Maintenance Therapy after a Transplant for Multiple Myeloma

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Maintenance Therapy after a Transplant for Multiple Myeloma

Presenter: Natalie S. Callander. Professor of Medicine and Director of the Multiple Myeloma Clinic Program at the University of Wisconsin.

April 29, 2024

Presentation is 43 minutes long, followed by 17 minutes of questions and answers

Summary: Maintenance therapy after a stem cell transplant is used to decrease early death, increase time to progression and improve the quality of life in patients with multiple myeloma. Dr. Callander provides an overview of the history of maintenance therapy and discusses the new and exciting treatment options available. She also delves into potential future therapies that are currently under study.

Key Points:

• Lenalidomide is the only FDA-approved maintenance therapy for multiple myeloma and has been shown to delay the progression of multiple myeloma and improve overall survival of patients.  It is important to start maintenance with Lenalidomide within six months after transplant.
• Medications such as Daratumumab and Carfilzomib have been studied as maintenance therapy with good results, especially in patients with high-risk disease.  Combinations using these and other drugs are being investigated to improve rates minimal residual disease outcomes.
• T-cell redirecting therapy, including bi-specific T-cell engagers (BiTE) and Chimeric Antigen Receptor T-cell therapies (CAR-T), may be included in future multiple myeloma maintenance therapy. Studies are currently ongoing.

Highlights:

(07:16) The goals of maintenance therapy include prolonged control of disease, reduced risk of early death and improved quality of life.

(16:45) Chromosomal abnormalities can be tested using FISH (fluorescent in-situ hybridization) or next-generation sequencing. These genetic mutations in multiple myeloma cells help determine the risk category of your disease. 

(19:35) Lenalidomide is the only FDA-approved maintenance therapy. Its side effects include GI problems, infections and secondary cancers. The GI problems can be well managed with low-fat diets and bile salt binders such as Colestipol.

(20:15) Routine Maintenance is associated with increased costs which can be a barrier to care for some patients.

(24:32) Maintenance therapy historically uses one drug at a time. Using multi-agent maintenance therapies may be appropriate for patients with high-risk disease. Studies looking at this are in process.

(28:26) Daratumumab is often used as maintenance therapy. It has minimal gastrointestinal side effects but does have an increased risk of infection and decreased response to vaccines as potential side effects.

(29:20) It has yet to be discovered if maintenance therapy can or should be stopped. Studies are currently underway to answer this question.

(29:45) Minimal residual disease (MRD) testing is now possible in multiple myeloma. If your MRD testing is negative, myeloma stays under control longer than if your minimal residual disease test is positive. This information can help guide maintenance therapy.

(35:46) T-cell redirecting therapy, including bi-specific T-cell engagers (BiTE) and Chimeric Antigen Receptor T-cell therapies (CAR-T) may be included in future multiple myeloma maintenance therapy.

(37:55) Three Bi-specific T-cell antigen engager drugs are available for the treatment of relapsed multiple myeloma. These include Teclistamab, Elranatamab and Talquetamab. They are currently being tested as maintenance.

(39:03) Healthy lifestyle behaviors, including good sleep, healthy diet, adequate vitamin D levels and social engagement can contribute to better responses in patients with multiple myeloma.

Transcript of Presentation

(00:02): [Susan Stewart]:  Welcome to the workshop, Maintenance Therapy after a Transplant for multiple myeloma. My name is Sue Stewart and I will be your moderator for this workshop.

(00:12): It's my pleasure to introduce to you today's speaker, Dr. Natalie Callander. Dr. Callander is professor in the Department of Medicine at the University of Wisconsin Carbone Cancer Center and the director of the Myeloma Clinical Program. Her research focuses on new therapies for all stages of multiple myeloma. She's the principal investigator on a national clinical trial looking at preliminary treatment for smoldering myeloma, and is currently involved in the development of cellular therapies for multiple myeloma patients. Please join me in welcoming Dr. Callander.

(00:54): [Dr. Natalie Callander]:  Well, Sue, thank you very much and good morning and good afternoon, wherever you might be. I am so thrilled to be part of this terrific symposium, and thank you very much for joining me to talk about a topic that I think is relevant to lots of us here, maintenance therapy after a transplant for multiple myeloma.

(01:16): Maintenance is from the French and old English. It is the process of maintaining or preserving someone or something. What we're talking about is, trying to preserve a response to an autologous stem cell transplant.

(01:33): The history of maintenance therapy in multiple myeloma. Many of you may be aware that the idea to give maintenance after initial therapy for multiple myeloma is not a new concept at all, and in fact, on this next slide, there was a study done in 1975 at a time when we really only had three drugs to treat multiple myeloma. That was steroids, Prednisone or other types of steroids, a drug called Melphalan, which was a pill, and then another pill called Cyclophosphamide. These were really the three big drugs that were in use starting in the late 1950s and into the 60s and 70s.

(02:09): Prior to the introduction of those drugs, people would only live about six months with their myeloma, but with the introduction of those drugs, it improved slightly to about 18 months, and so you can understand why people said, well, if we tack on some additional treatment after initial diagnosis, isn't that going to help?

(02:28): One of the things this very early study pointed out to us is that the type of intervention you're doing for maintenance, what type of drug, makes a big difference.  This was a relatively small study, only 137 patients, all of whom had received Melphalan and Prednisone prior to their maintenance therapy, but it turned out that the maintenance made no difference, and actually it caused many more side effects than it prevented, and so this strategy obviously fell off, and probably very few of you have ever heard of this.

(03:02): Now, of course, this idea has been around, and people wanted to see, okay, are there other ways to make this better? There was a study done in the middle 1980s where they gave just steroids every other day, and they did show that it improved progression free survival. We're going to talk about what that term means, but basically, it is the time before your myeloma becomes active again and you need your next treatment. But because steroids cause things like high blood sugar and can cause some muscle weakness, this intervention really never caught on.

