(Guest Lecture): September 2022 - Using REVLIMID as a Successful Treatment for Myeloma Patients with Kidney Involvement

Today's topic is going to be using Revlimid as a successful treatment for myeloma patients with kidney involvement. Lots of doctors that I've talked to are hesitant to treat myeloma patients with kidney involvement with lenalidomide or Revlimid or other drugs that could be potentially harmful to kidney production. In fact, in the past, they didn't do it, and now some do and some don't, and so it can be a complicated topic. I wanted to learn today with you if Revlimid can be used successfully in patients with kidney involvement and hear your questions on the subject. Here to talk to us today is Dr. Mark Brownstein. I wanted to read something that I got off the website for you because I feel like this expresses who he is as a physician, and just show who he is. He says, from a young age, I was interested in science. As a biology major, I was fascinated with the way cells divide and became cancerous. Through a series of translational research experiences, I witnessed how basic science findings could be brought to the bedside and improve patient health. My interest in cancer biology and passion for patient care research and teaching prompted me to pursue a combined MD, PhD degree, and subsequent certification in hematology oncology. Every patient that comes to me has the unique story and individual experience. I enjoy getting to know each person and providing personalized care and treatment options that suit his or her needs. At Perlmutter Cancer Center, I treat people with various types of malignant and benign hematologic conditions, with an emphasis on hematologic cancers. I have a special focus on plasma cell disorders, particularly multiple myeloma, as we know. I also see patients who have iron deficiency, bleeding, and clotting disorders and cancers involving the bone marrow and lymph nodes. We are really looking forward to hearing from you today, Dr. Brownstein, and thank you for taking the time to be here tonight. The time is now yours. Thank you so much, Audrey, for that kind introduction. Thank you for all the attendees for taking the late evening on this Wednesday night to share a presentation with me, where I will talk about Revlimid as a successful treatment for patients with myeloma and the answer to the question you asked, Audrey, is essentially yes, we can use Revlimid in patients with kidney involvement. I'm going to focus my talk primarily on newly diagnosed myeloma where patients may present with more advanced kidney involvement, and we'll talk about the role of Revlimid. Parts of the talk might be simple for some of you, others might be more technical, so we'll try to capture this more sophisticated audience. In our field, we work closely with industry to support many of the clinical trials, including the ones that have brought Revlimid into the clinic. I have done consulting for BMS, which makes Revlimid, but I have no conflicts in terms of this talk, I'm not promoting Revlimid in any way, I'm just going to talk about the data that's publicly available. The goals of tonight are to understand the basic biology of multiple myeloma. Now, many of you may already be familiar with this, but I think it's important to review some of that as it applies to how myeloma affects the kidneys. We'll discuss the implications of multiple myeloma on kidney function in general, and then we'll discuss the actual mechanism of Revlimid. Because when you talk about a drug, you want to know how it works, what the mechanism is, what are the side effects and what are the benefits, what is its efficacy? Then we'll identify where Revlimid actually fits into the therapeutic landscape for multiple myeloma. Let's start with some basic introduction. When we talk about multiple myeloma, it's the second most common hematologic malignancy. As you can see in this pie chart, non-Hodgkin-Lyfoma is the most common hematologic malignancy, primarily of B cells. Plasma cells are terminally differentiated B cells, meaning it's a B cell that's made its journey through developing and then became a plasma cell, as I'll show you on the next slide. These plasma cells develop within the bone marrow, which is the part inside of bones that makes blood cells. They secrete proteins, which we call immunoglobulins or antibodies. I'll go through all of this in more detail. A plasma cell originally was born in the bone marrow as a B cell, and then it goes to the lymph node to get educated. I like to joke that just like college students who get educated, it realizes how good it had it back at home and it returns home back to the bone marrow, where it develops into a plasma cell. Throughout this process, normally B cells, a type of immune cell, are trying to become smarter and educated to fight infection. Now, if they make a mistake and start attacking the body, that can lead to autoimmune disease, so they should die and undergo apoptosis or cell death. But if they make mistakes and the cell does not get destroyed, it can lead to various blood cancers, including lymphomas, or at the end stage of B cell development, a multiple myeloma, which derives from a plasma cell that grows primarily inside the bone marrow. So the protein that's produced by these cancerous plasma cells is an antibody, or we call it an immunoglobin, or Ig. And there's different types of antibodies, and everybody's myeloma might produce a different type, the most common type being something called IgG kappa. So there's a heavy chain, that's this longer part, they're kind of shaped like the letter Y. And then there's these smaller parts, which are called light chain. And some people produce both a heavy and light chain, and some people produce only a light chain. And that's relevant for kidney disease, because the smaller light chains are often the ones that get stuck within the kidneys and can cause kidney damage. So here's an example of a test result we would actually see in a real patient. We do a test called the serum protein electrophoresis, and that gives us a value called the M spike, or monoclonal spike, or monoclonal protein, or M protein. It has different names, but basically what it is, it's the antibody or immunoglobulin that's being produced by clonal plasma cells that are cloning themselves and dividing within the bone marrow. And that's the marker that we actually trend throughout treatment to see that it goes down over time, which correlates with fewer of those malignant or cancerous plasma cells inside of the bone marrow. And then there's a test called immunofixation, which tells us the actual type of that antibody or immunoglobulin that's being produced, because every patient is slightly different. And here's a test that looks at those actual light chain levels. Normally the body uses about 50, 50 of each type of light chain, either something called Kappa or lambda free light chain. But as you can see in multiple myeloma, where you're producing only one specific type, in this case, Kappa, that ratio is very much skewed and elevated. And those light chains can go from the bone marrow where they're being produced through the blood all the way to the kidneys. And that's the connection between how a cancer that occurs inside the bone marrow can actually affect a distant organ like the kidneys. So multiple myeloma is not a cancer of bone, that's a sarcoma. Multiple myeloma