Ide-cel Shows Efficacy, Safety in Multiple Myeloma After Transplant
Alfred L. Garfall, MD, provided a deep dive into the phase 2 BMT CTN 1902 trial of ide-cel in multiple myeloma after transplant.
Microscopic photorealistic image of mutliple myeloma cells - Generated with Adobe Firefly
Idecabtagene vicleucel (ide-cel; Abecma) showed impressive efficacy and a manageable safety profile in patients with multiple myeloma with suboptimal responses after upfront autologous hematopoietic cell transplant and lenalidomide (Revlimid) maintenance, according to findings from the phase 2 BMT CTN 1902 trial (NCT05032820).1
Topline findings showed that, at the 6-month mark, 63% of evaluable patients (n = 38) achieved a complete response, with Alfred L. Garfall, MD, noting that many of these responses occurred "quite early." Furthermore, 87% of patients achieved minimal residual disease (MRD) negativity, with 95% reaching this status at some point during the study. Further, only a single patient experienced disease progression after a median follow-up of 10.7 months.
Regarding safety, ide-cel proved to be well tolerated. While cytokine release syndrome (CRS) was observed in 81.6% of patients, the vast majority of events were mild (grade 1 in 68.4%, grade 2 in 13.2%). The median time to CRS onset was just 1 day, with resolution typically within 2.5 days. Notably, no cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were reported. Infections occurred in 26.32% of patients, predominantly bacterial or viral, and typically within the first 100 days postinfusion.
"This is the first study that utilized [chimeric antigen receptor (CAR] T cells in the BMT CTN," Garfall, director of Autologous Hematopoietic Stem Cell Transplantation, the section chief of Myeloma and Hematology-Oncology, and an associate professor of Medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania, Penn Medicine, in Philadelphia, said in an interview with Targeted OncologyTM, highlighting the significance of the trial's success within a network traditionally focused on stem cell transplantation. "It was a gratifying experience to run a CAR T-cell trial in the [Blood and Marrow Transplant Clinical Trial Network] to demonstrate that this network can expand to these new cellular therapies, especially if they are somehow paired or combined with bone marrow transplant or stem cell transplant, which is its conventional focus."
In the interview, Garfall provided a deep dive into the phase 2 BMT CTN 1902 trial.
Targeted OncologyTM: Can you discuss the background, methods, design, and rationale of this study?
Garfall: This is a clinical trial that tests the use of ide-cel, an anti-BCMA CAR T-cell product, to improve response for patients who have been through the standard intensive first-line multiple myeloma therapy and have failed to achieve a complete response. That intensive first-line therapy that these patients have been through is some form of multiagent induction therapy, followed by consolidation with high-dose melphalan and autologous stem cell transplant, and then some period of lenalidomide-based maintenance therapy. If after all that therapy, if they have failed to achieve a complete response, that group of patients has, on average, inferior long-term outcomes. The idea was whether CAR T cells, at that point, could convert patients to a complete response and hopefully improve their long-term outcomes.
This was a phase 2, single-arm study that focused on the safety and feasibility of this approach and a preliminary measure of effectiveness, which was based on the rate of conversion to complete response after 6 months after CAR T-cell infusion. The reason it was important to demonstrate initial safety and feasibility in a smaller study here is because there have not been many studies that have utilized CAR T cells early after an autologous stem cell transplant. We had questions about whether the T cells that you would harvest from patients early after transplant could be used for CAR T-cell manufacturing in the setting where the myeloma is at a very low level. Even though these patients haven't achieved a complete response, they have relatively low amounts of myeloma because of all the prior therapy they've had.
And then, because it is a standard approach for these patients to be on long-term maintenance with lenalidomide, and at the same time, it's also common for patients after CAR T-cell therapy to have low blood counts, we wanted to make sure that it was feasible to get them back on lenalidomide maintenance therapy. Because we were concerned that when you combine the effect of the auto[logous] transplant on blood counts, and then CAR T-cell therapy on blood counts, and then lenalidomide's effect, we were concerned that patients might not be able to resume the standard-of-care lenalidomide maintenance, which is an intervention that has been proven to prolong overall survival. So, a major objective of this study was to get a preliminary assessment of whether patients were able to resume lenalidomide after CAR T-cell therapy and continue the standard-of-care first-line therapy with lenalidomide maintenance.
As for the patient population, how were patients selected for this trial, and what specific criteria defined suboptimal response after autologous transplant?
The suboptimal response was defined as not having achieved a complete response. So practically, what that meant is that patients had to have some residual detectable myeloma on their serum or urine testing. In theory, you could have all the tests be negative and qualify on the basis of bone marrow biopsy, but I think for the vast majority of patients it was based on serum or urine testing.
What were the topline results of this trial? Were there any particularly surprising outcomes?
It seemed to be a very effective intervention. We know that patients at this stage of therapy do kind of convert to [complete response] on their own with just continuing maintenance therapy. We estimated from prior studies that that would happen maybe 10% of the time. And so, with CAR T-cell therapy, we saw that 63% of patients achieved a complete response, and 87% of patients upgraded their response in some way, even if they didn't achieve a complete response. We think it's still possible that some of those patients who upgraded their response but hadn't achieved a complete response, if we follow them for a little longer, that they will upgrade their response. We will kind of do that analysis.
