Guido Tricot, MD, PhD
University of Iowa
Interview Date: March 31, 2017

In the 1970's, intravenous vitamin C was tested against solid cancers and found to have some treatment benefit. Then in the 1990's, it was tried again but this time orally. The doses that could be given and absorbed into the body were not sufficient to kill the cancer cells. Researchers at the University of Iowa have now tested mega-doses of intravenous vitamin C in combination with standard myeloma drugs. Dr. Tricot shares how they tested it with carfilzomib, bortezomib and the chemotherapy melphalan. The vitamin C/bortezomib combination only reduced the impact of bortezomib. The vitamin C/carfilzomib combo didn't look much better than vitamin C or carfilzomib alone. Pairing it with melphalan showed fascinating impact. Pairing intravenous vitamin C with melphalan made the cancer killing effect more powerful than vitamin C or melphalan alone. Even lower doses of vitamin C paired with melphalan had greater impact than high doses of melphalan. The researchers now want to test vitamin C in smoldering myeloma as a single treatment and for transplant ineligible patients over 65 who would only be able to receive melphalan in reduced doses. Learn more in this fascinating show.

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. I'd like to thank our episode sponsor, Takeda Oncology for their support of the Myeloma Crowd Radio Program. Today is the end of Myeloma Awareness Month so I hope you've had a chance to share myeloma facts with your friends, family and online community, and to join our efforts to spread myeloma awareness while helping you get fit through our Muscles for Myeloma campaign.

The Myeloma Crowd will continue Muscles for Myeloma through April. If you haven't joined yet, Muscles for Myeloma is a fitness campaign you can join to set and achieve fitness goals because fitness is critical for myeloma patients in order for them to get the best responses and treatments possible. At the same time, this campaign helps support the research being done by your myeloma specialists because we have teams from myeloma academic centers. We encourage you to register, set a goal, personal goals, share that goal with your family and friends and invite them to donate to your page.

Donations will go to myeloma research at the facility of the team that you joined. This is our effort to help national research and gives you a way to thank your Myeloma team with something that's meaningful for them, research funding to help them find a cure for you. It's also a great way to work on your beach body and summer will be here before you know it. And we have great tools to help you track your fitness and your diet.

Now, today's show is an exciting one about the use of intravenous vitamin C or ascorbic acid to kill myeloma cells. Dr. Guido Tricot and his counterparts at the University of Iowa had been testing this in myeloma and we are anxious to hear more. Welcome, Dr. Tricot.

Dr. Tricot: Thank you.

Jenny: Let me give you a brief introduction. Dr. Guido Tricot is Director of the Adult -- I can never say this word -- Hematopoietic Stem Cell Transplant and Multiple Myeloma -- you can say it for me.

Dr. Tricot: It's good. It's good.

Jenny: Multiple Myeloma Program.

Dr. Tricot: Adult Myeloma and Stem Cell Transplantation Program.

Jenny: He is a Gary D. Arthur Professor of Adult Bone Marrow Transplantation and Professor of the Department of Internal Medicine at the University of Iowa Hospitals. He has practiced myeloma at top facilities including Memorial Sloan Kettering, MD Anderson, UAMS, the Greenebaum Cancer Center, the University of Utah and the University of Iowa. Dr. Tricot reviews publications including the American Journal of Hematology, Blood, Bone Marrow Transplantation, the British Journal of Hematology and the Journal of Clinical Oncology to name a few. He is also on the Editorial Board of Bone Marrow Research, Leukemia, the Journal of Blood and Lymph and the Journal of Cancer Therapy.

Now, Dr. Tricot has announced and he'll be retiring in July. I was hoping to get through this without choking up, but I don't think it's going to be possible. Dr. Tricot is very special to me not just as a renowned myeloma specialist and a member of our Myeloma Crowd Research Initiative Scientific Advisory Board, but he is also my doctor. He is one of the most caring doctors I have ever met, and he has helped me every step of the way in my myeloma journey and my efforts on Myeloma Crowd to help my fellow patients. His core focus has always been his patients. He has thousands that truly love him. His diligence at his work of more than 20 plus years has been to help patients obtain their best outcomes even when the protocols needed to get the deepest and long-lasting responses with the drugs available at the time were not popular.

Now that science has caught up with some of his earlier work, most patients also now receive induction therapies, stem cell transplant, consolidation and maintenance treatment which is a relatively new development, but one he's been doing for many years. Because of his care, I have personally enjoyed six years of complete remission which has allowed me to host this show on the Myeloma Crowd Program so I can help others. I'm forever indebted to him. I know you'll be greatly missed by many patients. My apologies for the emotion, but we are very grateful.