(03:36): There was a movement again in the 1980s to use something called Interferon, which is a substance that is secreted in the body normally against a viral infection, but it has some very interesting properties to augment the immune system. This was a drug that was being used to treat something called chronic myelogenous leukemia. Interferon was used as a maintenance after initial treatment, and it's a drug that has a lot of side effects and so people felt pretty terrible on interferon too. They had a lot of flu like symptoms, and so it really did not work out very well and interferon dropped off, besides the fact it really didn't show any particular benefit.

(04:18): The history of Thalidomide as maintenance therapy in multiple myeloma. There is Thalidomide, and I'd like to just share with you, if you're not aware of this, the story of how Thalidomide even got used in myeloma in the first place. It goes back again to the 1990s where there was an investigator working in Arkansas by the name of Bart Barlogie, who was looking around for a treatment for a patient of his who was doing very poorly with his multiple myeloma.  They had pretty much exhausted all of the available treatments including transplant, and through interventions of a patient's wife, there was a call made to an investigator in Boston called Judah Folkman who was looking at different drugs that might fight cancer. He was a person who suggested Thalidomide, a drug that had been developed in Germany in the late 1950s for use as a morning sickness treatment. It became apparent very quickly that this drug was associated with some terrible birth defects so it was pulled off the market and really not available, but Dr. Folkman suggested that perhaps this drug could be useful in the treatment of multiple myeloma. That turned out to be quite a big discovery and so Thalidomide started being used in the 1990s for treatment of relapsed myeloma.

(05:33): It is not surprising then that people said, well, this is a capsule, why don't we try it as maintenance? When used as maintenance, taking it on a daily basis, there was some inhibition of preventing a relapse of myeloma, but the drug had a lot of issues.  It caused what we call peripheral neuropathy, meaning people can start off with just some tingling and numbness in fingers and toes, which can progress to actually loss of movement and pain. This drug causes significant constipation and it is quite sedating, so then it was difficult to take in the morning. Of course, that potential for birth defects remains, and probably has something to do with how this drug is useful.

(06:18): But thinking about maintenance is still an important concept that people knew. I think this is one of the more important slides that I want to show you is, unfortunately we are still at a point where myeloma is not a curable disease, but we have better and better treatments for initial therapy, and so it is really important now we think to try to do whatever we can. After a person is initially diagnosed, and typically a younger or fitter individual is going to be offered a stem cell transplant, that we want to prolong the time that the myeloma is controlled for as long as possible. That circle where the red is, we would like to keep that time period to a number in many years if at all possible. That's really what the goal of maintenance is, whether it's delivered after a transplant like we're talking about or even after standard chemotherapy.

(07:16): The goals of maintenance therapy include decreased risk of early death and improved quality of life. What are the goals of maintenance therapy? Obviously, you are trying to control the myeloma, you are trying to decrease the risk of an early death.

(07:26): We'd also hope that maintenance therapy will enhance quality of life because it will avoid needing to start on more toxic chemotherapy combinations or something like an additional transplant.

(07:40): Ideally, a perfect maintenance would cause no possible harm, and it would also be a reasonable return for investment, meaning that you get more benefits than side effects and harm from it. This is really the ideal drug or drugs that we could think about.

(07:59): Now, Lenalidomide. Lenalidomide is chemically very close to Thalidomide, and this was first studied in the early 2000s. Many of you here may have heard on the media or conversations with others about targeted cancer therapies where a very specific protein is selected on a tumor cell.

(08:21): Probably the reason that Lenalidomide works so well is that it has many effects on myeloma cells as well as what we refer to as the tumor micro environment.  These are the cells that surround the tumor cells that are probably leading to survival of those tumor cells.

(08:40): Lenalidomide affects myeloma cells directly, but it also seems to improve immune function.  Patients will actually, if you test them in a test tube, show that some of their immune cells like T-cells actually seem to function better if they are receiving Lenalidomide than not. This is probably one of the reasons Lenalidomide has turned out to be such a useful drug in the treatment of myeloma because it really has all of these various effects.

(09:09): Definitions of median progression free survival and overall survival. Now, as we're moving along, I want to just define some terms here that are used a lot in medical research just so they are obvious what we're talking about.

(09:19): In medicine, we often speak of the median versus the average, and this is shown in the slides. An average is, you take a list of things that happen or a list of numbers and then you add them all together and divide by the number of items, and that's the average.

(09:36): Now, in medical science, we typically use a median, and that is felt to be more reflective of what's probably happening in actual individuals by selecting the middle event that happens or the middle number events in this series of items. That's what the median represents, and it's often similar to the average as you can see in these examples, but not quite the same thing.

(10:00): Now, we talk about progression-free in a number of types of cancers, meaning there's no evidence of relapse, in this case, of multiple myeloma. A median progression-free survival is when the middle patient in a group has a relapse of their myeloma, that's the time when progression-free survival ends.

(10:20): Overall survival is how long a person lives, whether or not they're in remission.

(10:27): Response in myeloma is defined by at least a 50% reduction in myeloma markers. Finally, in multiple myeloma, we speak of response as being at least a 50% reduction in their myeloma-produced proteins or myeloma-produced light chains. I don't have enough time today to talk about laboratory interpretations, but that's always a big issue for myeloma patients, I know.

(10:47): Lenalidomide as a post-transplant maintenance therapy. Let's turn to the trial that actually caused wide use of Lenalidomide for maintenance. This is the trial that was done here in the United States between those dates 2005 and 2009. This trial included anybody with newly diagnosed myeloma who had had treatments of some sort. The majority of these individuals had Lenalidomide and Dexamethasone as their initial treatment, then they went on to an autologous stem cell transplant. They were then asked to take either Lenalidomide or a sugar pill, a placebo drug. You can tell if we look here on the left, it is labeled progression-free survival, that people who received Lenalidomide had twice the time, almost five years before their myeloma became active, versus those who just had a sugar pill.

(11:38): Now, one of the other interesting things about this trial is that people who were given the sugar pill could receive Lenalidomide later on, they could do what's called a crossover. One of the things that we found out is, it looked like it was kind of important for people to start their Lenalidomide relatively soon after the transplant, so within that six-month time point after the transplant seemed to be important.

