Experts in the field of multiple myeloma gathered to discuss treatment options, including bispecific antibodies, CAR T-cell therapy, and current and future FDA approvals for treatments.
CancerNetwork® hosted a panel discussion on multiple myeloma as a part of a Satellite Sessions program focused on Levine Cancer Institute. The program brought together experts from the Levine Cancer Institute’s main center in Charlotte, as well as from Lincolnton and Morehead, to discuss the benefits and consequences of using bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy for patients with multiple myeloma. The panel also recently discussed FDA-approved treatment options for patients who have received prior lines of therapy.
The panel was led by Peter Voorhees, MD, chief of the Plasma Cell Disorders Division at the Levine Cancer Institute in Charlotte, North Carolina. Panelists included Kwabena Osei-Boateng, MD, a medical oncologist from Lincolnton; Amy Soni, MD, a hematologist and medical oncologist from the main campus; and Reed Friend, MD, clinical assistant professor at Wake Forest University School of Medicine.
Voorhees: For patients who have relapsed numerous times and are starting to run out of treatment options for their disease, we have 2 FDA-approved products: we have idecabtagene vicleucel [Abecma; ida-cel],1and we have ciltacabtagene autoleucel [Carvykti; cita-cel].2 We also have our first bispecific antibody, teclistamab-cqyv [Tecvayli].3 All of these are directed against B-cell maturation antigens (BCMAs). At what point would you consider referring a patient to someone for consideration of CAR T-cell therapy or a bispecific antibody?
Osei-Boateng: Typically, when all 3 treatments, like the immunomodulatory drugs [IMiDs], the proteasome inhibitors, and the monoclonal antibodies fail, my thought process is to send them [to receive CAR T-cell therapy] early because I know the logistics of getting [the treatment], so sooner is always better than waiting. I’m an early referrer.
Voorhees: That’s the right thing to do because, especially with CAR T-cell therapy, there are a lot of logistics involved regarding scheduling patients for apheresis, the collection of the T cells. There’s the manufacturing process, and there’s a lot of coordination of care that comes into play before apheresis. For example, what regimen are we going to use to control the disease in the lead-up to apheresis? When are we going to stop treatment prior to apheresis? We like at least a 2-week washout from chemotherapy before we do apheresis. There are certain drug classes that may impact the manufacturing process as far as the CAR T cells themselves, such as alkylating agents. We try to avoid those when we can. There may be circumstances where it’s unavoidable, and we have to use them. When we have a choice, though, we like to avoid the alkylating agents prior to apheresis. As far as the manufacturing process, for ide-cel, it’s about 4 to 6 weeks from apheresis to the time that the [patient receives treatment]. For cilta-cel, it’s about 5 to 7 weeks. Patients are typically going to get 1 to 2 cycles of bridging therapy. There’s coordination of care that’s involved in that as well, so there’s a lot of reasons to refer these patients sooner rather than later.
One of the challenges that we run into is the label for all 3 of these agents, ide-cel, cilta-cel, and teclistamab. The FDA has approved these therapies for patients who have had at least 4 prior lines of therapy. If patients tolerate a treatment, that means that they’ve relapsed 4 times before they’re going to be considered for treatment. There are going to be different lines of therapy that are used more frequently because of toxicity issues, and you move from one to the next. However, that creates a challenge. It’s this triple-class refractory group of patients that we want to refer for these potential therapies, but typically, a patient is classified as triple-class refractory after they’ve had 2 prior lines of therapy.
Friend: It becomes more challenging with everyone using the quadruplet therapy up front.
Voorhees: We run into this challenge all the time. This is where early referral makes a lot of sense. What strategy are you going to use to get yourself to that fourth line of therapy and be able to use teclistamab or one of these BCMA CAR T-cell therapies? That an important consideration.
Voorhees: I want to talk about 2 phase 3 studies that have recently been published in the New England Journal of Medicine. The first one that came out was the phase 3 KarMMa-3 [NCT03651128] trial.4 This was a study that looked at ide-cel vs standard-of-care therapy [SOC]. There are 5 different regimens that they could choose from for patients with multiple myeloma who relapsed earlier. Specifically, patients had to have had at least 2 prior lines of therapy, be lenalidomide [Revlimid] refractory, and have been exposed to prior daratumumab [Darzalex]. Since most people do not discontinue daratumumab because of toxicity, because it eventually stops working, most of the patients in the study were not only lenalidomide refractory, but they were also daratumumab refractory. A good proportion of them were proteasome inhibitor refractory as well. With all of that in mind, this study demonstrated a strong progression-free survival [PFS] advantage with the use of ide-cel over SOC therapy. The SOC therapy had a median PFS of about 4.5 months. For those who received ide-cel, it was about 13.5 months.