is a cancer of plasma cells, a type of immune cell that came from a B cell originally that grows inside the bone marrow where the bone marrow environment nourishes its growth. And these plasma cells produce antibodies, as I mentioned. So if you know those two essential features, you can understand all the symptoms, sometimes called Crab, that result from this disease. So as those plasma cells kind of invade into the bone locally, they can leach the calcium out of the bone and that can increase the calcium. They can affect the normal bone marrow function to produce blood cells like red blood cells and that can cause anemia. And those proteins that it produces can go further into the kidneys and irritate the kidneys and that can cause kidney involvement. So if we put a bar graph of what are the most common symptoms that patients present with, because this is a heterogeneous disease where some patients may be asymptomatic or others might have pain from a bone lesion, others might be symptomatic and have fatigue from anemia, or patients may present on their laboratory workup with kidney failure. And I'll explain how we do that laboratory workup further in the talk. So anywhere from 20 to 50% of patients may present with renal failure. And when we see a person who has kind of unexplained anemia or bone pain or renal failure, multiple myeloma is always on the list of possibilities. The most common presentation is usually someone with a mild anemia and maybe some bone pain. So let's get a little technical because again, I want this audience to be educated. And again, the importance of understanding the basic physiology will be helpful in understanding how it goes wrong down the road. And I appreciate all the resources that the health tree has to offer because a lot of them are very sophisticated. And so I think this will add to the education of patients. So everybody pretty much has two kidneys. Some people may be born with congenital absence of one kidney, but most of us have two kidneys. And the way they work is the blood comes in here and then the blood gets filtered through something called a nephron. It's basically a series of tubes. And anything the body wants to keep, it gets kept back in the blood. And anything that it wants to release, any of the byproducts of normal metabolism get released and they go through this final tube into the renal pelvis. And that goes out into the bladder and we excrete it through the urine. So if you do a cross section through the kidney, you'll see all these healthy, beautiful little tubes that have nothing in the center. And that's where the byproducts would pass to eventually into the urine. So in the next slide, I'll show you, you'll see how that gets affected in multiple myeloma. So how are the ways that the kidneys can be injured, all these little millions of nephrons can be injured in myeloma? Well, the most common injury is something called cast nephropathy. If you think of how a cast is made, or if you ever mix flour and water, it kind of becomes thicker. So as you add more of those antibody proteins, it like thickens the inside of those tubules. It's kind of like when you get hair clogged in the drain at home. So it kind of thickens those tubules and then it backs up and irritates the kidneys. And that's due to the proteins, usually the light chains that are produced by multiple myeloma. Myeloma patients sometimes present with high calcium or can be dehydrated due to that high calcium level, or they may be using NSAIDs like ibuprofen because of pain and they don't know they have myeloma. And those things can impair the blood supply to the kidney and further irritate the kidneys. Lastly, perhaps a little bit less common is where the light chains or the antibody proteins not only affect the inside of the pipes, but the actual tubes themselves. And that can lead to deposition of those antibody proteins within the pipes themselves in the kidneys. And that can be in the form of something called amyloidosis, which can co-occur with multiple myeloma or heavier light chain deposition. Again, where these antibodies are not just going in the tubules, but actually affecting the tubes themselves, as well as something called monoclonal gammopathy of renal significance, which is again where the plasma cells are producing these proteins and it's affecting the kidneys. So let's get a little bit even more sophisticated and don't get frightened by this complicated slide. It'll all make sense. So again, here is an example of one of the millions of nephrons or filtering tubes that occurs in the kidneys. The blood comes in, goes through something called the glomerulus, which is sort of like a mesh if you've ever kind of filtered out food through like a sieve at home. And all the products that the body is gonna get rid of go through these tubes. So in the beginning, some of the proteins that the myeloma makes, let's say the light chain shown in green, some of that will get reabsorbed. But when you overwhelm that reabsorption mechanisms, the light chains are just gonna continue to pump through the kidney into the later part of it called the distal tubule. And it will bind some transporter proteins there that is like the flour and the water mixing together and forming like a clump. And those are the cas that we're talking about in something technical called casinopropathy, which is where those antibody proteins that are being pumped out from those plasma cells are really kind of clogging up the kidneys. Now contrast that prior slide where we saw all those beautiful tubes with this slide of a kidney involved from myeloma, where you see all those clumps inside of the tubules, and we call those cas. And those are those antibody proteins that are clumping together in the tubules of the nephron in the kidney and ultimately leading to kidney irritation. Sometimes when those proteins continue to pass into the urine, we call that Benz-Jones protein area because the body can't reabsorb it because there's just too much of those proteins pumping out of the plasma cells. So how are we gonna treat this? Just wanna check the chat. Should I go ahead and answer some of these questions, Audrey, or keep going? No, we're good. I don't think there's any questions. They were just sharing where they were from. I don't know if you see questions directly, but I don't see any questions. Yeah, there's a question, how reversible is Casnopropethia like chain deposition, which is a really good question. We're gonna talk a little bit about that later in the talk. The answer is it is reversible as long as you try to reverse it early at diagnosis. So let's talk about treatment. So I think many of you may have seen this kind of typical patient journey. Sometimes we call it the myeloma marathon because myeloma sometimes behaves like a chronic process and it's more of a marathon than a sprint. So there's this at the Y axis here is the sort of level, the activity of the disease, the level of that monoclonal protein in the blood. And on the X axis is over time. So all patients with myeloma will progress from an asymptomatic phase, meaning they don't have any organ involvement. And that can be either MGUS or smoldering myeloma, which is a little bit more accelerated from MGUS. And eventually the disease will present with one of those crab symptoms I spoke about where they may have kidney involvement or anemia or et cetera. And we'll treat that and we'll