(12:03): Now, initially there didn't look like a benefit in terms of just living longer, so you controlled your myeloma longer, but it took this analysis, and this is called a meta-analysis. That's spelled M-E-T-A analysis. What those are is, it's a technique, a statistical technique where you take a number of studies that have very similar setups and then combine them to see if you can find an effect because now you have more individuals, more patients to look at. In this particular meta-analysis that was published about a decade ago, not only did they show that lenalidomide helped keep myeloma in remission longer, but people actually lived longer.

(12:46): On the right-hand side of this slide is what's called a forest plot. If you are heading towards the gray area, a gray arrow, lenalidomide is better than placebo, towards the red, it's less. Lenalidomide maintenance was able to help most people with multiple myeloma except for those who have highest risk myeloma. We'll talk about what that means in just a minute.

(13:13): Another intervention that was done... Lenalidomide was established based on that trial as really what we would consider standard of care, and then a subsequent trial was done here in the US again by a group called the Bone Marrow Transplant Clinical Trials Network. In this trial, people had the same setup, they could have any type of treatment, and within 12 months of that treatment, they underwent a stem cell transplant. That's the Mel (Melphalan) 200 milligrams per meter squared.  Then they were split up, randomized into either just starting Lenalidomide maintenance to receiving extra cycles of chemotherapy, in this case, Bortezomib, Lenalidomide and Dexamethasone, or to receive two transplants, that's what's called the tandem transplant. In each of those extra treatment arms, they then went on Lenalidomide maintenance as well.

(14:05): To everybody's surprise, what happened is that all of the groups did the same, that if we again look at progression free survival, that the percentage of people who were doing well at three years, no myeloma coming back, was equal between all three groups indicating that those particular patients who got the extra treatment, it didn't seem like they really needed to get that, and of course, the extra treatment causes extra toxicity.

(14:37): Now, it is true, however, again, going back to Lenalidomide maintenance, that we're now aware that not every person benefits the same from Lenalidomide maintenance. We're getting a little bit better at figuring out who is going to have multiple myeloma that ends up being harder to treat. This harder to treat problem isn't at diagnosis because often, with just a few exceptions, people respond very well to their initial treatment.  What we're talking about is really what the risk is that a person's myeloma is going to come back again and become more difficult to treat.

(15:15): Now, we know that there are certain factors for a long time that have been implicated in people who have harder to treat myeloma, such as having just a lot of myeloma around. There is a lab called lactate dehydrogenase, if it's high, that's a measure of the amount of myeloma.

(15:33): Cytogenetic abnormalities in multiple myeloma. But more and more we are focusing on chromosome abnormalities in myeloma cells. Now, this slide is showing you a picture of a chromosome, and basically what this is a bunch of nucleic acids, those are shown on the right here, that code for certain genes, and they are then wrapped up in this little sort of bundle here. Those little disks are proteins called histones and they arrange to form a chromosome. Now, we all have 23 pairs of chromosomes as shown here. We have what are called 22 autosomes, and then we each have either XX if we're assigned female at birth or XY if assigned male. The chromosome structure is the top part, is called the P part, and the bottom is called the Q part.

(16:25): Now, when we're talking about these mutations, it's important to recognize we are talking about mutations in the myeloma cells and not in your own normal cells, because I think sometimes people worry when they're told, well, you have these mutations. It's not in your normal cells, it's just in myeloma cells.

(16:45): Chromosome one abnormalities are common in multiple myeloma. We're getting better at figuring out about these mutations and what they may mean. One of the most common mutations that people have in their myeloma cells involves chromosome number one or the first chromosome as it's called. This is a very, very big chromosome, it has lots and lots of genes. About a third of people with myeloma, in some estimates a little bit more, have abnormalities of this chromosome in their myeloma cells. We think one of the reasons why they have that is, people often can have an extra copy of this, there's three chromosome ones shown here, or they have an extra copy of the bottom part. We think that that extra copy makes those myeloma cells able to grow faster than their neighbors.

(17:34): If you think of a foot race, myeloma cells that have this mutation have an advantage in terms of growth and multiplying. If they're missing part of the top part, the P part, that's where what we call a tumor suppressor lives, and tumor suppressors are naturally occurring genes that help put the brakes on growth, and so loss of those genes means that your tumor cells have, once again, a growth advantage. That's one of the reasons why chromosome one we think is so commonly abnormal in myeloma.

(18:05): FISH (fluorescence in situ hybridization) studies are used to identify common chromosomal abnormalities in multiple myeloma. Now, besides doing these chromosome studies, maybe even a better tool is what we call FISH, that stands for fluorescence in situ hybridization, and this is a way of looking at abnormal chromosomes in myeloma cells without doing that very fancy mapping that I showed you, which it takes a lot of time. We look in particular for exchanges of pieces of material between chromosomes 4 and 14, 14 and 16, 14 and 20. That 14 shows up a lot because that involves antibodies, that's the gene encoding for antibodies. That's one of the reasons why it's involved there.

(18:47): Double hit myeloma involves myeloma cells that have more than one mutation. P53 is another tumor suppressor gene located on chromosome 17p, and so when this is lost, again, that means that tumor cells have a growth advantage. We just talked about that 1q, meaning amplified, extra or gains, and then that deletion of 1p, and then now we have a category of myeloma that increasingly is referred to as what people call double hit mutations, meaning that the myeloma cells have more than one mutation, and people who have myeloma cells with two or more mutations, they seem to have more difficult to treat myeloma and myeloma that may come back faster. Now, moving on to lenalidomide approvals.

(19:35): Lenalidomide is the only FDA-approved drug for maintenance therapy. As I mentioned, Lenalidomide is very useful for maintenance, and because of that, it was approved formally by the FDA, by the Food and Drug Administration in February of 2017. More studies have been done since then, including a very large one from the United Kingdom with about 2000 patients that showed even people with higher risk myeloma benefited from Lenalidomide versus placebo. They don't just benefit as much. This is one of the reasons why this is currently the only FDA drug approved for maintenance for myeloma.

