a subset of patients. That's very, very exciting.

Dr. Jethava: I just want to point out one thing. People are afraid of using the cure word in myeloma and I don't know why. Let's just take the example of breast cancer. If someone gets breast cancer and if they are in complete remission for ten years, then they are called cured. Now, we all know that breast cancer can recur after 15 or 17 years but then beyond ten year remission point, they’re called cured. Why can’t we call myeloma cured if the patient is in complete remission beyond ten years?

Jenny: You talked about using all the drugs upfront. To me, it just makes a lot of sense because I know a lot of myeloma patients. We either get it all upfront or we get over a long period of time, so you're still getting all the drugs.

Dr. Jethava: Look at the trials, historical trials. People used Revlimid, dexamethasone and showed progression benefit in PFS. Then someone combined Velcade with Revlimid, dexamethasone and said that, "Oh, well, VRd is better than Rd." I mean honestly speaking, we don't need rocket science to say that VRd is better Rd or say daratumumab, Velcade, Revlimid, dexamethasone is better than VRd or that Dara/Rev/dex is better than Rev/dex. These are the foregone conclusions. The important thing is that what do we do with all these available drugs moving forward to achieve long term remission, deep sustained remission and possibly cure? 

Jenny: I agree. Well, that's hopefully why we think HealthTree will help with that so we can identify who is getting the best outcomes and why and go back retrospectively and look at it and say, "Oh, there seems to be a pattern," or, “Have you looked at the data and do the same?” so that we're all on the same page.

I would like to open it up for caller questions if that's okay for a few minutes?

Dr. Jethava: Sure. Absolutely. 

Jenny: Okay. If you have a question for Dr. Jethava, you can call 347-637-2631. Press 1 on your keypad and then I will know that you have a question. Go ahead with your question.

Caller: Yes. Hi. Can you hear me?

Dr. Jethava: Yes, yes. I can hear you. Good afternoon.

Caller: Okay. I have three questions for you. First one is I have a friend with a glioblastoma also. I'm wondering if you could just tell us a little bit more about what the Vitamin C or drug it was combined with and where somebody could get more information about that. My second question is when are you likely to get preliminary results from your Vitamin C and melphalan study? The third question is what about melflufen? That's being tested as a maybe more effective kind of melphalan. I guess the question is it turns out that melflufen is better than melphalan? Would that work with the Vitamin C as well? Thank you.

Dr. Jethava: So first question, glioblastoma and where I can find -- I can pass on the information to Jenny. I don't have direct email but, Jenny, you can pass it on. I can pass on information about the principal investigator on that trial here.

Jenny: That's great. Perfect.

Dr. Jethava: That's what I'll do. I mean I'll be unable to give you too many details on that because I'm not the primary investigator (PI). Secondly, I don't know much about glioblastoma as much as I used to know about it ten years ago. So I’m just going to defer that question to my colleague.

The preliminary results of our melphalan Vitamin C study will be available by the end of this year or hopefully early next year. Knowing my patient based here and what type of refractory population I see, I'm hoping to enroll patients this year and probably get some idea by the end of this year.

Then the last question, you asked about melflufen. And is it more effective and less toxic than melphalan? There are studies going on right now. It has shown a great promise in refractory setting. We don't know about it in animal models. This studies which we did with Vitamin C, we didn’t use this agent in them. I don't know about the combination of Vitamin C with this melflufen. Whether it will be effective or not, I just don't know, I mean. But that's a good question. I think we will explore it as we move forward 

Jenny: Okay. Great. Thanks for your questions. Okay. Caller, go ahead with your question.

Caller: Yes. Thank you. I was just appreciating the good work you're doing doctor and wanted to ask for those of us that have not been through a transplant. I was diagnosed a year ago. I've been through the Revlimid, dexamethasone and Velcade drugs. That brought my numbers down to -- I think the M-spike, the kappa light chain was about 4.5. Now, it’s come back up again. But at 64, healthy. Are there trials, will you have or are you aware of any around the country that someone that may not want to go through the transplant could still do the IVC with or without the melphalan at a reduced dose? 