lower the burden of the disease to achieve remission that might include chemotherapy, it might include immunotherapy, it might include transplant as I'll speak about. And then we try to achieve this remission for as long as possible where patients can have a good quality of life. They'll come into the office, we'll talk about their grandkids and they'll be pretty much asymptomatic. And then they may start having an uptrend in some of those proteins or worsening kidney function or anemia. And we'll have to try to achieve another remission. And so the disease tends to go through these relapsing and remitting courses. So the idea of treatment is to try to combine our best therapies as early as possible to drive the disease into as deeper remission, meaning remove as many of those plasma cells as possible so that there's no damage to any of the organs as a result of the plasma cells invading into bone or secreting some of those antibiotic proteins. So this is the general approach to treat multiple myeloma in 2022. The first question when someone is initially diagnosed is the patient going to eventually go for a stem cell transplant or are they too frail or perhaps of advanced age? And that's a moving target, that's a moving number. That is no specific number, but advanced age or just not interested in a stem cell transplant. So we generally divide those patients primarily based on a series of measures of how frail or robust they are or how many medical problems or whether there are other medical conditions or controlled or not. And so if they are going to go forward with a stem cell transplant after initial therapy, which we call induction, then they would get a three or four drug regimen upfront that might include Revlimid and then go for the transplant and then maintenance therapy, which also often includes Revlimid and then subsequent therapy as needed on relapse. If someone's not eligible for transplant, Revlimid still often plays a role in a two or three drug regimen. And that's typically continued until progression and then the cycle continues as I showed you on the last slide. So this may seem like a very busy slide, but it's busy in a good way because it shows the progress we made. Each of these landmarks in the timeline is a therapy that was approved to treat myeloma. Now it's not drawn to scale because this is from 1960 to 2000, there are only a few tick marks here. You see all the progress we've made in the past two decades with so many new treatments to treat myeloma. So I'd kind of broken these up into sort of eras. The first was of using the chemotherapy we had to treat any other cancer and bring it into myeloma and to try to decrease the burden of those plasma cells. And then we introduced stem cell transplant in the mid 80s. But then along came drugs like Revlimid or lenalidomide and it's other agents in the class like thalidomide or pomalidomide. Those are all drugs we call immunomodulators or imides as I'll speak about later in the talk. As well as proteasome inhibitors like Bortezomib or Velcade. And now more recently, immunotherapies like daratumumab which was the first antibody therapy for myeloma. As well as more recently in the past year or two, chimeric antigen receptor T cells or CAR T cells which are cellular therapies that use T cells which are part of the immune system to attack the myeloma. So we're not gonna go through all the slide but this is sort of a menu of the different drugs that were used to treat myeloma. And we're gonna primarily focus on this class of immunomodulators, particularly lenalidomide also called Revlimid. So you can imagine if you are going to design a treatment for multiple myeloma, you'd want to design one that's not going to really affect the kidneys. Because as I said, 20 to 50% of people are going to present with kidney failure. And as Audrey mentioned, there are some oncologists who may be hesitant to give Revlimid if someone has kidney involvement. So fortunately, as you can see here of the various drugs used to treat myeloma, the majority of them that are not highlighted in yellow do not require adjustment for kidney dysfunction. It's really Revlimid that requires adjusting the dose at diagnosis and then later on if there's still kidney involvement. But the majority will not require adjusting. The other one of note is exacimib or ninlara which is a cousin of Velcade that's oral and requires slight dose adjustment for kidney failure as well as zoledronic acid or Zometa which is a bone strengthening agent that does require dose adjustment for kidney involvement. But the vast majority do not, which is great because it makes it much easier for us and the patient to tolerate therapy when they have kidney involvement. So here's kind of a sciencey figure of the structure of the image or immunomodulators. And you can see they're all very similar. This here is Revlimid or lenalidomide in the center. And there's actually a newer class of immunomodulators that are not yet approved but likely to be approved called cell mods such as ibertamide, which have a role in overcoming resistance to the original class of immunomodulators. But they all have the same similar mechanism. So inside of the plasma cells, there's a target of these drugs called cereblon. And the purpose of this protein called cereblon is to target other proteins for destruction when the cell doesn't need them. It's kind of like the person who takes out the trash. The purpose of cereblon is to move proteins that the cell doesn't need into the trash and destroy them. And so Revlimid activates this protein which goes ahead and destroys proteins that are active in the myeloma cell and drives its survival. So by destroying those proteins, by activating cereblon, it leads to a decreased survival of the plasma cell as well as production of certain signals that are now going to be secreted by the myeloma plasma cell to stimulate other immune cells to destroy it. And that's why it's called an immunomodulator because not only does it cause the myeloma cell to be less capable of surviving, but also stimulate other cells of the immune system to go and attack the myeloma. But there are various other features of Revlimid or lenalidomide that make it effective. For example, it can affect blood vessel growth. Now, lenalidomide or Revlimid is a derivative from thalidomide, which you know causes birth defects. And the way it causes birth defects is that it affects blood vessel growth during a fetal development. So if you look in the bone marrow of multiple myeloma, if there are all these blood vessels, as you treat with Revlimid, you can actually see a decrease in those blood vessels as shown in this experiment. So there are multiple functions of Revlimid, including on the myeloma microenvironment, which is the neighborhood in the bone marrow around which the plasma cells grow. And Revlimid also decreases the function of bone destroying cells, and that helps heal the bone. So the short of it is that Revlimid remains a mainstay of myeloma treatment. It was approved since 2006. It acts synergistically with other agents that we combine to treat patients. Synergistically means that one plus one equals three. Basically, when you combine two agents, the effect is greater than the effect of each individual agent alone. And it's a standard part of most induction regimens that many of the patients on the webinar today have likely received, such as