Impact of High-Risk Cytogenetics in Primary Plasma Cell Leukemia | Wilson Gonsalves, MD | #ASH24

Hi, my name is Wilson Goncalves. I'm a hematologist and oncologist at the Mayo Clinic in Rochester, Minnesota. I primarily am involved in the field of plasma cell disorders such as multiple myeloma, primary plasma cell leukemia, amyloidosis, and so forth. I'm here today at the ASH 2024 annual meeting. It's an exciting time to be here. We're presenting various research that we've conducted over the last year. The one I wanted to highlight today was about primary plasma cell leukemia. We specifically have a research project titled The Impact of Multiple High-Risk Cytogenetics on the Overall Survival Outcomes of Patients with Primary Plasma Cell Leukemia. So just some background for the audience. So primary plasma cell leukemia is a very aggressive variant of multiple myeloma that roughly accounts for about 1 to 2 percent of all multiple myelomas. It gets a bad rap mainly due to the poor survival outcomes that have historically been noted for this condition. Our research really wanted to delve into what has changed in the outcomes of this quite rare condition given that so much of the treatment landscape has changed in the field of multiple myeloma. So for one, with the advent of novel agents and quadruplet therapies, have you made a dent in terms of improving overall survival outcomes? And what is the impact of disease biology on this condition? So more background is the definition of primary plasma cell leukemia really got redefined recently in 2021 where the cutoff for calling someone as having primary plasma cell leukemia has been changed from needing more than 20 percent circulating plasma cells in the peripheral smear to just 5 percent or more. As such, trying to understand the natural history of the disease now with this new definition is key. At the same time, we've also realized the genomic biology of multiple myeloma dictates the outcomes of patients at the end of it all. And so we've learned that the presence of multiple high-risk cytogenic abnormalities in multiple myeloma is an adverse prognostic factor, but we don't know whether that same aspect applies for primary plasma cell leukemia patients. So as a result, we took a stab at it with our cohort of primary plasma cell leukemia patients we've treated at the Mayo Clinic Comprehensive Cancer Center since 2014. We chose a population of this that's very homogeneous. They all had access to novel agent therapies. About half of them got quadruplet-based induction therapies with a CD38 antibody, a proteasome inhibitor, an immunomodulator, and dexamethasone. So in total, we had about 89 patients in here in this very rare subset. Now in that subset, some classic features which we've known for a while, we observed was that almost half these patients had the translocation 1114 abnormality, which is a key feature of primary plasma cell leukemia. And then when we delved in to look at the outcomes and how these high-risk features play a role here, we defined high risk by having any one of the following cytogenetic abnormalities, either deletion 17P or monosomy 17, a translocation 414, a translocation 1416, or any chromosome 1q abnormality. And as such, when we use this criteria, we were able to categorize patients as those patients who have none of the above, and so they truly had standard with cytogenetics. So these are primary plasma cell leukemia patients with no high-risk features. And then we had those primary plasma cell leukemia patients that you could put in two buckets, those who had only one of these cytogenetic abnormalities and those who had two or more of the cytogenetic abnormalities. And interestingly, you can really see the heterogeneity even in this rare subset. So as much as we say that primary plasma cell leukemia is an aggressive, unfavorable characteristic of multiple myeloma, clearly when we looked at the overall survival outcomes of those patients who had no high risk cytogenetics, so these were the patients that we would call standard risk cytogenetics, their median survival was well over 100 months. So we're talking about something close to nine years of a median overall survival in the era of these novel agents. On the flip side though, those patients who had one cytogenic abnormality and no more than one, their median overall survival was somewhere around the four-year mark. And those with two or more who truly are the bad actors, they had a little less than two years of a median overall survival. This really helps us kind of redefine as to who is this subset of primary plasma cell leukemia patients that we really need to tailor on next-generation therapies or clinical trials towards. And more importantly, also identify those patients who perhaps by being labeled as primary plasma cell leukemia and feel like they have a very adverse outcome in the future, shine some light on maybe it's not just the number of circulating plasma cells you have in the blood, it's truly the disease genomic biology of these plasma cells that really dictate the outcomes. And perhaps those patients can actually have as good of an outcome like a standard risk multiple myeloma patients. So I hope with this research we can further refine how we think about the disease biology of primary plasma cell leukemia and not just limit it to just the number of circulating plasma cells with an arbitrary cutoff, but actually focus more on the disease biology that would be dictated by genomic biology here. Our next steps in all of this is to really try to validate some of this work with other cohorts from other centers. And then take a deep dive into the disease biology of these very aggressive primary plasma cell leukemia patients. Some recent literature has already corroborated some of our findings. So for one, clearly genomic at the level of the RNA or transcriptome have already suggested the same feature that there are some patients who actually do quite well with primary plasma cell leukemia. And excitingly, it