We now have a more recent set of data from phase 3 CARTITUDE-4 [NCT04181827] trial.5 This was the topic at the American Society of Clinical Oncology (ASCO) meeting and at the plenary session at the European Hematology Association (EHA). This study looked at cilta-cel vs SOC. The 2 SOC regimens were daratumumab, pomalidomide [Pomalyst], and dexamethasone, or pomalidomide, bortezomib [Velcade], and dexamethasone. [Patients] could choose one or the other and were randomly assigned again to cilta-cel or one of these 2 strategies. In this study, data showed that the response rates and depth of response were better with cilta-cel, just like it was with ide-cel. The PFS was about 12 months for those who got SOC therapy, and it had not been reached for those who received cilta-cel. The HR for PFS in this trial was in the high 0.2 range. It was more than a 70% reduction in the risk of progression or death, which garnered a lot of attention. What are your thoughts about these data sets, and how we might see CAR T-cell therapy being used in the future?
Soni: Impressive data, certainly. I don’t have personal experience with it, but I wonder about using it earlier during myeloma treatment.
Voorhees: With CAR T-cell therapy, but also with any new treatment, people are hesitant to use it earlier because they want to be able to save it for relapse. [The question becomes], what am I going to use when this patient relapses after CAR T-cell therapy? What are your thoughts about that? If the FDA likes what it sees, and we get an approval for ide-cel in patients with 2 or more prior lines of therapy, or we get an approval for cilta-cel in patients with 1 to 3 prior lines of therapy, are you going to gravitate toward using these agents earlier or are you going to save them for later?
Friend: It’d be very appealing to use it earlier if we have bed availability. If it were a perfect world, then putting it earlier in the treatment algorithm is something that we should do.
Voorhees: There are logistical challenges to CAR T-cell therapy in patients who are heavily pretreated. This is a group of patients who may not have good drugs to control their disease before they get apheresis for CAR T-cell therapy. They may not have adequate therapies for bridging treatment to control their disease. The larger the burden of disease going into a CAR T-cell infusion, the worse the adverse effects [AEs] are going to be, the more severe and protracted the cytokine release syndrome [CRS] is going to be, the higher the likelihood of neurologic AEs, and the higher the likelihood of cytopenias and more prolonged cytopenias. With that comes the risk of infection. When you have drugs available to control the disease, both before apheresis and during the manufacturing process, and the burden of disease is low going into CAR T-cell infusion, it is so much easier for the patients. In the early relapse space, we’ll have drugs that we can use to manage the disease while we’re getting them scheduled for apheresis and while we’re in the process of manufacturing those cells. If the indication changes for both products, that will be a game changer, with the caveat being that there’s going to be more patients that are going to be eligible for these products. There’s going to be access issues, not from just a manufacturing perspective but also from a center perspective. We’re going to have to hire more people to be able to treat all of these patients.
Voorhees: How has the emergence of CAR T-cell therapy impacted your care of patients at the Levine Cancer Institute?What kind of patient would you consider for CAR T-cell therapy in your practice?
Soni: In today’s day and age, with [results from the] phase 2 GRIFFIN [NCT02874742] trial and the other regimens we have available, most of my patients do well with first-line therapy, or perhaps they’re on something as they’ve relapsed.6 My need for it, so far, has not been that great because patients are doing well.
Osei-Boateng: My experience is that, with CAR T-cell [therapy] for patients who are eligible, it’s not as rigid as transplants. Even some of these patients who are transplant-ineligible are eligible for CAR T-cell therapy, which is great. Regarding earlier treatments, just like with most things, it’s important to get good control of the disease. It makes a lot of sense to do it early.
Soni: Do you think we’ll get to the point where we’ll give people CAR T-cell therapy rather than doing transplants?
