Although BCMA-directed CAR T-cell therapy has shown early and deep responses in patients with relapsed/refractory multiple myeloma, there is much more to learn about optimal cytokine release syndrome and neurotoxicity management and treatment sequencing, particularly as off-the-shelf T-cell therapies, bispecific antibodies, and non–BCMA-directed therapies become available.
Although BCMA-directed CAR T-cell therapy has shown early and deep responses in patients with relapsed/refractory multiple myeloma, there is much more to learn about optimal cytokine release syndrome (CRS) and neurotoxicity management and treatment sequencing, particularly as off-the-shelf T-cell therapies, bispecific antibodies, and non–BCMA-directed therapies become available, according to a panel of experts that presented during an OncLive® Institutional Perspectives in Cancer webinar on multiple myeloma, chaired by Ken Shain, MD, PhD, an associate member of Moffitt Cancer Center.
“Clearly, BCMA-directed CAR T-cell therapy in relapsed/refractory myeloma leads to early and deep responses, even in penta-refractory patients, but BCMA is still in its infancy, so we’re still learning. These are [only] the first-generation [CAR T] constructs that we’re seeing,” said Omar Castaneda Puglianini, MD.
Shain, was joined by fellow Moffitt Cancer Center faculty:
During the meeting, the faculty spotlighted key take-away messages from their presentations on early and triple-class relapsed/refractory multiple myeloma, CAR T-cell therapy, and novel agents.
Blue: One of the things I want to leave you to remember is questions to ask when you have a patient who has relapsed or refractory disease. [In this situation, we must ask:] What is their sensitivity to a proteasome inhibitor or an immunomodulatory drug? How long has it been during their time of relapse? What type of toxicities did they have with their prior therapy? What type of baseline comorbidities does the patient have? How urgently or how immediately does this patient need to be treated? How aggressive is their disease?
If the patient has had prior autologous stem cell transplant, right now, our tendency is to treat patients sooner before symptoms emerge because we want to improve their quality of life [QOL]. If we do that, when we see things start to advance, then we can typically prevent bone fractures, kidney disease and dialysis, which significantly impact patients’ QOL.
Baz: When I’m faced with a patient who has triple-class refractory advanced myeloma, the question I ask is: What have I not used already? I remember that we have alkylating agents, which have a role to play in myeloma therapy. Is there therapy that the patient is not refractory to? For example, if the patient relapsed on carfilzomib [Kyprolis] or bortezomib [Velcade], can I retreat with those agents? Is there a personalized medicine approach that I can take, such as [for a patient with an] 11;14 translocation or a BRAF mutation?
We saw exciting data presented at this meeting on CAR T-cell therapy. Is CAR T-cell therapy a consideration here? We don’t really know what impact prior belantamab mafodotin-blmf [Blenrep] would have on future CAR T-cell therapy. This is something patients had been excluded from CAR T-cell therapy in general if they had prior belantamab mafodotin or BCMA-directed therapy. If CAR T-cell therapy is a consideration, I’ll try to avoid belantamab mafodotin. Also, the data may evolve on this, and we will learn more about that.
Castaneda: Cilta-cel [ciltacabtagene autoleucel], thus far, leads to the highest overall response rate in heavily pretreated patients, including the penta-refractory patients, which is something we haven’t seen with selinexor [Xpovio], melflufen [melphalan flufenamide], or belantamab mafodotin. However, despite all these promising results, the durability of the responses has been variable. We will likely [have a better understanding of the durability of these responses] once we have the real-world data in the next couple of years or so.
We need better constructs, better modulation of the immunosuppressive microenvironment, and new targets. We need probably adjunct therapy to further improve the outcomes and the safety of CAR T-cell therapy. Toxicities, even though they are manageable, are still surprising us. Newer strategies to maximize patients’ QOL are still needed.
Hansen: We saw unprecedented [response] rates with ide-cel [idecabtagene vicleucel; Abecma] in triple-class and penta-refractory disease. Cytopenias and infections were common. CRS certainly was very high. ICANS [immune effector cell-associated neurotoxicity syndrome] was reported in 18% of patients, but [these toxicities] are manageable.
We really do have an unmet need though, especially for some of the higher-risk patients. For example, CNS [central nervous system] disease, but specifically plasma cell leukemia, renal dysfunction, and patients on dialysis. ALLO-715 has shown promising activity as have other T-cell therapies, so we’re very excited to look at some non–BCMA targets. Certainly, long-term, these are new therapies. The longest follow-up we have is 24.8 months, so we really need to consider QOL in some of these patients.
Brayer: Bispecific antibodies and bispecific T-cell engagers [BiTEs] represent a potent, safe, and off-the-shelf immunotherapeutic option, demonstrating deep responses in heavily treated myeloma patient populations. As seen in the recent data [presented at the 2021 ASCO Annual Meeting], these agents are being delivered subcutaneously, meaning that this [approach] is going to be more convenient. We are also looking at QOL measures with these [agents] as well.
What we see with the ASH data is that there are additional bispecific T-cell redirector agents in development, and it’s expected that they’re going to fuel further excitement. Part of that excitement is that although we’re seeing great responses with BCMA-directed agents, there are other targets now, including FcRH5 and GPRC5D. Both [of these targets are] highly expressed on myeloma cells and look highly promising. It’s also important to mention odronextamab. Three of the patients [in that trial] who were previously treated with BCMA-directed agents were able to achieve deep responses, including 2 VGPRs [very good partial responses] and even a stringent complete response.
We need a better understanding of how these agents are working and how they compare with CAR T-cell therapy not in terms of efficacy but more in terms of how we’re going to utilize both [approaches]. Where are the optimal patients that might be better suited to CAR T-cell therapy vs bispecific antibodies and BiTEs and how can we, more importantly, fit them together?
In terms of how we apply these [approaches] at Moffitt, unfortunately, none of these [approaches] are FDA approved yet. We are applying them in the clinical trial setting though, and we’re seeing impressive results in that context.