(Guest Lecture): September 2023 - Essential Treatment Strategies for Newly Diagnosed Myeloma Patients

So for this, I know you guys have had a lot of slides today, so I thought we could do more of an informal discussion meant to be interactive. The topic that we're talking about in this room are patients with newly diagnosed myeloma. And so some of the topics that we can cover can be types of therapies, duration of therapies, other things like transplant. So really this is an opportunity and I can provide some broad strokes just in terms of what we think of in terms of newly diagnosed patients. Everybody's treatment journey, cancer center is going to have a lot of similarities, but there may be some differences. But I want to kind of go over on a fundamental level some of the things we've heard today about drug combinations. So when we treat newly diagnosed myeloma, in general we use a combination of Now there may be people in this room who have still anybody who is on their first line of therapy is newly diagnosed, okay, because it's a relative term. So even if you've been on that line of therapy and you are on maintenance, you are still on first line therapy. And so the first line of therapy probably in the timeframe that anybody in this room has been treated was probably three drugs or maybe four drugs. And so we use drugs in combination because they are complementary or synergistic in their combination. So lenalidomide, which is Revlimid, Velcade, Bortizomib, and dexamethasone are a classic combination. If you are under the age of 65, those are the classic descriptions of transplant eligible versus transplant ineligible. But the reality is, and those are really for the purposes of clinical trials, any person up to usually age 75 can be transplant eligible. And I think an important question is stem cell collection. We've heard that a lot today. I want to touch on that. And so choosing the combination of drugs was historically based on that. There was a clinical trial that was led at MGH that I was a part of called RVD Light, which is using those same drugs, but at a less frequent dosing schedule. So there's a broad range of triplets. Most recently though, there's been the Griffin study, which introduced the addition of quadruplets, adding a monoclonal protein that targets CD38 to upfront therapy. So that's being done for all newly diagnosed patients to some extent. For younger, more fit patients, that was who was in that Griffin study. So that was where that four-drug combination was approved. For older patients, there was the MYA study, which excluded the Velcade but used those other drugs. And that has become the standard of care or RVD Light. So using dose-reduce of RVD for older patients. But what Dr. Nadeem said is true is there are clinical trials going on to add the fourth drug for older patients. Those haven't read out yet, but we do it in practice, okay, because those drugs are approved, but we change doses. During your first line of therapy, it is okay to modify doses. It is better to be on treatment for the months that we plan to be on than to constantly interrupt it just so that you can get an intensified regimen. I tell people, when you first go on any therapy, whether it be first line, second line, third line, and so on, first it's a one-size-fits-all suit where we put on, we give you the doses that are part of it, and then we tailor it to you. And so the most important thing is the fit of any of these. So really bearing in mind, what are your specific features, whether they are the biology, obviously what dictates some of the considerations. Also, if you have other problems, whether you have something like peripheral neuropathy, which is numbness and tingling in your fingers or toes, do we choose a different dosing schedule for something like Velcata, or do we choose other drugs as our first line regimen instead? So there are general rules that apply that we use combinations, and those combinations may be influenced by your status, like if you are frail. So age is but a number, right? So some 75-year-olds look healthy as can be, and you would take them right into a transplant. Others may have other comorbidities or medical problems that would preclude them, but we really focus on the individual in front of us when we make those decisions. We talked today about stem cells. So stem cell collection is something that we do after a patient has achieved a good enough remission that there's adequate bone marrow normalcy to be able to collect the stem cells. There is no downside to stem cell collection. It is money in the bank, whether or not you use them for a transplant or we keep them in storage for opportunities that come up as are coming up where we treat people with CAR T cells and need to rescue their marrow, there is no downside to stem cell collection. They are good. They don't expire. Your hospital will not get rid of them. So please, if you are offered, even if you choose not to do an autologous stem cell transplant, do store your cells if offered. Now, I'm happy to make this an open discussion about newly diagnosed therapy. Anything is fair game. It's meant to be interactive. I'm sure there are people who have a lot of questions. So if people want to ask, please feel free, because otherwise I can talk forever. Go ahead. So the distinction between smoldering myeloma and multiple myeloma. Sure. So we are an unusual cancer where there is this lead-in phase of precursor disease, which is often incidentally found. We don't screen currently at large for plasma cell disorders. And so this was born out of work done at the Mayo Clinic over decades by a doctor by the name of Robert Kyle who is now in his 90s. And it speaks to longevity where