(Guest Lecture): May 2022 - Know Your Myeloma Therapy: REMVLIMID with Dr. Craig Cole

Eastern time. Now today's topic is know your myeloma therapy. We're going to be talking about Revlimid with Dr. Craig Cole. Now I chose this topic because I want you to be educated about Revlimid and how the therapy works to treat myeloma. Now for many of us, this drug is going to be something that we're going to be on for an extended period of time. And we need to understand how it works in our bodies. So it's now my pleasure to introduce to you our featured speaker, Dr. Cole. Dr. Cole is a board certified hematologist who completed his undergraduate degree at Michigan State University, and his doctoral degree at the Ohio State University College of Medicine. He began his postdoctoral training in internal medicine and hematology oncology at the University of Michigan Health System. He's had the opportunity to do post follow up laboratory research in the Jerome Leiper multiple myeloma Center of Medicine at Dana-Farber Cancer Institute, Harvard Medical School in Boston, Massachusetts. This opportunity led to a staff lectureship at the University of Michigan, concentrating primarily on clinical research in multiple myeloma. Dr. Cole then became an attending hematologist at Gundersen Health System in La Cross, Wisconsin for nine years. While in Wisconsin, he expanded his research interests to include multiple myeloma, non Hodgkin's lymphoma, therapeutic apheresis, and myelodysplasia, participating as the on site primary investigator for over 21 clinical trials. He then returned to the University of Michigan Rogel Center in Ann Arbor as an assistant professor in the division of hematology oncology with his primary clinical research in multiple myeloma. In May of 2019, he returned to Michigan State University College of Human Medicine at Breslin Cancer Center as the director of clinical research in hematology oncology and multiple myeloma. He is published and presented his research at the ash meetings and the Society of a Pharesis national meetings. He also has a commitment to patient empowerment and education working with several local and national patient advocacy association. Dr. Cole, the 10 is now yours. Thank you. Thanks for the kind introduction. And let me see. Do you see my slide screen or do you see me? Just you. We don't see your slides yet. Okay, so let me change that to. So that'd be some nice slide screen. Yeah, perfect. So thanks for the introduction, Valerie. And I am pleased, so happy to be here to discuss ravelement. And I was really excited about doing this talk because I was really fortunate enough to have been really in the mix of the history of ravelement. I remember when there was a day before ravelement. And so many people ask, you know, why when I was in Wisconsin, was I doing lymphoma and mild is basic research is because there was not much happening in myeloma until ravelement. And I'll show you kind of that kind of story in this little bit. So what we're going to discuss today is how, just like I mentioned, everything changed in the 2000s, in large part because of thalidomide and then ravelement coming to clinical trials and then to fruition. We'll talk about thalidomide, the grandfather of ravelement in the angiogenesis story, then a little bit of myeloma biology to really show how that applies to the action of the immunomyelodetoid drugs in myeloma. We'll talk a little bit about the clinical trial data that supports the use of ravelement, talk about the side effects management and then some conclusions. And so, you know, I do I back in the days when I had hair when I had a high tox fade, myeloma had a very it was a very different disease, the very different survival. In this curve, you can see the lines up towards the bottom and the dotted line is what the five year point was. And you see that the five year survival for myeloma in the 60s, 70s, 80s and 90s was actually very much, much different than it was after 2000. And so suddenly, the the survival of this disease went from, you know, being order being measured in the order of three to four years to suddenly significantly changing and the red line is, is kind of where is probably even an underestimate of where we are today. So what happened to cause this change around 1999 and 2000? Well, prior to 1999, everything we were using we were using was chemotherapy, high dose chemotherapy for transplant, melphalan, vincristin, adromycin, dexamethasone. And we actually and I did this when I was early in my training, we would use this high dose dexamethasone to treat newly diagnosed myeloma. And the survival was very different. And then the paradigm shift happened where all of a sudden, we started using these newer scientific drugs, and then the survival significantly changed, and we've never looked back from that. And it all began with thalidomide. And so what is thalidomide? And I think everyone kind of knows the story of thalidomide that it was a drug that was developed after World War Two in West Germany. And primarily, it was used as a non addictive way to, to treat what was later known as post traumatic stress syndrome from the from the people who fought in World War Two. So it was initially advertised as a sedative hypnotic. And the drug company that used that tested it actually tested it in mice and found that mice thalidomide was incredibly well tolerated. So well tolerated that around the world, it was available without a prescription and was basically a cure all for difficulty sleeping different anxiolytic or anxiety disorders. And it was actually given to pregnant women, because it helped with nausea and hypermysis gravidum. When women were early in their pregnancy. It was there and the and a lot of the toxicity, especially the birth defects that were found with the with the drug, were were kind of covered by the company. And when it went up for FDA approval, in the United States, Dr. Francis Kelsey, who won the Congressional Medal of Honor stood her ground and said this despite the drug company is saying this drug causes birth defects, and her efforts and her standing ground not only took the drug off the market, but it changed the FDA for forever. And the review process was completely overhauled to being very, very inclusive to make sure that the drugs are safe when they're released in the United States. But to her credit, the thalidomide was then put away in 1961 to not be seen again, because and the idea was that it caused the birth defects that it caused was from an inhibition of blood vessel formation. Right when it was withdrawn from the market, Dr. Olson wrote a paper and he gave you know, it was kind of again, kind of a cure all and they gave the thalidomide to patients with advanced cancer. And he wrote a paper on this that showed that some patients that had advanced cancer that using thalidomide actually slowed down their cancer, and actually patients had, and the end of their lives with these cancers, they were actually having an improvement in how they felt. And the two top cancers that that showed benefit were kidney cancer and multiple myeloma. And those two cancers are actually highly angiogenic. And that was kind of a note that was left that thalidomide worked for these two diseases. But of course, it was then put away. So then fast forward to 1999. And 1999 and 1998, people were incredibly excited about angiogenesis, that cancer required blood vessels in order to sustain and grow. And that tumors