Revlimid and Velcade and dexamethasone or daratumumab, Velcade, et cetera. So it's really the mainstay of upfront treatment, and it's the established agent to use as oral therapy for maintenance after transplant. And even patients who are refractory, meaning they've stopped responding to Revlimid, that may predict shorter responses to future agents. Although with the new drugs that are coming out to treat myeloma, we can usually extend that survival even further, despite being refractory to Revlimid. How about the, before we talk about the efficacy, how about the potential side effects? So we know that most of the drugs used to treat multiple myeloma have some impact on the normal cells that are in the bone marrow, like the white blood cells. So sometimes we may dose reduce or dose modify due to that side effect. It can sometimes cause a skin rash, and we try to suppress that with topical agents or dose modification. It can sometimes cause swelling, we call that edema. Patients who are on Revlimid need to be on a blood thinner, either like a baby aspirin or a full dose anticoagulant, depending on certain factors in their history. Fatigue is common with myeloma, either due to the disease or due to its treatment, but can occur with Revlimid. Some patients may have diarrhea, some patients may have constipation, or some may have neither. It varies by patient with Revlimid. It modifies the immune system as does the disease itself. So sometimes you can develop infections. And there is a risk of secondary cancers, meaning other cancers that develop, most commonly skin cancers that are treatable, but it can happen up to 4% of patients at three years. So there is an effort to look at how long we keep patients on these therapies, for example, in the maintenance phase after transplant, to try to derive the most benefit, but also limit the risk of longer-term side effects. So in the last kind of half of the talk, I wanna get technical because I think in order to understand kidney involvement in myeloma, you have to understand how we as physicians communicate about kidney function. So I think everybody is aware that the kidneys work to filter out some of the toxins in the blood. So they also have other roles like balancing our bodies pH and electrolytes. They also produce a hormone called erythropoietin that stimulates the bone marrow to make red blood cells. Sometimes we use that in myeloma patients to help boost their red blood cell count. So the way we communicate kidney function in myeloma is something that's either called creatinine clearance or glomerular filtration rate. And it's a way of discussing how functional a patient's kidneys are. And it's calculated based on a laboratory value of the creatinine, the patient's age, their sex and their weight. And so lower values of the creatinine clearance or GFR are associated with worsening kidney function and less filtering capability. And we can stage patients based on this number. So the normal glomerular filtration rate or GFR is roughly 120, but when it becomes less than 90, we call it stage one and various gradations down to end stage renal failure where patients may need dialysis. So the good thing about Revlimid is, and somewhat unique to other medications we use for myeloma is that there are many, many modifications of the dose as well as the dose frequency. So there are gradations from the 25 milligrams, which is the maximum dose, all the way down to 2.5 milligrams with everything in between. It can be given once a day. And sometimes we give that as maintenance or 21 days on and seven days off or 14 days on and 14 days off, depending on the regimen. And so the dosing though is based on that GFR value I mentioned, based on the creatinine clearance. We may also dose modify a little bit lower for patients who are on the older age end of the spectrum because they tend to be a little bit more sensitive to the side effects of Revlimid. So if I see a patient over age 75 or 80, I may not start at that maximum 25 milligram dose. I may start at 10 or 15 milligrams and move the dose up as tolerated. And you can see, and this isn't something we're gonna necessarily go through, but you can see there are various gradations based on that GFR level for each individual patient's kidney function to dose reduce as the kidney function becomes a little bit worse. So what happens then if someone presents with newly diagnosed multiple myeloma with very poor kidney function? So the key is really to intervene quickly to reverse that kidney function. Because if you can do that, you often have a chance at achieving long-term renal recovery of their kidney function. So in this case, we may not give Revlimid immediately with the first cycle of treatment. We may give something else called cyclophosphamide, which is a kind of traditional chemotherapy that's friendly with the kidneys. And there's a regimen called CyBorD or cyclophosphamide, belkaid, and dexamethasone that will often give a cycle of first. And you can see here, this is an actual one of my patients. They presented with a very high creatinine or very low glomerular filtration rate. So I didn't want to start Revlimid yet because it could impair that further. But once their kidney function improved, and you can see that correlated with the levels of their M protein from the myeloma, then we reintroduced belkaid into the picture and removed the chemotherapy called cyclophosphamide. And this study is representative of many other studies where when someone presents with kidney function, the best way to improve that initially is not necessarily to give belkaid, but to give a proteasome inhibitor like belkaid. And that's the dotted line here, rather than giving the amino modulators like Revlimid, which are shown in these other bars, because that can impair the rate of recovery of the kidneys. And so a common question that patients will ask, well, Dr. Brownstein, I'm getting only the five milligram dose of Revlimid. I want the 25 milligram dose, but I can't get that because my kidneys can't handle it. Is that going to lead to worse outcomes? But there are various studies that have looked at that, including this phase two study, which is called the RevLight study. They took 404 patients. About half or so got the full 25 milligram dose with dexamethasone, a steroid. And the other half or so got 15 milligrams, so slightly reduced dose, depending on their kidney function. And when they looked at various indices, and what you're looking at here are these kinds of survival curves. And basically the lower you are on the curve, the more you progressed or patients succumb to their disease. The blue bar is the higher dose of the RevLight and the red bar is the lower dose. And you can see that whether you're looking at the time to the next therapy or progression, or even the survival, life and death, there was really no difference between these curves, meaning there was no difference in outcomes. But when they did look at these two groups according to their glomerular filtration rate, either above or below 60, there was a difference in terms of survival. So it wasn't the effect of RevLimid so much, but it was just their overall kidney function and ability to tolerate future therapies that made the difference. So dose reducing the RevLimid does not necessarily lead to worse outcomes. So I'm gonna focus the rest of the talk for the next few minutes on really the newly