Dr. Sergio Giralt, MD Memorial Sloan-Kettering Cancer Center

Interview date: September 20, 2013

Dr. Sergio Giralt discusses the role of transplant as consolidation therapy and his current study of how the various approaches relate to a patient's cytogenetics.  He shares his experience showing high-dose melphalan with an autologous transplant is still the best way of achieving long-term disease control and how the road to cure goes through complete remission. He discusses the 5 stages of transplantation and describes how he is working to use newer combinations to both improve the effectiveness of transplants but also to reduce the time to recovery and side effects for patients, with the goal to make transplantation as tolerable as regular chemotherapy. He shares studies at Memorial Sloan-Kettering that are working to eliminate host vs. graft disease for allogeneic transplant and why young, high-risk myeloma patients may want to consider that option. He describes new approaches at Memorial targeting gene mutations (like BRAF and MET gene mutations) and how a vaccine approach is just beginning. He describes the near future of genetic-specific trials that are just beginning in high-risk myeloma, but that they require national support so that one particular study can target a sufficient number of patients.  He stresses the importance of patient participation in clinical trials to push forward new and better therapies in myeloma.

Jenny: Welcome to mPatient Myeloma Radio, a show that connects patients with Myeloma researchers. We would you like you to get to know these amazing specialists and learn about their latest work so you can understand their open clinical trials.

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I'm very happy to be talking today with one of the myeloma greats, Dr. Sergio Giralt of the Memorial Sloan-Kettering Cancer Center in New York. So welcome, Dr. Giralt or I should say bienvenido.

Dr. Giralt: Muchas gracias, Jennifer. Thank you for having me on the program.

Jenny: Well, thank you so much for joining us.

Dr. Giralt: I think we're all -- it's been an incredible decade for myeloma research although you know it's always a devastating diagnosis, but there is so much more hope now than there was 10 or 15 years ago. All of this is, as you stated, it's because the patients of ten years ago decided to participate in clinical trials that led to the standard of care today. If we want to make the same great strides that we have made over the last decade, the patients of today have to continue to support and encourage their physicians and their caregivers to participate in clinical trials so we can make this disease a lot easier and potentially cure a large proportion of patients.

As we discussed, just start with the regular patient. Fifteen years ago, most myeloma patients were actually being diagnosed with very symptomatic disease and a large proportion of patients were actually being diagnosed with very advanced disease with hypercalcemia and renal failure. Unfortunately, that still happens, but what we are seeing is that more and more patients because there are more and more people getting routine physical examinations, routine blood work being done are actually being diagnosed serendipitously as part of a routine physical.

They are found with mild anemia or increased total protein or maybe mild renal dysfunction, and that leads to the traditional workup that besides the history and physical involves standard blood work and X-ray. They're documented either some mild bone lesions or the paraprotein or the myeloma peak is seen in the blood or in the urine which leads to a bone marrow in which we see the infiltration of these clonal or malignant plasma cells.

Currently, today cytogenetics has become standard. Fifteen years ago, that was not the case. Although we know that cytogenetic abnormalities can define prognosis of the disease, we know that there are some chromosomal abnormalities associated with shorter remission durations particularly abnormalities of chromosome 17, of chromosome 1 or complex cytogenetic abnormalities. We still, as opposed to other blood cancers, cannot say these cytogenetic abnormalities require this (particular) treatment.

Initial therapy or induction treatment for myeloma has also changed dramatically. You probably remember ten years ago thalidomide-dexamethasone was the most commonly used induction treatment. Thanks to again large clinical trials, we do know that for patients particularly those that are being considered for high-dose therapy and stem cell transplantation, the use of bortezomib as part of the induction therapy changes the natural course of the disease.

For randomized trials, they have put together that in patients who are transplant eligible, the addition of bortezomib to the induction therapy, and bortezomib is the one that patients may recognize as the brand name Velcade. In combination with both lenalidomide or in combinations with lenalidomide and dexamethasone or in combination with thalidomide and dexamethasone has shown a significant improvement and response rate prior to transplant that also translates into improvements and disease control after the transplant.

What's happening today in that induction space? A couple of things. One of the difficult questions that we have today is deciding which patient requires treatment. Many patients with myeloma amongst those who are hearing us maybe say, well I have asymptomatic myeloma or smoldering myeloma, and my doctor says I don't need any treatment. Is that true?

