Presenter: David Vesole, MD, PhD, FACP, Director of the Myeloma Program at Georgetown University, and Co-Division Chief and Director of Myeloma Research at Hackensack University Medical Center.
This video is a recording of the live webinar hosted October 30, 2018 by BMT InfoNet.
It is a 45-minute presentation, followed by a 30-minute Q&A session.
Many thanks to Celgene, Sanofi and Takeda Oncology whose support help make this webinar possible.
Summary:
Myeloma represents 2 % of all cancers, affecting mostly older adults. Remarkable progress has been made in the treatment of patients with multiple myeloma, and new drugs and therapies are on the horizon.
Highlights of Talk:
- There are different types and stages of myeloma, each requiring a different approach to treatment.
- Autologous stem cell transplants are the standard of care for eligible patients, but research is underway to determine whether this will continue to be the case, given the effectiveness of new therapies.
- CAR-T therapy is a form of immunotherapy that has produced exciting, short-term results, and may become an important treatment option for myeloma patients
Key Points:
00:05 Myeloma cells don’t directly cause problems, but stimulate other cells to behave badly
00:08 Symptoms of myeloma
00:09 Survival for myeloma patients has improved
00:11 The different types of myeloma
00:13 Tests for multiple myeloma
00:19 Myeloma is more than one disease, which is why it is hard to cure
00:25: Usual course of treatment if you are eligible for transplant
00:26 Usual course of treatment if you are NOT eligible for transplant
00:27 Why is transplant standard therapy for patients with multiple myeloma?
00:35 Why do we need maintenance therapy after transplant?
00:39 New drugs on the horizon to treat patients with myeloma
00:44 CAR-T therapy shows promise for treating patients with myeloma
Transcript of Presentation:
00:01 Overview of Presentation: Thank you, Sue. It's a pleasure to be here on the night before Halloween, but I don't have any trick or treat for everyone online. I do have the opportunity to discuss myeloma, what has been going on over the last few years, as far as transplant options, and what is new in the future, what's new and exciting is regarding upcoming therapies using immune mechanisms to harness - usually the patient's own- immune system to fight and destroy residual myeloma in individual patients.
00:02 What is myeloma? It really is a pleasure to be allowed to participate in this webinar for the BMT InfoNet. We'll start with some basic premises and basic information so everyone's on the same page. We're going to start, what is myeloma? I'm showing you a picture here on the right hand side are myeloma cells in the bone marrow. Let me see if I can make the arrow work. These guys are the myeloma cells, not all of the same, this double omelet looking thing is generally, it's a binuclear myeloma cell. All myeloma cells, just like all patients' myelomas, are not created equal. Some myeloma cells look uglier than others and they actually act that way. In the past, before we had all the new molecular technology, we used to just look through the microscope and kind of have a feeling of how patients would do based on the way the myeloma cells looked.
00:03: Myeloma is a malignancy of the plasma cells: Multiple myeloma is a malignancy of plasma cells. Everyone has plasma cells in their bone marrows. Plasma cells normally make antibody to infectious agents. Any cell in the body can become malignant. When the plasma cells become malignant, we call them myeloma cells.
00:03 Measuring antibodies made by myeloma cells: These myeloma cells, because they're pre-programmed to make antibodies, still make antibodies or parts of the antibodies when they become malignant. And these are the antibodies that we can measure with various tests to figure out how bad the production of the antibodies are. And when we kill the myeloma cells, the production of the abnormal antibodies decreases over time, and you can measure those with blood tests. Many of you probably have heard of the different antibodies. The most common two are IgG and IgA, or the heavy chains, the light chains are either kappa or lambda.
00:04 M proteins It really isn't important, which type of antibody myeloma cells make. It's sort of like your eye color. You have blue eyes, you have brown eyes, you have hazel eyes. Well, you have an IgG kappa myeloma, you have an IgA lambda myeloma, for all practical purposes, they all act and respond the same. When they are abnormal proteins, these myeloma proteins, we call it the M protein and that's what we measure on a test called the serum protein electropheresis, or when it's done in the urine, we call the urine protein electropheresis. I'm going to show you some of the laboratory tests in a little bit.
00:05 Myeloma cells don’t directly cause problems, but stimulate other cells to behave badly: These myeloma cells, oftentimes do not directly cause problems, but it's due to cytokine networks or hormone like networks from the myeloma cells to other parts of the body. For example, as we'll see in just a little bit, approximately 80% of patients with myeloma have problems with their bones, but it's not due directly to the myeloma cells in our bones.
00:05 Myeloma can cause weak bones: As an example, we have cells that are called osteoclasts and in my simple version of how I understand that, they're like Pacman cells. People remember Pacman. Myeloma cells send a signal to the Pacman cells to eat too much bone. If they eat too much bones, they develop holes. Holes cause the bones to get weakened and then those bones could subsequently fracture, break and cause symptoms. Similarly, we see low blood counts. It's not because the bone marrow's full of myeloma cells. You can have just a few myeloma cells and yet be profoundly anemic, because the myeloma cells use a different network to tell the red cells not to grow, thus becoming anemic.
00:06 Illustration of antibodies: Even though you make too much of one antibody that doesn't work, you don't make enough of the other antibodies, so you have more common problems with infections. Those are some of the manifestations. We're going to see them a little bit, and this slide here shows, this is a leg bone. For those who don't know, this is the hip up at the top, and inside the bone is where the marrow lives and this is where the myeloma cells live, not the outside of the bone. These little kind of upside down or sideway wise are what an antibody looks like, shown here. This part here, the longer piece is called the heavy chain, of which there's five flavors, if you will, of which in general, myeloma patients only have IgG or IgA and then for reasons I don't know, the light chains are with Greek letters. They're either Kappa or Lambda, and this is actually the place where you measure the free light chains on this little piece of the antibody. These are again the myeloma cells, they make these antibodies. Antibodies have no purpose. They're non-functional.
00:07 Myeloma represents only 2% of all cancers and 105,000 people living with it in the U.S.: Myeloma is not a particularly common disease. It's number 14 on the list of different types of cancers present. There are now, in 2018, it's about the same number, the projected [new] cases are about 30,000, and there's about 105,000 people that have myeloma in the U.S.
Myeloma represents only 2% of all cancers. When you look at the average age of a patient with myeloma, the average age is 69 to 70. The number of cases of myeloma keeps increasing over the subsequent years because myeloma is a disease of the older population and baby boomers, those born from 47 to 64 are all in that 60 to 75 year age range. That's the big flux of population and the number of myeloma cases have been increasing by a couple thousand a year.