Dr. Jethava: No. I don't think there are any trials right now across the country of using high dose Vitamin C in the particular situation you described. I'm very much hopeful that with high dose Vitamin C when combined with one-fourth dose of melphalan, it will be very effective. When we do that trial, we will really some changes in the transplant strategy but that's not, right now, up and running. I don't think anyone else is doing it right now. I'm sorry. It's not out there yet. Probably, I would just encourage you to consider and go to a place where they are used to doing autologous stem cell transplant. To be honest with you, the mortality rate is very low with autologous stem cell transplant, so something for you to think about.

Caller: Okay. Thank you.

Dr. Jethava: Thank you.

Jenny: Okay. Thank you for your question. Caller, go ahead with your question.

Caller: Hi. Can you hear me?

Dr. Jethava: Yes, I can. 

Caller: Okay. Thank you for all the great information you’ve provided this afternoon. I have a question regarding your thoughts on stem cell transplant if a patient has reached MRD negative status after a prolonged course of induction chemo from the initial diagnosis. If a patient's reached that MRD negative status before even going into the stem cell transplant, do you believe there still would be improved outcome or do you think delay a transplant is a feasible option at that point? Or do you think the outcome would overall just be better if I were to go on for stem cell transplants now?

 Dr. Jethava: Right. Right. That's a great question you asked me. I mean there are multiple sub-questions to your question. The first question is that -- say, you have got eight or ten cycles of standard induction treatment and now you are in MRD negativity -- should we do early transplant or late transplant? There is the ECOG study. There are a couple of other studies which are single institute or two or three institutes combined studies out there where they are examining exactly the same question.

Say for example, you used VRd or Kyprolis/Rev/dex for six months or eight months. You achieve complete remission. Then you have two options. One is, collect the stem cells and just observe what happens. They’ll put you in some maintenance. When the disease comes back, you do transplant at that time. The second option is you go for transplant immediately and then go on maintenance. There are these randomized trials being done.

Now, what is my personal opinion on this one, there is -- I mean we’ve got to wait for these trials to really have a clear idea. My opinion doesn’t matter. What is important is that what hard data is out there. So we have to wait for that. But let me tell you my take on this whole thing. Europeans have done some interesting studies. What we have found is that early transplant is better than the late transplant. Now, mind you, this was when the concept of MRD was just beginning to happen. The patients were not in MRD negativity. They had some VGPR (very good partial response) or some PR (partial response). They found that doing early transplant was better than the late transplant. I personally go by, “How is the patient's comorbidity status?” Say, if I have a 65-year-old patient who is physically fit and healthy and he has achieved CR or, say, stringent CR, MRD negativity after, say, six rounds of standard induction treatment, I will offer him transplant. Say, if I just put him on maintenance, after three years or four years down the road, he relapses. He will be 69 or 70. He will be older. His physical condition will be a lot – probably there might happen in between and after 65, the risk of heart attacks, stroke, you name it and it can increase. My strategy with a patient is to go by what is their age and factoring other things as well. That's what I do in my clinical practice.

In your particular situation, I don't want to ask your age or anything but I think you need to discuss with your doctor about what is your disease profile. Did you have high risk disease 4;14, any of the high risk features? If there were high risk features, I would encourage to do transplant earlier than wait. 

Caller: Okay. Well, thank you so much for that information.

Dr. Jethava: You are most welcome for the question.

Jenny: Thank you for your question. These are great questions. Okay. Caller, go ahead with your question.

Caller: Hi, Jenny. Hi, Dr. Jethava. We've connected on Twitter many times so it's really a pleasure getting an opportunity to speak directly with you. Thanks for taking the call, Jen. Dr. Jethava, I'm a smoldering myeloma patient so I'm obviously very interested in this upcoming trial for smoldering patients. Did I understand correctly that it would only be Vitamin C, the high dose Vitamin C? 

Dr. Jethava: Correct. It's only Vitamin C, yeah.

Caller: Okay. So no melphalan for the smolderers. What is the definition for high risk smoldering myeloma for your upcoming trial? Because we get confused in the smoldering community with all these different definitions.