The reality is of today patients with asymptomatic or smoldering myeloma which means those patients that although they have an increase in plasma cells in their bone marrow, they have absolutely no evidence of what we call end organ damage. The X-ray shows no bone lesions. The blood counts are totally normal with no anemia. The kidney function is totally normal. Even with total body MRIs, we can't see areas of bone destruction.

These patients with smoldering myeloma, we are now trying to decide who needs treatment? Many myeloma patients probably have heard through the blogosphere the New England Journal Paper of Dr. Mateos in which patients with high risk smoldering myeloma, and they were defined as high risk, Jenny, because they had either very high protein levels or they had a very high plasma cell infiltration of their bone marrow. These patients were given lenalidomide or what we know is the trade name Revlimid, and they were randomized against patients who received just observation. To everybody's surprise, the patients who got lenalidomide actually lived longer.

Now, one of the problems with the Spanish study is that the control group never received lenalidomide. So we are still left with the question of if the patients in the control group had received lenalidomide or very good treatment for their myeloma once it progressed, would the results have been the same? But it does suggest that there may be a role for treating people earlier in the course of the disease.

Most patients however do not have smoldering myeloma. Most patients have at least some evidence of end organ damage, usually lytic lesions or usually anemia. For these patients now, the standard treatment in North America is a combination of bortezomib with lenalidomide-dexamethasone or a combination of bortezomib with cyclophosphamide-dexamethasone. For older patients or patients who are not considered transplant eligible, particularly those who are frail or have significant comorbidities, maybe the combination of either bortezomib-dexamethasone or lenalidomide-dexamethasone can achieve good disease control with significantly less side effects.

What are we exploring at Memorial in regards to clinical trials? We are involved in two very large clinical trials. One is the international trial of early versus late high-dose therapy and stem cell transplantation. All these patients get lenalidomide, bortezomib, dexamethasone induction for four cycles and then they are randomized to get early consolidation with high-dose melphalan in an autologous transplant or to only get high-dose therapy with high-dose melphalan and an autologous transplant in the event that the disease comes back after eight cycles of bortezomib, lenalidomide-dexamethasone and lenalidomide maintenance until progression.

We think this is a very important study and will answer the question about what is the role of transplant as consolidation therapy for all myeloma patients. It is associated with a lot of genetic testing that will allow us to discern in the context of modern treatment with induction therapy, consolidation and maintenance.

What are the prognostic factors? Particularly, what are the cytogenetic in the chromosome abnormalities? We are looking at total gene assessment to see what mutations may be predictive of a worse outcome and some of those mutations may be druggable, and we may develop targeted treatment for specific subsets on myeloma, very exciting times.

Jenny: It's very exciting and I think that's where we'd like to see it go. So I guess if you can help patients understand from a testing perspective, what tests do we need to be getting? What questions do we need to be answering so that we can understand what type of treatment might be most appropriate for us?

Dr. Giralt: I think that's an excellent question, Jenny. I think you also allude to the fact that an informed patient is an empowered patient and that we recommend that patients go to blog sites such as yours to patient advocacy sites such as the MMRF or the International Myeloma Foundation and the Leukemia & Lymphoma Society. There is a lot of good information out in the web. There is a lot of bad information also. So I think that we should direct our patients to the websites that we know have been adequately vetted and have information that's useful and up to date.

Going back to your question, what should a patient ask? There usually are always five core questions that a patient should ask. One is what do they have? What do they have in a patient with myeloma is they have a malignant plasma cell disorder. The next question they should ask is how much do they have of it? For that, they require a staging evaluation that means bone survey or skeletal survey where all the bones are x-rayed.

We are recommending today that an MRI is done of the axial skeleton that's the lumbosacral and thoracic spine; (1) to determine if there is extensive infiltrative disease; and (2) to determine if whether there are may be root compressions; (3) we are recommending a PET-CT to see if there are areas outside of the bone marrow in the bone that may be affected with myeloma or so-called extramedullary sites.

In the bone marrow, we are recommending that besides the traditional stainings that are done for CD138, for kappa/lambda that patients get cytogenetics and fluorescent in situ hybridization (FISH). These two studies, the conventional cytogenetics and the fluorescent in situ hybridization (FISH) are very informative in regards to prognosis. Although it still is today, they do not necessarily guide treatment, we think in the future the presence or absence of specific cytogenetic abnormalities will allow patients to participate in clinical trials targeted for specific cytogenetic abnormalities.