Vitamin C is nothing to cry over, but maybe we should get started talking about that topics and stuff that people are calling in to listen to.

When I was reading your paper, Dr. Tricot, I saw three key issues that you kind of talked about with today's melphalan and myeloma treatments. Maybe you want to talk about just the rationale behind why you decided to investigation intravenous vitamin C.

Dr. Tricot: Thank you very much for this extremely kind introduction. One of the goals, as always, been to try to get to treatments that are not so toxic and to treatments that are selective and kill the cancer cells while leaving the normal cells as much intact as possible. Unfortunately, most of our medications we have for myeloma, although they work well, they have considerable side effects, whether it's the high-dose melphalan which can cause sores in the mouth and can cause diarrhea and severe cytopenias to the bortezomib which can cause neuropathy to the iMiDs which can cause also neuropathy and also some suppression of the bone marrow. There's never free lunch with those drugs, and they have all the side effects.

We have been trying to find ways to use drugs that are less toxic. Vitamin C has been used as an anti-cancer drug since the 1970s by work of Cameron and Pauling showing that it has anti-cancer effects. Unfortunately, in the 1990s, some of those experiments were repeated at the Mayo Clinic but instead of by intravenous ascorbic acid or vitamin C, it was given by mouth. When I say intravenous, I mean by vein. It's clear that there is a major difference between giving it through the vein and by mouth. The amount of vitamin C you can absorb by mouth is very limited, and you can never reach levels that are necessary to kill cancer cells. There has been more and more recent evidence that if you give high doses of vitamin C -- and we are not talking about one time a day but we are talking about doses of 75 to 90 grams -- and you give it intravenously, that there is indeed potent anti-cancer effect.

Jenny: When the tests were performed in the 1970s, how did they give it and at what dose?

Dr. Tricot: It was given intravenously and the doses were variable but were lower than what we are using now but higher than what could be reached by giving it by mouth even at high doses. We now know that the doses that are necessary are in the 75 to 100 grams at one time.

The role has been studied in multiple academic centers including the University of Iowa in which it's one of the major players in the field of vitamin C. However, the cancers that have been studied, they have all been solid tumor cancers such as brain tumors and pancreatic cancer and ovarian cancer and breast cancer and prostate cancer, but it has not been studied in liquid tumors such as leukemia and myeloma.

We also have started to understand better how Vitamin C works, although there are still some parts that we still don't know well, and we know that in the presence of certain metals such as iron, that high-dose Vitamin C leads to the formation of what we call reactive oxygen species or ROS which basically cause oxidation and damage to the DNA and make the cells die.

Our studies have shown that when you look at myeloma cells and cells in smoldering myeloma, that the levels of iron in the cells is much higher than normal cells. But in patients with MGUS, the monoclonal gammopathy of undetermined significance, the iron levels were not very high. And we have tried to find out why the iron levels are so much higher in cancer cells  than in normal cells, and it's basically because of two mechanisms. You have to imagine a cancer cell and on the left you have a pump that pumps iron in, and on the right you have a pump that pumps iron out. The pump that pumps iron in is called transferrin, and the one that pumps iron out is ferroportin. We know that in cancer cells, transferrin is much higher than the normal cells, so it pumps more iron in. And also, at the same time, the ferroportin which pumps iron out is much lower in cancer cells. You have more pumping in, less pumping out. You increase the concentration of iron in your cancer cells.

In normal cells, there is an equilibrium where you have a certain amount that is pumped in and a certain amount that's pumped out, but you never get really high concentrations of iron. If you don't have high levels of iron in your cells, the vitamin C will not do any damage. This is a way where we can now do something that's quite selective where the more malignant the cells are, the more iron they have and the more they are sensitive to vitamin C and the lower vitamin C levels are in the cells, the less sensitive they are. The normal cells, you almost see not any effect while in the cancer cells, the more iron they have, the more they are going to be affected by vitamin C.

When you look at patients with myeloma in the beginning and at relapse or patients with little disease and more aggressive disease, relapsed patients and more aggressive disease, those patients have myeloma cells with much more iron than the patients with more benign types of myeloma. This is the type of treatment that will be especially effective and not necessarily up front but certainly in relapsed patients. We have done series of studies in myeloma to evaluate the role of vitamin C. These studies were basically done by Frank Zhan who is our major researcher and his group especially Ivana Frech and so although I report those studies to you, the heavy lifting was done by other people, by our researchers here at the University of Iowa.

Jenny: They’re a great team.