you just stay at the same place year after year. And they amassed huge amounts of data using healthy controls from the population up in Rochester, Minnesota. And what they found is when they screened the blood, 3% of the population over the age of 50 has MGUS, and that number increases to about 7% by age 80. And beyond that, though, he characterized smoldering myeloma. And these are artificial distinctions because it's really just a continuum. But the numbers that he used as he looked back over decades worth of data was that if a person has three grams per deciliter of monoclonal protein, so that M spike, whether it be IgG kappa or IgA, that number means that you're at slightly higher risk of progression to multiple myeloma. The other factor that he identified was having greater than 10% plasma cells in the bone marrow. Some people call this asymptomatic myeloma versus smoldering myeloma. So to your question, what is the distinction? So we use those numbers as the precursor line for smoldering. Multiple myeloma. First of all, what is a myeloma? A myeloma is a tumor of the bone marrow. Multiple tumors of the bone marrow. So if you have imaging that demonstrates, remember I mentioned before lytic lesions, they're very specific because there are other types of lesions and other cancers. So if you have imaging that shows more than one lytic lesion, then that is one of the criteria. The second criteria is high calcium. There are a lot of reasons people can have high calcium. Here in particular, it's because when you have lytic lesions that destroy bone, your bone is made of calcium, it releases calcium, and you can see an elevation of calcium. The third criteria that distinguishes smoldering from multiple myeloma, and there are only four, all right, just for those of you who are, is anemia. And there are many, many reasons for anemia. Iron deficiency, GI bleeding, and so on. When it is due to multiple myeloma, it is because the plasma cells within your bone marrow, normal is 1% plasma cells, smoldering is 10%. When that number starts to get really high, 60, 70, 80, you can imagine there's only a fixed amount of space, so it starts to crowd out the good cells, and the red blood cells get crowded out. And so in myeloma, we define anemia where it's due to actual involvement by the bone marrow and the hemoglobin is less than 10. And the last criteria is kidney dysfunction. Why do patients, so you can have kidney dysfunction, diabetes, hypertension, there are a lot of reasons. When it is due to myeloma and when we call it myeloma kidney, it is a very specific thing. If you think of your kidneys like a filter, because that's what they are, so picture a sieve. If you're trying to put too much sticky protein through it, and you're flushing it with water, at some point, if there's too much protein, you will clog that filter. And so myeloma kidney is a clogged filter. It is an obstructive nephropathy, and it is typically due to be the light chains being extremely high in the thousands. So those are the four criteria that distinguish somebody from smoldering and multiple myeloma. And you may have anemia or you may have kidney dysfunction, but it has to be specific to the plasma cell disorder causing it for it to be myeloma. We have a microphone for those who want to ask questions. So if the diagnosis is intermediate to high-risk smoldering, is there going to be a point fairly soon where that person would be treated outside of a clinical trial, or is it still just clinical trial? Especially for intermediate, strictly clinical trials. Okay, so why are we treating high-risk? And I know this was talked about earlier, but basically, going back to that Mayo work, there are different risk stratifications, and the Pangea model also does that. But it's most compelling, because there are a lot of people, and I've followed people for over a decade, so I think that there's a very true balance to this argument that we'll never have myeloma, despite having a precursor. In fact, the majority of people will never have myeloma. And so where we target the high-risk is where you have a greater than 50% chance of getting treatment at two years, and for some people it's even higher. And so most of us don't like those odds. If you're told that you should at least have the opportunity to pursue treatment if you're at a high risk. But as you go further away from that high risk, the certainty that you would have myeloma becomes less, and the questions of balancing risk of treatment to risk of benefit become even more important. So right now, high-risk moldering is under investigation, and we're only starting to think about intermediate risk. So there are a couple different criteria, and I think that they were talked about earlier in terms of risk stratification. So there are different models that are used. The easiest one to remember is the 20 to 20, which is 20% plasma cells in the bone marrow, and that's a model that has a total of 2 grams per deciliter of monoclonal protein and a light chain ratio of 20 or more. There's a fourth criteria that if someone's had a bone marrow biopsy, you would include cytogenetics as well. And so there are risk calculators that are born out of it that assign numbers to each of those and give you a weighted risk. The Pangea model, which is a calculator online, will do something very similar, and it will give you two-year, five-year, ten-year risk. But high-risk is typically defined as having two or more of those 20 to 20 criteria. You could be eligible for clinical trials, or you can be treated with lenalidomide and dexamethasone. So lenalidomide and dexamethasone is the only combination that is approved for the treatment of high-risk moldering myeloma, and that's