Dr. Jethava: That is such a big question, isn't it? I mean, every -- you can go to ten different institutes and they might have their own definitions.

Caller: Oh, absolutely.

Dr. Jethava: I mean there are so many models out there but what I typically tend to follow is if they have, say, 50% plasma cells in the bone marrow, if they are IgA lambda, if they have immunophoresis with more than two uninvolved immunoglobulins, say if they have two uninvolved immunoglobulin decrease. Do you understand what I'm saying? So normally, --

Caller: I do. And even that confuses us because we tend to wonder, “What's the definition of immunophoresis? Does it have to be literally right at the bottom end of normal leading into the bottom end of -- or the top end of abnormal or is it a 25% reduction?” There's just so many different things that different elements of this that confuse us so I appreciate you explaining that.

Dr. Jethava: So uninvolved immunoglobulin. Suppose if a patient has IgG monoclonal protein and because there is excess of IgG, the normal immunoglobulin, other parts of immunoglobulin such as IgA and IgM, will be suppressed. Now, how much they should be suppressed, that's the question. I would say anything more than 25% suppression below the baseline, so say if the range is 100 to 200 and if it is less than 75, then I would consider it as a suppression. 

Caller: Very good. Thank you.

Dr. Jethava: Yeah. So uninvolved immunoglobulin, immunophoresis. And then if they have, say, any focal lesion on MRI. We all know that new guidelines say if there are more than two focal lesions, then it becomes myeloma, more than five millimeter in size. But then, say, if they have one focal lesion on the MRI scan or a PET scan one FDG with focal lesion, then I think this all will -- and then on the bone marrow, if they have 4;14, 1qgain and all those high risk FISH, then they become high risk.

Caller: Okay. That's very fair. It's a very fair set of guidelines because it does truly sound like it's a combination of a lot of the risk progression models.

Dr. Jethava: Yes.

Caller: Do you hypothesize that this could work in any myeloma subtype including FISH and GEP, whether you're identified as a high risk smolderer or actually not high risk smolder because that's a different terminology as far as progression but as far as the phenotype.

Dr. Jethava: I understand your question. This is where the 4;14 was identified.

Caller: 11;14, yes.

Dr. Jethava: Yes. That's a great question. That is what we are going to understand from our first round of the trial. Say, if a patient is end of the road, 11;14, is this working or it's better working with 17p? Let me tell you one thing. What we have learned from the literature is that patients who have TET2 mutation -- so this is a type of mutation which is present on molecular studies. TET2 is a part of epigenetic regulating pathways. The patients who have TET2 mutation, they seem to respond better to Vitamin C. That's from the other centers. That's what we have understood.

Caller: That’s interesting.

Dr. Jethava: Now, let's just consider, say, one subset of myeloma, 4;14. When you do a DNA sequencing of 4;14, how many of them are TET2? We don't know that. We have included these sub-studies as a part of our study. We'll get to know more about it.

Caller: That's excellent. That really, really is excellent. I appreciate that because that seems to be missing in a lot of different studies especially when you read these outcomes, we don't really know which subtype is actually responding. Obviously, you're starting out with high risk smoldering myeloma patients and I understand why. But with a Vitamin C only therapy, it seems to me, this layperson, that it's quite a benign approach, very little toxicity. Typically and historically, the reason why they haven’t treated smoldering myeloma patients is because of the toxicity. Let's say for someone who has an intermediate smoldering myeloma or even low risk smoldering myeloma, do you foresee these patients being -- if it’s in high risk smoldering myeloma, it's successful. Do you see moving it into the lower and intermediate risk patient population?

Dr. Jethava: That's a great question. Let me tell you something. The Vitamin C -- I mean, you will know it is very benign. The high dose Vitamin C can sometimes cause kidney stones, uric stones. It can mess up the glycemic control of diabetic patients. These are by far the two most common side effects we have seen. Now, they are nowhere compared to chemotherapy but they are real side effects.

Caller: Oh, sure, they are.