(20:15): Downsides to Lenalidomide therapy include cost and side effects.  Now, what are the downsides of Lenalidomide maintenance therapy, because it is a immunotherapy? One of the big ones, as I'm sure many people on this call are aware, is cost. Currently, Lenalidomide in the United States costs anywhere between 18 to $25,000 at the retail level. Some years ago when people were trying to get a little creative in terms of dosing, the move was made to make every capsule cost the same, so whether you get a five milligram capsule or a 25 milligram capsule, which is the largest size, they all cost the same.

(20:52): Some of you may be aware that recently there has been a decision to make lenalidomide generic in the United States, but so far the amount of lenalidomide that is actually generic is a very tiny amount, and it really has not caused any price decreases yet in this country. Some of you may be surprised to know that in other countries around the world, the lenalidomide is maybe 25 to $50 per month, but we do hope by 2026 that we will see that that cost decrease. What that does mean, practically speaking, certainly in my practice is, for some people, Lenalidomide can't be used as maintenance because it's just too expensive.

(21:32): Now, there are also other side effects to Lenalidomide. If you look at people who are not taking Lenalidomide, the risk of infections, these are usually not very serious, infections are about 25% higher. There are GI side effects, and then there are secondary malignancy that can occur. We're going to talk about each one of those.

(21:53):  Diarrhea and gas are gastrointestinal side effects of Lenalidomide that can be managed with low fat diets and bile salt binders such as Colestipol. In terms of the gastrointestinal side effects of Lenalidomide, these are really legendary. Most people will tell you that they will have things like diarrhea, often surprise diarrhea, and they'll have bloating, they'll have bad gas and a passage of gas. This can be quite annoying for people, and sometimes, at least in my patients, has been a reason that people stop the medicine altogether.

(22:19): There are some tricks that you can do to try to make this better, and one is, this is coming from the UK, is to try to consume less fat in their diet. That seems to help, but it looks like bile salt binding drugs, and one of the big ones that we use is called Colestipol. This was originally designed to lower cholesterol, but this drug used either once a day or twice a day can be very helpful for people who have lenalidomide related diarrhea, and in many cases, for my patients, it's eliminated it altogether.

(22:52): Let me talk a minute about a more serious topic here. This is secondary cancers, and this comes up quite a bit these days. Secondary cancers are unfortunately a part of lots of different types of cancer treatments for lots of different types of cancer. For other examples outside of myeloma would be, leukemia can occur and other blood disorders as well after treatment for breast cancer.

(23:20): Secondary cancers have been associated with autologous (auto) transplant in Myeloma. For example, if a younger individual, say, in their teens or twenties, receives radiation therapy to the neck or chest, it turns out that they have an increased risk later in life of developing breast cancer or lung cancer, and unfortunately, children who are treated for cancer also have an increased of new cancers that continue throughout life.

(23:40): Now, specifically speaking about myeloma, and there was just a very large study that's listed here, looking at what is the risk of developing a different type of cancer after an autologous stem cell transplant and maintenance for myeloma? It's about 4%. That is calculated over about 20 years. People say, okay, that sounds like a bad number, however, we know statistically that the risk of a person dying from their multiple myeloma is much higher than that.  Even though that risk exists, and we're trying our best to understand how to minimize that, I think most experts would agree that the risk is worth it to take maintenance and an autologous stem cell transplant.

(24:32): Bortezomib has been used as a maintenance therapy in myeloma. It is often given in combination with other drugs. Now, there are other drugs that have been studied for maintenance in myeloma, one of those in that sandwich in the middle there is Bortezomib or Velcade. This has been used more a decade or so ago before we had some other choices. Bortezomib, as many of you know, can cause peripheral neuropathy, which can be quite debilitating for people. I mentioned that earlier. It has been used as a bi-weekly sometimes or monthly treatment, and it has shown some advantage, but usually it has been given in combination with other drugs.

(25:12): Ixazomib given alone as a maintenance therapy does not show overall survival benefit. Oral Bortezomib, which is Ixazomib, has been studied by itself. It is a once a week pill, which makes it very attractive, however, there have been two large studies when it has been given only by itself that have been kind of disappointing because the overall survival compared to placebo was not better, it was actually inferior, and so most individuals are not going to give Ixazomib by itself unless there is really a need to use an oral medicine.

(25:44):Carfilzomib is used in combination with Lenalidomide for maintenance therapy in patients with high risk disease. Carfilzomib, which also goes by the trade name, Kyprolis, has been combined with Lenalidomide in a number of studies now, most coming from Europe and, particularly in people who have higher risk myeloma. This may be a maintenance strategy that can provide some better control. Now, Carfilzomib is an intravenous drug if you have not received it before or not aware of this, and therefore that means that that is more visits to the clinic. A lot of individuals are a little bit hesitant about offering this just because of the amount of time. But I do think if a person falls into that higher risk myeloma category, particularly with those extra chromosome abnormalities, that it may be a consideration.

(26:30): Anti-CD38 monoclonal antibodies including Daratumumab and Isatuximab appear to improve Progression-free survival as compared to no maintenance therapy. Now, let me turn to antibody drugs for maintenance therapy. Now, anti-CD38 antibodies have become a mainstay of treatment in multiple myeloma both at diagnosis and at relapse, and there are two of them available. One is called Daratumumab, or Darzalex is the trade name, and then there's also Isatuximab or Sarclisa, which is available. These drugs have really shown benefit, particularly when they're used as part of initial treatment for multiple myeloma. I suspect going forward that many, many, many more individuals will receive this drug as part of their initial treatment. But as maintenance, there have been now a number of studies that have examined the use of, in particular Daratumumab as maintenance.

(27:22): They have certainly appeared to improve progression-free survival compared to no maintenance. This should state in newly diagnosed patients who are receiving a transplant, and so I think that it is very reasonable to consider this as a maintenance at this point.

(27:39): Advantages for Daratumumab outside of a clinical trial right now appear to be, you can give it as a monthly or even every two-month injection. It has been tested as a single agent. There's still one consideration is, if you receive an anti-CD38 antibody as part of your initial treatment, will you benefit from it as maintenance as well that that is being studied?