been demonstrated to be efficacious in two phase three clinical trials. What's the statistical probability of the offspring of two parents with multiple myeloma? I definitely don't have the answer to that question. And what Catherine was saying is we think that there's potentially, again, risk of disease is somewhat based on the prevalence at large in the population. And so this is not a common cancer. There are only 30,000 cases of multiple myeloma per year in the United States. So the probability that a child of two parents who had myeloma is probably twice as high, maybe four times as high, but it's such an unusual thing that there are no published data that I would know of. So I'm newly diagnosed with multiple myeloma on the fourth drug regimen, and I'm at cycle four. So it's kind of like a turning point. Now I have to figure out, they offered me a trial with CAR T versus doing the stem cell. I'm really responding really well to my numbers are really down 10% of the plasma cells and protein. And so my question is, is that, first of all, if I decide to wait to the spring to do the stem cell or do a CAR T, but I have to do the CAR T upfront because that's the type of what they're offering, that trial. So say if that particular trial, it's not the CAR T, it's an OBATAS trial, which we don't know is effective as the CAR T. And so if I wait, how long will I have a remission, you think, because how deep of a remission with the GRIP and Trial, with those medications, and then being on maintenance, like how long can I do that before I go back and have a relapse? Yes, so everybody is different, and there are a lot of factors that influence the rates, what's called the progression-free survival. Does everybody understand what progression-free survival is, just so we're all speaking? It's the amount of time before your disease progresses. And so when you look at the progression-free survival, there are differences based on some risk that we see. And you would look at the Phase III data from the Griffin study, because that's what your treatment is based on. And so overall, we are seeing that patients are having very durable, long remission. The overall response rates are in the very high 90, close to 100% for that study. So people are responding, meaning that their disease, their M protein is going down by at least half. There are differences, though, in terms of the depth of remission, and that also can dictate the duration of your response. So you could go many years without requiring a change of therapy. Important, and I can't speak to the specifics without knowing the specifics from your actual medical record, but there are some important points that come up in this. So CAR T cell clinical trial, that has to be done after four cycles. Those are dictated by the trial itself. So that's an opportunity, but there's an opportunity cost, right? Because you're asking the question, this is a novel CAR, it's not one that's already, so is it better than what we know of CAR-VICTi or ABECMA? And we don't know the answer to that, but those are the tough trade-offs. So these are hard questions that come up all the time, and unfortunately, there are so many therapies and clinical trials in myeloma that we can never give an answer that can address every single one of these questions. So yes, there's an opportunity cost. However, the good news is, you know that those CAR T cells are available to you for that target, should you relapse. The longer you have a remission, too, the field is going to change. So, you know, when I think about my career, which began in 2012 in the myeloma space, they were just starting to do triplets. There were even people still using doublets. So triplets became a mainstay of therapy. Now we have quads. There was no daratumumab when I started. 2015, there was no CAR T cell, no tuclystumab. So these, the rate of development is so great. And so while it's hard when you're offered a clinical trial, I think everybody would struggle with what ifs, okay? But just also know that we are caught in that amount of time, regardless what you choose, there will be great therapies available to you, and novel ones. The switch from Velcade to Kyprolis, you mean? So, when, sometimes when we switch, and you never got RBD or anything like that, or DararBD, you just... And so sometimes we switch drugs because of toxicities or intolerances. So the good example would be, let's say you were on Velcade and you were getting peripheral neuropathy. We might switch someone to carfilzomib. And so, Kyprolis. So that would still be the same line of therapy if we changed it for toxicity, okay? But if you change it because a patient is having evidence of progression, then that becomes a new line of therapy. So if it's... That's right. That defines a second line of therapy. So when you, when, so if you think of first line therapy, you may be on Darar, lentilin, or linoleum. Darar, lentilin, linoleum, lydimide, indexomethazone continuously. Or you may get DararBD, a transplant, and then maintenance. Or you may get consolidation, maintenance. That's all one line of therapy, okay? So when it is your initial entree, and that is what they are, your doctors are doing to get you in remission, even if there are different things involved, you know, an induction regimen, a stem cell transplant, consolidation, maintenance, even though the drugs may be different, you may just use two or three at some point, as long as they're all the same and there's been no progression, that is one line of therapy. But if you're a disease that monoclonal protein goes up, you have a new bone lesion, and you have to change therapies, that is called second line therapy, or third, and so on. All right, I had a