Voorhees: There’s a randomized phase 3 study that’s addressing this question called CARTITUDE-6 [NCT05257083].7 This is a study where patients will get induction therapy with daratumumab, lenalidomide, bortezomib, and dexamethasone [Dara-RVd], and they’re going to be randomly assigned to transplant or cilta-cel CAR T-cell therapy. They’ll get a defined duration of lenalidomide maintenance afterward, not indefinite. We’ll see which group does better. That’s a study that’s actively enrolling patients in Europe. The FDA wanted more safety data before the United States sites would be allowed to participate, but that’s something that’s on our radar at Levine Cancer Institute to participate. We’ll get an answer to that, hopefully in the not-too-distant future. That said, it’s going to take a tremendous amount of follow-up to see a difference in how these patients do because the patients on the GRIFFIN trial who received Dara-RVd transplant and then maintenance did very well.
Voorhees: Regarding bispecific antibodies, the first one I want to talk about is the one that we alluded to earlier, which is teclistamab. This got accelerated approval from the FDA not that long ago from the phase 1/2 MajesTEC-1 [NCT03145181; NCT04557098]8 study results, which we participated in at Levine Cancer Institute. This was a study that looked at teclistamab monotherapy in patients with heavily pretreated relapsed/refractory multiple myeloma. The overall response rate was 63%. Most of these patients had very good partial responses (VGPR) and complete responses (CR), with durable responses as well, which led to the approval. How would you decide whether you would consider a patient for teclistamab vs a BCMA-directed CAR T-cell therapy?
Friend: What’s unique about our institution is the collaboration that we have at our Morehead site with our plasma cell experts. I have a little bit of a unique situation where I can meet with you all weekly and discuss my patients at Morehead, the main institution, but also at our outreach sites. It makes it helpful to determine when would be the best time to incorporate these drugs. Bispecifics are nice because they’re off the shelf and you don’t have to manufacture these T cells. It’s a little bit easier in terms of logistics. We’re using teclistamab at our institution. I haven’t personally, but I’ve seen them in follow-ups and starting them, and it’s a great option. I think using it earlier is always better.
Voorhees: Your point about them being off-the-shelf is an important one. I’ve talked about the logistical difficulties in getting patients to CAR T-cell therapy when they’ve relapsed multiple times, and you’re running out of therapy to control their disease. Between the delays in time from referral to apheresis, and then from apheresis to actual infusion of the CAR T-cell product, you can run into some significant problems, especially if the disease is progressing at a very rapid rate. In those instances, an off-the-shelf option can be incredibly powerful. For those patients, teclistamab is probably a better option than a CAR T-cell treatment if you don’t have drugs that you can use to control the disease during the CAR T-cell manufacturing process. There are also patients who are frailer and perhaps might not tolerate the CRS and the neurologic AEs that come with these therapies. It’s important to note that CRS is very common, both with CAR T-cell therapy as well as bispecific antibody therapy. However, there tends to be more higher-grade CRS with the CAR T cell products relative to the bispecific antibodies, most of which are grade 2, grade 3, grade 4, and grade 5.
CRS is very rare with BCMA CAR T-cell therapy. Neurologic AEs with bispecific antibodies are significantly reduced relative to CAR T-cell therapy, which is important to realize as well. There’s this interesting phenomenon, which is that we’re seeing less frequent neurologic AEs from CAR T-cell therapy more aggressively early on. In the initial phase 1b/2 CARTITUDE-1 [NCT03548207] study, there were a number of patients who had Parkinsonian-like toxicities related to CAR T-cell therapy.9 One of these patients came from our institution. The mechanism remains to be fully defined. This remains to be seen clearly, but there’s the possibility that BCMA may be expressed in the same regions of the brain that are affected by Parkinson’s [disease]. It remains to be seen. Now that we’re treating neurologic AEs early on more aggressively, we’re seeing far less of that issue. If you had a patient with preexisting neurologic disease, particularly Parkinson’s, you might gravitate toward a bispecific [antibody] rather than CAR T-cell therapy. We haven’t seen the Parkinson-like effect with the bispecific up to this point.
Osei-Boateng: Being the only person treating patients in Lincolnton, which tends to be more rural, it’s exciting to know that you have these bispecifics because they are off the shelf, and you can use them a little bit more quickly. I happen to have access to you guys, but I can see a scenario where, if you’re in a community and you don’t have access to CAR T, it’s great that you can do this.