(28:03): One of the things that really helps us in the clinic when we're picking treatments for people is, Daratumumab and Isatuximab are covered by Medicare part B, so that the drug Medicare D coverage that comes up frequently for people when we're thinking about drugs like lenalidomide doesn't come into effect, so it can be quite a bit easier.

(28:26): Daratumumab has minimal gastrointestinal side effects but does have increased risk of infection and decreased response to vaccines as potential side effects. And then of course there are the GI side effects. Those are really pretty minimal with Daratumumab, unlike Lenalidomide. Disadvantages however, are it is apparent that there is an increased risk of infections. Most of these are mild respiratory infections, but there are people who have been receiving things like intravenous gamma globulin, which is an antibody solution collected from donors, and that is sometimes used to prevent that in people who end up having very low normal antibody levels. There is some information, and this was studied when Covid was much more active, that people who have been receiving anti-CD38 antibodies don't seem to have as good a response to vaccinations as those who are not receiving the drugs at the time they're getting the vaccination.

(29:20): It is currently not known if it is possible to stop maintenance therapy in Multiple Myeloma. A really big, big topic going on right now in maintenance is this one, is it ever possible to stop maintenance? Which of course we would all like to know because nobody likes to come in, nobody likes to take medications, it's expensive. I think I've outlined some of the side effects. This is an area of really, I think, very, very exciting research and something that'll probably change.

(29:45):Using Flow Cytometry or Next Generation Sequencing can be used to measure minimal residual disease in Multiple Myeloma. In many, many types of tumors, there is a concept called measurable residual disease or minimal residual disease. We are now starting to try to track for that last little myeloma cell, typically in two different ways. One is by doing flow cytometry, which is a way of passing a blood or bone marrow through a laser and you can identify cells based on the way the laser bounces off the cells, or sometimes we use fluorescence to locate which type of cell we're looking for.

(30:23): There is what's called next generation sequencing where we take genetic material out of the cells in a bone marrow and then we're looking for evidence of myeloma cells being in there. One of the hopes is that if we get to a situation where we are able to... Let me see if I can make this advance. I'm having a little bit of trouble here, sorry about that.

(30:57): Reaching a state of minimal residual disease (MRD) negativity appears to be an important marker to improve progression free survival. There we go. Sorry. This is a picture of an iceberg, and what we're looking for here is that historically we've been able to see the myeloma on the top, but not so much the myeloma that's lurking below. The hope is that if we are able to find that proverbial needle in a haystack shown here, that we will be able to get a point where perhaps we were actually curing some people with multiple myeloma.

(31:29): Again, this is another one of those meta-analyses where we're looking at people on different types of myeloma treatments, and these are in different particular studies, but here the curves grouped on the top showing you again that progression free survival. If your testing shows that you are minimal residual disease negative, your myeloma stays under control longer than if you tend to be minimal residual disease positive. One of the nice things about this study was, it showed that it made a difference in multiple types of myeloma treatment getting to that minimal residual disease negative state.

(32:11): Some of you may be aware that very recently there has been a recommendation to the Food and Drug Administration to start using MRD negativity as an endpoint, as a point to reach in myeloma studies when we're looking for new drug approvals, which might be very important. The importance here would be, it would help you get a drug released to market, released to people to use faster by this minimal residual disease time point or end point rather than waiting for, say, a period of time or in some cases, survival. This is very, very important.

(32:52): 4 drug regimens, including Daratumumab, during initial treatment showed improved complete response rates. Right now, there was a very noteworthy study that was presented in December at one of our hematology meetings and then published shortly thereafter, looking at what's called a quadruplet induction using all of our drug classes, Daratumumab, the anti-CD38 antibody, Lenalidomide, the imid (immunomodulatory) drug, Bortezomib and Dexamethasone versus Lenalidomide and Bortezomib and Dexamethasone followed by an autologous stem cell transplant, and then people either receive Daratumumab with Lenalidomide as maintenance or just Lenalidomide by itself. Again, the study was set up as if you have Daratumumab as part of your initial treatment, you receive it as part of your maintenance. This study compared to what has been the previous standard that RVD with Lenalidomide, that it increased the numbers of complete remission and reduced the chances of progressing when compared at about four years by about 60%, which is pretty big.

(33:58): The other interesting thing that this study did was, if you were MRD negative, meaning that in a bone marrow test two years after treatment, if there was no evidence of myeloma, then people were able to stop the Daratumumab part, and so about two thirds of patients were able to do that, and this is very exciting. Now, they did continue on lenalidomide, and that brings me to one of the next really important studies here, which is the DRAMMATIC study which is going on right now. I hope perhaps several of you in the audience are part of this.

(34:30): Clinical trials are ongoing looking at combination therapy for maintenance in Multiple Myeloma. This particular study is going to, again, just like our other US studies, any type of initial treatment, then a stem cell transplant. Then you're asked to either receive Lenalidomide or Lenalidomide and Daratumumab as maintenance. After two years, everybody undergoes a repeat bone marrow biopsy to look for minimal residual disease, and if you're negative, then people are then going to be asked to either continue their maintenance or stop it.

(34:58):We think that this trial, which nearly has as many participants as it's going to have, probably by the end of the year it will have sufficient participants.  We hope in the next couple of years we'll be able to tell people in general, are you able to stop maintenance or not? We think that this would be a major, major advantage if people can stop everything.

(35:19): Carfilzomib as a single agent has been shown to improve remission time. There’s also a study that was completed out of the UK, again, where they looked at Carfilzomib maintenance just by itself after treatment for relapsed myeloma. This is one of the few studies in relapsed myeloma that looks at maintenance, and they were able to show that this particular Carfilzomib maintenance given for about a year really did keep people in remission longer, and so that is a strategy to consider when people are being treated for relapsed myeloma.

(35:46): T-cell redirecting therapy, including bi-specific T-cell engagers (BiTE) and Chimeric Antigen Receptor T-cell therapies (CAR-T) may be included in future Multiple Myeloma maintenance therapy.