00:08 Symptoms of myeloma: We already covered some of this. The clinical manifestations. We use this acronym called CRAB. You're going to see this on another slide in a second. So if your Pacman cells are eating too much bone, your calcium goes up and you get hypercalcemia. If you get too much calcium in your blood, and sometimes due to the myeloma proteins themselves, you can have problems with your kidney or R for renal. Anemia we talked about because the myeloma cells tell the red cells not to grow, and we did talk briefly about bone disease. This is our bone, our leg bone and in the middle here, you see this kind of black color. That means there's a big hole there, which should be about the same color as up here, higher up on the arm.
This thing has almost no bone left. A patient like this sneezes, burps, moves, tries to open their car door, it can fracture. So we have CRAB for calcium, renal, anemia and bone disease and these are the general manifestations of patients with myeloma.
00:09: Smoldering myeloma – myeloma with no symptoms: That being said, about 10% to 15% of the patients are diagnosed without any symptoms. They don't have CRAB symptoms, but they're found to have an elevated protein in their blood. They're found to have anemia, for which they're not symptomatic. They're found to have some problems with their kidneys but they didn't know it because they don't have any symptoms from mild renal insufficiency, so 10% to 15% of the patients have what we call smoldering myeloma, and those patients generally are not treated except in the setting of a clinical trial.
00:09 Survival for myeloma patients has improved: We've improved our outcomes drastically. When I first started doing myeloma back in the 1990s, the average five year survival was only 30%. Fortunately, 25 years later, average survivals now are over 50% and when I look at the next set of data by the government statistics, I anticipate that this number is going to be going up even more. Survival is markedly better than it was in the past. This is due to better supportive care. The use of bisphosphonates are the class of drugs that help your bones heal. It's due to better antibiotics and more often than not, it's due to much better treatments than we had 20-some years ago.
00:10 We don’t know what causes myeloma: One of the questions patients will ask me when they walk into my clinic is why me, and I don't have an answer for why me. We do know that there are only two government recognized entities that are associated with increased risk of myeloma. Vietnam veterans exposed to Agent Orange, and individuals who worked after the 9-11 disaster that had extensive exposure to 9-11 dust and the like, have an increased risk of having myeloma. The rest of the time, other than rare family trees that have increased numbers of individuals with myeloma, for the most part, we do not know what causes myeloma.
00:11 Types of myeloma: smoldering myeloma: Myeloma has a categorization. We already talked a little bit about smoldering myeloma. That's when you do have myeloma, you make too much of that bad protein in your blood or your urine or you have too many of these bad cells, these myeloma cells in your marrow but you have no CRAB symptoms and you have no symptoms whatsoever.
00:11 Types of myeloma: MGUS: There is a precursor condition which is common. I've only got it abbreviated here as MGUS, but it stands for monoclonal gammopathy of unknown significance, which in English means you make a single protein and we don't know why, so rather than spit that all out, we call it MGUS.
MGUS is common. As our bodies age, eyes get bad, knees and joints get bad. Sometimes our hearts don't work quite as well as they do. Our immune systems also get tired to some degree with age, and sometimes they make a protein that they shouldn't make, an antibody they shouldn't make, but it means absolutely nothing. It's just part of probably the aging process.
00:12 Incidence of MGUS: The incidence of MGUS, this benign, pre-malignant condition is about 3.5% of all 50-year-olds and when you get to 80-year-olds, and most people will say there's not a whole lot of 80-year-olds in the country but if you think of all the 80-year-olds in the country, if we actually tested them, about 10% of all 80-year-olds would have this pre-myeloma condition that's benign.
These patients do need to be followed, because a small percentage of them will eventually go either to smoldering myeloma or myeloma that requires treatment.
00:13 Criteria for diagnosing myeloma: There are some new criteria for diagnosing myeloma that was changed about four years ago. If you have more than 60% of these abnormal cells in your marrow, if your free light chains - remember that's part of the antibody molecule -the ratio is more than 100 or if you have one or more lesions on the MRI or CT, then you should have myeloma even though you don't have any symptoms with any of these three criteria.
00:13 Tests for multiple myeloma: What are the typical lab tests? We covered some of these already. A protein electrophoresis. This tells you how much myeloma you have in your blood or your urine. Chemistry panels are necessary to look at your kidney function. Blood counts are essential, so you can look and see if you're anemic. These free light chains are another test to see how much myeloma you have.
00:14 Bone marrow biopsy is needed to diagnose multiple myeloma and determine risk factors: Everyone needs a bone marrow [biopsy] as much as one detests the idea, doesn't like to have the procedure done, but you need it for (a) you have to have it to absolutely diagnose the disease and (b) more importantly, is that's when we find out your risk factors. And the genetic makeup of the myeloma cells can only be determined, in this day and age, by a bone marrow [biopsy].
In the future, we may be able to do some of the same testing with blood samples - not ready for prime time yet. And imaging skeletal surveys, skeletal surveys were traditional tests that look to see if you had bone lesions, but they're kind of like looking at black and white TVs, which probably no one on the conference call has a black and white TV anymore. So more sophisticated tests - MRIs, CTs or PET CTs -give you much more information and should be done in select situations.
00:15 Staging System for Myeloma: Staging. I'm going to give you two slides with staging on it, one of which is fairly simple, the other one's a little less simple. The staging system originally was based on how much myeloma you had in your body. It was called the Durie-Salmon staging system, so the old timers on the line, they'll probably remember they have a Durie-Salmon one two or three. Myeloma doctors are not very intelligent. We only have three stages whereas almost every other cancer has fou.
But that staging system wasn't very accurate, particularly because the bone problems and the number of bone lesions you have is not necessarily correlated to how bad the myeloma is. It's just a measure of how active those Pacman cells are. But there are two blood tests: one's called a Beta-2 microglobulin, and the other one is albumin, and these are markers of disease activity. So based on your Beta-2 microglobulin or albumin, you get placed into stage one, two or three. This staging system was first published in 2005.
00:16 International staging system for myeloma: What this staging system didn't take into account was the importance of genetic abnormalities in your myeloma cells. So 10 years later, the International Myeloma Working Group came up with a revised international staging system. This is the original one of one, two or three based on the Beta-2 microglobulin and the albumin. But with the revised one, we included LDH, which is an enzyme that is increased in people that have aggressive myeloma. And it included some of the genetic risk factors: deletion of chromosome 17, a trading if you will, of material between chromosomes four and 14, or a transfer of material between 14 to 16. So instead of just using the Beta-2 microglobulin or albumin, we now include the LDH and the genetic abnormalities and we came up with a revised staging system.