Dr. Tricot: Yes. The first set of studies was what we call in vitro or studies in a test tube. The first thing we did is we took myeloma bone marrow, patients with myeloma, we took their bone marrow and we separated this in two fractions: their myeloma cells and their non-myeloma cells, the normal bone marrow. The myeloma cells died in the presence of the high-dose vitamin C while the normal cells were totally not affected by it. The same effect was seen in smoldering myeloma but not in monoclonal gammopathy of undetermined significance which we knew had lower concentrations of iron in the cells.

he next question we had is, is the killing indeed due to oxidative damage, to the oxidation of the DNA? To anwer that, we incubated myeloma cells with agents that protect against oxidative stress such as NAC (N-acetyl cysteine) and catalase. Those prevent basically the reactive oxygen species to be formed and protect against the damage done. What we saw is that when we incubate the cells with those agents that prevent oxidative stress that we didn't see vitamin C killing myeloma cells.

The second thing we wanted to see is iron indeed critical to kill those myeloma cells? One of the ways we could do that is by incubating the myeloma cell with deferoxamine, and deferoxamine is an agent that collates, that binds iron and makes it inactive. If you do that, then you don't see any more killing of myeloma cells which already gave us a good clue that iron was indeed critical.

The other thing we did is we increased the gene for ferroportin and if you remember, erythropoietin is the gene that is the protein that pumps out the iron. If we increase the gene that will see much more protein, ferroportin protein, and much more pumping out of iron. And again, when we did that, we saw much less killing of myeloma cells. However, if we increased iron in the medium where we incubate the cells with, then there was increased iron in the myeloma cells and that increased iron resulted in increased killing of myeloma cells, making it very clear that iron was a critical player in the toxicity of vitamin C.

And then a second set of experiments was done in mice which we call in vivo experiments to see whether not only these would work in a test tube but also in vivo, in mice that had active myeloma. We used a severe combined immunodeficiency mice, and we also made the myeloma cells visible by having the myeloma cells express luciferase so that you can monitor the tumor progression by imaging. And we incubated the myeloma cells with carfilzomib, with melphalan, with Velcade and with high-dose vitamin C. The dose of vitamin C was 4 mg per kilogram which was the dose that can be reached easily in patients when you give 75 to 90 grams of vitamin C.

When we did those studies, we saw that melphalan showed the best killing. As we all know, melphalan is still the best drug if it's given in high doses for myeloma. But we also saw that if you give vitamin C only and you compare that to carfilzomib, that carfilzomib did not kill more cells than the vitamin C. Vitamin C was equally --

Jenny: That is crazy.

Dr. Tricot: And then we also tried Velcade but it became very clear and we also could confirm that vitamin C basically inactivates Velcade and that you cannot combine those two together.

Jenny: Let's talk about that for a minute because -- well, we'll come back to that. Keep going because that's an important point that I think patients need to understand.

Dr. Tricot: Most patients will already know that when you take Velcade that you should not take vitamin C and that you also should not take green tea at the same time. Then we went to combinations of treatments. We combined carfilzomib with high-dose vitamin C, and we combined melphalan with high-dose vitamin C. With the melphalan we did at the dose that we typically would give, 5 mg per kilogram, but also at 3 mg and 1 mg per kilogram. To our surprise, we saw that the effect that the mice survived equally well with the lowest dose of melphalan if it was combined with vitamin C than with the highest dose.

We were now able to reduce the dose of melphalan to 1/5 and even with 1/5 of the dose and adding vitamin C to it, we had the same killing as with melphalan given by itself at the highest dose. But whatever dose that melphalan used and we added vitamin C, we always saw better effects when we added vitamin C. We saw the mice surviving much longer when you added vitamin C whether it was at the lowest dose or the middle dose or the highest dose. But again, at the lowest dose with vitamin C, we saw the mice surviving equally well as with the high dose of melphalan alone.

Jenny: And then when you combined it with carfilzomib and vitamin C, what did you find?

Dr. Tricot: If we combined carfilzomib and vitamin C, we basically did not see any more effect than with carfilzomib alone or with vitamin C alone. We did not see any additive effect or synergistic effect when we added those two together. It worked really best with melphalan alone. That made us think of how should we go from here? And there are two things that -- well, first of all, what we still need to do is to try to find out how the mice become resistant to the vitamin C because ultimately all the mice relapsed. They relapsed later, but how did they become resistant to it, and how can we prevent the mice from becoming resistant? What do we need to add to it?

But in terms of clinical studies, there are two ways we would like to go. One way is to use it in patients who have smoldering myeloma and use it as a single agent to see whether we really see effect when we use it as single agent alone. And the other thing that we would like to do is patients who are not candidates for transplantation, who cannot tolerate the full dose of melphalan to see whether we can give those patients a fourth or a fifth of the dose of melphalan add high-dose vitamin C to it and see whether they do equally well than patients who have melphalan alone at the full dose.

