CAR T Cells are Taking Hold in the Multiple Myeloma Space

Christopher R. D’Angelo, MD

For patients with multiple myeloma, novel immunotherapies such as chimeric antigen receptor (CAR) T cells are proving effective and are taking their place as a new standard of care.

Currently, multiple types of immunotherapies are being used for the treatment of patients with multiple myeloma, including antibody-drug conjugates, bispecific antibodies, and CAR T cells. The FDA-approved agents showing efficacy in this patient population include blinatumomab (Blincyto), and 2 CAR T-cell products, idecabtagene vicleucel (ide-cel; Abcema) and ciltacabtagene autoleucel (cilta-cel; Carvykti).

However, questions remain regarding how to best use these agents and manage toxicities for patients with multiple myeloma.

During a session at the National Comprehensive Cancer Network (NCCN) 2022 Annual Meeting: Hematologic Malignancies, Christopher R. D’Angelo, MD, explained the benefits of these agents as well as their challenges.

“I think the key to using immunotherapy, which at this point is mostly CAR T, some antibody drug conjugates, and some bispecifics, is understanding the toxicities and early recognition. Particularly with CAR T toxicities, it is important to prevent some later toxicities,” said D’Angelo, assistant professor in the Division of Hematology and Oncology at the University of Nebraska Medical Center in Omaha, Nebraska, in an interview with Targeted Oncology^TM.

In the interview, D’Angelo discussed recent approvals in the multiple myeloma space and how to treat patients using immunotherapy.

Targeted Oncology: How does one incorporate immunotherapy into the treatment plan for patients with multiple myeloma?

D’Angelo: [At NCCN], we were asked to speak on the topic of immunotherapy in multiple myeloma and how and where to incorporate it, and what we've learned when using these drugs. It is an exciting time for our patients with myeloma.

We follow the FDA approval guidelines and use it for patients that have relapsed after and have received 4 prior lines of therapy. The questions that are going to be emerging after this are, what kind of lymphodepleting chemotherapy to use, particularly in the moments of fludarabine shortages, as we're talking about a little bit at our session, and then ultimately how to sequence these agents as we're seeing new approvals for new, emerging immunotherapies and bispecific antibodies.

Can you discuss some of those recent approvals?

We have FDA approvals for blinatumomab, which is an antibody drug conjugate that's used to treat myeloma and targets the BCMA antigen. That antigen is popular right now for immunotherapy because it's also used for either idecabtagene, ide-cel and cilta-cel, 2 different CAR T-cell therapies that target BCMA. There are some slight differences between ide-cel and cilta-cel. Ide-cel has just 1 target or 1 chain to target the BCMA and cilta-cel has 2. That may result in some differences in CAR T binding to the myeloma cancer cell.

What is the mechanism of action of blinatumomab?

BCMA is a popular myeloma. The reason why it's popular is because it's expressed not solely on the plasma cells, and not universally on plasma cells, but is quite common. Many patients, nearly all patients, will have some BCMA expression, which is part of the reason why BCMA was not part of the initial trial inclusion criteria. When you're thinking about immunotherapies, CAR T, in particular, you want an antigen that is uniquely and uniformly expressed on your cancer, and not so much expressed on other normal, healthy cells in the human body. A perfect world would be 1 that's solely expressed on the cancer cell and not on any healthy cells. BCMA does a pretty good job of that. The problem that can happen though is if you've got 1 target, the cancer cell might learn how to mutate by not expressing that target anymore.

On the treatment, it has evolved and we're learning more about CAR T cells and how to use them. Getting the right situation, the sort of construct, that's engineered and then introduced into a patient's own lymphoma cells, which is how the current FDA approved CAR T cells are, involves a combination of the right target, the right activation, and signaling within the T-cell itself to get the right amount of activation. The right amount is something of an unanswered question. Do you need something that activates and robustly kills at the time of introduction, at the time of meeting that tumor antigen? Or do you want something that does a little bit of that? It's kind of like a Goldilocks situation like something that does activate and target but then lingers a little bit. Sometimes with too much activation, that T-cell can lead to exhaustion and impair your CAR T response.

There's different signaling domains that come into place that have differences there and are something that we're learning about. For CAR T cells in the evolving future therapies, there are constructs that are designed to have better co-stimulation, to better activate that T cell when it targets and hits that BCMA antigen, and T cells that are capable of secreting their own cytokines. Those are exciting and promising new therapies.

Which patients with multiple myeloma are most likely to benefit from treatment with immunotherapy?