We looked at minimal residual disease, also in the bone marrow, by flow cytometry, and we were pleased to find that at some point after T-cell infusion, in those first 6 months, 95% of patients achieved MRD-negative status, which is better than the 29% of patients who are MRD-negative in the bone marrow at the time of starting the CAR T-cell therapy. We were really pleased that for the most part, patients have not progressed. There is 1 patient who has progressed, but the remaining patients remain progression-free.
We also saw encouraging safety, where we saw no neurologic toxicity. While [CRS] was common—82% of patients developed cytokine release syndrome—all the events were low grade. I think this is a more favorable [adverse event] profile using CAR T cells in this consolidation setting than we would see in patients who received CAR T-cell therapy for relapsed disease. Then we were able to see if patients were able to resume lenalidomide maintenance, and we will follow these patients to see if they are able to continue and maintain lenalidomide therapy. But all patients were able to start lenalidomide maintenance, and for the most part, that occurred within the first couple months after CAR T-cell therapy. So, I think that did address the main question that the study was asking: whether CAR T cells are clinically active in the setting. They are. They were able to convert most patients to complete responses. Those responses seem durable right now. Overall, the manufacturing of CAR T cells in the setting was feasible, and patients were able to resume their standard of care lenalidomide maintenance therapy.
How does the safety profile of ide-cel in this trial compare with other treatment strategies for this patient population?
The standard in this population is to just do standard lenalidomide maintenance therapy, so patients wouldn't, typically, in this setting, be exposed to the risks of CAR T-cell therapy like cytokine release syndrome and neurologic toxicity. That is why I think it is important that if we intervene here, that we do so with a relatively low-risk strategy. That is why I think it's a positive and encouraging finding that we did not see any neurologic toxicity, and the cytokine release syndrome that we saw was all low grade, meaning that was not a toxicity that caused a lot of medical complications for patients, and it was a transient toxicity, not something that sticks with patients for a long time.
In terms of other therapies that are being investigated in this setting, there are other trials going on that are adding other agents into maintenance therapy to improve maintenance therapy, whether those are trials that add daratumumab [Darzalex] into maintenance therapy at this stage, or there are some trials investigating bispecific antibodies in this setting. To be honest, there are many trials that are that are looking at different ways to augment first-line myeloma therapy with some of these novel approaches that have initially proven effectiveness in the relapse setting. It is kind of a confusing mix of trials that are going on right now and a lot of data are going to come out. Ultimately, we will need prospective studies that compare these approaches to figure out which one is best and should become the standard.
How do you think these findings might influence current treatment paradigms for these patients?
I think it would ultimately need a larger study to be practice changing. There were a couple of other small studies similar in size to ours that investigated similar approaches. One was with ide-cel before maintenance therapy started. Trials largely happen at the same time, and we are similar in size, and we've heard reports of them over the last couple years, and they all collectively report similar findings. We have data with CAR T cells in patients who have recently relapsed in the 1 to 3 prior lines of therapy setting. We have data in the very relapsed setting, and now we have some data using them as part of first-line therapy. I think we all feel that getting CAR T cells to patients at some point in the course of their myeloma will improve their long-term outcomes, and now we have some randomized data in the 1 to 3 prior lines of therapy setting that there is an overall survival benefit to getting CAR T cells.
I think the question is, when? Ideally, you would have a clinical trial that tested this consolidation approach that we're using. But on the other hand, maybe you do not treat these patients with CAR T cells right now, and they relapse a little sooner, but you give them CAR T cells at that point and ask, which of those approaches is better from a safety and long-term efficacy standpoint? I think that's the kind of clinical trial that we'd want to see to change practice. As a prerequisite to that, you have to have data that the approach is generally safe and feasible, because we do not want to expose patients in this setting to very risky therapy unless there is a real payoff down the road. Because, remember, these patients have just been through a fairly intensive course of multiple myeloma therapy, and while they haven't achieved a complete response, they are clinically well. They are not suffering from active complications of their multiple myeloma. And even with less than a complete response, they could probably enjoy a good period with low-intensity therapy. If we are going to escalate in this setting, I think we want to have good evidence that there's a long-term benefit to doing CAR T cells now vs waiting until disease progression and doing them at that point.
It is worth noting that this clinical trial was run in the Blood and Marrow Transplant Clinical Trial Network [BMT CTN], which is a [National Institutes of Health (NIH)]-supported clinical trial network that has traditionally focused on hematopoietic stem cell transplantation [and] autologous and allogeneic stem cell transplantation. This is the first study that utilized CAR T cells in the BMT CTN, and so I think it was a gratifying experience to run a CAR T-cell trial in the BMT CTN to demonstrate that this network can expand to these new cellular therapies, especially if they are somehow paired or combined with bone marrow transplant or stem cell transplant, which is its conventional focus. I hope this will be the first of many clinical trials that utilize novel cellular therapies in the BMT CTN. The clinical trial accrued very successfully and on schedule, despite being a complicated trial with the safety run-in and significant stagger between patients in the beginning that was built into the protocol and discussion with the FDA and so with the FDA. I think it is a nice demonstration of the ability of an NIH-sponsored clinical trial network to quickly complete and successfully report a clinical trial using CAR T cells.
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