Why is this important? Not to judge any individual who's on the line but stage one patients, which is the least aggressive form of myeloma, have lifespans that we think exceed 10 to 15 years on average. Everyone's different. That's important for everyone to know. Whereas the patients who have stage three disease have a much worse prognosis. That's one staging system.
00:17 Mayo Clinic’s mSmart system: The Mayo Clinic – there are three Mayo Clinics in Rochester, Minnesota, Jacksonville, Florida, and in Scottsdale, Arizona - between the three Mayo Clinics, there are about 35 doctors who do myeloma. They have this thing called mSMART. You can get this online. It's called msmart.org, and on that, you can actually get a lot of information about how to manage myeloma, and information about myeloma per the Mayo Clinic.
Not to say that this is all encompassing, but these are consensus opinions, and the Mayo Clinic recently changed. They had three categories that are high risk, intermediate risk and standard risk and they decided to ditch the intermediate risk group and just divide the high risk and standard risk. Ad in their categorization, there's an additional five genetic abnormalities that are considered poor prognostic features.
Interestingly, not all genetic abnormalities are considered to be unfavorable. There's some that actually are in the standard risk group, so there's a group of genetic abnormalities that are high risk that's associated with the ISS Stage Three. There are gene expression profiles that you could have done commercially now that could give you more information about the DNA to categorize how severe and how aggressive the myeloma may be.
00:19 Myeloma is more than one disease, which is why it is hard to cure: One of the other questions that patients ask me is besides what the treatment's going to be is, can I be cured. And in general, we don't use the cure word very leisurely. And one of the reasons we don't use that term very leisurely is shown as an example on this slide.
When I was in training, we used to say myeloma was one disease, one clone, one disease. We now know that there are eight to 12 myelomas at the same time within any individual, and these myelomas can change over time. So what this was supposed to be, I'll show you all these different colored dots. This is the original myeloma clone, if you will, this blue dot. And over time, you see some other clones that have developed. There's a green clone, there's a red clone, so ultimately, the patient needs to be treated. We treat the red clone, we may eradicate the red clone, but look, some of these other clones are oblivious to that. Some of the other clones or new clones can develop. Here's the yellow clone that was never seen before. Here's a combination of yellow and red clone, and so forth. The myeloma keeps mutating and evolving over time. We're constantly chasing our tails to try to eradicate the clone that's active at any moment in time, and this is one of the main issues of why we're not able to routinely cure this disease.
The other issue we have is we don't really know for sure what the grandpa or grandma clone of myeloma that starts the whole process looks like, because ideally, you'd like to kill this cell, not these cells down here. But we don't know for sure at this point in time what the cell looks like so we can generate specific therapy to eradicate the myeloma stem cell.
00:21 Types of remission with multiple myeloma: Myeloma is very complex. If you have acute leukemia, which I wouldn't wish on anyone, but if you have acute leukemia, you're either in remission or you're not in remission. It's very, very simple. If you have lymphoma, you can be in a partial remission, or you can be in a complete remission so there's two choices.
Look at the choices that you have with myeloma. There's complete remission, there's stringent complete remission, there's very good remission, there's partial remission, there's stable disease, and there's patients who are getting worse, and this is not the whole story.
And there's different criteria how we decide which category you fit into. For example, stringent, complete remission, I'm not going to go over all these, you have no protein we can measure in the blood or the urine. A more sensitive test than that, SPEP or UPEP, is called immunofixation. It's negative. Your bone marrow, we don't see any abnormalities by looking at the microscope, by staining the cells and we also have a normal free light chain assay. If you need all of this, you have a stringent complete remission.
00:22 Measuring minimal residual disease or MRD: We used to think that was the best way to go. That was the best response you can get. We now have measures that can look for a thing called minimal residual disease. Minimal residual disease is if you think of a complete remission as 100 points on a test, a stringent complete remission is 110 points on 100 point test. Minimal residuals disease is like getting 125 points on 100 point test. This is tumor burden. This is an iceberg. We only see the top of the iceberg originally, which is like 10 billion cells. When patients get complete remission, we're down to 10 to the eight cells, which is still a lot of cells. Stringent complete remission's another level lower.
We can find out - there's more sensitive technology - by either painting the cells or doing DNA sequencing. That gets you down to one to the fourth cells and hopefully over time, we can get down to zero and actually hit the bottom of the iceberg and patients will truly be cured.
00:23 What MRD means for patients: Does this matter clinically? MRD, this minimal residual disease - and when you see these plots like this, these are called Kaplan-Meier survival curve plots - the line on top is the one that does the best. The line on top, here, is a patient who has favorable genetics, the favorable stage and is MRD negative. They've got 125 points on the test and their likelihood of staying in remission is up here. When you look at the halfway point, it's about four years that they stayed remission. When you look at how long they survive, this group of patients has not reached the average survival and they're out over eight years so that's in contrast to people that have bad genetics and are MRD positive after treatment. They have a fairly dismal outcome. So the MRD, is associated with improved remission duration and improve survival.
00:24 Treatment for myeloma: That's kind of background. We're going to talk about treatments before I get off schedule here.
MGUS, we watch. Smoldering myeloma we talked about, this is when you actually have myeloma and have no symptoms. Patients are observed unless they're a candidate for a clinical trial. And active myeloma, we need treatment, and treatment is a variety of different treatment options, which we're going to cover some of them. Plus you need supportive care for people to maintain healthy bones.
00:25 Many new drugs have been approved for myeloma over the last 15 years: Over the last 15 years, we've had 11 new drugs - 11 new drugs shown over here - in a disease that's rare. Myeloma has actually had more drugs approved for the number of cases than any other disease. And the number of drugs that are forthcoming in the next couple years - there's at least two more drugs that may be available within the next two years, one of them I think, may be approved next month.
00:25: Usual treatment if you are eligible for transplant: So you look at treatment. So we have all these drugs. You get initial therapy. And if you are considered to be a transplant eligible candidate - you're young enough, you're in good enough health, you have adequate organ function - transplant for consolidation is recommended and considered standard of care. Most individuals also go on maintenance therapy. Ultimately, if you're not cured, the disease may come back and then you have to be treated again. And we're going to cover some of that as well.
