(Guest Lecture): March 2024 - Advancement of Life-Changing Care for the Newly Diagnosed Myeloma Patient

Thank you everyone. It's a pleasure to be here and thank you for taking time out of your Saturday. So today I wanted to talk about the advancement of life-changing care for the newly diagnosed multiple myeloma patient. I want to start with some basics in terms of what is myeloma, work up for myeloma, staging, and also give a little bit of a primer on reading some clinical trials, some of the common terms that come up, and then we'll talk about some of the most relevant trials for newly diagnosed patients. I'll focus first on induction, which is treatment up front, followed by the transplant process and whether or not patients should get transplants, how to decide, and lastly we'll touch on maintenance. So a lot of goals, we'll see how much we can get through. But first I wanted to talk about what is multiple myeloma. So inside of our bone marrow we make all of our different kinds of blood cells, including our plasma cells. Our plasma cells are a normal part of our bone marrow and they make antibodies, which are important to fight infraction. What you see here on the right is an example of an antibody. It has two components. You have your heavy chain, which can be IgG, IgA, IgM, IgD, IgE, and that's the blue. And then you also have your light chains, which are your kappa or your lambda. In multiple myeloma you have abnormal plasma cells. These abnormal plasma cells produce one particular kind of antibody in excess. And so when you talk about your myeloma you may hear IgG kappa, IgA lambda, et cetera, and that's where that comes from. All right, so in terms of workup, so you can see that there's an extensive panel of tests that you may get at the beginning. In order to think about first how patients come to attention with multiple myeloma, sometimes these abnormalities are detected when a doctor is just checking for regular labs and detects anemia, detects an abnormal creatinine. However, other times patients will come in with symptoms. So patients might have fatigue, patients might have bone pain, et cetera. This is sort of a panel that is often done. Your doctor will do a complete blood count to assess for anemia. Your doctor will do a comprehensive metabolic panel. The labs there of interest are your calcium, your kidney function, and also sort of your full electrolyte panel. What you see here on the top right is an S-PEP, or a serum protein electrophoresis. And what that tells us is a quantitative number of how much of this abnormal protein there is. In our body we have different types of protein, albumin being the predominant one, but what you can see here is that there is an extra peak, this gamma protein, that is seen here and you can get a measure of how much of that there is. In contrast, there's the immunofixation. The immunofixation is a qualitative test. So remember when we were talking about the antibodies, the immunofixation will tell us which type of protein we're dealing with. And then again, there are different types of myelomas, IgG kappa, IgA lambda, etc. So what we will do is we'll measure the amount of free light chains, kappa or lambda, and typically they should be in an equal amount. And we measure the immunoglobulins and we can use those numbers and track them over time. At diagnosis, your doctor will also check a beta-2 microglobulin, an LDH, and an albumin, and those are part of the initial staging process. In terms of urine tests, sometimes patients who have a significant amount of protein in the urine might have symptoms like bubbling urine, foaming urine, but regardless, you should at the onset assess for how much proteinuria there is. So your doctor may do a squat urine test or a 24-hour urine to measure the protein and also to run that UPAP, which is a similar test as the serum protein electrophoresis and an immunofixation. At diagnosis, a bone marrow is part of quantifying how many myeloma cells there are. The bone marrow biopsy has a few different components. The aspirate, which is the fluid, the core, which is a small sliver from the bone marrow itself. The bone marrow will give us information about cytogenetics and FISH, which we'll talk about. And then lastly, there's some form of imaging that's done. We don't do a lot of just x-ray skeletal surveys anymore, so we typically are doing a CT skeletal survey or a PET scan. All right, so I do want to use some pictures to give a sense of what myeloma may look like. So here you have a PET scan of a patient, a sort of diffuse or salt and pepper type of spots throughout the bone marrow. And you also can see some focal lesions, in this case at the humerus, which is being shown by C and D, and in the left side of the sacrum. The PET scan is helpful because it shows us how bright a lesion is, how active a particular lesion is. And then you can also use imaging to track response. So here you have a patient with multiple lesions. The arrow is pointing to a cytofractor, but you can see that in this particular example, this is a patient who got induction chemotherapy