There has already been one of those where patients who had a 14:16 abnormality were able to participate in the clinical trial that unfortunately was not positive, but we are viewing that patients with MMSET abnormalities, FGF abnormalities that as new drugs become available for these different mutations, these specific subset of patients may be targeted because we think that these drugs may have a particular benefit for these patient subsets.

What else should a patient have? All patients should have a Beta2 microglobulin, a comprehensive chemistry looking at calcium and creatinine. In very young patients, we are also recommending that they get HLA typing done because for very young patients particularly those with high-risk disease, we think that a serious consideration should be given to an allogeneic or a donor transplant.

What else do you think we should be telling our listeners, Jenny?

Jenny: Well, when it comes to the gene testing, which test does that? Is it the cytogenetics or is it a gene expression profile or which test is looking at the actual gene? I have seen some studies now targeting (you have one) targeting specific genes. Which test is for those?

Dr. Giralt: Not all states have the gene expression profiling test available. This is a test that's commercially available through signal genetics. It's called my PRS score. They do the gene expression profiling that was described by the group at Arkansas. It's a very informative test, but it's not available to everybody throughout the United States. The standard cytogenetics and fluorescent in situ hybridization (FISH) is what most patients should do. This is available across the United States.

In some specific protocols, for example, we have a BRAF protocol and a cabozantinib protocol. In the BRAF, we are looking for BRAF mutations that are seen in 10 to 15% of patients. This is primarily for patients with advanced myeloma, the same way that cabozantinib is for patients who we have over-expression of MEK. This is not an inclusion criteria but we want to try to enrich the protocol for patients who have MEK abnormalities because this is a MEK inhibitor.

I think the other thing that patients should start asking is what is the role of stem cell transplantation in transplant eligible patients? This is currently a very interesting question, a very controversial one particularly in patients who have major responses to induction therapy. But do not forget with thalidomide-dexamethasone, the complete response rate was only 5%, but with triple therapy such as lenalidomide, bortezomib and dexamethasone, the complete response rate is now somewhere up to 30%.

These are patients when before I could tell them, look, you still have disease. The high-dose melphalan will get you into a complete remission, and we know that achievement of complete remission is the single most important factor that predicts long-term disease control. I think you should get high-dose melphalan. But in the patient who has a complete remission, I can't have that conversation.

Now, mind you, I still think that for these patients, high-dose melphalan with autologous transplant remains the best way of achieving long-term disease control. Before the era of immunomodulatory drugs and proteasome inhibitors, that means before thalidomide, lenalidomide and bortezomib, five randomized trials showed a benefit for high-dose melphalan consolidation.

Currently today, the Palumbo trial is showing that patients who get high-dose melphalan have a longer remission duration than patients who do not. So I still think that should be considered the standard of care. The randomized DFCI/IFM trial will do a lot to inform us what the role is and what the magnitude of benefit is in getting high-dose therapy consolidation for all patients.

The other very controversial aspect and I think it's becoming less controversial as the data matures is the use of maintenance lenalidomide on all patients who received high-dose melphalan. Lenalidomide maintenance in two randomized trials, one conducted here in North America through the CLGB showed that patients who were randomized to lenalidomide have longer progression for survival and it's showing a survival benefit.

Again, had patients not agreed to participate in this randomized trial where the computer decided who was getting the maintenance or not, we would have never learned the magnitude of benefit of this intervention and it would probably have not become available to all patients because insurances would not have approved of it. Because patients participated in this trial, it is now for many become the standard of care. Even for patients in complete remission, there may be a benefit for lenalidomide maintenance until the time of progression. Major change in standard of care, major change in prognosis for patients with myeloma.

We are now talking about 60% to 70% of the myelomas after high-dose therapy and autologous transplant not having to deal with their disease for five years or more. We had never seen those data until recently. Lots of newly investigational strategies were just looking at a new protocol at a new conditioning regimen with carfilzomib and melphalan.

As you know, carfilzomib is the new proteasome inhibitor. It is not associated with neuropathy. It has anti-myeloma effect even with patients who have failed to respond to bortezomib. When combined with melphalan, we think it can make high-dose melphalan a better conditioning regimen. This is a phase one that is being done together with Dr. Luciano Costa at the Medical University of South Carolina. We now finished the phase one and getting ready to the phase two.

Any questions, Jenny, do you think so far?

Jenny: That trial is before transplant, that conditioning regimen?