matches the cohort of patients that we have in our group too. Our standard risk patients with no high risk cytogenetics, they were predominantly patients with a T1114 translocation and no other high risk cytogenetics. And that's exactly what other institutions have found too. So we hope again now with all this data coming out, we can move the needle forward in terms of next steps of care and understanding disease biology and planning future therapies and clinical trials and so forth. I think that one of the, I would call, earlier follies in our clinical trial design was excluding patients with primary plasma cell leukemia with the thought that, all right, this is just a different entity and we want to kind of focus on the bread and butter, multiple myeloma. But truly what we need to show here is that the subset of primary plasma cell leukemia with these high risk cytogenetics or multiple high risk cytogenetics, they can actually be included into some of those newly diagnosed trials, especially when they're tailored to high risk patients. And the nice part is over the last few years, you're starting to see that change take place. Like for example, there was the optimum study by the folks in the United Kingdom that included patients with primary plasma cell leukemia in that group. We have current ongoing trials specifically for high risk multiple myeloma that specifically allow patients with 5% or more circling plasma cells to enroll. And I think this is the step that really all future clinical trials need to take. And knowing that that's the only way to move the field forward, it's the only way to get these patients to get access to some of the best novel therapies up front. I think that right now in the phase, especially since some of the phase three clinical trials have established that there's a standard of care for myeloma, I think bare minimum they should be getting that. But I want to say that there is nuance in this. So if you see enough of these patients, sometimes you have that clinical intuition that their disease is really in that very aggressive subset. They have features that you worry that whether even the quadruplet is good enough. And in those particular patients sometimes we may have to up the ante and actually do some of the more high-dose hospital-based intensive induction chemotherapies to get them to stabilize and then go on the quadruplet. I think we are out of the era of debating for primary plasma cell leukemia with aggressive features of whether we should do doublets or trippers. The only reason maybe we would consider that is when you look at the other clinical factors. If somebody's too frail, they can handle that therapy and so forth on there. But if you take somebody with a very good comorbidity score and who's able to tolerate therapy, bare minimum quadruplets, but know that the clinician sitting in front of the patient sometimes will have looking at various features. If there's extra medullary disease, very high LDHs, the proliferation rate of these cells are very high and says, I'm not sure this is going to chip away fast enough for this. Do I need to calm the storm down first and then get you to the quadruplet therapy? So I think when we take just a philosophical standpoint on how to tackle this problem, our first thing we need to do is understand the problem and define it. And I think we have done quite a lot of work that we are better understanding it. So in the subset of primary plasma leukemia, if we focus on those with multiple high risk cytogenetics on there, those with this median overall survival of two years, and now take that cohort and delve in further as to why do they not do so well. And one of the key features is trying to get them to undergo those deep permissions, but not just deep permissions, but durable deep permissions. And I think this is one of those things where you need to use the phrase of, if all you do is what you've done, all you'll get is what you got. So I think we really have to come up with innovative ways of maybe moving some of our most promising therapies earlier in this particular subset. Like for example, in our clinical practice, we start to get a sense, a clinical sense that this is that subgroup that we're dealing with. Perhaps once they're progressing or so on, let's just say often autologous stem cell transplant, we need to start thinking of whether this is the subset of patient that you would probably want to get to some of the more exciting novel immunotherapies like CAR T cell therapy, or by specific antibody therapy, be able to get those sustained durable responses. Now only good prospective randomized clinical trials will help answer that question, but we have to start somewhere. But I think the future will be in that direction. Thank you to Health3 for doing all this and raising awareness of primary plasma leukemia. I think it's a person, I think it's highly underserved from, you know, the last two, three decades here. But you know, I think we're getting better at understanding the biology. I think some of the movements that have taken place in the last decade to redefine the bar for calling somebody primary plasma cell leukemia, and knowing that it doesn't matter whether you had you needed 21% or 18% that was still primary plasma leukemia. That's a huge shift because it's hard to study things when the population or the incidence is very, very low. And so if the bar is really the same, whether you're at five or 20, which with multiple studies have shown that, then perhaps we improve the chance of actually conducting studies in real time that would help this particular population. And then with everything that has come out with novel therapies, with some immunotherapies like CAR T, by specific antibody, several of these patients I've talked about in our research have actually, I think, even done well, even with high risk cytogenetics, because they've been able to access some of those therapies. And I think that's a big, big factor, having access to some of these key therapies.