Dr. Jethava: It is fairly a tolerable treatment but these are important side effects. We’ll have to see what happens with that. Now, I just don't know the answer to your question. I mean should we be using it for intermediate risk? If it is benign and if it proves to be effective moving forward, maybe subset of intermediate smolderers where – so all the studies, it tells us there is a signature of patients who will respond to high dose Vitamin C then we can use that signature to use Vitamin C for intermediate risk, you see?

Caller: Yes. I understand that. I appreciate that very much because you really do need to be conservative with this. But on the other hand, you have patients that have this smoldering myeloma situation and just living with it. I think sometimes, it does more damage than the actual disease does, so it would be nice to know that there would be potentially an option out there to just really just wipe it out and let us move on with life.

Dr. Jethava: Yes, Finding the right subset of patients who will respond best to the Vitamin C, that's the crucial thing.

Caller: Yes. Absolutely.

Dr. Jethava: I mean, not one treatment works for everybody so that's something that we'll have to find out.

Caller: Right. Right. Just my last question, concerning MRD testing. I realized that you're using this for endpoints and things of that nature but I'm always quite baffled by MRD testing and the sample bias that's associated with it because, quite honestly, especially when the disease comes a lower tumor burden, it's really a hit or miss as to what cell population you may be grabbing with that particular bone marrow sample. How do you overcome something like that?

Dr. Jethava: Well, that's again a very interesting question you asked. There are two techniques of MRD. I'm sure you know. The one is clonoSEQ where you actually identify an immunoglobulin heavy gene mutation and then you follow that for longitudinally. But then for that, you need to have a primary sample at the time of diagnosis.

Caller: Right, a baseline sample.

Dr. Jethava: Baseline sample which is important. Then the second is Flow which is more convenient to do. But then there is this fallacy of it, like say if you hit a space in the bone marrow which has 5% plasma cells, what do you do with it? There is no answer to it, right or wrong answer to it. In clinical practice, what we have seen is that, say, if patient is in stringent complete remission and if they become MRD positive, they might have 1% plasma cells in the bone marrow or say, 10%. But if they become MRD positive, they relapse within a year. That's what our clinical experience is. For me, I think any MRD -- so for me, if a patient is in stringent complete remission and if they are becoming MRD positive, I take it seriously.

Caller: Okay. Even at very, very low levels.

Dr. Jethava: Even if very, very low levels because I have consistently seen -- consistent actually, almost every time -- that when a patient becomes MRD positive, within a year, they will relapse. The M protein will start coming up after about four months. Then we'll still observe because we don't want to start treatment too early as well. But then eventually within a year, it starts showing up its true nature. I personally take any MRD positivity seriously. Again, no one changes a treatment or no one starts a treatment just based on MRD positivity but it's something that we must take seriously. 

Caller: Yes, I see. Very good. Well, thank you so very much for your time, sir, today. I appreciate the research that you do.

Dr. Jethava: Thank you. Thank you for your question.

Jenny: Okay. Yeah. Great questions, everybody. Fantastic. Okay. We have one more question if that’s still okay. I know we're overtime.

Dr. Jethava: No problem.

Jenny: Caller, go ahead with your question.

Caller: Yes. Dr. Jethava, thank you so much for the time you’ve given us. This has been an amazing talk. This is a practical question. Given that Medicare patients, Medicare will only pay for one autologous stem cell transplant. In the clinical trial that you're doing for relapsed refractory patients who may have relapsed from a previous transplant, is re-transplant covered as part of the trial? 

Dr. Jethava: When we will plan the trial, so this -- melphalan and Vitamin C, we are not transplanting. It's one dose of melphalan. It’s 25 milligrams. So we are not giving any stem cells back. It's a very tiny dose of melphalan. We don't think that it will be severely toxic or myeloablative. But then the trial which we will be planning eventually for upfront elderly patients with melphalan and Vitamin C, 50 milligram of melphalan and high dose Vitamin C, that will be --

Caller: Yes. I'm sorry. That's the one I was thinking about.

Dr. Jethava: Yes. That will be a transplant definitely. The answer to your question is that I don't know. I know it's very difficult with Medicare but something that I have not thought about actually and you just have started a new train of thought in my mind so I have to really think about it, what to do. 