Dr. Giralt: That is the conditioning regimen for transplant. It is part of the transplant process. Remember that in transplant, we have two components: the high-dose therapy which in the autologous setting. It is the anti-myeloma treatment and then the stem cell product that's given back to rescue patients from the high-dose therapy.

Then there are the five phases that we talk about. The first phase is the chemotherapy phase. This is the high-dose treatment. The standard treatment across the country is melphalan 200. This is a new protocol combining carfilzomib to melphalan 200. We are now in the phase two expansion cohort. We'll see what those results show.

The second phase is the low count phase. This is the time when patients feel the worst -- fatigue, some nausea. We are expending a lot of time looking at protocols to try to reduce the symptom burden after transplant. Dr. Landau in our institution just finished a study looking at maybe fractionating the stem cells to see if that will make the transplant recovery quicker. We are also starting to look at giving the high doses of stem cells to try to make the recovery quicker and therefore reduce the burden of treatment.

The third phase is early recovery. Currently, white counts will recover within nine to ten days, and then it's early convalescence which is the next couple of months in which patients' immune systems still remain weak. What we are trying to do is seeing if we can enhance the recovery after transplant. We will reduce the symptom burden and actually, reduce the interference and hopefully we can make high-dose therapy and autologous transplant as easy as regular chemotherapy.

Post transplant, we are trying to do ways to prevent relapse. You have already heard of lenalidomide. We are now exploring two different vaccine strategies. We just finished a study with MAGE which is an antigen that myeloma cells express. One of the concerns we have is that we think that by just doing a vaccine against one antigen, we may not be covering all the different type of myeloma cells a patient may have.

Dr. David Chung is exploring a new way of developing vaccines with something called electroporation where he can get the dendritic cells, the antigen-presenting cells to express different antigens, so essentially, with one vaccine, you get various targets and we hope that that will improve the efficacy of vaccine therapy for myeloma that unfortunately until today it has yet to be proven of any benefit although a lot of people are studying it.

A big program looking at donor transplants for myeloma particularly for younger patients with high-risk disease, Dr. Guenther Koehne is exploring this. With this process of T-cell depletion which would take the T-cells out of the donor graft, we can virtually eliminate graft-versus-host disease which was one of the most feared complications of donor transplant.

Ongoing studies, preliminary results look very interesting. In the upfront setting, we only think about it for young patients with high-risk disease, but when people realize after primary therapy, we think it is very appropriate to consider an allogeneic transplant because some of these patients can achieve long-term disease control.

What do you hear from your readers, Jenny? Is there a lot of questions about role of maintenance and whether they should go on it or not?

Jenny: Oh, I think it's a very interesting question about should you be on maintenance, because I know sometimes when you think about just a combination therapy approach either versus a transplant approach or a combination with a transplant approach, there are I guess symptomatic effects of being on those combinations. So a patient kind of thinks, "Do I really want to be on those for a long-term duration?" And I don't have any personal experience with lenalidomide, so I don't know if that's any different than the other drugs.

Dr. Giralt: You are educating me. What do your listeners think about the issue of transplant? Do they feel that it's all over the place or what field do you get when listeners call you and talk to you about what should I do about transplant or no transplant?

Jenny: Well, I think the people that I found that have gone through transplant and feel confident with that approach still feel confident with that approach, that it's an aggressive approach. I think everybody gets pretty emotional sometimes when we start talking about this transplant approach versus combination therapies and everybody has their own opinion about it.

Dr. Giralt: No, we understand. I have to tell you though. I mean, when I have been asked I say, look, I think there are some things which are facts that we all have to recognize and in fact number one is that those single most important surrogate for long term disease control is a complete remission. In patients who get primary therapy and have not achieved the complete remission, they should seriously, seriously consider receiving the high-dose therapy and autologous transplant because it's their best way of achieving a complete remission.

For patients who have achieved a complete remission and have low-risk disease, I mean we are going to again encourage them to participate in all clinical trials particularly the randomized trial of early versus late transplantation that is the trial that will give us the information we need to be able to give patients clear guidance on what they should do. At the end, transplant is a choice. It's not a necessity. We do strongly encourage patients that their cells should be collected earlier rather than later. Even though with plerixafor, which makes late collections more feasible, it is still better to collect the cells earlier rather than later.

Jenny: Just because the preconditioning makes it more difficult, that's what I understood.

Dr. Giralt: Correct. The quality of the stem cell is going to be a lot better if it's collected earlier rather than later.