Ideally, we'd like to be able to offer this therapy to everybody. The emerging trials that are ongoing are looking at using it earlier on. We want to make sure that patients have sort of an ideal lower tumor burden where possible and are fit enough for CAR T-cell therapy. In general, we look at fitness that's related to disease or fitness that's related to comorbidities. I wouldn't say there's any age limit in my mind for using this therapy. I would say that although it's a little bit nuanced and needs to be currently in the hands of cancer centers that have the resources to do it, it also offers 1 of the first things for our myeloma patients that they haven't seen in a long time, which is time on therapy after a single infusion. They get 1 drug or 1 therapy, and that's that. I would like to be able to offer it to everybody, but there are people I'm worried about right now. You have to have good caregiver support, for some of those toxicities that come up, you need to be able to remain locally for that therapy. Patients that live far away or don't have a whole lot of support, and their cancer centers may be just a couple of minutes away, and they're able to maintain a good quality of life right now, are people that I think might not get as good of a benefit from CAR T cells.

Until we can cure myeloma, whatever we do should help you live longer or live better. There are some situations where you may not be living better with CAR T or might be harmed by some of the toxicities that can happen with it. If someone was comorbid from other diseases that are unrelated to myeloma, those would be the people I'd be more worried about. In general, I think we should be trying to offer this therapy to as many patients as possible, and earlier on before they get too sick or too comorbid from something else, where maybe they're not candidates anymore.

What unmet needs still exist in this space?

I think the unmet needs are bridging therapy, so how and what are the best therapies that we can use to to prepare patients for CAR T. Currently, manufacturing for CAR T does take some time, it's many weeks. Sometimes those patients don't have that time to wait and are in need of some therapy right now. Ideally, a bridging therapy should control the disease, minimize the toxicity of the therapy itself so that you're not harming or causing a complication that might impair their fitness for CAR T. Theoretically, the best-case scenario would be a sort of bridging therapy that helps augment the CAR T. We don't know the right answers to those right now, but a couple of emerging candidates that are exciting are radiation therapy because it hits on some of those things, it can be effective, relatively safe, at least in the short term.

It probably is not going to impede their ability to proceed a CAR T and might help improve CAR T responses by some sort of generation priming of the immune system that can happen naturally with radiation exposure of more antigens that your immune system might pick up that it wouldn't have been able to before. It might help recruit other parts of your immune system. Again, CAR T cells are living therapy and sort of providing an environment that's most conducive to their growth and activity.

Finally, the post-CAR T relapses are going to be where the emerging need is. I don't know that any of us have the answers here, but sometimes we can borrow observations from other diseases. Bispecific antibodies are also being used in the research setting and hopefully the clinical setting soon in lymphoma. Some of the trials that used bispecifics included people that were on prior CAR T-cell therapy and observed pretty good responses. It did not seem like prior CAR T therapy impaired that, at least in the limited data that we have. Considering bispecific antibodies that target BCMA after a BCMA directed CAR T failure, certainly a very reasonable approach, and hopefully we'll have those bispecifics FDA approved soon.

I think there's other strategies that can be incorporated as well, including whether additional doses of CAR T-cell therapies are needed or effective against something that would need to be assessed in a research clinical setting first. There are certainly some options here and there is a lot of hope and a lot of encouraging therapies for our patients with myeloma. Every time we look at survival differences in our myeloma populations over the last decade or the previous decade, they get better and better. Certainly, more of a call for us to continue to step on the gas here and continue to improve and come up with therapies that work. I think we are where we will achieve what we're all hoping for myeloma, which is a cure.

What are the key takeaways for community oncologists?

I think the key to using immunotherapy, which at this point is mostly CAR T, some antibody drug conjugates, and some bispecifics, is understanding the toxicities and early recognition. Particularly with CAR T toxicities, it is important to prevent some later toxicities. I advocate for early management of [cytokine release syndrome], neurotoxicity, toxicities with blinatumomab, again, early management recognition of the ocular keratopathy that can happen with that are key to ensuring that this drug can be continually used in our patients. Patient counseling happens here too with having them advised to recognize that keratopathy will likely happen and that it's reversible, usually recoverable, and can usually allow continued dosing once it's resolved. Setting that expectation early on can help reduce some of the anxiety and fear that can come with our patients that are on effective therapies that are suddenly asked to hold on to them.

CAR Ts are exciting therapies. They offer a single time infusion to treat these diseases that a lot of other myeloma therapies require continuous therapy for. It is a real advantage for many of our patients that are looking for some time on therapy.