produce lots of angiogenic growth factors, growth factors that make blood vessels in order for the cancer to be fed. And one of the chief angiogenic growth factors was vasculine-anthioid growth factor or VEDJF. And the and at the same time, about 1999, there was a paper that changed my life and the direction of my career change. And I read this paper by Angela Vecka that talked about 67 patients had myeloma. And it showed a connection between blood vessel growth and myeloma growth. This wasn't anything new. Dr. J. H. Wright, back in 1900, showed that myeloma was a highly angiogenic, had lots of blood vessels in those bone marrow biopsies that were done, you know, in the very first bone marrow biopsies that were done. Very, very lots of blood vessels seen at that time. Angela Vecka then using new technology showed, yes, that the panel A where someone had active myeloma in 1999, lots of blood vessels seen, lots of those brown squiggly lines are blood vessels and patients that had plateau phase or quiescent myeloma had less blood vessels. So the idea, of course, is that if you could slow down blood vessel formation, maybe you could slow down the disease. And in 1997, this idea of angiogenesis and cancer really came to myeloma. And what happened is that in this story, there are different versions is now basically legend of what occurred. But Dr. Bartologi, which is, which gave us maintenance therapy, which gave us, who gave us a high dose chemotherapy and transplant and myeloma, really one of the one of the famed, the most famous myeloma doctors in history. Dr. Bartologi had a patient who had had several transplants was on chemotherapy. His patient was doing very poorly. And the patient's wife went to Dr. Bartologi and said, you know, my husband is not doing well with his myeloma. Could you I've heard about these angiogenesis agents, could you find an anti angiogenesis agent for my husband. So Dr. Bartologi then takes up the challenge and calls Judah Folkman. Judah Folkman is a Nobel Prize laureate, is a pediatrician, a pediatric surgeon. But he was doing research in anti angiogenesis agents, predominantly for childhood diabetic retinopathy or childhood diabetic eye disease. Because when diabetic retinopathy or diabetic eye disease, it's an overgrowth of blood vessels that cause blindness due to diabetes in these children. So he was using anti angiogenesis agents to try and decrease the amount of blood vessels in children's eyes so they wouldn't go blind with diabetes. So Dr. Bartologi and Little Rock, Arkansas, a myeloma doctor calls Judah Folkman at at Harvard, and says, Can I have an angiogenesis agent for my patient here with myeloma? And Judah Folkman gives him the one drug that would be least likely they would ever give a child with that as an anti angiogenesis agent, he gives Dr. Bartologi thalidomide. Dr. Bartologi takes that thalidomide and gives it to his patient that had multiple rounds of chemotherapy, and it helped them, which then led Dr. Bartologi to do a clinical trial and 37% reduction in myeloma protein, which was this pill was outperforming chemotherapy in the early 90s, with a follow up at 3.5 years and patients were still alive, that had relapsed refractory myeloma refractory to chemotherapy, it really was and this is when I first came into And this was an incredible result of how this drug worked, that a patient's wife went to the doctor and asked for a treatment. And that doctor then goes out seeks out that treatment builds a clinical trial and changes the world changes myeloma and a new class of immunomodulatory drugs was then discovered. So thalidomide was the first in class, but did have quite a few side effects, particularly neuropathy and sedation. So then linolytomide, which is a derivative that was less toxic, was then developed and released in 2006. And was more, and not only did they decrease the side effects, but made it more potent. And a phase two trial show how that it worked better than any other agent at that time for newly diagnosed myeloma. We'll talk about that in a bit. Subsequently, pomalidomide was released, which was even more potent. And iburetomide is currently in late phase clinical trials for the use of myeloma and the whole area of the immunomodulatory drugs. And now the cerebron inhibitor drugs are really a incredible fountain of new drugs for myeloma built on the backbone of what thalidomide is. So how does how do these drugs work? How does thalidomide and ralphamide and the other drugs actually work? Well, that'll take a little for us to talk a little bit about myeloma biology. So here's a myeloma cell. And there's the interleukin 6 receptor on myeloma cells. Myeloma cells are very dependent upon interleukin 6. And there was a great effort to see how can we understand how myeloma cells grow. When the IL-6 engages its receptor, it activates a number of pathways inside the myeloma cell. One is the JAK-STAT pathway, which activates BCL2 and MCL1, which tells the cells not to die. That's a bit cells are supposed to die. But if they're told not to die, they have anti apoptosis, then they're immortalized, they won't die. It also activates raffmat kinase pathway, which tells the cycles to reproduce faster, and increase cell proliferation. And then it activates the PI3 kinase pathway, which turns on NF-CaPB. And nucleonar factor CaPB is the source of more supportive cytokines. So the cycle keeps on going. This leaves the myeloma cell immortal against chemotherapy and resistant against steroids, which is why from the 1960s up until the 1990s, these drugs were not very effective for multiple myeloma. And if IL-6 is so important, where does it get it from? It gets it from the bone marrow stromal cells, which is why myeloma is confined primarily to the bone marrow compartment is because it gets the IL-6 that needs to grow and proliferate from the bone marrow stromal cells. So once a myeloma cell finds a bone marrow stromal cell, it releases a little bit of vascular endothelial growth factor to then find out is this bone marrow stromal cell going to cooperate in my growth and proliferation. The bone marrow stromal cell then turns on its own NF-CaPB, which then produces IL-6, which is a signal to say that this my this bone marrow stromal cell is going to work to help proliferate the myeloma. So the myeloma cell then produces lots of IL-6, which pulls in more myeloma cells into this microenvironment that is conducive for myeloma growth. It then produces more VEGF to pull in blood vessels to feed the more myeloma cells in the micro environment and produces other supportive cytokines, which then causes the circuit to go around again, producing more IL-6 and more supportive cytokines, which then pulls in more myeloma cells. Remember how IL-6 kept the cells proliferating, not dying and resistant to chemotherapy and to steroids, which then makes the myeloma cells immortal. And that circuit between the bone marrow stromal cell and myeloma cell is why myeloma cells proliferate. They then run out of room in the bone marrow and then go to the long bones and to the skeletal bones. And they attach to osteoclasts, the cells that wear bone down, and they hijack the osteoclasts to produce IL-6. So they leave the bone marrow to find other cells to feed them. And in turn, they try to produce more osteoclasts to give more room for myeloma cells by using rank ligand and decrease osteoprotegra to increase osteoclast activity, which causes the bone destruction of