Jenny: You have such deep expertise in transplantation. Do you have any thoughts or ideas about percentages of the potential to cure the disease using the allogeneic transplant?

Dr. Giralt: I would say, this is a question full of emotions. I mean first, I have told patients that I don't think our goal should be to cure myeloma. Our goal should be to give patients the longest life with the best quality of life with the minimum treatment necessary. If with that, we get patients to live long enough to die from something else, we have cured their disease.

Having said that, I mean we -- it's a question, "Dr. Giralt, are we curing myeloma in 2013?” The answer is yes. There are patients who have now been in remission for more than ten to 15 years, and they have never had to deal with their disease again and they have died from other causes when they are 70 or 80. So those patients were cured. Now, unfortunately they are not very many of them. We think that number stands somewhere between 10 to 15%. Most of them received high-does therapy.

Again, because the road to cure goes through a complete remission. And if the most effective way to get a complete remission is high-dose therapy and autologous transplant, we think that that is definitively in the cards. Now the donor transplant becomes a harder issue, but again if you look at patients who have had disease come back after primary therapy after the initial therapy and the only ones with long term disease control, the majority of them have undergone the donor transplant.

Even in patients with relapsed disease in which most of us know this in incurable, some of them, again, it's a small fraction, 10% to 15% can achieve long-term disease control and go on and probably be cured of their disease with a donor transplant in that context.

Jenny: If you can mitigate the graft-versus-host which is one of the biggest issues, then you reduce the risk.

Dr. Giralt: That's why we are very excited with Dr. Koehne's program of T-cell depletion. He has also incorporated a WT1 cytotoxic T-lymphocytes in the group of patients whose donors are brothers or sisters. We think that there is a significant future there. Again, the studies are just beginning, but we expect that there will be -- this is going to hopefully impact the natural course of the disease. I think we also have to remember that there are other things coming down the road. There is a national elotuzumab-lenalidomide trial versus lenalidomide alone. Dr. Lonial and his colleagues at Emory have shown that the use of elotuzumab in combination with lenalidomide makes lenalidomide a better drug.

We are all extremely excited with the anti-CD38 monoclonal antibodies. So there is a Sanofi antibody and daratumumab which is a Johnson &Johnson antibody. These antibodies have shown activity in patients who have failed all sorts of therapy including transplants, including bortezomib, including lenalidomide and combinations. The fact that these drugs work in this situation means that we now have another potentially very powerful drug with very few side effects. So you can think about these antibodies will be combined with all standard therapies and we are hoping that's going to make a significant difference in disease control.

There is a new oral carfilzomib that's being explored in clinical trials. There is a new oral bortezomib which is also being explored in clinical trials. So I think the reality is that in the next years to come will be a variety of new drugs, particularly new drugs with different mechanisms that will hopefully continue to change the natural course of the disease the same way that bortezomib, lenalidomide, thalidomide and high-dose melphalan and transplant has changed the natural course of the disease over the last ten years.

Jenny: Those you mentioned were considered to be immunotherapies, right – elotuzumab and daratumumab?

Dr. Giralt: Exactly.

Jenny: I have a question about a trial that you are running. It's called cabozantinib. I'm probably not saying that right.

Dr. Giralt: You are saying it correctly.

Jenny: It impacts a specific gene and this drug is already being used in lung cancer. So we talked about…

Dr. Giralt: And thyroid medullary cancer.

Jenny: Oh, okay. So how did you make this connection to myeloma and can we make this kind of connections in other circumstances?

Dr. Giralt: It's interesting. So the answer is how and why did we decide to explore cabozantinib in myeloma? So cabozantinib was also being developed here at Memorial for prostate cancer. There was an internal interest to look at it. As discussed, there was -- we do know that hepatocyte growth factor and MET are two genes that seemed to be over-expressed in the context of myeloma. This is interesting that cabozantinib can really inhibit the growth of tumors that depend on hepatocyte growth factor receptor and MET. So the hepatocyte growth factor and MET are the combinations. There was in vitro data that suggested that cabozantinib could inhibit myeloma cell lines.

Based on that, there was other data that hepatocyte growth factor concentrations correlated with Durie-Salmon stage, elevated HGF levels were associated with worst prognosis. We did know that myeloma cells and cell lines do express HGF and have over-expression of MET. So we felt that this was a drug that was worthwhile exploring in advanced myeloma. It was interesting that we already had a dose that was being used for prostate cancer and for thyroid medullary carcinoma. It's associated with very acceptable side effects primarily fatigue and gastrointestinal toxicity.