00:26 Usual treatment if you are NOT eligible for transplant: If you're not considered a transplant candidate, you get your initial therapy and, for the most part, you stay on that therapy. Unfortunately, for the people on the phone listening in, the standard of care for myeloma in 2018 is once you start a treatment, you never stop it. There's data to support that concept.
00:26 Three drug therapies: In general principles of therapy, we usually give triplets for people who are either candidates for transplant or not candidates for transplant. The most common triplet in the U.S. is, I'll give you the trade names, not the generic names, Revlimid, Velcade, and dexamethasone is the most common triple used.
There are some individuals who like to use Cytoxan, Velcade and dexamethasone, - we usually reserve this in our practice for patients who have kidney problems. But the up and coming regimen that is not approved yet for initial therapy is Kyprolis, Revlimid dexamethasone or KRD.
00:27 Two drug therapies: For patients who are not candidates for three drugs - they're too ill, they have kidney problems, they have heart problems - we often give doublets of either Revlimid Dex or Velcade dex.
00:27 Maintenance therapy: Then maintenance therapy, at least in 2018, which could change in the very near future, is generally considered to be Revlimid, although there are some people with high risk disease that we give doublets of Revlimid and bortezomib or Revlimid and Ninlaro, which is an oral proteasome inhibitor.
00:27 Why transplant is a therapy for myeloma: Why do we do transplants? Well, we give high doses of drug, a drug called melphalan. Melphalan is indiscriminate in what it kills in the bone marrow. It kills good cells as well as bad cells. It's good thing that it kills the bad cells. It's not a good thing that it kills the good cells. So we have to rescue the patient from the chemotherapy by giving them back stem cells till their bone marrow grow again. This is essential for the proper recovery of your bone marrow after the high doses of the melphalan. It's really a rescue operation to allow us to use melphalan.
00:28 Types of transplant: The most common type of transplants is autologous, using your own cells. Investigational studies are still undergoing using donor cells or allogeneic cells.
Almost everyone who has an autologous transplant gets peripheral blood. When I first started doing transplants, we used bone marrow. Almost never do we use bone marrow anymore and now for those who do have donor transplants, you can use, although they're extremely rare, umbilical cords.
00:28 Most people get a single autologous transplant: When we look at transplants, the vast majority of people get a single transplant. Some patients get two transplants, two autologous transplants, and there certainly are clinical trials of doing autologous followed by a donor transplant.
00:29 Stem cell process: How do we do a transplant? We collect the stem cells, the bone marrow- like cells from the bloodstream. We hook you up to a blood processing machine. We collect the stem cells. We put them in the freezer.
When the patient's ready to come in for the transplant, they get their high dose chemotherapy which, if you use melphalan, which is the standard of care worldwide, it takes 30 to 60 minutes. Twenty-four to 48 hours after that, we take the stem cells we've collected. We thaw them in a water bath. We infuse them back into the blood.
They have little homing devices and it takes 10 to 12 days for those cells to grow, thus, the 14 day period for the transplant. Chemotherapy takes one day, 24 to 48 hours after the cells are infused and then it takes them 10 to 12 days to grow.
00:29 How stem cells are collected: There are a variety of ways to collect stem cells. Again, we don't use bone marrow.
We can give growth factors. The growth factors that you may be aware of are Neupogen or some of the newer formulations of Neupogen, Zarxio or Granix. And sometimes we use a drug called Mozobil, which helps Neupogen re-stimulate the bone marrow to make more stem cells that fall into the bloodstream so we can collect them. There are ways to collect even more cells or a juicier number of cells by giving chemotherapy regimens with the growth factors. And some of the centers use that combination of chemotherapy with the white cell growth factors.
00:30 Are transplants really necessary? The question we're going to raise right now is, is transplant needed? Why would I pose that question?
These are some of the more recent regimens. RVD, we talked about. This was the Kyprolis Rev Dex and if you look at the likelihood of getting into a VGPR - to remind you, VGPR means 90% reduction of the bad protein - look at this. RVD and KRD, almost 100% of the patients respond and almost 80% of the patients go into a very good partial remission. If you get such good responses without a transplant, why subject an individual to two weeks, loss of hair and all those potential side effects from the transplant procedure?
00:31 U.S./French trial of transplant vs. non-transplant showed transplant superior: In the past, using old drugs that we don't use anymore, they found a transplant was superior to non-transplant. So ,to ask the question whether we still need transplant?
There's a U.S. French trial - part of it's been published, the other part isn't quite ready yet - where they looked at new therapies, RVD or VRD. And in this trial, patients got three cycles of VRD. Everyone got their stem cells collected. Half the patients did not have a transplant, half the patients did have a transplant. Both groups got more RVD consolidation and both groups went on to maintenance therapy with Revlimid. In the group that did not get the transplant initially, they were to get the transplant later when they relapsed. What was the results of this trial?
When you had a transplant early, you stayed in remission for an average of 50 months versus 36 months if you didn't have the transplant early. Now I should point out that even though that there's a 14 month difference in how long you stay in remission, at the time this study was analyzed, it's too early to see if one group actually lives longer than the other group. So transplant early provides longer remission.
This is another look at the same data with longer follow up. Again, the line on the top is the line that does best and the line on the top with longer follow up again shows that the transplant group had an improved remission duration versus those who did not have the transplant.
What about the likelihood of getting that 125 points on that 100 point test? If you had a transplant, the green line up here shows that the likelihood of getting that MRD negativity was substantially better than for those patients who did not have the transplant, and you stayed in remission longer.
And this is another one. The likelihood of getting MRD negativity - that previous one was how long you stayed in remission, this is the likelihood of MRD negativity - was 80% in one group, 65% in the other group.
For those individuals who are listening, who are not interested in transplant, I want to be fair and equal to all. If you became MRD negative, these two lines are the same. The yellowish line is the group that had a transplant. The dark line is the group that did not have the transplant. If you are MRD negative, you did the same, but the likelihood of being MRD negative was higher in the group that had the transplant.
00:34 New trial testing whether transplant is superior treatment: What do we do with that information? Well, this is a trial that's ongoing right now. You get induction therapy. You get checked to see if you are MRD negative. If you're MRD negative, you get randomized to either an early transplant or late transplant. If you're MRD positive, you get more induction therapy until you're MRD negative and then you get a transplant. So we're trying to find out if you need the transplant if you're MRD negative, to do a large trial to look at that exact concept. We don't want to put patients through a transplant unless they need it.