followed by a transplant, that there was a reduction in these areas that are lighting up, and the PET scan subsequently looks significantly better. Bone marrow biopsy. So on the left, you can see these plasma cells. These are the abnormal cells that the pathologists can look at and stain for, and they'll give you a percentage on the bone marrow biopsy of how many plasma cells there are. And then on the right, you see two different techniques that are done. One is a karyotype, which looks at the chromosomes. We normally have two copies for each chromosome and a total of 23 chromosomes. The karyotype can tell us if there's missing numbers or extra. And then the FISH, or the fluorescent in situ hybridization, uses a special fluorescent DNA probe to look to see if there's other changes. So you can detect translocations where there is a switch in different parts of the chromosome, smaller levels of deletions. So this is being done at diagnosis. So I did want to also talk about the fact that myeloma comes on a spectrum. So starting with the very right. So the presence of any what we call CRAB features is considered to be multiple myeloma. So the presence of an abnormal calcium, an abnormal kidney function, abnormal hemoglobin or anemia, and then one or more lytic lesions by CT scan or a PET scan. So that is considered sort of classic myeloma. However, over time, the definition of myeloma has evolved. Now we do include what we call the slim features, the S being 60, so 60% myeloma cells in the bone marrow, L being light chain. So when we look at involved versus uninvolved, so if your predominant light chain is a kappa, then it's kappa divided by lambda. If your predominant light chain is a lambda, it's the other way around, lambda divided by kappa. And then also an MRI, if there's more than one lesion, that's five or more millimeters. Those are now considered to be diagnostic criteria for myeloma. The general approach is for people who are either early active myeloma or full on myeloma. These patients get treatment and then the patients who are on the left side, the MGUSs and smoldering will be monitored. When we look at the percentage of myeloma cells in the bone marrow, if we have less than 10%, that's considered to be MGUS and 10 to 60% is considered to be smoldering. And again, MGUS and smoldering are patients who don't have any of these evidence of end organ damage. So then staging is important too and sometimes patients come into it with sort of an understanding of what staging is. I mean, for example, solid tumors like lung cancer. In myeloma, we don't do stage one to four. There's a few different staging systems. Probably the most commonly used is this revised international staging system or RISS. It includes a few different variables. So your beta-2 microglobulin, albumin and LDH. So these were parts of the labs that your doctor will do at diagnosis and also it includes cytogenetic risk. So the high risk features that are included in this staging system are deletion 17P, translocation 414, translocation 1416. However, there are other features as well that are considered to be high risk, including So I also wanted to mention in terms of looking at clinical trials, these types of terms will come up. So progression free survival. So basically we're looking at, you know, from the time point a patient starts treatment, how long does that treatment work until it stops working and you have to move on to another type of therapy and then overall survival. And that may be reported in months or years. And for simplicity, I've used years just so it's easier to look at it in the subsequent trials we'll talk about. And then a Kaplan-Meier curve. So they can make Kaplan-Meier curves for both progression free survival and overall survival. And you have the time along the x-axis. And then this is one for survival, but you can also do progression free survival. And you have sort of a kind of a ladder type of image and you can see the outcomes from two different treatments here. The wider the space, it tells you that one treatment is better than the other. Of course, in these trials, sometimes patients stop the treatment for, you know, various reasons they drop out of the trial, they have side effects, etc. So also in terms of looking at clinical trials, and also your doctor may use these terms, depth of response. So this is a little bit oversimplified, but partial response is when, you know, if a patient does have a measurable M-spike, you have a 50% reduction in that. Very good partial response is a 90% or better reduction. Complete response is when the M-spike is negative, that immunofixation is negative as well, and the bone marrow has less than 5% myeloma cells. And stringent CR is everything in CR plus the light chains I've normalized. And the lower you get, sort of the deeper the response is. And then this term MRD, I'm sure you've heard of or has come up in some conversations. So MRD negative means no residual myeloma cells. And this is using, you know, a variety of techniques. You can use flow cytometry, you can use next generation sequencing, and