One of the things as you think about when we treat advanced relapsed/refractory myeloma, patients' marrow reserve or their bloods counts aren't that great. This is a drug that didn't affect blood counts very much, so we felt that it was a good candidate to explore for patients with advanced disease. We are just starting in the phase one and although the phase one doesn't require patients to have a MET over-expression or HDF over-expression. Eventually, we want to try to see if we can enrich the study for those patients because we think those are the patients that are going to benefit the most based on the mechanism of action of the drug obviously.

We just started. The first couple of patients are on it and we'll see. We are hopeful that our assumption that this will be an active agent of myeloma therapy is going to prove correct.

Jenny: Well, I just think it's a fascinating idea to take an existing drug and apply it to a different target. It will surely be faster than trying to develop a new drug.

Dr. Giralt: Correct. I think when we are -- as every new drug comes around and we have -- there is a BRAF inhibitor that's commercially available and we are exploring that one in patients who have BRAF mutated myeloma.

Jenny: Okay. I think it's great. It's a targeted approach.

Dr. Giralt: Again, I think as we hear from our listeners, people will always say, "Well, why do I want to participate in a clinical trial?" One is because it gives these patient access to new drugs that otherwise aren't available and two because we are participating in developing the new treatments of tomorrow.

Jenny: That's why we are doing this series is to give exposure to trials so people can understand them and better join them. Before when we talked, you were talking about national trials and the importance of running national trials. That will be my last question and then I think I'll open it up to caller questions.

Dr. Giralt: I think when patients have asked me, so national trials are usually phase three trials or phase two trials looking at very rare disorders or very rare entities. The phase three trials are usually trials where the computer decides amongst two treatments: One which is considered the standard and the other one which is considered the investigation. If we as researchers knew which study was going to be better, we wouldn't be doing a trial in which the computer decides one treatment over the other.

So the fact that we don't know is what makes us do this trial ,which although for many patients that we understand the fact that the computer decides always is uncertain, is unnerving, it's the only way to show that one treatment is better than another. Otherwise, there is a lot of potential bias. Before these randomized trials were done, there are many instances in which we have been led astray by our perceptions of what treatment is better. Sometimes these treatments, these trials are humbling because we, you know, usually the investigational arm has been something that's touted by different investigators as much better than the standard and when put head to head when it shows no difference it’s humbling, but at least we know for sure that that treatment is not better than the standard.

On the contrary, when lenalidomide maintenance has shown to be significantly better than no maintenance, when we go to government payers, when we go to third party payers, when we go to the different people who actually decide what treatment gets approved, this is irrefutable evidence. This is the gold standard, so this is really very difficult to say no to. The fact that we had more than 200 patients participating in the Phase B trial with the study that showed what it showed has allowed now all myeloma patients across the United States to have access to lenalidomide maintenance.

The other large national phase two trials are diseases which are very rare, so you can think about high-risk smoldering myeloma or as we talked about myeloma patients with specific cytogenetic abnormalities. There probably are not enough patients with the deletions 17 in any institution, even Memorial or Dana-Farber that we could do large trials in our own population of patients, so we have to unite forces and get together. If we want to explore new drugs through the National Cancer Institute, the NHLBI, we have to do it together through a cooperative group mechanism. I think, the public also should be aware that the federal government has really been a champion of all these studies. Thanks to them myeloma care has improved significantly over the last decade.

Jenny: Well thank you so much for what you are doing and for what others are doing to push us forward. I know you have to go, but I'd like to open it up for caller questions, just a couple. So if you have questions about Dr. Giralt's research, you can call 347-637-2631. Once you are on the call, you can press one on your keypad.

Caller: Thank you for taking my call. I had a question. Just on what was said about the target of treatments for the subsets of myeloma. Really my question is how can we tell or when can we tell to look to like a standardized treatment program versus a specialized treatment program? Is there a way patients can know that maybe their particular -- that they need to look for something more specialized versus taking a standard path?

Dr. Giralt: Our caller called in, how does the person decide whether they should go on to a target of trial that has a "targeted therapy" versus a standard trial that has no targeted therapy? I think as I have restated initially, as of today, there really is no front line trial that is targeting specific chromosome or cytogenetic abnormality. This is going to change in the next year because there will be trials targeting specifically high-risk myeloma.