00:35 Why do we need maintenance therapy? Maintenance therapy. Why do we do need maintenance therapy? Well, the reason to do maintenance therapy is to prevent [progression] and prolong your remission, to change, if you weren't in a complete response or you were not MRD negative, to try to convert you and ultimately to improve how long you live.
00:35 Studies show survival is prolonged with maintenance therapy: This is data from a recent trial from Europe, from the U.K. They looked at maintenance therapy versus no maintenance therapy. The group that has a maintenance therapy had much longer remission duration from 30 months without maintenance therapy to 57 months with maintenance therapy. This same exact numbers were true on an older study done in the U.S.: almost identical duration of remission with and without maintenance therapy.
In this particular trial, that was true regardless of your genetic risk. The other trials did not show that. All the trials -there's three trials, I only showed you one - so that you stay in remission (progression free survival is how long you stay in remission) if you go on maintenance. Only one of the trials so far has shown that you live longer, even though you stay in remission longer, but there's always a downside.
00:36 Side effects associated with long-term use of Revlimid: Long term Revlimid could cause problems with your bone marrow. You can have low blood counts. There is a risk of getting a second cancer, it's 3% to 4%, if you go on Revlimid. There's always, the most important thing is, if you're going to be alive and be in remission, what's your quality of life comparing maintenance to no maintenance? We don't have that data yet.
00:36 Cost of long-term use of Revlimid: Then, as some of you probably know, if you have large co-pays and you're going to be on this drug, if you're going to be on Revlimid for up to five years, it could be very costly over time.
00:37: Ninlaro prolongs remission when used as maintenance therapy: I should tell you because I don't have a slide, that there is, at the upcoming national American Society of Hematology meetings, they're going to show you, there's going to be data shown of oral, essentially oral, Velcade, it's called Ninlaro versus observation, similar to the trial I just showed you. And they sent out a press release. We already know that the Ninlaro had an improved remission duration compared to observation.
We now may have not only one drug, Revlimid, but also Ninlaro that can improve remission duration. And just as an aside, in the future, there's going to be combinations of both those to see if we can improve it even more.
00:37 Summary of current treatment options considered standard of care: Before we go on to new therapies, I just want to conclude that autologous transplant - standard of care worldwide. Using consolidation after transplant is considered -there's data from Europe that says this has beneficial, data from the U.S. that doesn't agree with that. And maintenance therapy is considered standard of care.
We can get deeper responses when you give very potent regimens such as KRD, which may or may not be stronger than VRD with the transplant. Early transplant is superior to late transplant, that's still the standard of care. Allogeneic or donor transplants maybe curative, but they come in at a much higher risk and remain investigational at this time.
00:38 Drugs currently available and in development to treat myeloma: Drugs. We have a lot of drugs. Most people have heard and I apologize - these are the generic terms of the drugs, Revlimid, Pomalyst. There are two new drugs that are cousins of Revlimid and Pomalyst in clinical trials. They look very, very encouraging.
We talked about Velcade, Kyprolis, Ninlaro. There's another two oral drugs in that class, probably not going to be ready for prime time. They have different side effect profiles.
There's a variety of drugs that look very promising that attack the cells by different mechanism, called kinase inhibitors.
00:39 Drugs about to be approved for myeloma – Selinexor and and Venetoclax: The next drug that probably is going to get approved for myeloma is a drug called Selinexor. It's in front of the FDA right now. This information should be forthcoming in the fairly near future. Venetoclax is approved for chronic lymphocytic leukemia, has some very nice activity in myeloma. And this particular drug, which I can't even pronounce, was devised specifically for patients who had that 17P deletion. They're giving this drug with Velcade in patients with 17P and the preliminary results look encouraging.
00:39 HDAC inhibitors Panobinostat and Ricolinostat: There's a class of drugs, it's called HDAC inhibitors, Panobinostat is one. Ricolinostat is one, but the ones that are the most exciting of the monoclonal antibodies is immunotherapies which I'm going to spend the rest of my time on
00:40 Combinations of drugs for treatment of myeloma: Just so you know when disease comes back, you've got all these different regimens that are possible. I'm not going to read them out but these drugs across the top are all FDA approved, as individual drugs or in combination. And look at all the combinations that people could get to treat their myeloma. We are really blessed and that with this number of combinations - and these are effective combinations.
But what other combinations can we do? Monoclonal antibodies are proteins that target specific markers on the myeloma cells, which we'll spend a lot of time on. We can give immunomodulatory drugs, checkpoint inhibitors, which can try to break down the way that tumor cells hide from the immune systems to try to stop them from hiding. Vaccines, which are very encouraging in some diseases, are still being actively pursued to try to boost your own immune system to fight the myeloma and one thing that's the most exciting aspect right now are these things called CAR-T cells. We're going to go over that in a little bit more detail in a moment. Monoclonal antibodies are directed against the surface of myeloma cells. If you think of myeloma cells as having houses on them, you may have a brown house, you may have a white house, you may have a blue house, you may have a greenhouse, monoclonal antibodies can be directed against specific houses.
00:41 Darzalex: Darzalex, daratumumab is an agent that attacks the white house. It only attacks the white house and there's not white houses on very many cells besides myeloma cells. Very few other cells in the body have white houses on them, predominantly in myeloma cells. This drug is now approved for initial treatment. It's approved for relapse treatment and being studied for maintenance therapy. It's not convenient. It's intravenous. The first dose of the drug takes eight to nine hours and even after three or four weeks of the drug, it still takes about three and a half to four hours. What's in the future? They're going to be able to give this drug over three to five minutes by an infusion subcutaneously into your fat . So this is in studies, very, very promising, is equally efficacious as the IV form.
Infusion reactions can occur almost only with the very first time it gets administered, which is why it takes so long the first time. 40% to 50% of the patients who have infusion reactions when the data with the sub-Q, it's about 10%. So not only is this faster, it's safer. If we get to sub-Q, not going to be approved anytime in the next year.
00:43 Monoclonal antibodies to treat myeloma: There's different kinds of monoclonal antibodies. There are those that are naked. You can have them connected to a chemotherapy drug that we call drug conjugate. So you can attach the antibody to a drug, so the antibody could attach to the myeloma cell and attach to the antibodies - a drug that can be injected right into the cell.