myeloma. And they get rid of those osteoblasts by using cytokinesis, DKK1, and RUNX2. You get rid of the osteoblasts and use the osteoclasts, which is why we have lytic lesions and myeloma, because the myeloma cells are looking for that IL-6 in order to for growth proliferation, and so they don't die. So how do these drugs work against myeloma? Knowing how the myeloma cells are so dependent upon the microenvironment? Well, they use science. This is how these drugs work. So the first way that we look at it, how do the imides, thalidomide, and ralpamid work? Well, again, they use science. They inhibit DNA synthesis in myeloma cells to a very small degree, not much. It works a tiny bit like chemotherapy would. It doesn't really decrease blood vessel synthesis so much, but what it does do is it gets rid of that VEGF. So remember, VEGF is how those myeloma cells initially talk to those bone marrow storm cells. Without VEGF, yes, blood vessel synthesis decreases, but they don't know where those bone marrow storm cells are. They inhibit the adhesion of myeloma cells to bone marrow storm cells. Remember, they're dependent upon it. If a myeloma cell isn't attached to a bone marrow storm cell in the acid class, they'll die in just a few days. And so inhibiting that adhesion has the myeloma cells die. They don't have those supportive cytokines. Again, these drugs get rid of IL-6. That is what we've been looking for from myeloma for decades, is how can we get rid of IL-6 from its source and the imides, ralpamid, and pomalidomide, and thalidomide, decrease IL-6. Without IL-6, the cells can't proliferate. They can't produce more cytokines, and they apatose. They die away. And after years, we found out that one incredible thing that these drugs do is they activate the patient's own immune system. They activate the T cells to go after the myeloma cells and destroy it. And that was revolutionary. There wasn't hardly any drugs that did that. And so these were really an incredible breakthrough. And I remember being so excited when this was discovered. So again, their cytotoxic effects, due to multiple mechanisms of how the imides work, they increase the proapoptotic factors, which cause the cell to die, and decrease those factors that helps keep the myeloma cells alive. They inhibit that NF-Kappa B pathway, which is how you get all those supportive cytokines, and disturb the PI3 kinase pathway so the cells have a difficult time proliferating. They increase, they have an effect of decreasing bone destruction by decreasing the supportive cytokines, especially rank Y-gam. So now they can't talk to those osteoclasts, like, and receive cytokines from them. And of course, we talked about how they activate the immune system against the myeloma cells by decreasing tumor necrosis factor IL-6 and IL-12, and increasing IL-2 and interferon, which gets those T cells to kill off the myeloma cells. So it really is a Swiss Army knife that this pill that a patient's wife told Dr. Bartolovia about, had so much activity against this disease, it was really incredible. So then the hunt went on, how exactly, how exactly does the Swiss Army knife work? And a blood, and as an article came out in Science, that figured it out. It was cereblond. Cereblond is a, is a chemical that is inside cells. And that's what the emits thalidomide, ravelmide, and pomalidomide bind. By binding to the cereblond, which usually uses, has lots of other different functions, binding to cereblond then causes icaros and alos to then get degraded by the cell, they get ubiquitinated and get targeted for destruction and down regulation of icaros and alos, which is seen in this cartoon as, as IKZF1 and 3, garing of those and down regulates IFR1 and mit, which then causes the cells to die and increases those other effects such as IL2, which activates T cells to go after the myeloma cells. And this is the incredible thing that thalidomide fits right into that cereblond receptor, fits right into that cereblond receptor. Linolidomide and pomalidomide even fit into cereblond receptor even better than thalidomide. And by binding into that cereblond receptor, it gets icaros and alos to then be destroyed, and then causes all those incredible effects. The incredible thing is, is that this it wasn't like ravelmide was or thalidomide was designed for this purpose. It wasn't like it was purposely made. It just happens that a patient's wife told Dr. Brardologi to get a drug from for her husband, which then led to just happens if it had been a lung cancer patient, it wouldn't have worked if it had been colon cancer, we had never heard of it. But it just happens that this drug just happens to work for this disease. And it changed everything. I think that was truly, truly a miracle that that key happened to fit into that lock and, and saved so many lives. And so again, thalidomide has some activity, more into angiogenesis than T cell regulation and T and NK cell activation. But look at linolidomide and pomalidomide, much more powerful at turning on those T cells, turning on the immune system to destroy the myeloma cells that have those anti inflammatory properties, properties and direct tumor effects. And that is really, I think an incredible story. ravelmide was then tried in the mid 2000s for relapse myeloma. I clearly remember having patients rolling patients on the linolidomide dextrile for relapse refractory myeloma, and having patients fly from all over the country to enroll in this trial back in the early 2000s. And it had these incredible results that outpaced chemotherapy at that time. And then what really, really changed my life is I was working in the lab at Dana Farber. And I got on the and I had a late night in the lab and I got on the elevator at about like 10 o'clock at night. And I got on the elevator with Dr. Ken Anderson, who's the director of the of the of the Dana Farber myeloma group there. And he said, Craig, I got a secret that tell you said, there's this new drug fluid in mind, I mean, linolidomide gave it to newly diagnosed myeloma patients. And the overall response rate was 91%. Prior to that, I was writing for melphalanopregnizone for myeloma patients, and the overall response rate was 30%. So when he told me that this new drug, I got on the elevator just trying to go home, he gets on the elevator and tells me this drug works 91% of the time, I knew that the entire world for this disease was completely different. That changed my life. And that's why I stay in doing this. And I still am so excited to see how many things have happened. I can't wait to show you some of the data that's coming up. But but only one patient didn't respond. And I remember giving melphalanopregnizone to patients and having all half the patients responding at best. So this was really a revolutionary breakthrough. Then the SWAG S 777 trial came out of Revdex versus Revmadelcate index, and that the three drug RVD outpace RD for progression-free survival in overall saliva, which is now our standard of care for newly diagnosed patients is RVD. And then Emory, I love the the Emory RVD 1000 study, because it gives us an insight of how of what the performance of RVD is. And the overall response rate 97% after induction therapy and 98% after stem cell transplant, progression-free survival with that first 65 months as compared to like four months with melphalanopregnizone. My goodness, it's incredible. I've been doing this for like 20 years. This is incredible. And immediate overall