Voorhees: That is one of the challenges in the smaller practices, but we’d certainly encourage those groups to work with us. There is a need for step-up dosing for teclistamab. At least in the prescribing information, there’s a recommendation for patients to be hospitalized for a couple of days after the initial step-up dose, the following step-up dose, and the first full dose. If providers who are referring patients are considering teclistamab, they’re referring them to us first. We will take them in on our inpatient service, and we will treat them with the step-up dosing until they get to their first full dose. Then, the risk of CRS or neurotoxicity beyond that third dose is next to nothing. At that point, we refer them back to the referring provider, whether that’s within the Levine Cancer Institute regional sites or beyond us as well. That’s worked out very well, so definitely a lot of opportunity for partnership on that front.
Vorhees: Let’s transition to results regarding the phase 1 MonumenTAL-1 [NCT03399799] trial.10 This was a first-in-human, phase 1 study that looked at talquetamab-tgvs [Talvey] for patients with heavily pretreated relapsed/refractory multiple myeloma. The interesting thing about talquetamab is it’s a GPRC5D-directed therapy. GPRC5D happens to be expressed in plasma cells, more so in malignant plasma cells than normal plasma cells. With BCMA, that’s not so much the case. There’s a strong expression of BCMA in both the normal and malignant plasma cells. The other thing of interest is that there are some late B cells that express BCMA, whereas with GPRC5D, that tends to not be the case. The other thing that’s interesting is that talquetamab is expressed in hair follicles. It’s expressed in the nail beds, and it’s expressed in certain structures of the tongue. That leads to some on-target, off-tumor toxicities of talquetamab.
Regarding MonumenTAL-1, in this group of patients, the response rates looked at 2 different dosing strategies, a weekly and an every-other-week dosing strategy. Just like with teclistamab, there’s a step-up process. There’s a need for coordination between the myeloma physicians and the regional sites, but the response rates, whether the dosing was weekly or every other week, were 71% to 74%, with an impressive duration of response in this group of patients. Not surprisingly, we saw some degree of CRS and a much lower rate of neurologic AEs. What we also saw with this is less infection, and that may be due to more targeted activity against the malignant plasma cells vs the benign plasma cells. [We also saw] less targeting of mature B cells and perhaps less severe acquired hypogammaglobulinemia associated with talquetamab, so less severe infection. On the other hand, we saw more skin toxicity that was alleviated with topical corticosteroids, and we see this dysgeusia, or an alteration of taste, which can be quite profound for patients and, in some circumstances, can be bad enough that it leads to weight loss. What are your thoughts about this data set? Are you excited about the prospects of using talquetamab in your patients? If so, who would be the patient that you would consider for something like that?
Friend: You brought up a valid point about patients who are frail and maybe bringing that in as part of the treatment algorithm. That would be something to consider.
Voorhees: Let’s move on to the phase 1b RedirecTT-1 [NCT04586426] study.11 This was a study that was presented at both ASCO and EHA just a short while ago. It also garnered a lot of attention, just like CARTITUDE-4 did. This study combined the 2 bispecific antibodies together, so this is teclistamab and talquetamab for patients with heavily pretreated relapsed/refractory multiple myeloma. Remarkably, in this clinical trial, the response rate was close to 98%, which is very similar to what we saw with cilta-cel in CARTITUDE-1. Most of these responses were quite deep. There were VGPRS, and there were CRs. Those responses will deepen over time. It’s a relatively short follow-up at this point, but impressive results. There also weren’t a lot of patients with extramedullary disease, but there were some patients with extramedullary disease. The response rates in that group of patients were quite good and much better than what we saw with teclistamab alone or talquetamab alone in that group of patients, suggesting that the combination of the 2 bispecifics may be particularly advantageous in patients with extramedullary disease. The AE profile was very similar to what you would expect with the individual agents, and at least in for a relatively short follow-up, the infection signal does not seem to be any worse than it is with teclistamab alone. Any thoughts on that data set?
Osei-Boateng: It’s exciting, especially when you look at this extramedullary disease. Perhaps because of this synergy, that’s why you have this great response. I’d be curious to know the cost and the financial toxicity of these 2 drugs being combined.
Voorhees: I’m sure that the price tag of a combination bispecific antibody therapy is going to be significant. The data on extramedullary disease are exciting and, at Levine Cancer Institute, we’ll be participating in an expansion cohort specifically directed at those patients. It’s a great opportunity for those patients with extramedullary disease who perhaps may not be candidates for CAR T-cell therapy, whether it’s due to frailty or the fact that their disease is advancing too quickly, and they need something off the shelf right away. There’s a planned phase 3 study that will potentially have a teclistamab/talquetamab combination arm as one of the experimental arms in the study. That will be very interesting to look at.