Or you can have an antibody that attaches to two cells. This particular antibody, this bispecific antibody attacks, in this particular case, it's a red house on the surface. This is the antibody here. It's attacking the red house on the surface. But look, there's another part of the antibody that brings in your immune cells. This antibody has two prongs with, if you will, it's got two forks on both ends. On both ends, one of the forks is stuck into your immune cells, the other fork, the end of the fork is stuck into your myeloma cell. So you could bring these, your own immune cells in close proximity to the myeloma cell so they can work better.
00:44 So you can do this with drugs. You can do this with bispecific antibodies. All of these are in clinical trials and these are a variety of different bispecific antibodies and clinical trials. Data is very sparse right now. I'm anticipating in our national meetings in December, we're going to hear a lot more about bispecific antibodies. Again so I can allow time for questions, I want to move ahead.
00:44 CAR-T therapy to treat patients with myeloma: I want to talk about CAR-T cells. This is a CAR-T cell. CAR-T cells are your own immune cells. Your own immune cells. We take them out of your body. The next slide is going to show you a cartoon of how this is done. We take them out of your body and we call up our engineers and the engineers are going to engineer, construct those cells, and they're going to do two things by engineering them.
One, is they're going to make them angry. They're going to put genes in these cells to make the cells angry. And the second thing they're going to do is they're going to arm these angry cells with missiles. We're going to take one of your normal immune cells, put it in culture, genetically engineer it to make it angry and give it missiles to attack your own myeloma.
This shown schematically here. They hook you up to a blood processing machine. You just get hooked up. You don't get growth factors. You don't get chemotherapy. They just hook you up to the machine. They take out your immune cells, called T cells. We add this genetically engineered information into the culture and these genetically engineered cells will grow. We take them, infuse them back into your arm. They go to the tumors. They go to your bone marrow. They go throughout your body and they do their dirty work to kill myeloma.
00:46 Is CAR-T therapy effective for myeloma patients? Bluebird study: What are the data with this?
I only want to show you, there's five different types of CAR-T cells shown on this slide. I don't want to go over all those specifics. I want to talk about just one, not to be preferential, I want to talk about just one because it's the one that was presented most recently on our national meetings. It's called the Bluebird study. They actually presented 44 patients in the actual trial. They had 94% of the patients - again, there's no chemotherapy, we're just giving these angry armed cells back to you - 94% of the patients had a response. Almost 60% of them went into complete remission. This is all fantastic information for no chemotherapy. These patients were very heavily treated. They had an average of seven types of prior chemotherapy regimens.
00:47 Side effects of CAR-T therapy: This does come at some price. These cells, when they're all juiced up, they do interesting things to your body because they're angry armed cells, and you can have reactions to them that we call cytokine release syndrome. It's rarely severe, grade three or four means how severe it is. It's only 10%, but it's fairly common to have some type of response, the most common thing is fever. It goes away after a few days. It's done. Interestingly, they don't know how this works.
You can have some neurologic side effects from these cells as well. Again, it's not permanent. And then when you look at these other constructs, the other trials, some of them do not have any neurologic side effects.
These are different ways to make CAR-T cells. One's a Lamborghini, one's a Maserati, one's a Rolls Royce, so different ways to make these CAR-T cells and they don't all have the same outcomes. These CAR-T cells are very exciting. They have very, very good response rates, unbelievable response rates, including complete remissions. What's not shown on this slide is that we're still not sure how long they last.
00:48 Remission after CAR-T therapy: In this particular trial, again it's not a very long follow up, but the average time people stayed in remission was about 11 months, not 11 years, 11 months. We still don't have, this as a process that's ongoing to try to improve the outcomes.
00:48 Current research on CAR-T therapy to treat myeloma patients: Where are we going with CAR-T cells? There's a current trial called the KarMMa trial that is hopefully, if it's a positive trial, will be sent to the FDA to see if this can be approved and be available outside of clinical trials. Right now, the only way you get a CAR-T cell is through a clinical trial. This particular trial is at 19 sites.
But there are over 20 different CAR-T cell companies. And not only that, within even one company, there are multiple different ways they're making CAR-T cells. We still don't know how they work and we don't know why they stop working, and we're trying to get even better CAR-T cells that last longer and have better missiles.
00:49 Research on ways to improve CAR-T therapy: We're trying to find ways to decrease this risk of this toxicity, the cytokine release syndrome, that can cause fevers and a variety of other symptoms, including nerve problems. And one way to do that is to put a switch in it, so that if you start having problems like that, you give them a drug, turns on the switch and the cells die.
In the future, this process of making the CAR-T cells I showed you previously, that I showed you here, this takes about four weeks of time. Ideally, we'd like to have a mechanism where we get the CAR cells faster. Some of the patients can't wait four weeks, and one way to do that is to generate these cells from other donors. They'll be specific for an individual's myeloma cell but can be made in the laboratory for anybody. Also very little information on that. We're all excited about CAR-T cells, don't know when they're going to be approved.
I would tend to think, for those who are interested, [it’s] not going to happen till the end of next year. The only way you can get CAR-T cells right now is on a clinical trial.
00:50 What remains unknown about CAR-T: We still don't know long term outcomes of these clinical trials. We don't have hardly any individuals that are out more than two years. We don't know outcomes beyond two years.
There's a variety of different ways, I told you. Right now, we're using - the most common target is this green house - but we may need to find out that you need to attack the red house or the blue house, not the green house to come up with the best target for the missiles. Or missiles that can attack both green and blue houses. Those are all in process.
And then we talked about drugs or the antibodies that are attached to drugs, the antibodies that are attached to bring in other cells from the immune system, and maybe that'll be a better way to go or maybe a combination of the CAR-T cells and the antibodies may be the way to go.
With that, I'm going to finish and open the forum to questions and answers.
[Sue Stewart]: Thank you, Dr. Vesole. That was a very clear and very informative presentation about the options for treatment for people who have multiple myeloma. We're now going to open the forum. The first question.
00:52 Which IMids are up for approval by FDA: These two, the CC-220 and -122, they're in phase one clinical trials. So just so you have an idea, these drugs are three to five years away from being FDA approved. They're very early in the clinical trial process. They look very promising but this, nothing moves that fast for drug approval. I can't imagine less than three to five years.
00:52 What are the lab values that indicate a return to active multiple myeloma disease in a patient who has had an autologous stem cell transplant?