MRD positive is that there still are some residual myeloma cells. And I like this graph because what that is showing is that, for example, in a patient who had a partial response, they didn't get to as deep of a response, and they came out of remission more quickly versus, you know, patients who had a deeper level of response might be able to, you know, stay at that level of response for longer. And really the goal is we try to get as close to MRD negative as possible, but, you know, and over time you can see that patients may have deepening of response as they get further treatment. So why do we treat? One is to prolong survival. Two is to also prevent organ damage. So as we talked about, some of the myeloma features are the presence of kidney dysfunction, bone lesions, and some of those can cause symptoms. People can have back pain, nerve damage, et cetera. So we're trying to prevent as much of that as possible. And then we're always working towards the cure. So looking at data over the decade. So what you can see is that this is our first Kaplan-Meier curve that we'll look at, that survival has continued to improve decade by decade. And the reason is that we have more and more treatments available. So you can see that as the decades have gone on, we have more categories of drugs available. In the past there were just steroids and alkylators. Transplant came along. And then now a lot of the modern therapies we use, the immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and then now also CAR T cells and bispecifics. So I wanted to talk about the myeloma toolbox and talk about the different classes of drugs and the basic mechanisms. So first up you have your proteasome inhibitors. So these include drugs like bortazomib or Velcade, hemixazomib, urnanlaro and carfilzomib or carpolis. So the proteasome is a part of the cell that recycles protein. The purpose of these drugs is it inhibits the proteasome. The cell's recycling system is altered. And as a result, you have extra proteins that build up that's toxic to cells and cause these myeloma cells to die. Your immunomodulatory agents or your IMIDs, so ravelmid and pomelist are the most common ones used. They either both directly kill cancer cells and also help your immune system better fight cancer. So it's sort of an immunomodulatory effect. And then you have your monoclonal antibodies. So these are very specific to a particular target. For example, daratumumab and esatuximab specifically target CD38 cells on plasma cells. And then you have your alkylators as well like cyclophosphamide and melphalan, which is now used for transplants, which alter the DNA. And as a result, it leads to abnormal DNA replication and cell death. These drugs can be used in newly diagnosed multiple myeloma and then also can be used sort of in the early relapse space. And then for late relapse, there's other therapies available, which we'll talk about later today. So in terms of our treatment, I wanted to first talk about induction. Let's see where we are with time. So I put this up there just to show that there's tons of treatment options available. And it's really a matter of trying to find the right regimen for you. And over time, the landscape for myeloma has evolved such that we've gone from using two drugs to three drugs to now four drugs with the goal of trying to get better remissions. But we also have to keep in mind the added side effects of combining more therapies. So I wanted to talk about the PERSIUS trial. This was presented at ASH in 2023 in December. And it looks at this combination regimen, deritumumab revlimid velcaden-dex compared to revlimid velcaden-dex. This was already previously studied in the Griffin trial, but that was a phase two trial. The PERSIUS trial is a larger trial of 700 patients and it's international. And the primary endpoint was progression-free survival. So these are patients who are 18 to 70, transplant eligible. And we talk about this term ECOG. And it just means sort of general fitness and how able a patient is to tolerate treatment. So in terms of the trial design, so patients got either DERA, revlimid velcaden-dex for four cycles or the same regimen without the DERA for four cycles, then went on and got a transplant and then got two cycles of consolidation with the same regimen that they got at induction. And then ultimately went on to maintenance. So the two maintenance strategies, one was the DERA and revlimid, and then if patients got to that goal of MRD negative, then the DERA was stopped and they were continued on the revlimid alone. And then the other option was in the patients who were in the revlimid velcaden-dex arm, they just were put on revlimid maintenance until progression or side effects. And this MRD guided approach was different from the Griffin trial. In terms of the MRD negativity, what they showed was that patients who got the DERA revlimid velcaden-dex had a deeper remission. And what they mean by that is if you look at the graph on the left, we talked about the levels of response of CR and stringent CR. The red you see, the four drug regimen, the