diagnosed setting, because this is where the kidney function might be really most impaired when the person has the highest burden of myeloma. So we're gonna start with a study that was affectionately called the FIRST study. And it was a randomized study, meaning some patients were randomized to one arm or some to another. They took more than a thousand patients with new myeloma who were not planned to go for transplant. And they were allowed to have renal impairment, but not beyond dialysis. And some patients got RevLimid and dexamethasone until progression. Some just got it for 18 cycles and stop. And others got a more traditional therapy of melphalanine, prednisone, and thalidomide. So they compared these groups. And what they found again in this survival curve, which is looking at how many patients eventually needed the next therapy, fewer patients needed more to move on to another line of therapy if they got the continuous RevLimid therapy compared to the other arms. And when they broke this down by subgroups, the patients who had higher GFRs or creatinine clearances did better with RevLimid than with the other therapies, suggesting that RevLimid is very effective, even in patients with reduced kidney function with creatinine clearances as low as 30. The ones who had creatinine clearance less than 30 did not necessarily do better with RevLimid. So how about this common regimen we use called RevLimid Velcade dexamethasone or Velcade RevLimid dexamethasone. Sometimes we call it VRD or RVD. So this study called the SWOG study randomized patients to the three drug regimen of RevLimid, Velcade, and dexamethasone compared to RevLimid and dexamethasone alone. And then everybody got RevLimid and dexamethasone maintenance. And patients were allowed to have kidney failure as low as a GFR of 30. Remember less than 15, those patients usually need dialysis. And what you can see here in these survival curves, red is the patients who got the three drug regimen and blue is the one who's got the two drug regimen. And there was clearly an improvement in the time to next therapy or overall survival in the patients who got the three drug regimen. And that's how this study sort of established the three drug regimen of RevLimid, Velcade, and dexamethasone for newly diagnosed myeloma. Then along came more recently in the past year, daratumumab, which was the first monoclonal antibody therapy that targets something on plasma cells called CD38. And the investigators tried to see if we could substitute the Velcade for daratumumab. So this study, which looked at patients who weren't intended to go for transplant called the MYA study, where they were allowed to have kidney dysfunction, but again, they had to have a creatine clearance or GFR greater than or equal to 30. And they randomized to the three drug regimen of the antibody daratumumab with RevLimid and dexamethasone compared to RevLimid and dexamethasone alone. And again, the outcomes were significantly better in terms of the time until next therapy with the daratumumab, RevLimid, and dexamethasone. And that benefit held true even for patients with reduced renal function. Now there's been no study to date that's compared Velcade, RevLimid, dexamethasone, the daratumumab, RevLimid, and dexamethasone. So for patients who are not intended to go for transplant, we may advise one or the other. And finally, there's a newer regimen that's still being investigated of four drugs. And this is intended for patients who are a little bit more robust and plan to go for transplant, where they're looking at daratumumab with that VRD regimen compared to VRD alone. And that includes transplant and maintenance. And what you can see is, again, with the four drug regimen, there seems to be an improvement in time until next treatment or progression free survival compared to the three drug regimen. And when they looked at minimal residual disease, which means if it's absent, that means you've eradicated as much myeloma as possible. There was a better reduction in minimal residual disease with the four drug regimen compared to three. And for our newly diagnosed patients at NYU who are fit for transplant, this is the preferred four drug regimen that we use. And lastly, just wrapping up the talk, we talked about maintenance after transplant. The idea of maintenance is to try to prolong the remission after transplant. And this has been shown in studies that are called meta-analyses that have combined various other studies, that when you give lenalidomide or Revlimid maintenance compared to just a placebo, it does prolong survival, both time to next treatment and overall survival. So it's sort of the mainstay of maintenance after transplant. And I imagine many of the patients on this call have been on Revlimid maintenance. We're not going to go through all the various studies of the relapse and refractory myeloma, but suffice it to say that Revlimid inclusion in various combination studies has always shown to improve outcomes in three drug regimens compared to two drug regimens, even in patients with reduced renal function. So the last couple of slides, we still don't know though, which is the best maintenance regimen after transplant or just for patients who have finished their initial induction and going to the next therapy. So there have been a number of studies that remain ongoing that are looking at, can we do better than just Revlimid alone? Can we add a proteasome inhibitor with Revlimid? And there's a study called the Forte study that did show that combination maintenance with Revlimid does seem to do a little bit better than with Revlimid maintenance alone. And there are various, in the interest of time, I won't go through all of these, but there are various innovative studies that are looking at combining immunotherapy with Revlimid or even discontinuing Revlimid maintenance based on the patient status of minimal residual disease. And Revlimid continues to be included in upfront studies of novel agents, like I showed you in the study of DRTumorMap, RBD upfront for transplant eligible patients. So I really hope this talk was educational for you. I tried to include some technical elements of how we discuss kidney function and how we use Revlimid, but the conclusions are that kidney impairment is something we have to take very seriously, especially upfront in myeloma, because it can impact the prognosis and it can impact the quality of life, especially if someone ends up on lifelong dialysis after diagnosis. So you really have to be attentive to this at diagnosis and intervene quickly. When we think of catching myeloma early, it's really about catching it before it causes end organ dysfunction, like kidney failure. And as I've shown you, Revlimid really remains a mainstay of most regimens that are used to treat myeloma. It's very effective. It can be used in patients with kidney impairment, although we may reduce the dose. And ongoing studies are exploring the place of Revlimid as maintenance therapy, but it does remain as a mainstay of treatment. So with that, I'll just say thank you. This is some of my colleagues at the Perlmutter Cancer Center and my mentors, Dr. Davies and Dr. Morgan. And I wanna thank all our staff, our fellows. I serve as our fellowship program director and the future is very bright, I can tell you that much. But I also definitely wanna thank our patients and their caregivers who really inspire me