Caller: Well, that's good. Right. Good, because otherwise it wouldn't be covered. Then just let me see. Did I understand you correctly? When you do the trial for the newly diagnosed, it will be mil 50 and it will be as a myeloablative and it will be a transplant with the Vitamin C. But for the relapsed refractory, you're approaching it more, I would say, gently. You're just doing flat 25 mil and no transplant approach.

Dr. Jethava: Correct. Absolutely, yes. 

Caller: Is that because the bone marrow has already taken, I guess, such a hit from all of the previous treatments?

Dr. Jethava: Right. Exactly. Actually, you hit the nail at the right spot. I mean these are the patients who have had proteasome inhibitors, Revlimid, daratumumab, one autologous transplant so they have seen so much chemotherapy that if we do anything more, my worry is that will cause more toxicity. So the FDA wants to see exactly this thing. What is the toxicity of Vitamin C? So 25 milligram of melphalan on its own, one flat dose, well, it might be toxic but not as bad as, say, 50 or 100 milligram.

Caller: I see.

Dr. Jethava: But then if we combine with Vitamin C, is it severely toxic? That's what exactly FDA wants to see. That's why it's a gentler approach with melphalan.

Caller: Okay. Then my last question is really just about what you perceive is one of the benefits of doing an upfront autologous stem cell transplant at this time given that unfortunately, your idea is not yet available? Do you see it as bone marrow sparing versus more years on even novel agents? In other words, we think of transplant as being a very toxic treatment, a very taxing treatment. But for somebody who delays transplant or doesn’t go to transplant and therefore has a progression-free survival and spends more years on not traditional chemo but on novel agents, does that wear down the bone marrow more than the IV vitamin C with the transplant?

Dr. Jethava: Have you had transplant?

Caller: No, but I am the caregiver advocate. It's my husband. He’s newly diagnosed. We have to make the million dollar decision about upfront transplant or not. He's standard risk.

Dr. Jethava: He's standard risk. If you don't mind me asking, where are you based? Which state?

Caller: We go to Sloan. We got to Sloan Kettering.

Dr. Jethava: Sloan Kettering, okay. This is my take on it. We don't know how much novel agents are going to be successful. So if you're talking about novel agents like CAR T-cells or by specific antibodies --

Caller: No, I meant just even DARA.

Dr. Jethava: Even DARA.

Caller: Between Dara/Rd. Yeah. I don't want to make it too personal for the show but he was in the trial with the DARA KRd for the very reason you mentioned. We wanted a four drug upfront approach. Unfortunately, he was not able to stay in the trial because of a cardiac toxicity. Now, he's on Dara/Rd. He's actually only in a PR after four cycles.

Dr. Jethava: The disease has a rebellious nature, right? I mean the fact that such treatment which is supposed to be for relapsed patients, he gets it upfront, Dara/Rd and in spite of four cycles, he's still in PR, it means that the disease is behaving in a more relapsed/refractory way. I mean it's a refractory disease because see, Dara/Rd is the -- the DARA, Revlimid, dexamethasone or Dara/Pom/dex, these are the combination in relapse setting. When you are using it upfront, you want to see a good response. You want to see MRD negativity but after four or even six, if he’s not achieving MRD negativity or he’s not going to VGPR, then it is the refractory nature of the disease. In this situation, I would highly recommend transplant upfront.

Caller: I understand. I understand. Thank you so very much for taking the time and giving me your opinion on that. It's very valuable. Thank you.

Dr. Jethava: No problem. Best wishes to you.

Jenny: Okay. Yeah. Thank you so much. Thank you so much, everybody, for your questions. Dr. Jethava, thank you so much for answering everybody's questions and also for such a great show today. We learned a lot about this new protocol. We look really forward to your studies.

Dr. Jethava: Thank you very much, Jenny. Thank you very much for having me. Thank you very much to all the listeners and also all the questions and for the active participation. I really hope that I will have some answers by ASH this year. If not this year, then definitely by ASH next year. 

Jenny: Okay. Well, we look forward to it. Thank you so much. We thank everybody for listening to Myeloma Crowd Radio today. Tune in next time to learn more about the latest in myeloma research and what it means for you.