This would make the melphalan available to many more patients than at this point in time because as you can imagine when you give the lower doses on melphalan, those mice had much less toxicity than the mice that got the full dose of melphalan while it was equally effective. And that's what we also would expect in patients that if we do this in patients, that they will have much less side effect and that they will be able to tolerate those relatively low doses of melphalan with vitamin C much better while they couldn't tolerate the high-dose melphalan by itself.

Jenny: Can I ask you a question about that? Sometimes I know melphalan can be given not in the transplant setting. If you lower the dose of melphalan and you do the vitamin C with it, is that sufficient to do a full stem cell transplant? Does it kill enough for you to reset the immune system like the stem cell transplant is supposed to do, or how does that work?

Dr. Tricot: Based on the mice data, that's what you would expect. But as you know, not everything that you see in mice translates directly to humans. We need to do the clinical studies to show that you can indeed lower the dose of melphalan by 80%. And if you combine it with vitamin C, you're still going to see the same effect as if you would give full-dose melphalan alone.

Jenny: Okay, interesting. Let's just go over that again because you did explain how bortezomib is not to be used, but I just want to make sure because when I posted this show, I saw a lot of people kind of say, well, my doctor told me not to take vitamin C so why is this going to kill myeloma cells? Or someone is posting how lemons cure cancer and things like that. I just want to be very clear about if your doctor has told you not to take vitamin C, the reason would be…

Dr. Tricot: The reason would be that the vitamin C is going to inactivate the Velcade and make it not work to some degree. It all depends upon the dose of vitamin C you give and how much is absorbed of the vitamin C, but you will lose a certain amount of activity by taking vitamin C at the same time as you take your Velcade.

Jenny: Okay. Because I have been on vitamin C and been told not to take vitamin C and when you go back on vitamin C, it's mostly to boost your immune system while you're in a remission type status, is that correct?

Dr. Tricot: That's one of the reasons. Vitamin C is an antioxidant agent so it helps people whether it's at low doses as any major effect on the immune system or not, that's still all debatable. It's good to take some additional vitamin C. (if you are not on Velcade)

Jenny: Right, okay. I know earlier you explained the presence of iron. When you were doing this experiment, you used patients with MGUS, patients with smoldering myeloma and patients with active myeloma. You were saying that you didn't see the impact on the MGUS as you did on the active myeloma, and they had less iron than the smolderers did. What about on smoldering myeloma patients? I guess that depends if they are high-risk smoldering. I wonder.

Dr. Tricot: The problem is that we have relatively limited numbers of MGUS and smoldering myeloma patients that we studied. But the smoldering myelomas in terms of how much iron they had in their cells was relatively similar to myeloma while it was much, much lower in MGUS patients. You would expect that they would do relatively well with vitamin C alone. As a proof of principle, to give those patients vitamin C for a while and see whether we can really kill their smoldering myeloma cells I think would be important for us to show that.

Jenny: Well, it would be a pretty benign clinical trial, right? I mean you are being infused with vitamin C. Are there any risks of doing IV vitamin C that you're aware of?

Dr. Tricot: There are risks. The main risk is when your kidney function is not good. If you're creatinine is more than two, you might have kidney problems with vitamin C. Those patients are typically excluded. Patients who are on warfarin also are typically excluded or they have to go toa different anticoagulation treatments. The other thing that vitamin C interferes with, if you are diabetic and you test your glucose by a glucometer, that is clearly influenced by the vitamin C; it gives you false readings. If you take a glucose test on the blood, there is no problem but not on the finger.

Jenny: Oh, interesting. You would have to get a lab pulled, a blood sample taken.

Dr. Tricot: Yes, because your glucose levels are going to be totally unreliable for about six hours after you start the vitamin C.

Jenny: Okay. When the historical research was done in the 1970s and I know you said that oral administration was done in the 1990s, was it repeated or was it just given once? Like, let's say, you're going through stem cell transplant. Usually, you get melphalan once and you don't get it repeated. You just get it once and you get your stem cells back. I guess this would be part of future work to study, but what would be your guess or your hypothesis about the use of vitamin C?

Dr. Tricot: In solid tumors, they usually give it twice a week for three weeks so a total of six doses, and that's where they had the most success. I think that we should probably stick to that. That doesn't mean that every time they have to have melphalan, but the vitamin C would still help in killing cells that were damaged initially by the high-dose melphalan.

Jenny: I think what you said earlier was really important that you tried it at three different doses - that was really important. In your paper, it says no survival differences were observed between low and high doses of Melphalan when combined. How would you be interested in testing how this might work in conjunction with other types of myeloma treatment like dexamethasone or the IMiDs or the monoclonal antibodies and those types of drugs? Because you've tested one iMiD, the carfilzomib and you did one proteasome inhibitor, the Velcade?