survival of high risk patients was 78. But for standard patients, it hasn't been reached yet. And I if you were to ask me in 1999 and 2000, if this would have been possible, I would say no. That and then they said, Oh, if it works, well, why don't we have patients restart and stay on Revlimed after transplant, and data from four large randomized trials where patients that either either given relevant maintenance, no maintenance at all, over 2000 patients, it showed that relevant maintenance post transplant, it was associated with significant improvement, and overall progression-free survival, and improvement in overall survival. And we still don't quite know how long patients would be on Revlimed maintenance. But here are all the trials to the left, that looked at Revlimed maintenance versus no maintenance. And all those trials showed that there were improvements, improvements in overall survival and progression-free survival, which led to the FDA approval of Revlimed for maintenance therapy for myeloma. A couple years ago, the Stamina trial looked at how long people should stay on Revlimed maintenance. And they had patients elect to either after transplant, either stop relevant maintenance after three years or continue on. And by stopping Revlimed at three years, patients started to relapse. And continued Revlimed patients didn't relapse at the same rate. And so that told us that we still don't know how long people need to stay on Revlimed maintenance. But staying on Revlimed maintenance beyond three years still remains a good idea. The thing that, you know, to come to complete to fruition of when we found out that the Revlimed was so good for newly diagnosed patients, to today, the Griffin trial that I'm sure everyone has heard about, of the addition of Derrick-Tumumab, the antibody against myeloma plus RVD, versus RVD alone for newly diagnosed patients. And in this study, transplant-eligible patients were either given DERRA-RVD or RVD, which is, of course, the current standard of care, followed by stem cell transplant, consolidation of RVD, and then maintenance with either Revlimed or DERRA or Revlimed for approximately two years. And what I think is incredible is how well the response, the overall responses at the end of consolidation, 99% overall responses for DERRA-RVD and 91% for RVD, which is incredible, still incredible, but a little bit more with the addition of Derrick-Tumumab. And the important part is deeper responses by the addition of Derrick-Tumumab. And in transplant-eligible patients, there were more patients that had a stringent complete response by addition of Derrick-Tumumab to RVD at 51% versus 42%. And again, those responses deepened over time with more and more patients becoming MRD negative, especially during the maintenance phase. But we still need some more data on progression-free survival, although, and talking to my own colleagues, really, DERRA-RVD is becoming a standard. In fact, this is from the latest ASH meeting. You can see that in those curves for progression-free survival, that the curve for DERRA-RVD is absolutely flat, which means patients aren't relapsing, haven't had any further relapses at 36 months, while the RVD patients still, 81% at 36 months is very good, but just a little bit better with DERRA-RVD. So when you look at the regimens for my along the over the years, when I first started doing, when I was in training, in the very early days of my career, when we were using melphalanoprimeosome, or even chrysineadrin, mycin and dexamethasone chemotherapy, the best that we could give was about a 63% response rate. And really, I had never written down the term VGPR for my own patient in the early 90s. So I never saw it happen. I never, I'll be honest, I never back in the early 90s wrote down complete response, because I never saw it happen. All the responses were, were very short and never a deep response. Then you look at what happened when we introduced thalidomide and birtuzumab, Velcade and linolytomide, the responses went up dramatically. And then we started combining the old with the new melphalanoprimeosome, thalidomide and the imides plus the old drugs, response rates and the depth of response are going up. So now you get to our current standards with ravelment being kind of the center point of the of those regimens, you're looking at 100%, 98% response rate, the deep response is well over 50%. And then the four drug regimens that I mentioned where we have responses that are 99 and 100%. And the deep response is much, much higher. And so in just in just a few years, in just 20 years, we went from having 35% response rate to 100%, 99 and 100% response rate, because of one drug, and I can't under emphasize because a patient's wife talked to their doctor about a clinical trial. So let's talk about side effects. And I swear that I see all these commercials on TV, this is exactly what I think I mean. Everyone in the commercials seem very happy. Everyone's like, Oh, so what about the side effects of ravelment? And in the image? Well, there are in the first trial, which was a trial that was done in the in the I think it was 2010, which was between melphalan, pride in the zone and thalidomide versus ravelment, dexamethasone. We saw that there were there, there are cytopenias associated with ravelment, and specifically for the absolute neutral foot count being under 1000, which is, you know, officially neutropenic happened about 26% of patients on the linolytomide or ravelment dex arm, and was a little bit higher when patients were on continuous ravelment dexamethasone. I think we see that we see not that the immune system is too compromised with the use of ravelment, but it does decrease the neutrophil count a little bit. And thrombocytopenia that all and I do tell my patients that the platelet count can go down over time with the use of ravelment. At the initial startup therapy that the that the counts of course are compromised, because myeloma is in the bone marrow, and is causing problems, but we usually see the counts improve as we get rid of the myeloma. And then ravelment itself can cause a bit of thrombocytopenia, but usually not to the point of needing transfusions. And of course, there are a number of non hematologic or non blood related side effects, infections. And I think that especially in that first month of the diagnosis of myeloma, when the myeloma is very active, and in decreasing the immune system, the immunosuppressive effects of ravelment, that combination does take a toll. So infections are not are not infrequent with multiple myeloma and at the onset with ravelment. Fatigue, I've heard, I would say that even though these numbers are from the clinical trial, I would say the fatigue number is a bit higher than 9% of cardiac disorders, especially heart rhythm problems are not uncommon with with ravelment. And then we'll talk about venous thrombemblism or blood clots in a bit. There is a risk of secondary cancers that we discuss with our patients. In fact, in the early days of ravelment, there was a brief hold that was put on the clinical trials with ravelment because they saw that some patients were having secondary cancers. However, in close analysis, it was in those randomized trials where patients were either getting ravelment, or they were being followed in not receiving ravelment, those clinical trials that that approve how well maintenance therapy work, that the advantage of control of the myeloma gave a much, much