In general, we monitor individuals first, second, third month after a transplant and then every three months after that. Seventy-five percent of the individuals will have an increase in that protein, that M protein in their blood or urine as the first manifestation that their disease is back. Twenty-five percent of the rest of them may show some other tests besides that protein increase, they may show some evidence of anemia. They may show some new bone disease. They may show some problems with their kidneys but the vast majority of individuals, the first sign of it coming back is slow increase in the abnormal myeloma proteins.
00:53 What, if any, is the advantage of a tandem stem cell transplant?
That's a great question. I wish I had a great answer. There's an old study, when I mean old studies, 1994 study that was published in 2003, that showed two transplants were better than one, particularly in those patients who did not achieve this very good partial remission. But 1994, we had none of these drugs that are listed on this slide right now.
To bring it up to date, there were two trials that were done. One done in the U.S., one done in Europe, using modern therapy. They had completely opposite outcomes. In Europe, they showed that two transplants were superior to one transplant. In the U.S., they showed that two transplants were equivalent to one transplant. There's differences between the two trials. We're still not absolutely certain how you can explain the dichotomous difference between the two trials but currently, most of the transplant centers do not routinely perform two transplants. We usually reserve it for specific indications.
That being said, almost all transplant centers will collect enough stem cells to complete two transplants, in case we want to do one in the future. The exception to that statement is that Medicare will only pay for a single transplant. So I can't give you a good answer of two versus one. We do two transplants in the concept of a clinical trial.
00:55 Are checkpoint inhibitors are dead?
Are they dead? Jack wants to know that? I'm willing to bet that if he asked that question, he knows the answer.
Checkpoint inhibitors are a very, very important class of drugs. For those of you who are not familiar with that class of drugs - everyone knows Jimmy Carter, the president who had melanoma, that he had melanoma that went to his brain. Checkpoint inhibitors are what potentially cured him. It's a different class of drugs. Due to time, I don't want to go over how they work but they're very, very important in a number of solid tumors and actually in lymphoma as well, particularly Hodgkin lymphoma. Checkpoint inhibitors in myeloma have been tested fairly vigorously in combination with either Revlimid or Pomalyst in large clinical trials. And in those large clinical trials, they showed no advantage of giving checkpoint inhibitors in myeloma with those combinations. And not only that, the group that got the checkpoint inhibitors had more side effects.
Checkpoint inhibitors right now are not dead, but they're being limited to very few patients in clinical trials and I don't foresee them becoming popular anytime soon. Potentially down the road, as maintenance therapy or in combination with other drugs. But as far as active treatment for active myeloma, I don't see it happening anytime soon.
00:57 Is there any data to show a specific kind of treatment that is more effective with 1q+ or 13q deletions?
13q deletions are not considered high risk. If I can go back to my slide, I'll show you the Mayo Clinic one. 13q deletions are present in over half the patients with myeloma using current technology so you don't see 13q on this list. It's not part of the staging system. The 1q is on this list. It's not in the staging system. 1q to the best of my knowledge, there is no specific targeted therapy for 1q at this time. The only specific targeted therapy we have are in clinical trials are for 17p and this one, and this one, the P53 mutation. There is no drugs specifically designed right now for the other abnormalities listed here.
00:58 If post-transplant, starting M protein of 0.2 GdL, is increasing by 0.1 GdL per month, when do you change the treatment?
I didn't give the definitions, or maybe I did give you the definitions for progressive disease. This is the definition of progressive disease of when you should definitely consider changing treatment. That's when you have an increase of the M protein, the bad protein by 25%, but what's not listed here is it has to be a minimum of 0.5 grams per liter. If it went from 0.1, if that was the lowest point, it had to go to 0.6 before it would be considered progressive disease and think about changing treatments and myeloma.
00:59 Why do skin rashes and hives happen with to thalidomide?
Skin rashes and hives? Hives, yeah, it can happen with Revlimid, Pomalyst or thalidomide. There are probably about 20% of the patients can have reactions.
I don't think we have an absolute mechanism of how that occurs. It's usually, I won't say never, but almost never serious. Almost always, just with withdrawing the drug, whether it's Revlimid, Pomalyst or Thalomid, the rash will go away. And the truth of the matter is, that once the rash resolves and you re-challenge the individual, about 80% of the time they don't have recurrence of the rash. Only about 20% of the time do you have recurrence of the rash, but even then it's usually managed reasonably well with other ways to control the rash, and very few patients truly cannot take one of those three drugs because of true allergies manifested as a rash.
01:00 After BMT, how long do you stay on Revlimid in maintenance?
In the U.S., the standard of care is to continue indefinitely. In France, you only get it for a year and in Spain, you get it for two years.
There's actually a trial, the trial I showed you briefly. Let me see if I can find it. This trial here where it says 18 months, that’s a mistake, this slide's wrong. This trial is being done in the U.S. and France. In France, they completed the trial. They gave a year of maintenance therapy. The U.S. is doing this same exact trial as shown here ,except where it says 18 months, which was 12 months in France, it's going to be for three years and they're going to be able to answer whether you need one year or three years, and they're going to let the people at three years to stay on the drug if they want. In the U.S., the standard of care is indefinite.
01:01 Are there any trials exploring the impact of CAR-T on younger, earlier stage myeloma patients? Could better results be produced by CAR-T using it earlier in the diagnosis?
The very simple answer, because there are more questions, is yes. There's currently a trial for, I think first relapse, where patients are going to get either CAR-T cells or one of three conventional regimens for treatment, moving it way up faster or I should say earlier to answer that exact question.
01:02 Are patients who have had an allogeneic stem cell transplant eligible to get CAR-T?
None of the CAR-T cell trials that I'm aware of allow allogeneic transplant patients on them, currently. Whether that'll change in the future is likely, but the answer, currently, to the best of my knowledge is no. There is no CAR-T trial right now that allows allogeneic transplants.
01:02 Is the treatment for multiple myeloma also used in the treatment of amyloidosis as well?
The treatments are almost in parallel except the difference is that in amyloid, we're not giving consolidation and we're not giving maintenance therapy. The disease burden in amyloid is much lower, and most people could stay in remission for an extended period of time. The symptoms and the organ involvement with amyloid can be much more problematic than it is with myeloma, but if they respond, they actually have very nice outcomes. But same regimens can be used for both, including transplant, which is standard of care for individuals who are considered transplant candidates.
01:03 How important are second opinions?
I think everyone should see a specialist but that's because I am one.
01:04 Are there are any problems with creatinine supplements in patients with multiple myeloma?
I'm not sure what a creatinine supplement is but the bottom line is, if it doesn't hurt you, most people would say if you want to do it, do it. You're supporting the health food stores.