percentages are higher there. So you can see that these patients were having a better response than the patients who had the three drug regimen. And then in terms of MRD negativity rate, you can see that this improves over time in both populations, but that overall the MRD negativity rate was better in the four drug regimen. And it's measured here at two different scales, at 10 to the minus five and 10 to the minus six. In terms of efficacy, so after a mediate follow-up of 48 months, the patients who received the four drug regimen had an improvement in progression-free survival. What they're citing here is that at the 48-month mark, the patients who got the four drug regimen, 81 percent had not progressed compared to the three drug regimen, 67 percent had not progressed. And it's too early to make any conclusions about survival based on this. I also wanted to briefly bring this up, the Endurance trial, which looked at a regimen of Kyprolis Revlimid Index compared to a Revlimid Velcade Index. So here, you know, looking at if using Kyprolis rather than Velcade makes a difference, so comparing two different three drug regimens, notably high-risk patients were not included. And really the main takeaway here was that the side effects were different. So you have to think about the pre-existing patient features when choosing a regimen. So carfilzomit was not associated with neuropathy, that's often seen with Velcade, but had more sort of cardiac toxicity. So shortness of breath, high blood pressure, and then very rarely heart failure. In terms of progression-free survival, those curves essentially overlap, as do the overall survival. So this study concluded that in patients who are not high-risk, that both of these regimens are reasonable options. Some may prefer the KRD regimen in people who have high-risk features. And then I wanted to transition to talk about the ISKIA trial, which was also presented at ASH in 2023, again, sort of fitting with the theme of adding more drugs and seeing if we're getting a better response. So it looked at isotuximab, Kyprolis Revlimid Index, and isotuximab is like daratumumab, it's an anti-CD38 monoclonal antibody. It's comparing the four versus the three. Looking at MRD negativity rate. And these are patients who are 18 to 70 and transplant eligible. And without going into all the details, you can see overall that people are either getting the four-drug regimen or the three-drug regimen up front, go for a transplant, and then get more consolidation and sort of a light consolidation afterwards. So it is a pretty intensive regimen that this trial was looking at. And then this is still very preliminary information. So they had 20 months of follow-up, and what they saw was that in patients who got the four-drug regimen, they had a higher rate of MRD negativity. I wanted to talk about the MYA trial as well. So this is considered to be sort of a lighter regimen. It emits the Velcade that is used in the Griffin trial and Perseus trial. So it's looking at dararhevulamidexamethasone versus revlimidexamethasone. This was intended for older patients. In the trial, they had patients who were 65 and older or those with other medical problems. And these patients were considered to be transplant ineligible. Notably, there is excellent responses in terms of progression-free survival, where the patients who got the three drugs had a progression-free survival of five years compared to three years in the doublet. And the patients who got the triplet drug also had a higher rate of MRD negativity. So this is really a great outcome in patients who didn't go through the transplant process. I also wanted to bring this trial up. So a group of doctors in France looked at revlimidexamethasone versus daratumumab and revlimidexamethasone, and really the goal to see if we can get away with doing less Dax, especially because, as many of you know, Daxamethasone can have a lot of long-term side effects in terms of bone health and blood sugars and also short-term in terms of, you know, mood, sleep, anxiety, et cetera. So what they showed here was that the patients who got the daratumumab and the revlimidexamethasone was admitted actually had a better response compared to those who got the revlimidexamethasone. And it's a better response, a quicker response, and more MRD negativity. So in terms of choosing an induction regimen, it really should be a personalized decision between you and your doctor. Things to think about are your age, the genetic features of the myeloma, overall fitness, really whether or not you're a transplant candidate, other medical problems. And you know, you have to think about the side effects of each of the different therapies. And then also convenience is important as well. So some of these are IV versus pill, and then some of them are more intensive in terms of going to the infusion center. So then the next question is, you know, to transplant or not to transplant, and the transplant process. So many of you have already been through this, but it involves first the collection process, where we give shots to increase your