higher survival advantage than than not using ravelment maintenance. The risk of having dying from a secondary cancer is less than 1%. And the end and the cumulative index of having any cancer is less than 1% at one year, and climbs very slowly. A lot of those cancers are skin cancers, like basal cell carcinomas, and and skin squamous cell carcinomas. And that's but more importantly, patients are living longer with this disease than they ever have. And so we do have to be very cognizant of the fact that patients can develop cancer with ravelment. But the important thing is more important to not have the myeloma be the cause of death, and very carefully observe patients when they're all in ravelment, make sure we do skin exams, make sure that patients get their their standard cancer screening for prostate breast cancer, lung cancer, if applicable, and watch very carefully for that. But again, most of the cancers are fairly quote unquote benign cancers, such as skin cancers that can be remedied by a local resection. Some of the long term effects of ravelment that actually didn't come to fruition until we had patients and maintenance was the chronic diarrhea part, which is really important to talk about. And when we were first using ravelment, we had patients that diarrhea, we didn't understand it. And unfortunately, a lot of patients didn't tell us that they were having diarrhea, because they didn't want to stop the ravelment. We now know that with long term ravelment use can result in a very specific form of diarrhea called the bile salt mild absorption syndrome. And what happens is that the the ravelment causes a slight damage to the lining of the intestine, where there's an accumulation of bile salts. bile salts are kind of the soap that dissolves fats in the intestine. And so if you have an accumulation of these bile salts, and some of the food that's fatty slips around this accumulation, then you can actually have diet kind of a fatty diarrhea, then that can lead to debilitating episodes of diarrhea. And again, I've seen patients that that wouldn't tell us that they had diarrhea because they didn't think they had any solutions for it. Now we know it's a bile salt mild absorption syndrome. And so if it occurs, we usually have patients hold their hold their ravelment for a bit, especially that maintenance have the diarrhea resolve, they can try to use imodium if it's if it's more of a mild bile salt mild absorption syndrome, and try low fat diet to decrease the fat that is escaping the bile salt malabsorption syndrome, which then can decrease the diarrhea. But one of the mainstays is using bile salt acid binders to get rid of those pools of bile salt and colostiramide, which I do prescribe to my patients that have diarrhea, and it really does work quite dramatically. And it really is a test the lots of causes of diarrhea. But if you use colostiramide, or no low fat diet, diarrhea resolves, then it's that bile salt malabsorption syndrome that is seen with ravelment. Now I encourage you if you have diarrhea to definitely discuss that with your doctor. So you don't have to live with that. Another thing that we found out with the use of ravelment, especially when we use it in combination of the drugs, is the risk of blood clots. There are a number of different risk risk factors of blood clots. And every time I see a new patient with myeloma, I go through this checklist in my head to see what are we going to do about about blood clot prevention in this patient. And if especially if patients are newly diagnosed and myeloma is reactive, that's or any cancer is a risk for blood clots, but active myeloma is definitely a risk factor. The use of chemotherapy and association of ravelment increase the risk of clots. And high dose dexamethasone like 40 milligrams of dexamethasone dates one through four, nine through 12, and 17 through 20, which isn't used very much these days also with ravelment have increased the risk of blood clots. If you're using your blood cell stimulating agent, it can increase risk of blood clots. I always ask and you should definitely volunteer if you've had a blood clot, a history of having a blood clot to definitely that is one of the big things that we need to know that would be causing them to have a high risk of having blood clots with ravelment, or family history thrombophilia, having genetic conditions, which are which predispose people to blood clots. And of course, having surgery or broken bones can increase the risk of having blood clots. Not many patients with myeloma have central venous catheters these days because we don't use chemotherapy, but also also having something abnormal in your blood vessels, like an instrument can increase risk of blood clots. So a patient doesn't have a lot of those risk factors, we just use a daily aspirin. And I usually use an 81 milligram aspirin a day to prevent blood clots. However, if patients have one or more of those risk factors, and I would say older age is primarily getting at someone who isn't who is very sedentary, who can't move around a lot and has active myeloma. But if they have two of these risk factors, and we would give consideration of using one of the oral blood thinners like eliquis or alto, not much warfarin anymore, or as subcutaneous blood thinners such as lobenoids. We're very cognizant of people having blood clots in the first six months. So we definitely watch people very, we watch people all the time, but we watch them in those first six months carefully. And the in the signs and symptoms of blood clots is having one leg swell larger than the other redness in that leg, or pain in that leg. And is usually in the lower extremities where they where they occur. And for and what's interesting is, I think a lot of the commercials that you see will talk about blood clots and people having pain, interestingly enough, from patients on relative med and they have blood clot, it doesn't always have pain, primarily be that swelling in one leg, that really should have you immediately seek the advice of your physician. And we tell patients the best they can when they're diagnosed in the first six months, to really be as mobile as possible, but moving around circulates of blood keeps her from pooling in the lower extremities, which can cause the blood clots. Some of the other side effects that we see with relative med fatigue. And it's important to really when I my patients say they have fatigue, the second question I ask is, how is their sleep? Because as you know, the dexamethasone can really cause havoc with the sleep, to make sure the hydration is adequate, then they have good exercise. Sometimes in patients on relative med maintenance, that will do a dose reduction, or we'll have them take a holiday. And when my patients go on vacation, and they're in maintenance relative med, they usually take a vacation from the relative med to us is leaving relative med at home, being off of med for a week in the order of maintenance therapy isn't going to have any effect on myeloma. For the leg cramps that can accompany a relevant that glutamine, the supplement can help definitely hydration and normalizing the magnesium potassium levels. One way to do that, and I have a couple patients who swear by this is pickle juice, which has a lot of magnesium phosphorus and potassium in it. They drink pickle juice right before they go to bed, which helps the muscle relax and and it helps decrease the cramps. But moving and