01:04 Is there a standard interval between the end of induction therapy and the harvest and transplant?
The old standard was four to six cycles, but that was based on regimens that aren't as potent as some of the ones we use currently. So most people could probably get by with three to four cycles and then proceed to stem cell harvest.
There are going to be myeloma guidelines coming out, probably by the end of the year, from the American Society of Clinical Oncology. It's going to be published in the Journal of Clinical Oncology where they're going to say, two to four cycles. I believe it says three, four, I'm on the committee. I think it says three to four cycles of induction therapy, whereas traditionally people said, four to six. You probably don't need that many with the potent induction regimens we use now.
01:05 Why is it important to use dexamethasone with myeloma drugs?
Dexamethasone, the bane to almost everyone - not everyone because there's some patients who really like dexamethasone - dexamethasone has really good anti-myeloma activities. If you give high doses of dexamethasone by itself, you'd get a 40% response rate. And as it turns out, when you give dexamethasone with other drugs such as Revlimid, Pomalyst, Velcade, Kyprolis, you get a situation where one plus one equals three, not one plus one equals two, because they actually interact positively together to give you a better result than they would individually.
01:06 Is there an advantage to get Velcade in the abdomen versus the leg? This patients has had stronger adverse reactions in the abdomen than the leg.
Now that's just a localized phenomenon. What I should like to point out is I'm hoping that no one on the line is still getting IV Velcade. IV Velcade is approved but causes substantially more neuropathy than the injections. And the fall back for that is even if you have neuropathy from Velcade, the oral type version of Velcade causes almost no neuropathy. You can stay within the same class and still benefit from it and not be as concerned about developing neuropathy.
01:07 I heard that there may be some promising results from quad therapy for initial treatment, Dara plus CRD or Dara plus KRD. Can you speak to that?
Dara plus VMP is already approved. Quad therapy's already approved for frontline therapy. VMP is Velcade, melphalan, oral melphalan, not the IV melphalan we use for transplant and prednisone. Essentially no one in this country uses VMP. It's inferior to the regimens we use, which would be RD or KRD.
Right now, daratumumab's already approved for frontline. There are ongoing studies of Dara KRD, Dara VRD. The same thing's true for the other monoclonal antibody. It's a different target that attacks the “gray houses”, if you will, of myeloma called Empliciti or elotuzumab. It also is being utilized in Quad formulations with VRD.
01:08 How difficult is it to get accepted into an immunotherapy trial? What would be the criteria for acceptance?
Essentially, clinical trials are only eligible for individuals who are progressing. If he's in remission on daratumumab, he's not going to be eligible for a clinical trial. The likelihood of getting into clinical trials is [that] you have to find a center that is close enough that has something you'd be eligible for to enroll. We talked about CAR-T cells. Everyone wants a CAR-T cell, but it's very, very difficult to get on CAR-T cell trial. They're still in the early phases. They're limited to a number of patients. They are limited to a number of institutions that have the CAR-T cell technology, so it's hard to just set time to get on those trials.
There are different organizations and websites that can help you find clinical trials. One of the easiest ones is clinicaltrials.gov, which you can search for clinical trials to see what's there and where they're located. But even when you do, that doesn't mean you're eligible. And even if you're eligible doesn't mean they have a slot for you. It's not easy just to get on a high profile clinical trial.
01:09 Are there any vitamins to avoid if you have multiple myeloma? What is your feeling about using marijuana while you have myeloma?
To the best of my knowledge, there are no studies that show marijuana has a positive or negative effect in myeloma, so I don't think, again, you need marijuana. Whether it's a good supportive care measure is up to the individual.
Vitamins, the only thing I'd recommend is that if you're on Velcade or Kyprolis or Ninlaro, you shouldn't take vitamin C or drink green tea the day you get those drugs. They can limit the efficacy of those drugs. So, vitamin C and green tea are no no’s on days of Velcade, Ninlaro or Kyprolis.
01:10 What kind of lab tests should be done for those with smoldering multiple myeloma, and how frequently they should be done?
The lab tests are the same for smoldering myeloma, and the frequency really depends on the type of protein, the number of myeloma cells and how high the protein is. And these are the M protein or the free light chains, and it can vary from three months to six months to a year but they have to be monitored indefinitely. T
The risk of evolving into myeloma from smoldering disease that requires treatment is 10% a year, so it's cumulative though. It's 10% the first year, 20% the second year, 30% the fourth year, and so forth. Once you've hit the five year mark, actually, the risk goes down to 3% a year. So it really depends on the level and how comfortable the oncologist is in spreading out the frequency of the test.
01:11 Why don’t researchers routinely break down and report results separately for high risk versus low risk patients?
The high-risk patients have a poor outcome. We're still trying to find a better mousetrap and try to improve that group of patients. We've improved the outcomes for the standard risk patients by almost four fold over the last 20 years. We have not improved maybe twofold for the high risk patients, so there's a substantial difference in how much improvement we've accomplished in the standard risk versus the high risk and we keep trying to improve the outcome in those patients so that everyone will live long and fruitful lives with good quality of life.
01:12 On the ISS staging slide, translocation of 414 had an asterisk in the high risk category. Can you explain this and what is the best maintenance plan after transplant?
414 is definitely considered to still be in the high-risk group by the ISS. 414, unlike the other genetic abnormalities, appears to be somewhat sensitive to that class of drugs that Velcade's in - Velcade, Kyprolis and Ninlaro. So for those particular patients, my personal preference is if they have a transplant, is to put them - even though I've told you that Revlimid is the of standard of care - I generally put them on Ninlaro and Revlimid, even though Ninlaro's not approved for that indication yet, because I want to give them the benefit of attacking their myeloma twofold. One is the standard myeloma mechanism with maintenance with Revlimid, and then Ninlaro to particularly help the group of the cells that have the 414 translocation. But it is a group that that class of drugs has changed from high risk to a lower level of high risk if you will.
01:14: Contact information for BMT InfoNet and thanks to Sponsors Celgene, Sanofi and Takeda Oncology.
All right, and with that unfortunately, I think we need to bring the webinar to a close. I want to thank Dr. Vesole for an excellent presentation and an excellent Q&A session. Again, if you have any questions or need help, you can phone us at 888-597-7674 and once again, many thanks to Celgene, Sanofi and Takeda Oncology for generously supporting this webinar.
Everyone, have a wonderful evening and good night.
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