Now, what's coming up in the future? Well, I think everybody thinks that the future for maintenance as well as myeloma in general is probably T-cell redirecting therapy. By T-cell redirecting therapy, T-cells are types of immune cells that are abundant in the body and we think that they are supposed to be natural cancer fighters, but when people develop myeloma, and this is a very hot research question, we don't know really what's happening, whether those T-cells are just not seeing myeloma or they're not in big enough numbers or maybe they've been hurt by other types of chemotherapy and so they really can't be as active as we would like.

(36:30): There are two types of T-cell redirecting therapy. One is called a bi-specific engager, which is shown there on the left. Simply, it's an antibody drug that binds an immune cell by this protein called CD3, a T-cell, but it can be then connected to a tumor cell through a different protein on that tumor cell. Bi-specifics are being used in many, many types of cancer now. Lymphoma is one of the big ones. This is used in leukemias too. These are drugs that we expect to see many more of as time goes on, and these drugs are available right now for relapsed myeloma, which I'll show you in a minute.

(37:09): And then of course there's what's called chimeric antigen receptor T-cell therapy (CAR-T). This is where we harvest T-cells through leukapheresis, through that process where we take an IV and put it in your arm and then we pull out blood cells. We then select out the T-cells, we give the rest of the blood back to you, and then we take those T-cells and we engineer them by actually infecting them with special viruses. This is the most common way to do this. They carry genetic information, and then these cells are re-infused into the body. Essentially they become a living drug. Their ability now is to actually fight the myeloma directly, which is a pretty amazing thing.

(37:55): Three Bi-specific T-cell antigen engager drugs are available for the treatment of relapsed Multiple Myeloma and are currently being tested as maintenance therapy. These include Teclistamab, Elranatamab and Talquetamab. There are three bi-specific drugs approved for treatment of relapsed myeloma. These are Teclistamab, Elranatamab and Talquetamab. Two of them looking for the protein B-cell maturation antigen (BCMA) one for GPRC5D. These drugs are now FDA approved for use in relapsed myeloma, and these drugs are now being tested as maintenance as well. We'll see in the next few years whether these replace drugs like Lenalidomide as being a better way to treat myeloma.

(38:24): Car-T therapy is also being tested as a maintenance therapy in multiple myeloma. Just like that, CAR-T transplants are also being studied as a kind of maintenance therapy as well to either do a CAR-T transplant after a stem cell transplant or to maybe just do a CAR-T transplant by itself with some limited maintenance.

(38:41): Those studies are underway. It's very conceivable in the next couple of years we're going to see a major sea change in how myeloma is treated around the world. Now, I think other people also ask, okay, we're looking at drugs and things like that. What are some other things that you could consider doing to try to help keep your health good and try to keep your myeloma at bay?

(39:03): There is some very interesting information about vitamin D. Vitamin D levels can be low, particularly in people in the northern half of the United States where they don't get as much sunlight, which helps a vitamin D synthesis. Vitamin D is also found in foods like fish and eggs and then it is found in fortified milk. But vitamin D has a lot of different functions in terms of calcium metabolism, it helps insulin work better, it's necessary for growth of babies, it makes your colon work better and it also helps with immune cell function.

(39:37): Low Vitamin D levels may be correlated with shorter remissions and decreased overall survival. There have been some studies that have shown that vitamin D deficiency in people with myeloma made the time that people in remission shorter and there was some worse overall survival. Vitamin D levels are an easy test, a blood test. I don't think you should take this as saying run out and take a lot of extra vitamin D because that's not a good thing. It is something that your doctor could check for you at some point and just make sure your vitamin D levels are okay, and then it's easy to supplement it either with food or another way.

(40:11): It is unknown if diet plays a role in multiple myeloma. Now, what about other types of diet? People ask all the time. I think this is one area where we are really not, or have done not a very good job in studying this. There are people out there now trying to look at whether having less red meat or a more plant-based diet is associated with a less of a chance developing myeloma in the first place, and there's some interesting data about that. Less clear is, if you have myeloma and you change your diet, could you then maybe prevent myeloma from coming back? We really don't know about that.

(40:47): Some studies have shown that increased alcohol consumption is associated with lower risk of developing Multiple Myeloma. Now, a peculiar thing that has come up in a couple of studies, we know that alcohol use is associated with the development of several types of cancer, in particular breast cancer and head and neck cancer and also some GI cancers like esophageal cancer, but oddly enough, a couple of studies from different parts of the world have shown that increased alcohol, now we're not talking about excessive alcohol consumption, has been associated with a lower risk of developing myeloma, which is very peculiar and probably needs to be figured out whether this is real or not.

(41:22): Healthy lifestyle behaviors, including sleep, healthy diet and  social engagement can contribute to better responses in patients with Multiple Myeloma. Now, what about other things that you can do? Well, we do believe that some of the things that are in your control are important for maintaining health, and that would be things like sleep.

(41:33): We mentioned food and having adequate intake, particularly of fruits and vegetables. Exercise is important. This is me just working out at the gym this morning-and then doing things with other people. In this case, these individuals are bike riding. We have very good research data that people who are socially engaged, whether that is with a partner or friends or institutions like churches or clubs or whatever, they tend to do better with their myeloma as well as other types of cancer. Finally, things that give people pleasure have also been associated with an increased chance of your myeloma staying in better shape. I think we should not neglect things like this.

(42:20): There is good evidence that supports maintenance therapy after stem cell transplant in Multiple Myeloma improves time to progression and overall survival. In summary, I think there's very, very good evidence that maintenance treatment for myeloma, particularly after a stem cell transplant, it clearly extends the time before you need a next therapy. It probably, based on the information that I showed you, increases survival. I really think it does.

(42:39): The agents right now in use with the strongest evidence are probably Lenalidomide (Revlimid) and Daratumumab (Darzalex) and I also mentioned Carfilzomib (Kyprolis) In people who have that highest risk myeloma, meaning that they have mutations, more than one present in their myeloma cells at the time of diagnosis. We are increasingly recommending more than one drug at the time they are thinking about maintenance that is, about 10, maybe 15% of individuals with multiple myeloma.