stretching, stretching and being active helps a lot with the cramps. And then the wrench, the relevant wrench. And when and I think I had mentioned earlier that when relevant med inhibits it grows and a loss and it causes changes in those cytokines that help destroy the myeloma, a lot and activate those T cells that when you first start relevant, it can cause a rash with activation of those T cells and activation of those cytokines. So it's not uncommon about 10% of the time patients will start relevant and have a rash. We tell patients to hold the relevant, give us a call hold relevant and call us from the rash of result. We'll recommend antihistamines, topical steroids. And sometimes if the rash is is severe, or is worse, they will help you have and take oral steroids to help with the rash. rashes can occur later on with relevant med especially after transplant. Some of those are are rashes due to dry skin, because they can also cause dry skin. So definitely wintertime tell people to use more surprising lotion. So what's new with relevant? Well, there is in development. There is a transtermal patch for relevant that is in development, I think is in kind of the later phases of development, where instead of having the relevant med, you know, you take a relevant pill, the drug effect, you know, peaks, particularly when patients take it at night, and then decreases, while a transtermal patch relevant med would have a more continuous administration of the drug over a longer period of time. And I think a lot of us have been, you know, and I have been praying for, for a long time, for about a decade, is generic relevant med. And that there are actually two companies that have FDA approval for generic relevant med occurring in May and October of 2021. The generic relevant med, especially by Tiva, is being rolled out in a volume restricted basis, which means that available at some places, but not available at all places, and is slowly being increased in its release over time. And the availability of generic one will live might vary from state to state. And we are calling right now to see if it's available in Michigan yet. But the one trick is we don't know what the cost is going to be. But we suspect it's going to be lower for sure. But we don't exactly know the cost. Because the company sells it to a wholesaler, sells it to a drug company that I'm sorry, to the pharmacy, that the pharmacy would probably be the individual pharmacies would probably be the best idea of how much a drug would cost. And it would still require the REMS program. And just one word about the REMS program. The REMS program was actually developed again for thalidomide. And it was developed with the help of the thalidomide, the people that were affected, the children that then grew up with the with the teratogenic effects of thalidomide, help develop the REMS program so that it would be rolled out in a safe manner. And so every time that patients you know use the REMS program, that was actually developed to keep it safe. So we wouldn't have more thalidomide occurrences, thank goodness. So in conclusion, there have been dramatic improvements in the treatments for myeloma with the application of immunomahogetor drugs, especially rafflomib. And again, I am so thankful for that patients, why for that patient, and Dr. Barlogi and Juve Folkman for bringing this to to fruition is now the standard induction therapy and maintenance therapy. And most patients that have myeloma will be on rafflomib. It has side effects that we talked about. So it's important to be frank and open with your nurse and doctor to really give the best advice. I would also say it's important to be open with and frank with the care coordinators and the social workers to help because these drugs are very expensive, and to help with the cost of those drugs. But it's it's critical. I always end every talk that I do with how important it is to be informed and empowered. And I thank you so much for listening to me talk about these drugs today, because it's important to be empowered in 2022. So many exciting things are happening in myeloma that it's important to be able to talk to your doctors, but all the new things that are happening, because you can cope with this disease better by empowering yourself with knowledge to learn what you need to gain control, to surround your people, surround yourself with positive people that can help you fight this disease. And that's it. Thank you. Awesome. Thank you, Dr. Cole. That was truly an excellent presentation. You always come with some great animations with really helped with understanding there. So thank you so much. It's time for our Q&A now. And we have quite a few questions that's already in the chat box there. So we're going to jump directly into those. If you do have a question, just feel free to put it in the chat box there. And my team is going to funnel those into me so we can get them answered there. But we're going to go ahead and get started. Dr. Cole, the first question that we had is, what are your thoughts on receiving medications to stimulate the red and white blood cell production versus using the RVD treatment? Yeah, I think that that using and I think so the I'm trying to think what this question is asking. So I think that when can you use those drugs while you're receiving RVD treatment? Yes. That is not infrequent that patients that have myeloma have anemia, which the red blood cell producers help with and neutropenia, which helps the white cells with, especially when you combine the disease with the medications. And so I think it's important, you know, especially to reduce risk and that patients feel better to use those stimulators to help stimulate the blood cell production. Using it instead of Revlimid, you know, if you're anemic and you have a white blood count from myeloma, you know, stimulating the cell production to correct the anemia instead of using definitive therapy. It's like putting a bandaid over. It's like putting a bandaid over a wound that a wound that you need stitches for. So it won't help that much. Just to stimulate the white and red blood cells need to get rid of the cancer that's causing those counts to be low. Thank you. Very good question. The next question would the use of Revlimid increase O and J DOS and of course this of the draw activity? That's a very good question. They're all good questions. So it has a little bit of that very small degree, you know, definitely compared to the bone strengtheners like Zometa and Xgeva, which definitely has more effect on the bone and does increase the risk of O and J much higher. The Revlimid is kind of small potatoes and increasing the O and J risk. And so definitely when patients are getting teeth work done, they're getting a tooth pulled and they're on Xgeva or Zometa or Famidrinate, I definitely hold those drugs. If patients are getting to teeth work done and they're on Revlimid maintenance, what I'll usually do is I'll ask them to hold the Revlimid for about a week. The week before they have their dental procedure done, in part because there is decreased healing associated with the use of Revlimid that patient that with any surgery that it'll just take longer to heal from things. And so I'll usually hold the Revlimid briefly. So usually about a week before or maybe a week after they're having major dental work done, just to make sure that things heal very well. Thank you. So the next question, can you explain the VGPR, the very good