Dr. Tricot: We didn't test the IMiDs and the reason why we didn't test IMiDs is because --

Jenny: Oh, yeah, yeah, you're right. Carfilzomib, sorry.

Dr. Tricot: Yes, in an immunodeficient mouse and as you know, IMiDs are immunomodulatory drugs, we didn't know how much of the activity of the drug we would lose if patients had no immune system.

Jenny: Oh, I see.

Dr. Tricot: If there is no immune system that can work. The same thing for the monoclonal antibodies. You need to have cells that are eating up the myeloma cells that are covered with this monoclonal antibody, and the immunodeficient mice that we used are not optimal for this type of work.

Jenny: Do they see the same thing in other blood cancers where there are high levels of iron on top of these cells like leukemia and lymphoma?

Dr. Tricot: As we all know, if you look at ferratin levels, they are very high in most malignancies and the more aggressive the malignancy is, the higher the ferritin levels are. Cells need some degree of iron for them to grow and proliferate. The cancer cells are extremely worried that they don't have enough iron in their system, and that it will limit their growth that's why they take excess amounts of iron up while they prevent the iron from being pumped out of the cell.

Jenny: They hang on to it.

Dr. Tricot: Yes.

Jenny: Can you help differentiate also? Because you mentioned this earlier which is true that it's only impacting the cancerous cells versus regular healthy cells, why that's important.

Dr. Tricot: An ideal drug for cancer is a drug that only kills the cells that you want to kill, the cancer cells while it has no side effects to the normal cells. It doesn't cause the bone marrow cells to decrease. It doesn't cause diarrhea. It doesn't cause nausea or vomiting because it has no effect on those cells. Vitamin C seems to be a drug that has major difference between normal cells which are at very low levels of iron, and therefore are not going to be damaged by the vitamin C and cancer cells which happen to have a large amount of iron in the cells, and therefore are going to be much more damaged by the vitamin C.

Jenny: Are there any other cells in the body that have higher iron uptake in general or just normal cells have a normal level?

Dr. Tricot: There are some congenital diseases which we call hemochromatosis where the cells pick up much more iron than they should, and that causes ultimately liver and pancreas damage because of all the iron that's accumulated in the cells.

Jenny: Well, maybe you get some side benefits by giving this type of treatment. Maybe it could kill not only cancer cells but other help of other diseases before too.

Dr. Tricot: It could be, yes. It's any type of cell that has a high amount of iron in theory should be selectively killed while the normal cells with low amounts of iron should have no side effects.

Jenny: In the future, I know you mentioned this a little bit, what you'd like to do but if you could map out a strategy for future investigations, what would that strategy look like?

Dr. Tricot: First of all, the first thing I would like to do is see if we give vitamin C alone in smoldering myeloma if it's going to work, if it's going to kill the smoldering myeloma cells. And if it is, how can we combine it with another drug that we typically don't use in myeloma for the myeloma treatment and that we can add to the vitamin C so that in case those patients ultimately develop myeloma that we already have not lost quite a bit of drugs that we need later on. So that would be my ideal combination. Whether it's immune related like monoclonal antibodies or the PD1 inhibitors, those are all things that we are looking at at this point in time.

Jenny: Are there other drugs that you think, when you're thinking about combining it with another drug, that is not used in myeloma therapy beyond the monoclonal antibodies or PD1 like other drugs and other diseases or you're kind of thinking just along those lines like the immunology kind of drugs?

Dr. Tricot: That's what I would like to do at this point in time. Since the general belief is that why do patients develop myeloma out of smoldering myeloma or MGUS is because their immune system becomes affected and the immune system is not as effective as it should be, and that's why they develop myeloma because the immune system that could control the disease before and make sure that for every cell that was produced that another cell was killed, that mechanism dies off and now the cells can proliferate and there is much more growth than this killing of myeloma cells. That's how the disease goes to myeloma.

Jenny: Okay. You first like to test it in smoldering myeloma and then what would be your next step?

Dr. Tricot: The next would be, especially in patients over the age of 65 who are not candidates for full-dose melphalan to see whether we can have good survivals by combining a quarter or a fifth of the dose of melphalan with the high-dose vitamin C.

Jenny: Okay, that makes a lot of sense.

Dr. Tricot: We should be able to have, based on the mice data, should have the same outcomes as if we would have given full-dose melphalan.

Jenny: When you look at something like this that's not a drug company drug, it’s vitamin C and think about costs to create a clinical trial for smoldering myeloma patients or a clinical trial for these over 65 patients who aren't transplant eligible (with full doses anyway), how do you structure that to create a clinical trial over that and is it less expensive than a standard myeloma clinical trial?