(43:09): Unfortunately, the maintenance treatments that we do offer still are associated with cost and side effects, but we are working on strategies to shorten time on maintenance and perhaps some new interventions that will be very clearly time limited.

(43:26): I want to thank you very much for joining me for this talk today and I will stop here and I'd be happy to take questions.

Question and Answer Sessions

(43:35): [Susan Stewart]: Thank you, Dr. Callander, that was a great presentation, very comprehensive. I know we do have some questions already coming in for you. If you have a question that you would like to ask Dr. Callander, type it into the chat box on the left side of your screen and we'll try to get to as many of those questions as possible. We will start with the first one. Will the recent recommendations for MRD status as a clinical endpoint to be used to determine if and when maintenance therapy can be stopped?

(44:10): [Dr. Natalie Callander]: I think it most certainly will be. As I mentioned that study, the dramatic trial that is being run by something called the Southwest Oncology group, that involves ultimately 1400 individuals, and I think information from this will be used to guide discontinuation of maintenance. I think that the big question is, are we going to have information about how long the time is that you may have before your myeloma becomes active again? Because I think we're still not talking about cure in the vast majority of people yet, but I think most definitely MRD is going to be an endpoint that is now going to be incorporated in most clinical trials.

(44:54): [Susan Stewart]: Great, thank you. Next question is, what is your experience with Daratumumab and Venetoclax for maintenance with T(11:14)? (translocation of chromosomes 11;14)

(45:09): [Dr. Natalie Callander]: Yeah, that's a great question. People who have eleven-fourteen, that's another mutation that you can see in myeloma cells and it's present from the time of diagnosis. What it tends to confer, it means that people are sensitive to a group of drugs that are called BCL-2 inhibitors, and Venetoclax happens to be one of those. Venetoclax has not yet been approved for use in multiple myeloma, and part of the problem has been as there was a very big study done that showed some negative outcomes and I think that's really stopped the development of Venetoclax.

(45:51): But outside of a clinical trial, when people have an eleven-fourteen translocation, particularly at relapse, a lot of individuals are currently using the combination of Daratumumab with Venetoclax for treatment of relapse. I know some of my colleagues have used this as kind of a maintenance. I think that we're hoping to see that there may be some data emerging from this, but as I mentioned, Venetoclax is not FDA approved for use in myeloma right now and that has slowed down the development of the use of this drug. But there are other BCL-2 inhibitors like Sonrotoclax that are in development that may be coming out soon.

(46:33): [Susan Stewart]: Great. All right, the next question is, how impactful is deletion of chromosome-thirteen?

(46:39): [Dr. Natalie Callander]: Yeah, it is not considered that impactful and it is a common one. It is seen very often either by both FISH or by what we call standard cytogenetics. In terms of having presence or absence, it's usually not felt to be one of the ones that we would consider high risk.

(47:01): [Susan Stewart]: All right. This person wants to know what is a reasonable amount of alcohol that can be consumed and not be risky about upsetting myeloma treatment or inviting trouble.

(47:12): [Dr. Natalie Callander]:  Oh, boy, that's a tough question. I mean, like I said, depending on who you're reading about this. If you are looking at breast cancer risk, I mean there's some data that even a single drink daily can have some detrimental effects, but in the studies that I was citing, they were looking at one or two beverages several times per week, certainly not anything excessive. I think that this is always a very tricky subject.

(47:43): [Susan Stewart]:  All right, next question. Upon relapse after transplant, should you immediately undergo another transplant or is there a medication that's okay to take?

(47:52): [Dr. Natalie Callander]:  Well, I think that's a very good question and it also depends, it's a little bit nuanced. Let's say you had a transplant and very quickly had a relapse, say in a year and a half. Most people would say that is kind of a warning sign and different kinds of treatments are indicated other than another stem cell transplant. Of course, one that is coming up now, and that has to do with the recent FDA change in indication would be for CAR-T transplants, that might be an option. A second stem cell transplant, however, if you've had a relapse years later, it's a very good option still I think, at least in my opinion. Some people would still offer newer drugs like those T-cell engagers. The timing and then the risk assessment makes a difference in terms of whether or not a second transplant at that time point would be a good option.

(48:48): [Susan Stewart]: Okay. Do you have any suggestions to help with a Revlimid (Lenalidomide) rash?

(48:53): [Dr. Natalie Callander]:  Yes. Usually, Revlimid (Lenalidomide) rashes are dose related. In most people, I wouldn't say every single individual, if you bring the days of dosing down or you change the number of milligrams, then you can usually get rid of it. For example, when we're doing maintenance, we typically won't give more than five milligrams, 21 days out of 28. We even have some people who are using a 2.5 milligram dose. Every once in a while, I've seen an individual who seems to not be able to tolerate Lenalidomide at any dose, you could then have an option of using steroids once a week. But steroids, as I mentioned briefly have their own issues and so you may not want to do that.

(49:38): [Susan Stewart]:  All right, this person wants to know whether multiple myeloma is hereditary.

(49:42): [Dr. Natalie Callander]:  Okay, great question. There is information that if you have a first degree relative with myeloma, you have about three times the risk that as someone in the general public. Now, the lifetime risk of developing myeloma is pretty low, it's about five in a hundred thousand, meaning therefore your risk becomes 15 in a hundred thousand, so still very low. There are some very interesting screening studies underway right now looking to see whether that question could be answered. One of the issues have been, even in families that have had multiple generations of myeloma, they cannot find the same genetic change in the cells. They cannot say, oh, if we look for this, everybody who has this in their cells is going to develop myeloma. It's been very different from other cancers that clearly have sort of the same genetic change. That would be, for example, something like BRCA1 that is seen in breast cancer. There are types of colon cancer that are clearly hereditary. Unfortunately, we are not there yet with myeloma, there is some increased but small risk.

(50:57): [Susan Stewart]: All right, the next question, what are the signs, even the subtle signs of kidney damage from multiple myeloma?