every day to continue doing what I'm doing. And thank you all for attending. With that, I will take questions. Awesome, Dr. Brownstein, thank you. I think I'm seeing this in the chat and I would just like to say, you sure have a talent for presenting. That was excellent. We've done. Thank you so much. I think it was very clear. You explained it very well and you went into complicated matters in a really explainable way. That was really impressive. So thank you. Thank you. I received questions before the event and there's also awesome questions coming in. So I'll kind of toggle between the two of them. However, I know you did get a question that I don't see. So let's start with that one so that I don't forget it. I think it was how reversible is casting a property that position. Basically the question is how reversible is the renal impairment that occurs from multiple myeloma. So again, the earlier you intervene before there's more clogging of those tubules, the better. In the case of light chain deposition or amyloidosis, it's sometimes harder to reverse because it's not just that the tubules are clogged up and you're gonna try to unclog them, but the actual cells of the kidneys are impaired because the light chains are depositing into the kidney. So sometimes that's more difficult to reverse. I think if someone is on dialysis, sometimes we can reverse that and get them off of dialysis, but you really have to intervene early from their diagnosis as soon as they present and get them on treatment to lower the burden of those antibodies in the blood. Yeah, so let's, Doug, if you don't mind me asking your question here, he has been a multiple myeloma patient for over 10 years. He had GFR typically between 20 and 40 and finally got into remission with CAR-T two months ago. You know, when a myeloma patient's been this long under therapy, can they expect any recovery of kidney function? Well, thank you, Doug, for sharing your story and for your question. So if someone has long-standard kidney dysfunction, it's less likely that they're going to recover to normal kidney function where they were before the diagnosis, but that doesn't mean they won't achieve some improvement enough to tolerate essentially any therapy, because as I mentioned, most therapies are not going to affect the kidneys. So if someone has chronic kidney disease from multiple myeloma, they may not improve to have normal kidney function, but there is a good chance that they will recover some of their kidney function, provided that you dose adjust the Revlimid if they're going to get that initially appropriately based on their kidney function and be very aggressive about avoiding toxins that are going to affect the kidneys like ibuprofen or other medications. So I will often collaborate with a nephrologist who's expert in kidney function in order to make sure I'm optimizing all their other medications to protect the kidneys. Yeah, thank you. A question that was submitted was how often do you see patients who begin myeloma treatment on diet, they're already on dialysis, not because of other issues, but because of the myeloma affecting their kidneys. How often do you see them being able to recover and get off of dialysis when the myeloma treatment starts working? Right, probably somewhere around five to 15% of people will require dialysis when they present with kidney failure. And about half of those patients will eventually come off of dialysis and it really is phenomenal to see that when we are able to take patients off of dialysis and keep them off of dialysis by being attentive to their kidney function and treating them early. But again, the key is really to decrease the burden of disease quickly. Sometimes, and it's debatable, sometimes we'll do something called plasmapheresis where we'll quickly try to remove those light chains by filtering them out of the blood and then targeting the plasma cells with treatment. But there's some controversy about how effective that is. But again, the key is that even if someone is on dialysis when they're first diagnosed because their glomerular filtration rate is so low, there is a possibility of getting them off of treatment provided you can intervene once you identify that. Interesting, thank you. Sherry's wondering if a patient has complete response following stem cell transplant, and this is where you're gonna have to help me. Proteinuria reemerges, all other labs are fine. Would you recommend a dose reduction of Revlimid in this type of patient? Well, thank you, Sherry, for your question. So I think there's two parts to that question. One is, do we dose reduce Revlimid at all after transplant? And the answer is generally yes. The purpose of maintenance therapy is, again, to prolong the remission after transplant, but also in a way that's well tolerated. We don't wanna cause excessive toxicity that's going to compromise someone's quality of life in the maintenance phase. So the maintenance dose of Revlimid is generally less than the initial treatment dose, although it might be given more frequently, like once a day. So if someone has achieved a good remission after transplant, like a stringent complete remission, or their minimal residual disease negative, which is as good as a remission as you can get, it may be reasonable to even stop the Revlimid after transplant. And there are ongoing studies actually using minimal residual disease to guide whether we can stop Revlimid whatsoever. But I think I feel a little bit more confident about dose reducing the Revlimid as needed if someone's having side effects during the maintenance phase, if they've achieved a very good remission after transplant. But I wouldn't necessarily base the dose on their remission status. I mean, assuming most patients will have some form of remission after transplant, but whether they had a very good remission or a complete remission or an MRD negative remission, I wouldn't necessarily adjust the dose of Revlimid based on that. Right, that makes sense. Another question that I got, does a patient ever experience all crab symptoms significantly or do the heavy majority just manifest in one crab area? This was because it seems like some patients have bone, super bone involvement, other patients with this kidney failure, others significantly anemic. Is there ever a poor person that has to experience all of them? And then also, if you could explain kind of, well, I don't know if you know the answer to this question, but why, why do people manifest in different ways? Yeah, really great question. This is a very dynamic disease. Not only does it present in various ways, every individual patient is different. The genetics of their myeloma might be different, although there are some commonalities that can be found. So it really depends on several factors, how quickly they progress from a precursor phase, the status of their myeloma genetics, which drives the plasma cells to become more or a little bit less aggressive, and how long the disease has lingered and how long it's been undetected before presentation. And because it's so dynamic, primary doctors or even oncologists may not detect it so early until there's a clear sign that this is multiple myeloma. So a lot of people at a, myeloma presents at a median age of 69. A lot of people in that age group may have a mild anemia or may have back pain, and it may not be recognized that it's multiple myeloma. So patients