Dr. Tricot: Well, that all depends as you know on how much vitamin C will be used. If it's going to be used in a much larger scale, there will be more companies making vitamin C and there will be competition and the price will go down. If there is not a lot of vitamin C used in high doses, then it's going to remain a relatively expensive drug, and we can only do those studies if there is some support by another mechanism like the NIH or the Leukemia & Lymphoma Society or any other myeloma support group.

Jenny: That's really fascinating because you think about vitamin C as being this ubiquitous vitamin that's everywhere. You don't really think about it as having high cost potentially.

Dr. Tricot: Yes, if you give it orally, it's cheap but we know that doesn't work.

Jenny: Tell me about dosing again because you mentioned the dose but I didn't it write down.

Dr. Tricot: The dose is somewhere between 75 and 90 grams with each administration. While if you and I take vitamin C, we typically take 1 gram of vitamin C.

Jenny: Yes, that's almost a hundred times.

Dr. Tricot: Yes. And if you give the same amount by pills, you get about 40 times more higher levels if you give it intravenously than by pills. The same amount. That's why the oral will not work. You have to give it intravenously.

Jenny: When you talk about the mice relapsing, I wonder if some of the strategies in myeloma are get rid of the bulk of the disease and then give something else like a vaccine or a T-cell therapy or something like that that can boost the immune system back up now that the disease is kind of been cleared out and freed up, and then there are others that are just actual myeloma killing, get to the root of the problem kind of strategies. How would you see this working? I know you're working on finding out why it came back, why are the iron levels going back up maybe?

Dr. Tricot: Ideally, as you know, when you have gone through transplantation, you would like to have treatments that are not going to affect you a lot and that you can go back to normal life as quickly as possible. And so that is what we are trying to do is instead of giving the two years or three years of Velcade with an IMiD or carfilzomib with and IMiD, then dexamethasone that we can go to something that selectively kills your cancer cells but doesn't impact your quality of life.

Jenny: Right. Well, that would be a game changer, a complete game changer because post-transplant, it takes a long time for you to feel like normal again and then I would much rather go on a vitamin C maintenance regimen if that's possible than something else that's going to cause other worse side effects that'll inhibit quality of life.

Dr. Tricot: And again, the thing that we always have to remember and that we have clearly seen with the IMiDs is that all those other drugs that have effects on other cells can cause problems in the long run. Like if you give Revlimid for too long, you increase your risk of leukemia and secondary tumors. If you have drugs that are only working on the cancer cells and leave the normal cells intact, you don't have those risks.

Jenny: Right. And you mentioned some other possible side effects but they didn't seem very severe with vitamin C. Have there been other studies that have been done that have given high doses of vitamin C over longer periods of time so you already have that data about impact or potential side effects, if any, of vitamin C?

Dr. Tricot: If you are talking about has is given for more than three or six months, I don't think that that has been the case. All the studies that I have seen, they have been relatively limited in their scope. It was given for three cycles and then people went on to the classical treatments.

Jenny: You don't know any diseases right now that use mega doses of intravenous vitamin C to treat any particular disease?

Dr. Tricot: We know that by itself, it's not going to be sufficient, that we have to give this in combination. And in myeloma, we know that the best combination is with melphalan but in other disease, it's being tried with Cisplatin, with Paxil, with all those other drugs that are typically used in solid tumors to see which one of those is the best combination.

Jenny: The reason for being maybe more effective in blood cancers versus solid tumors, I think you kind of briefly mentioned that before, but do you want to go into more detail about why am I being an attractive target?

Dr. Tricot: Yeah, because in solid tumors, you have this mass of cancer cells and it's very difficult for any type of product to basically penetrate into the middle of that solid tumor. It will do it around the cells and the cells that are going to be the most affected are the cells at the out layers, the cells that are closest to the blood vessels. But in liquid tumor cells, all the cells are basically equally exposed to the blood vessels into the blood. It should work better if you do it in the blood.

Jenny: I would think so because it can reach it like you're saying.

Dr. Tricot: It's easier to reach the target cells than in solid tumors.

Jenny: Well, in clinical trials, in terms of a next step for a smoldering myeloma or  an over 65, a non-transplant eligible kind of clinical trial, are you and the research team working on constructing a follow-on trial? And if so, how long does that typically take?

Dr. Tricot: Well, we are trying now to develop protocols that we can get through the FDA and can get out to IRBs or Institutional Review Boards for approval. But as you know, if you have to have something approved by the FDA, it takes its sweet time and I think 6 to 12 months are probably what we will need.