question for you. When you talked about working with doctors, like in another state, I see that the medications, therapies change, and there's all these choices out there. Can you get them as quickly being somewhere else, or do you run out of them, or do you get so many here in this location? No, no, no. So the tough thing in terms of CAR T cells, for example, is slot limitations, and not everybody, community hospitals won't be able to do those. But for FDA approved drugs, there should not be any differences in availability. Your practice may have different preferences. I think we all practice by a little bit how we're trained and the people surround us. So if you go to different hospitals, not in Boston, but if you go around the country, you will see that there are different practice preferences. But the availability of FDA approved drugs, like the immunomodulatory drugs, lenalidomide, pomalidomide, and the diprolis, Velcade, they should be uniformly available. Thank you. So this is really a question about smoldering myeloma, if that's all right. And it has to do with whether early intervention has been shown to extend longevity. And if not, is that due to their just not being dated yet because the studies are so new, or is it because in fact it doesn't increase longevity? So there has only been one randomized study, and this was the Spanish study that led to the approval of lenalidomide and dexamethasone, which was a randomized study that was powered to detect differences in overall survival. It took 18 years for that study to read out, and it just did in April, and did show an overall survival benefit to the combination of lenalidomide and dexamethasone. That study was published based on progression-free survival because we understand in myeloma that people live a long time with the disease. And so overall survival is not a great endpoint for us, so we typically use progression-free, but yes, there is overall survival data for lenalidomide and dexamethasone. I do not think there will ever be overall survival data for some of these newer combinations because it would be meaningful, they are more potent regimens potentially, we can talk about that as well. But 15 plus years, the field, as I just said, is gonna move so differently. It showed overall survival, and it is the only one that's read out, and it just read out in April after I think it was 18 years. So it just gives you a sense of how slow, because I think we often focus on the bad actors, but there's a large world out there of slow-moving precursor disease. I'm in induction diagnosed in last December, coming to the end of my treatment to go on medical maintenance. I donated my cells for the stem cell, but it doesn't look like that's gonna be a good idea for certain reasons, which spikes my question about the CAR T. That can be used if a stem cell transplant cannot be used, is that correct? That is not correct. So right now, the approval for CAR T cell is only for relapsed disease. The only incidence where you can get CAR T cell is in the case that you just mentioned, in a clinical trial. The way that FDA approvals work, and this is to understand the ethics of it, you can only use novel therapies, meaning first in human, in people who have no other treatment option, because that would be unethical if we offered, you know. And so the first approvals are always in patients who are highly refractory. Once you demonstrate the efficacy, the drug or therapy can then march its way forward into the newly diagnosed setting, which is exactly what we saw at DERA2-MAB over the past five to seven years. For CAR T cell, they are now approved and marching their way forward. And the clinical trials that will make them accessible as a standard of care for newly diagnosed patients are happening right now. But they are not currently available as an approved therapy for what you're talking about. What would be the fail mark out of CAR T? Multiple times. So there was, but we believe that the indication for CAR-VICTE will change based on a recently published study so that it will be available earlier. And this is how, unfortunately, it's fortunate and unfortunate. It's a safeguard, but it takes years for things to march forward, but that is happening very quickly, and we've been very fortunate in Milo more where we've gotten a lot of breakthrough designations that the FDA has moved things along for us. And that's not uncommon, but it's there, you banked your cells. So people worry about what the risks are, and this is worth talking about if people are thinking about why not to or why to have a stem cell transplant. And that's a really good topic of conversation, you know, if we're short for those. What are the benefits or what are the merits of doing that? And what are the risks of doing that? And what are the risks of doing that? And we're going to be talking about what are the benefits or what are the merits of doing that? And one of the concerns is that you're introducing, a stem cell transplant is not really a transplant. So if you have leukemia, okay, we get someone else's bone marrow, you have a donor, and we give you their bone marrow, and part of how it works is that their immune system that you've transplanted is actually fighting the leukemia. That's not what we do in myeloma. That's been tried in myeloma, and it's not a security approach, and it actually has higher mortality than other leukemia. So we don't do that unless it's on a clinical trial or in rare cases. What we do all the time are our, our, excuse me, autologous stem cell transplants. And that is where you take your own cells, okay, you save them, and you're given a high dose of Meltlamb, which is an old school alkylating chemotherapy. And the goal of