production of stem cells and have the stem cells leak out into the blood. Then the collection process, which may take one day, which may take three days, where a patient is connected to a machine that's similar to a dialysis type of machine. The machine collects blood, separates out stem cells, and gives the rest of the blood back. The patient is then admitted to the hospital. It can be done, you know, the week post, or it could be done, you know, months later if the plan is to defer the transplant upfront. And the patient gets chemotherapy, high dose melphalan, followed usually two days later with the reinfusion of the stem cells. The most important thing I wanted to relay here is that, you know, when you first get diagnosed, there's a lot of information. You don't need to make a decision on day one whether or not you're going to have a transplant. You can see how things go in terms of treatment. You can let it sit. You can get more information from other patients and your doctors before you decide. If a patient is going to go through a transplant, we will do a full assessment of organ function to make sure that you're healthy enough to get a transplant. Usually, you know, the transplant process, we tell patients that it involves a two-week stay in the hospital and side effects of the melphalan itself. It can be, you know, low energy, nausea, vomiting, diarrhea, mycositis. And then really the reason we're following you in the hospital is that, you know, your blood counts will go low. You'll need transfusions and there's a risk of infection. The, you know, going through a transplant involves time off work, caregiver support, and then, you know, we cite sort of a three-month recovery process after which we start talking about starting on maintenance therapy. So I wanted to bring up that in terms of the data behind transplants. A transplant is still considered to be standard of care in patients who are eligible. Sometimes patients may not be eligible because of other health issues. However, you know, the determination trial looked at progression free survival benefit and showed that in all comers, patients who did go through a transplant had a five and a half year remission versus three point eight years in those who didn't. And this difference was especially marked in patients who were high risk where the difference was four and a half versus one and a half years of remission. Although the overall survival curves overlap, this trial wasn't studied for the primary end point of overall survival. So the question of is transplant right for me? Again, this is a personal decision. Similar factors to consider in terms of age, fitness, genetic features of your myeloma, other medical problems, organ function, and that may impact, you know, dosing of melphalan, for example, how well you did with the induction, and then also how you responded to the induction. And then one thing I wanted to get across is if you're unsure, you know, definitely consider the option about at least banking your stem cells. And, you know, people who have been extensively pretreated, sometimes the collection process is harder if you wait many, many months. So if you have the option to, you know, at least consider banking your cells. And then just last couple of minutes on maintenance. So maintenance ravelemid is often one of the mainstays of treatment. There's data that shows that maintenance ravelemid prolongs survival many years down the line. This study on the left is looking at ravelemid versus placebo and showed the progression free survival benefit of three and a half years versus two years in a hazard ratio of 0.5. And, you know, there's been data across multiple trials that have showed that maintenance ravelemid actually prolongs survival. So there are side effects associated with it, as many of you know, and sometimes dose reduction and changes in schedule are required. Doublet maintenance, so this is a question that sometimes comes up as well. So sometimes in addition to ravelemid, we'll use a second drug as well, such as daratumab or others. Some trials like the Griffin trial gave ravelemid indefinitely but used two years of daratumab maintenance sort of as fixed duration. Now some trials are looking at an MRD adapted strategy, meaning, you know, doing ravelemid continuously but, for example, assessing MRD status at the two-year mark to assess whether to continue the dara or to stop it. So more to come on that. I want to just put this up there for your reference, but now a lot of the therapies that you'll hear about later today, so bispecifics, CAR-T even, which were normally thought of as therapies for people who have failed multiple initial therapies, these therapies are now being studied in the upfront space. So more to come on that. So I wanted to thank you all for coming on to thank the patients and caregivers for everything. And I wanted to thank the UCSF Myeloma team, the other doctors, nurses. It's really a collaborative effort. The BMT coordinators, social workers, nutrition, you know, everyone. So thank you, and thank you for spending your Saturday with us.