Jenny: Well, I think it's a very exciting work. I know that you and Dr. Zhan and the team have worked together for a long time also and been really instrumental in helping understand the genetics of myeloma. You really understand the deep dive into the research and what would work and what wouldn't. This kind of option would be terrific for patients, just terrific, so it's very exciting.

Dr. Tricot: If it would work as well in humans as it is in mice, it would be very exciting.

Jenny: Were the 1970 studies done in humans or were they mouse models also?

Dr. Tricot: No, no, they were done in humans.

Jenny: What were they done for? I'm curious.

Dr. Tricot: All solid tumors, only solid tumors, again breast cancer and prostate cancer and brain cancer and all those type of things.

Jenny: It's so fascinating. Well, we're so happy you're looking at it. I'm going to open it up for caller questions, and then I may have some other follow-up questions after some of our callers are finished. But if you'd like to ask Dr. Tricot a question, you can call 347-637-2631 and press 1 on your keypad. I'll open it up for our first caller.

Caller: Good afternoon, Dr. Tricot. My name is Dana Holmes, and I'm a smoldering patient. I have been finding this discussion this afternoon just fascinating. Before I ask my question, I really just want to express how grateful I, as a smoldering patient, am for your dedication and commitment to not only your myeloma patients but to the multiple myeloma patient community. I personally wish you only the very, very best. I'm just always so grateful that specialists such as yourself take the time out to educate us and inform us and give us hope. So thank you.

Twenty minutes into the discussion, I was so excited when you mentioned that this was something that could potentially be used in a smoldering clinical trial. It just seems to be a dream come true for smolders to consider something that is so much less a toxic approach than what we actually have on the table right now. I'm wondering, would this be something that would be for all subtypes of smoldering myeloma or multiple myeloma? In other words, all of the different cytogenetic abnormalities or is it more or less for the lower risk type profile?

Dr. Tricot: Our work seems to indicate that the more aggressive the disease is and the more high risk the disease is, the more the cells accumulate iron. The more iron they accumulate, the more they should respond to the high-dose vitamin C. This is not like only for the relatively benign types, but this is especially for the more high risk patients with smoldering myeloma where I would think it would work the best.

Caller: Interesting. Obviously, for the smoldering myeloma trial, it would be as a single agent. How do you see such a trial design? Would it be a single dose? Would it be multiple doses? I know that these are probably all questions that you have to answer, but would you see it that we would need it as a long-term use in especially if someone responds to it in order to continue that response?

Dr. Tricot: I would think that we should try with giving six doses twice a week for about three weeks and then see what the response is. Patients who respond, then we need to come up with some type of maintenance dose that is doable for the patients that is effective enough to keep the disease under control. Those are things that we need to find out but unless you do the clinical trials, it's very difficult to find out. And again, if we do a clinical trial, we will include all the smoldering myelomas and not just say, well, we should only take the high risk. We want it in all of those patients. Is there effect of the vitamin C by itself? If you give then in combinations, then people will always say, but how do you know what the effect was of the vitamin C and the effect of the other drug? If you only take vitamin C, then you know if you see effect, it must be the vitamin C.

Caller: Oh, my gosh. What an interesting approach. Would this be a trial, a single trial center at the University of Iowa or do you see this as a multicenter trial?

Dr. Tricot: I would like to have this done as a multicenter trial so that we can move on quickly. All of us don't have that many smoldering myeloma patients. I would like to, as quickly as possible, have evidence in about 30 patients whether this is working or not.

Caller: It's just fascinating, Dr. Tricot, to think that after three weeks' time that you'd be able to establish whether there would be a response or not. How would you monitor a patient? Are you looking just simply blood biomarkers, serum biomarkers or are you looking also at bone marrow biopsies?

Dr. Tricot: I think if you want to have a complete picture of how well patients are responding, then you need to look at the blood. You need to look at the bone marrow and you need to look at imaging.

Caller: Imaging also.

Dr. Tricot: And combine those three, then you have a pretty good idea whether you really had a clinical response.

Caller: Oh, my gosh. Well, honestly, I have nightmares about my smoldering myeloma. I think that this has just removed some of those nightmares, just the thought of it and the hope that it holds. I thank you and I wish you the very, very best of luck for it. I'm hoping that it comes to a center near me because I will be at that front door and lending my support to something like that for sure. Thank you again. Jenny, thank you so much for taking my calls.

Jenny: Thanks, Dana. Okay. Our next caller, go ahead with your question.

Caller: Oh, yes. Okay, I didn't realize it was me. Sir, thank you very much for your efforts in this regard. I am currently in remission after having a stem cell transplant last June and because of pretty severe neuropathy in my feet. I am taking just Velcade maintenance therapy. I take a somewhat reduced dose of Velcade once a month. I had never heard an association between Velcade and vitamin C. I drink about eight ounces of orange juice each morning. Is that something I should discontinue?