administering that very high dose of that chemotherapy is that it wipes out all the cells in your bone marrow, okay? And the reason that you then get your stem cells back is to repopulate and to regrow your blood cells. Otherwise, too long a period of time would go before they would grow back naturally, putting you at risk for infection. One of the risks, and when you talk about genetic risk, sometimes people have mutations that we don't know what the significance are, but if they get a big hit of an alkylating chemotherapy like that, and I'm, this is what you're trying, yeah, I'm seeing you nod, there's a risk that you could be at a, potentially get a secondary leukemia or myelodysplastic syndrome. And so these are rare, we are learning about these chip mutations is what they're often called. And so that is an important decision point. If you know you have a mutation and you're doing well, then it may be better not to do that, because the low risk may be a higher risk for you with a mutation like that. I just love it when you talk about transplants if it wasn't, it would be a risk for the non- Right, and so, but that's an important, just making sure everybody understands what that transplant is. It's really, it's a high dose of chemotherapy with a stem cell rescue would be a more accurate description. Can I ask my question, like, sorry, can we use the microphone, because we're recording? Oh, sure. No, it's okay, it's my fault. It's okay. If she can go first. All right, sure. Sorry about that. Go on. Okay, it's just the kind of piggyback of what you guys were just talking about. Oh, piggyback of what you guys are talking about with the stem cells transplant. What are the odds, or what is the percentage of using the transplant, other than the risk factor, on survival rates? So the largest study we have is the IFM 2009 study, which is paired with the RVD study led by Paul Richardson at Dana-Farber. And what we saw was that when you get the transplant, there is a progression-free survival advantage, but there is not an overall survival advantage, meaning you don't necessarily, you have a longer first remission, or remission associated, but don't necessarily live longer. There are other data in different studies that do suggest potentially a benefit. The trouble is, the path for myeloma is so long now that the overall survival data becomes obfuscator, it becomes a little bit murkier as time goes on because we have so many new therapies that are creeping in. What I would say is that we know with certainty is that when you get a transplant from those studies, it does lengthen the remission, that initial remission. If you get it at your first relapse, though, you see the same benefit, okay? So you can see, but whether or not that will ultimately translate into longer survival is a little less clear. I'm sorry, I didn't mean to interrupt, I apologize. All right, I looked over at you. I just wanted to understand the difference between collection and transplant. So they go in and they collect just stem cells. Now, so you're brought down to basically zero. You're in the hospital. No, no, no, no, no, no. That's not the transplant. Yeah, I'll walk you through it. So we don't create any confusion on this. So a collection, okay? So what we do, you have to be in a good enough remission. So let's say you start at 60% plasma cells in your bone marrow. We have to treat you so that we get rid of enough plasma cells that when we give you medicines, you will be given medicines. Anybody had a collection in here just by show of hands? Okay, good number. They give you medicines and what those medicines do is they stimulate the stem cells to come out of your bone marrow into your circulation. All right, going back one step further, your bone marrow is mostly in your pelvis. Think of it as the place, it is the nursery for all your cells where they're all growing and at different stages of development. It's the incubator. So you take that medicine and it pushes some of those cells into your body, into your circulation, okay? And then you go to a blood bank, a center, and they hook you up to a machine almost like dialysis where they're filtering your blood. And they sort out the stem cells only, okay? So they're only taking out your stem cells using their molecular weight. It fills a bag, the bag is not that big, okay? It's not taking out your blood. It's filtering just for one cell. Once they reach a high enough number where they have enough cells that they could confidently do a transplant, they stop and they freeze those cells. That is all the collection is. Just to reiterate, it's you get a medicine, pushes your stem cells out, you filter the blood, fills a bag, frozen. The transplant happens in the hospital. You get a high dose of chemotherapy, wipes out your blood counts, and then you get your stem cells back to bring them back up, to bring your blood counts back up. Two very different things and they don't, yeah. You could wait until you're not feeling well or something. It would then, do the transplant, like if they would hold onto the collection until they felt they needed to. No, so we don't transplant people when their disease is extremely active. So this is also really important. The use of a transplant is to deepen the response, okay? So if someone had disease that was not well controlled, we wouldn't go right into a transplant. Let's say you relapsed. You've been on Revlimid maintenance for years and years and years. All of a sudden, your disease spiked up fast or something. We would control it again and then do the transplant. You don't go into a transplant when your disease is not well controlled. Okay, I would like to have us give a round of applause to the doctors.