partial response and other related responses there? What does that mean? Sure, if I can share my screen again, if that's okay. And let me share. Come on. And so there. So could you see my screen? Okay. Perfect. So on to on the right, there's the myeloma iceberg model. And when patients are first diagnosed with myeloma, usually it's pretty obvious that they're having anemia, bone lesions, and their myeloma burden is very high. And as we treat the myeloma, then as you get rid of it, then the myeloma begins to go beneath the waves. And so when you have, and we measure how much myeloma there is by the M protein or by the light chain protein, and if you if you're if your light chains go from 100 to 50, that's a 50% reduction in the protein level. If your M protein goes from five to 2.5, that's a 50% reduction. And that's a partial response, which is very good. But a true very good partial response means that you've had a 90% reduction, where the M protein from the day that you start therapy, to the point that you are right now, if 90% of the protein has been decreased, then we call that a very good partial response. If the M protein disappears, and the amino fixation, the most sensitive test to tell if there's an M protein disappears, then that's a complete remission. And a stringent complete remission is when you do a bone marrow biopsy, you don't see any plasma cells. And the free light chain ratio is between the abnormal and normal light chains has normalized. And even below that, there are lots of clinical trials. And really, it's becoming part of standard practice to measure MRD. Because the tests that we use to measure myeloma burden, so I talked about the M protein using the SPAP, that is back to the 50s. That's an old test. And the light chain test dates back to I think about 2012. So there are older tests. And even if those tests are negative, there's still some residual myeloma there. And the mineral residual disease testing, either by flow cytometry or next generation sequencing can give us an idea of deeper, deeper responses, looking for one in a million or one in 100 1000 myeloma cells. Thank you for that explanation. It surely has in the chat. This is such good information. I agree is awesome information that we are receiving here today from Dr. Cole. Thank you. So Dr. Cole, the next question is you mentioned the side effect of diarrhea. But what about severe constipation and stomach pain? This patient, I had an endoscopy and a colonoscopy and the doctors found nothing. A CAT scan was also performed and found nothing. I have tried several medications to help but nothing seems to work. Do you have any suggestions for this patient? Yeah, I have I have seen that occur for patients instead of having the diarrhea, especially early on in their myeloma course, that they can have a pretty bad constipation. And a couple things is one thing that has that, you know, that I'll mention a million times over is is increasing the fluid intake. But there can be mobility issues where you know, the colon and the bowel and the intestine should push things along in an orderly manner that the squeeze here and it pushes things to squeeze here and it pushes them. And sometimes that doesn't work very well. And so increasing the the fluid intake kind of helps keep fluid in the bowels, which can help things move along better. But also things like increasing the amount of fiber in the diet, and fruits, especially things like prunes can help a lot because that helps keep the fluid that is our foods to help keep fluid in the intestine that's not absorbed by the body. And that increased fluid mixed in with everything else can help keep things running well. I think one other important thing is to make sure your thyroid is doing okay. Because one thing I didn't put on I didn't put as one of the side effects that definitely happens when people have are on ravel med is they can have low thyroid function. And so it's and I've seen I've seen a number of times where patients have been on ravel med for a while. And I remember in the first clinical trials that we have with ravel med, the patients would have constipation, and they would have a hoarse voice. And we would check that thyroid and thyroid function was very And it's easily correctable with thyroid replacement therapy, just a thyroid pill. So in addition to everything else, I would definitely increase the fluids increase the bulk, you know, using things like, like fiber in the diet, but also make sure you check your thyroid function. And a follow up on that, Dr. Cole, if there is an issue with the thyroid function, is that would that be ongoing as long as you're taking the revenue or it is? Yeah, yeah. And so I haven't found it to be prohibitive for and and you and they and people don't require lots of thyroid medications to correct the thyroid with ravel med. So even in the first clinical trials, we didn't stop the ravel med because it caused thyroid dysfunction, we just replaced the thyroid and on people. Awesome. Thank you. Is it more effective to take breath of mid at a certain time of day, say the morning versus at bed time? So that's that's I left because we in the early because I'm just gonna keep saying in the early days and back in the old days, but back in the old days, because the lidamide was so sedative, and really, it wasn't really good sleep agent. We were treating patients an issue with myeloma. We always had patients take it at night, because it helped patients sleep. And when ravel med came out, even though you know, they made sure it didn't have a lot of sedative effects, we still had patients take it at night. And I still think that's not a bad idea to take it at night. So if there any side effects that people just kind of sleep through it, I think is more important to take it at the same time every day. I have had patients have a bit of insomnia with the ravel med. So they take it at night and I really am having poor sleep. And then I'll say, well, try and change it to the middle part of the day or the morning. But because really, the it taking at night is more of a historical significance more in its relationship to the lidamide, than it is actually something that is therapeutic. Thank you. So this is a good question there. If pomalidomide is more powerful, why is it not used more than the linolytomide? That is a very, they're all good questions for that. That's a very good question. That I've asked that question to the company. And this, that may change. The standard, at least what I was told is that the ravel med is has really shown its proof in that in that upfront therapy for myeloma. And pomalidomide has such good effects in the relapse setting, especially in some of the trials using pomalidomide of how it was active, especially in patients that have the 17 P deletion or have high risk relapse myeloma, that it was like, you know, leaving your your bigger punch for your last punch or for the next punch, that use a standard therapy for upfront. And then when the myeloma comes back, if and especially if it's a high risk relapse, that the pomalidomide is there to save the day. Given that there are a number of different drugs, you know, the two things that really changed that paradigm is one that there are other now very, you know, I had mentioned how it is blind luck, that pomalidomide and ravel med and thalidomide fit into that cerebral keyhole. Now there are pure cerebral and it grows and aloes inhibitors that are much more