(51:03): [Dr. Natalie Callander]: Yeah, kidney function is measured usually with two blood tests. One is called creatinine, which is kind of a measurement of how good you are at getting rid of protein or nitrogen out of your blood through the urine. The other is called blood urea nitrogen. A person can feel absolutely fine but start to have some changes in those two numbers that can signal some kidney dysfunction. The other thing that can happen in people with myeloma is, those two numbers can be perfectly normal, but you are starting to have a lot of protein show up in the urine, either as light chains or sometimes as a normal protein called albumin. A person who is concerned about their kidney function should probably have all three of those things examined; your blood urea nitrogen, your creatinine, and probably some tests looking for protein in the urine. If those all are normal then the chances of kidney function or kidney failure being there are really minimal.

(52:14): [Susan Stewart]: All right, thank you. This individual wants to know how often do you see peripheral neuropathy developed after a stem cell transplant when the patient has not been on any drugs that are associated with neuropathy?

(52:27): [Dr. Natalie Callander]: That's a great question. Melphalan is not a drug that typically causes neuropathy, but what I have seen many, many times is that if a person has received drugs that do cause neuropathy, say such as Bortezomib or I mentioned Ixazomib, maybe had  little subtle changes. Sometimes after a stem cell transplant, it gets much worse for a period of time. The people who said, well I had a little bit of tingling now, a couple of months after the transplant seemed to have a lot more neuropathy. Usually, in that situation it tends to get better within six months to a year. The other thing to mention to everybody is, for reasons that are really not clear, there has been association with vitamin B12 deficiency and myeloma. People with myeloma have a higher than expected rate of B12 deficiency. Some of your audience may know that B12 deficiency can cause neuropathy, so if a person has neuropathy that isn't very well explained by other causes, that would be something to check, and that's just a blood test.

(53:35): [Susan Stewart]: Okay. All right, that's easy enough to do. All right, this particular person said her son, who is 26, has multiple myeloma and amyloidosis and she's wondering would the myeloma have possibly caused the amyloidosis?

(53:49): [Dr. Natalie Callander]: In that case, they are probably interrelated. We believe that multiple myeloma and amyloid are caused by abnormal plasma cells. Plasma cells are the cells that make antibodies. What really distinguishes multiple myeloma from amyloid is, in amyloid, the antibodies that are made are incorporated abnormally into material that gets deposited in organs. You can have a person who has amyloidosis as it's called, where they don't have any anemia, they don't have bone disease, but they will have deposits made out of antibodies or pieces of antibodies in all sorts of tissues and they can have a whole bunch of problems related to that.

(54:39): Multiple myeloma, usually the issue is that it's the abnormal plasma cells that are growing in such large numbers they're causing anemia for that reason or causing bone problems by turning on bone cells to chew up bones. People can have both simultaneously and they're usually related, and particularly in that individual at a young age like that, my guess is that they probably are connected by the same type of antibody that's causing that. There are ways to check for that, but at the end of the day, most of the same treatments that are given for amyloidosis are coming from treatment for myeloma. I suspect they would be the same in that case.

(55:28): [Susan Stewart]:  All right, this is a question that's interesting. Are cold-caps during stem cell transplant recommended?

(55:35): [Dr. Natalie Callander]: I think that's a very interesting question. I mean, obviously that is something that has come up in women receiving treatment for breast cancer. Cold caps, for your audience who doesn't know, these are caps that are put on with the idea that if you cool the scalp, you'll keep the chemotherapy from flowing over and affecting the hair follicles. I don't believe this has been tested in large numbers in myeloma. I think there was a small study that I'm aware of. I think there has been some concern about whether or not that might not be the best because as the questioner succinctly a very astutely pointed out that, yes, you do have to worry about myeloma lesions in the skull. We do not routinely look at that, although people have talked about doing that.

(56:24): [Susan Stewart]: All right, and this will have to be our last question, our time is getting short. Does drinking protein drinks or eating yogurt cause protein to increase in my body? My creatinine and BUN counts are fine, but the creatinine to BUN ratio is high. Why is this? Is it something I should be concerned about?

(56:44): [Dr. Natalie Callander]: Yeah. Not knowing all the specifics, besides kidney function affecting creatinine and BUN, there are a whole host of other things that affect it, like medicines that are used to control blood pressure, things that are called ACE inhibitors or ARBs can do this. People who are on diuretics like Furosemide or Lasix or Hydrochlorothiazide can have an increased BUN and creatinine ratio. If your doctor is pretty comfortable with that, that sounds fine. The amount of protein that you eat has some effect on this, but you'd have to really, really load up with protein well above probably a hundred grams daily for that to be likely the cause of it. When people do have kidney problems, often our nephrology or kidney doctor, friends like people to limit their total grams of protein a day from around 60 to 90. There may be other reasons for this individual to have that finding and, again, it sounds like they were reassured that that was okay.

(57:45): [Susan Stewart]: Great. All right. Actually, I think we can sneak in one last question.

 (57:49): [Dr. Natalie Callander]: Okay.

(57:49): [Susan Stewart]: How is MRD measured after stem cell transplant, and at what interval?

(57:54): [Dr. Natalie Callander]: Yeah, right now the studies that I did show the MRD is being checked usually at about day 100 after the transplant and then usually a couple of years after that. Establishing a norm for that still is kind of in its infancy.  Most of the studies are looking for that. As I mentioned, there's two ways that MRD is measured. One is by looking for abnormal plasma cells in the bone marrow aspirate by something called flow cytometry, which a hospital can do.

(58:28): There's more involved techniques where you extract nucleic acids DNA from the actual myeloma cells and then analyze it looking for traces of myeloma cells. This does require that a person needs to know something about the DNA in your original myeloma cells or in some sample that's been done. The most disappointing thing right now, I think for people, is we are talking about trying to come up with peripheral blood tests for minimal residual disease. There are some of those in other types of cancer but they are not here yet in myeloma, but boy oh boy, there are a lot of people working on that. Right now you need to do a bone marrow biopsy to test it.

(59:13): [Susan Stewart]: Great. All right, and with that we will need to close the workshop. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Callander for a very informative presentation, and thank you the audience. You had some wonderful questions and I'm glad you posed those. If we can, at BMT InfoNet, help you in any way, please don't hesitate to contact us. Enjoy the rest of the symposium.