do not present with all four crab symptoms. And if they do, it usually signals a slightly more aggressive presentation based on their genetics having more aggressive mutations. But most patients will present with either anemia or a lytic bone lesion, but not all four crab symptoms. In order to have a high calcium level, you usually have to have pretty substantial bone involvement or like lytic bone lesions that are leaching the calcium out of the bone. And you have to have a pretty high burden of plasma cells in the bone marrow, meaning like 50 to 100% of the bone marrow is replaced by plasma cells to the point where those proteins being produced by that heavy plasma cell burden are affecting the kidneys. So most patients will not present with all four crab symptoms, but when they do, it's pretty impressive. And again, a reason to kind of really intervene quickly. Yeah, thank you. Judy explains the need for advocacy. She shares her sister's story. She was diagnosed in 2005 with kidney failure and has been on dialysis ever since. It's worse than the multiple myeloma and treatments. And just there's so much need for advocacy. And honestly, that's one of the reasons why I wanted to get this community together. Lots of patients that are experiencing kidney involvement aren't qualified for clinical trials, or there's other painful problems presented that need advocacy and proper education. And I hope that together, as we combine our stories as a community, we can use those as a form of advocacy for treating physicians and other organizations and nurses and things so that we're able to spread awareness and make appropriate changes. So thank you, Judy, for sharing that. Doug followed up with saying, but the things that you said about Revlimid also be applicable to pomelist and newer cell mods. We actually just had an event about pomelist last night. So I'd be interested to hear your take on this. Yes, so these cell mods are very similar to the immunomodulators like Revlimid. Their side effect profile is remarkably similar, but the benefit is that they have been shown to be effective even in patients who were no longer responsive to Revlimid or pomelist, the currently approved immunomodulators. And they're also synergistic with other myeloma drugs like daratumorab. So definitely, I think they will gain approval within the next year with any luck. I mean, we've been involved in some of the trials that have looked at the cell mods and they're very familiar based on their side effect profile, very similar to the drugs like Revlimid, but they have a slightly different binding target on that molecule called cereblon that allows them to overcome resistance to Revlimid. So I think- Are there still the same concerns? Sorry if I'm interrupting you. Are there still the same concerns for patients with kidney involvement? Is there still dose reduction needed of cell mod? Yes, it's very similar to Revlimid. There would be a need for a dose reduction. And with pomelist, that's not true because it's processed through the liver. Is that true? It is true that pomelist doesn't require a dose reduction like Revlimid does. It's really just Revlimid. So if someone does have kidney dysfunction in the second line setting or beyond, we often do not have to dose reduce the pomelist. Interesting. Thank you. Jeff says he was on Revlimid and Velcade maintenance for several years. He had to get a pint of hydration prior to a shot of Velcade and was told that's because Velcade was difficult on the kidneys. Is that correct? So thank you, Jeff, for your question. No, Velcade is fairly safe with kidney failure because it's not metabolized through the kidneys like with Revlimid. And in fact, that's why we're showing early in the talk that we often use it upfront for patients who present with kidney failure. Now it is possible that you can get dehydrated during your treatment and that could irritate the kidneys. And you might need that hydration, but it doesn't necessarily impact the kidneys. Right, thank you. Greg is saying he was not aware of renal function issues due to myeloma but had a tumor on his kidney that was found during a CAT scan, has recovered and is going in for a stem cell transplant next week. Should he talk to his myeloma doctor about scheduling GFR tests going forward to see how kidneys are doing because of that tumor? And then should they also discuss adjusting Revlimid maintenance after that stem cell transplant? Yeah, thanks for your question, Greg. I actually had a patient who presented with a kidney mass that turned out to be a kidney cancer, but incidentally there was a mass on his spleen and it was a plasma cytoma and he turned out to have multiple myeloma. So again, this disease can present in varying ways. Anytime you have your blood drawn, they'll usually draw the creatinine level which is used in the blood test to calculate the GFR. So it's not really that you have to schedule special tests to check the GFR. It's a routine test that's typically done on all blood work. But I'm sure that your transplant, I do stem cell transplant myself and I'm sure your transplant team is looking at your creatinine level, looking at your GFR and dose adjusting the chemotherapy even that's given with a stem cell transplant based on your GFR level. But it's definitely something to discuss, especially if you've had one or part of one kidney removed, it's important to discuss your kidney health with your oncologist and your transplant team. It will be a good way to impress the healthcare physicians. Right. I'm here to talk. Don't tell them. We talked tonight. Cindy's wondering, did she understand right that Kappa generally tends to have more kidney damage than Lambda patients? Great question. No, not necessarily. There tends to be a Kappa predominance, just I'm not clear why, but there does seem to be a Kappa predominance both in amyloidosis and in multiple myeloma. But no, they're both similarly sized and they can both impair the kidney. So there's really no impact of one or the other. Yeah, unfortunately, the question was that easy to determine. That's true. Just for better treatment. Okay, so this person saying their initial line of therapy included Revlimid had excellent success with those therapies and actually was able to stop maintenance because they achieved MRD negativity and continue to be in remission. They're wondering if Revlimid could be used again after the relapse because it was so successful initially. Oh, great question. So it is possible to re-challenge or recycle medications, especially if you've been off of them for anywhere from six to 12 months. There are studies that have looked at restoring sensitivity. So if you're not refractory to the drug, meaning you've progressed while you've been on it within the past 60 days, then it may be reasonable to re-challenge and you may still have sensitivity to that drug if you've not been on it within the past few months. Fascinating. David gave us a hint. He said, you can usually find the GFR or EGFR in the results for a comprehensive metabolic panel, which I do appreciate as those labs are so complicated and sometimes you get them and read them like what is going on? We also have a patient experience team that can help guide you through labs. If you get your labs and are like, how do I read this or where do I find this? So we'll make sure to include their contact information if you're interested in that