If you are a patient with high-risk myeloma because you have an abnormal chromosome 17, you have plasma cell leukemia, you have very high risk features, you have 4:14 or 14:16 abnormality or an abnormality of chromosome 1, then there will be a trial specifically for you. I think again, we cannot say that that trial is better or worse than the standard, but we do think that the results with standard therapy leaves somewhat to be desired that this is usually standard therapy plus some. It's either you get more intensification, you get a different maintenance and now we strongly encourage patients to participate in that clinical trial.

In the context of high-risk leukemia, there will be a "targeted therapy" regarding that we are targeting high-risk leukemia more than we are targeting the specific target that they may have, but it's more intense treatment and I strongly encourage patients to participate in that. Now in regards to our trial at Memorial BRAF mutated myeloma, we are really at this moment in time just recommending this for patients with advanced diseased who have failed prior therapies, probably because we want to get the signal that it actually works before we recommend that earlier in the course of the disease.

Jenny: Okay. Thank you so much for your question and your call.

Caller: Great. Thank you.

Jenny: We have one more caller.

Caller: Sorry about that. I had you on my mute. My question is when it comes to clinical trial, who typically pays for that. Is that insurance or is that part of the study itself?

Dr. Giralt: That's an excellent question. The question was when it comes to clinical trials, who pays for it? The standard care of clinical trials is paid by your insurance company or your third party payer. The investigational part, the part that's not considered standard care whether it be the new drug, whether it be the studies that are done because you are on the new drug are paid by the study.

Generally speaking, the medical care that standard is paid by your third party payer or should be paid by your third party payer and the investigational stuff, the drug, if it's not commercially available is provided for free and or if it is commercially available and is part of the study, it also should be provided for free.

Caller: I just have a follow-up question about that. When it comes to needing to travel for example to spend with those appointment, is that paid for by the patient or by the study itself?

Dr. Giralt: That is something that you patients need to discuss with the study staff and their doctors because that changed different from one study to another. Each study will have different support for patients in regards to extra travel and the extent to the support may be different.

Caller: Okay. Thank you so much.

Dr. Giralt: Thank you for that very important and interesting question.

Jenny: That is a very important question. Well, Dr. Giralt, we know you have to go. I'm going to do this a little bit backwards. I'm going to let you go and then give the introduction so people have a little background on you, but thank you so much for joining us today and thank you for your great work and dedication to eliminating this disease. We were very grateful for you and all that you are doing.

Dr. Giralt: Jennifer, I want to thank you for what you are doing for this disease, for the amount of information that you are providing our patients and for your support for clinical trials which as we both stated is without doubt the way to the cure for this disease. And I want to thank all the myeloma patients out there for their attention and their dedication and for the continued support of all the different myeloma activities that are currently being done across the country. Together we will conquer this disease. Thank you all very much.

Jenny: Thank you so much.

Dr. Giralt: You're welcome.

Jenny: I wanted to take a minute to introduce him to our listeners. Dr. Giralt is a fellow of the American College of Physicians. He is the chief of the Adult Bone Marrow Transplant Service and chief of the Myeloma Service at the Memorial Sloan-Kettering Hematologic Oncology Group. He is also a professor of medicine at Weill Cornell Medical College in New York. He is originally from Venezuela. He received his medical degree from the Universidad Central de Venezuela in Caracas and completed his post-graduate internship in the University Hospital of Caracas with a residency at Good Samaritan Hospital in Ohio and a postdoctoral fellowship in hematology and oncology at MD Anderson.

Dr. Giralt is a member of ASH, ASCO, the North American Society of Blood and Bone Marrow Transplantation and the International Society of Hematology. He is on the international Bone Marrow Transplant Registry executive committee. He is the president elect of the American Society for Blood and Marrow Transplantation. He is a steering committee member and past chair of the Blood and Marrow Transplant Clinical Trials Network and is on the National Marrow Donor Program Board of Directors.

He is also on the clinical advisory board of the website Managing Myeloma which is targeted at doctors but actually has really good information for patients. He is also the past chair for the Center for International Blood and Marrow Transplant Research. Dr. Giralt has published over 400 articles and abstracts and has written chapters for several books and is an editorial board member for several journals.

Thank you for listening to another episode of Innovation in Myeloma. Join us next week for our next mPatient Radio interview as we learn more about how we can help find a cure for myeloma.