Dr. Tricot: Well, you need to discontinue that on the days that you get your Velcade. The other days it is fine.

Caller: Okay. So it's only the day of the Velcade?

Dr. Tricot: Yes.

Caller: Okay, okay. Sir, thank you very much again for your efforts and taking my question.

Dr. Tricot: You're welcome.

Jenny: Thank you so much. Well, Dr. Tricot, I have a follow-up question from one of the questions that Dana asked and it has to do with the iron levels being higher in the high-risk gene profiles? I mean you have attended and spoken at our Myeloma Crowd roundtables before where we talk a lot about high-risk disease. There is a chart that you and others have shown that shows the progression of someone's myeloma and how it morphs and picks up changes over time.

When you say it's more effective for the higher risk, does that mean because maybe they have been under treatment for a longer period of time and these cells are holding on to iron and pumping more in and pumping less out over time, or do you think that a particular genetic mutation like, let's say, a deletion 17 or something like that regardless of the length of time someone has been treated if those have higher iron levels? I guess my question is if you have ever assessed just like a newly diagnosed patient with some of those things and looked at their iron levels. Does that make sense?

Dr. Tricot: Well, yes, that's going to be part of the study that we are going to do when we do this smoldering myeloma study and when we do the myeloma study to see whether there are differences in the different genetic groups. But again, based on what we have with limited samples of myeloma patients and many, many different forms of myeloma that are existing, you need to have a much larger sample to say anything meaningful about that. But in theory again, the more aggressive the disease is, the more they are going upregulate the pump that pumps in iron and the more that they are going to downregulate the pump that pumps out iron and the more they are going to hold on to the iron and the more iron there is in the cells, the better the vitamin C should work.

Jenny: Okay. Well, I wonder if that'll give you any indication also as to why the iron is getting pumped in and less is getting pumped out, if it will help indicate how to just shut that down over find something else at all, reset those I guess to normal levels because that would be fantastic.

Dr. Tricot: We can do this artificially in cell lines and that's what we did. The pump that pumps out iron, we can make sure that it pumps much harder and there's much more of that protein in. If you do that, the levels of iron decrease in the myeloma cells, and you see less killing of myeloma cells with vitamin C. On the other hand, if you bind iron with deferoxamine, you see the same thing while if you incubate cells with iron and they take more iron up and the levels are increasing in the cells, you see more killing. It's clearly related to the level of iron in the cells, but what level of iron you need to have to see killing and below what level you will not see any killing, those are all things that we don't know yet.

Jenny: Well, this is a very important discovery, and I am just really thrilled that you have joined us today to describe how it works and to clarify things for patients and to give us something new and exciting to look ahead for. This is terrific and we're really, really grateful that you joined us today. I don't know how retirement works, but I don't know if you can continue to be involved in research like this. But if not, you are going to be incredibly missed. We want to see these as patients. We want to see these keep going.

Dr. Tricot: But I will always be involved to some degree, more as a consultant than really as an active member, but I will always be involved to some degree because I think I have some experience that can be helpful.

Jenny: Well, in my opinion, you're one of the great examples of the value of seeing a myeloma specialist, and I say this almost on every show I feel like. But going to someone like you has been treating myeloma for 20 plus years versus going to a local oncologist, you can just see the depth of experience. In every aspect of the treatment and on the research side, you’ve seen some of everything. You know how these interact and relate with one another. Sometimes serendipity comes from looking at some work that's been done 20 years ago that you remember or 30 or from the '70s. To me, this is just a great example of that.

Dr. Tricot: Yes and being an institution that that interest in vitamin C. I have asked many times in life, sometimes those things happen by accident and not really planned.

Jenny: Tell us a little more about the history of vitamin C research at the University of Iowa because that sounds like it's an important piece.

Dr. Tricot: Yes. Our radiation therapy group, they have major interest in Vitamin C. Initially, we didn't know that but after a while, when working with people here, we saw that that was potentially interesting. We went to the seminars and we heard what they were doing and we thought, well, we need to try this out in liquid cancer. You would think that this is going to work better in liquid cancer than in solid tumor cancers. That's how we started to do those things.

Jenny: Well, it's just so fascinating. Thank you for your incredible work. Thank you for being such a wonderful doctor for both me and everyone else. I don't want to cry again. I'm going to try not to, but I just want to thank you for your decades of service to the myeloma patient community.

Dr. Tricot: Thank you very much.

Jenny: Well, thank you to our listeners for listening to Myeloma Crowd Radio. We invite you to listen to our next episode to learn more about the latest in myeloma research and what it means for you.