in our follow-up email. Right, I will just briefly mention that, sometimes when you get your lab results, it shows that something's in the green, meaning normal, or in the red, meaning abnormal. Just because it's in the red, especially when it comes to GFR, doesn't mean it's abnormal. It just could be your baseline, as long as it's not down trending. Yeah, trends are important when it comes to reading labs. Sure, sure. Okay, Bob's saying he came off dialysis four months after beginning chemo with Velcade-dex. What is the correlation between the two? Bob, are you saying correlation between the Velcade and the dex or correlation between coming off of dialysis? I was coming off of dialysis. I was out for maybe five months and my kidney function improved long enough where I could get off dialysis. And I just wondered, is there direct correlation, the chemotherapy, with the kidney function, or is it just something that just happened? Sure, thanks for sharing Bob. And I saw Cindy clap and I'll clap for you too. Congratulations, that's good news. And again, usually if we're going to get patients off dialysis, it happens early on, but it sounds like it took several cycles of treatment and it's remarkable that you were able to come off dialysis. Again, you want to start with medications that are friendly to the kidneys. So we usually don't start with Revlimid upfront. We start with cyclophosphamide and Velcade-dexamethasone. But it is possible depending on the burden of plasma cells you have in your bone marrow when you start and the degree of light chain or immunoglobulin or antibody burden you have in your blood when you start. Again, we do try to get patients off of dialysis. That is the goal. We try to restore their bone health. We try to restore their bone marrow function. So there's not necessarily correlation with the number of cycles. I think it really depends on how quickly you intervene to sort of shut off the sink, so to speak, to prevent the overflow of those proteins from going into the kidneys by really targeting those plasma cells. Awesome. Thank you. Darlene, it shares she had a really not fun experience with Revlimid, that rash, which I actually got a couple emails about that as well, that they wanted to talk about how frustrating the rash is from Revlimid. And then also was not able to tolerate pomelists very well. And she read that some people can be desensitized to imids. What's your opinion on how you've seen this in your patient population? Yeah, thank you, Darlene. It's a great question. So every patient is different in their journey, in their presentation, in their tolerance of therapy. And that's the art of oncology, is balancing the benefit with the side effect profile. So sometimes when there's a side effect, we try to either suppress it, dose adjust, or at worst discontinue the drug earlier than we hoped for. So with the rash, the first step in my approach is to try to suppress it with topical agents, sometimes with systemic steroids as best we can within reason to try to suppress that rash. And sometimes it can be very debilitating or substantial. And if that happens, we may have to stop it altogether if there's no improvement with a dose reduction. And just because someone didn't tolerate Revlimid doesn't mean they won't tolerate pomelists, but they can have similar side effects, especially if they've had an impact on their bone marrow function. So if someone had a very low white blood cell count as a result of Revlimid, it may happen again with pomelists, but not necessarily the rash. So if someone is intolerant of Revlimid, we may try to challenge them with pomelists to see if the rash is less with the pomelists. Yeah, I, Darlene, have met patients that also feel that they're desensitized to inmates as well. So you're definitely not alone, but it's extremely frustrating. We have a desensitization program at NYU. I usually reuse it for antibody therapies. I've not done it for Revlimid, but it's conceivable that you could slowly introduce the dose in a controlled setting and try to desensitize someone. But in all honesty, I've never done it for a patient. Let's see. All right, Cindy's wondering after stem cell transplant, do you tend to put patients on 21-day regimens or 28-day regimens at Revlimid? Oh, good question. Yeah, you know, they say if you ask five myeloma doctors a question about that, you'll get 10 different answers. So it's going to vary across the board. The most studies have looked at giving a daily dose and that's what I aim to achieve. If someone's having a lot of fatigue with that daily dose, usually I give 10 or 15 milligrams daily. If they're not tolerating it that well, I'll go down to a lower dose or to 21 days just to try to give them the benefit of maintenance, but with less side effects. But in most studies, they've given a daily at a lower than the 25 milligram dose, usually around 10 or 15 milligrams. Yeah, thank you so much. Well, Dr. Brownstein, that was amazing. That was a great presentation and I feel like a very productive question and answer session. Looks like Greg was able to find his appropriate lab values. So, so glad you're here, Greg, and thank you everyone for the feedback. Thank you all for being here. Is there anything else Dr. Brownstein, before we go that you would like to say to the audience? Just briefly, I want to thank you Audrey and the Health Tree Foundation. I think the work you do is wonderful. I want to thank the people on the call and the patients and their caregivers again, for all the things they go through. In the chat, I put my Twitter handle. Feel free to contact me through Twitter or follow me on Twitter, it's at Dr. Brownstein and hopefully we'll get to meet again. Thank you so much. Thank you. Darlene, I see your other question. I'm going to contact you, I'll email you and then we'll keep talking and maybe our medical professional team can help as well with that question. All right, everyone, thank you so much. Remember to fill out that survey as you exit. I'm just going to finish with a couple of outro announcements, but I know we're over. So if you need to leave, go ahead. We'll be meeting again in January, unless you tell me that you want to meet sooner in the survey. And we're going to be talking about the best diet to follow with kidney involvement. What foods should you avoid? What foods should you focus on? And I'm really looking forward to continuing to meet with this community. You may be interested in other community events we have upcoming. Tomorrow night, we have the Moves for Myeloma chapter. We're going to be talking about how to stay motivated. Then on the 20th is our newly diagnosed myeloma patients chapter. We're going to be talking about what to ask your doctor at diagnosis, hear from different myeloma patients and a caregiver. And then the 21st is our Mountain West regional chapter. We're going to be discussing infection prevention. Excuse me. I'd like to sign up for any of those events and even more events I didn't mention. It's found at the bottom of the slide and will be sent out in our follow up email, token on my own spit over here. I'm very professional. All right, everyone. Another thank you to our sponsors, Bristol Myers Squibb, GSK, Janine Tuck, Jansen Oncology, and Abbie and a big thank you to each of you. So good to see you and meet some new faces and we'll stay in touch. Thanks everyone. Have a great night. Take care.