potent than ravel med, pomalidomide and thalidomide. And when those drugs are currently in clinical trials, such as iburetumide. And when you look at those drugs coming in, and the generic use of ravel med, the pomalidomide is going to be under a bit of a squeeze, and it'll be interesting to see if using even that drug for rainy day, if we're not going to move that up bit more upfront, as we're having newer drugs come down the pipeline that occupy that same space. That's a very good question. That's a I have asked that question repeatedly. Thank you. And we'll make this the last question here. There's plenty questions in the chat there. We will, we have your email, we will get responses to you to these questions. But we have to make this the last question here. For ravel med maintenance post stem cell transplant, do you prescribe 28 days or 21 day with the seven day off regimen? Which do you prefer? So I'll be I'll be honest. So when we were so there, there are two there are two schools of thought, and I can tell you I've attached my school to the 21 days on one week off. And what and for the long term. So soon after soon after transplant, when I started, I usually will start with the 21 days on one week off, especially because after transplant, when we start that there that the counts may be a bit rocky, and it's a bit more palatable doing the 21 days on one week off. Once they kind of get into the groove of it, and once the counts and they've like really recovered from the transplant, like six months or year after transplant, then I'll move to the 21. They'll move to the 28 day. There isn't really a solid answer for that. They're both very efficacious. I think if you survey most of my patients, we have negotiated to the 21 day on one week off. I think it's actually kind of helpful to see when patients have that one week off, especially if a patient tells me, oh, my goodness, you know, that one week off is the best week off ever. Then I'm like, okay, we need to have that week off. If they have that one week off, and I said, really, I feel fine, I can't tell the difference. So maybe I'm moving to the 21 to the 28 day. But there really isn't a solid answer. And I think the bulk of my patients are on the one week off kind of regimen. As I think it's just easier, and it gives them a week off. And, and, you know, one, one thing I might tell patients, one thing that I would encourage you to talk to your doctors about is, I'm six foot five. And so when I get on an airplane, it's a kind of a pain. But I'm willing when I get on a little small in a puddle jumper, I'm willing to put up with having my knees at my chin, because I know it's a short ride. And that's like induction therapy, that you put up a lot of pain, put a lot of hassle, side effects of the drug, because but it's a short flight that you know, if you're going to transplant, you're only going to be in about four or five months. Or if you're not going to transplant, you'll be in 12 months, then you'll be on maintenance. And so you want to put up with this, like I'm willing to put up a lot of pain on short flight, I'm willing to put up with some pain. So I'm flying to California for Michigan, or flying from Hawaii, I need to be comfortable flying. And maintenance therapy is like that long flight, you have to make the seat comfortable, that I make sure I pay a little bit more money for not first class, I can't afford first class. I haven't even been in first class before. But I'll get the you know, the larger seats and everything, make sure I'm comfortable because it's a longer flight. So when I talked to patients on maintenance therapy, it's like that launch flight, what can we do to make this the most comfortable ride? Because it's the long haul. So I have patients on 10 milligrams, I have patients on five milligrams, I have patients on three, three weeks on one week off, I have patients on five milligrams every, you know, every day. But I find what is most comfortable for that long haul, because thank goodness in 2020, that after that transplant, and that maintenance every that is a long ride to the mile that comes back, you need to make it comfortable so you can enjoy your life. Thank you. Thank you, Dr. Cole. Thank you for being here with us today. We always enjoy having you. But thanks for listening to my you know, it really it, it still is, you know, moving to, to see where things have come. And I do, you know, I know that most of the people here weren't, we're doing other things back in 1999, and 1998, and the 19, you know, in 1991. But gosh, it is it really is incredible what's happened. And, and I would never, never had dreamed that things would be like they are now. And things are going to be so much better. It really is incredible. So thanks for listening to me kind of reminisce about the old days. Thank you. The good time to have my Loma. I really believe that with everything that's going on there. So thank you for being here with us today. You may be interested in other my Loma crowd community events that we do have coming up on Saturday, April 30. We had the Chicago my Loma Roundtable held in Chambourg, Illinois. The morning session is going to focus on introductory my Loma with Dr. Murray Gers. He always gives a great speech on the weeds in the garden. If you haven't heard that yet, you want to tune in for that. And he's also going to be talking about other important issues to patients that have the precursor conditions, newly diagnosed patients or patients that are in their initial treatment phase. It's going to be a good experience, a good, you know, good meeting for refresher experienced patients, wherever you add along the journey is going to be a good meeting for you. The afternoon sessions topics are going to be centered around treatment issues for patients with relapse refractory disease, and how new therapies are being integrated into patient care. There's going to be a great panel of my Loma specialists there. So there's still time to register for that, either the in person event or the live webcast there. Now join us next month on May 27 at two o'clock, we're going to hear from Will Wright. He's an African American man who made an incredible transformation in his diet and in his life. He made this his mission to educate other African Americans on how they can improve their diet and still keep their culture. So Will is going to break down many of the myths associated with a plant based diet, and how we can prepare our meals in a non traditional manner, but still maintain that flavor and goodness that we're accustomed to. I always say healthy eating doesn't mean giving up our rich culture there. Also, Tuesday, May 3 at one Eastern, the my Loma financial chapter, it's going to talk about how to pay your expensive medical bills without going bankrupt. Wednesday, May 4 at 7pm Mountain Time, the health tree moves for my Loma chapter is going to be discussing how Pilates can benefit my Loma patients. The link to sign up for any of these events and even more that I haven't mentioned today is found at the bottom of the slide, and will be sent out in a follow up email within 48 hours of the events completion. So as always, I want to thank our sponsors without whom this would not have been possible. Bristol Mark Squibb, GSK, Genentech, Janssen Oncology and ABBE. And thank you all for being here to help us build a strong my Loma crowd community. I appreciate each of you and hope you enjoy the rest of your day. Bye bye.