When CAR T Fails in Myeloma, Can Nivolumab Help?

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March is Multiple Myeloma Awareness Month. This month, Targeted Oncology is highlighting research in the field of myeloma treatment.

While chimeric antigen receptor (CAR) T-cell therapy remains a promising treatment option for patients with multiple myeloma, it is not necessarily a curative approach and will not work for every patient. Investigators at Fred Hutchinson Cancer Center in Seattle, WA, including Rahul Banerjee, MD, wanted to know why and see if there was a way to make the T cells persist.

Banerjee specifically looked at nivolumab (Opdivo), an immune checkpoint inhibitor, with the hopes that it would help reverse T-cell exhaustion in patients with lymphoma and multiple myeloma who had failed CAR T-cell therapy.

The study found that nivolumab had a 22% response rate for patients with multiple myeloma. While this is not a high response rate, Banerjee noted that for the patients where nivolumab worked, it delivered fast and durable responses.

The inclusion of checkpoint inhibitors for patients who failed CAR T-cell therapy remains an area of interest and warrants further exploration.

In an interview with Targeted Oncology^TM, Banerjee, assistant professor in the clinical research division at Fred Hutch, delved into findings from the study presented at the 2024 Transplantation and Cellular Therapy Tandem Meetings.

Rahul Banerjee, MD

Targeted Oncology: What was the rationale for the study?

Banerjee: I presented a poster about post-CAR T nivolumab. The idea being is for patients where CAR T stops working for them, both [in] lymphoma and myeloma, treatment options are very limited for them. Most of the presentations at this conference have been about how do we get more people to CAR T, how to make it work better when CAR T stopped working or it never worked to begin with, so either relapse after CAR T [or] refractory disease. It isvery tricky to figure out what to do with those patients.

We were interested in the idea of nivolumab, which is a checkpoint inhibitor. The idea is that it wakes up T cells that helps reverse T-cell exhaustion. Nivolumab has changed the paradigm for many solid tumors and has not really done that much in most blood cancers necessarily yet. We were saying, maybe we could change that paradigm for patients where CAR T stopped working or never worked at all. Perhaps using nivolumab in a prospective manner, [in the] same dosing as in solid tumors, might be able to unleash those T cells or initiate a response.

What unmet needs exist with CAR T-cell therapy?

In the CAR T space, the biggest challenge is getting people to CAR T and what happens after CAR T. Fred Hutch also put out other research here led by our [bone marrow transplant] fellow looking at pre-CAR T attrition. For example, patients who are referred for CAR T would never actually make it, either because of disease-related factors, social latent factors like not having a caregiver [or] not being able to relocate to the big city for CAR T therapy, and so forth. Of course, even downstream of that, there are patients who are never even referred for CAR T therapy because their local oncologist does not think they are a candidate where they might be.

The barrier that most of my research is focused on is what happens after CAR T cells are infused. There is the acute toxicity window [with] cytokine release syndrome, neurotoxicity, low blood counts, cytopenia. I am interested in what happens thereafter. One of the biggest causes of death for patients receiving CAR T for myeloma remains myeloma. CAR T for myeloma is not curative. I was really excited about this study with the idea that perhaps if we use this, we could use it almost as maintenance after CAR T therapy to keep the T cells going and hopefully healthy for longer.At least in myeloma trials, we might see that the T cells do not stick around. They come in, they hopefully knock out a lot of myelomas, and then they disappear a couple of months later. It is not that simple. It could be that even if they were able to stick around, oftentimes myeloma cells learn tricks to downregulate BCMA, the protein that the CAR T cells attack, or they have other ways of blocking the immune system. But if we could just keep these CAR T cells healthy and keep them fit and keep them functional for longer, I am sure that would help many patients.

As we will talk about this study, in brief for myeloma, we had a 2 of 11 response rate at 22% response rate for patients who received nivolumab for CAR T failure in myeloma, [which was] not as high as I would like, but for the patients where it worked, it worked dramatically for months and months and months. I think for some patients, nivolumab might be an option for them. It is not FDA-approved; it might be in the future, [but] we just need to figure out who those patients are.

What were the goals of the study?

The main goal we were looking at was progression-free survival [PFS]: how long this works [with a] benchmark from [the patient’s] first dose of nivolumab. We had intentionally tried to make this kind of a basket study, so we had patients with lymphoma and myeloma. We had patients with primary refractory disease where they did not have much of a response or a [partial response] is the best response. We had patients with true progressive disease after achieving a [complete response] and so forth. Our primary endpoint was regardless of all those patients coming in when they got nivolumab, what was their PFS and [overall survival (OS)] thereafter?

The other coprimary endpoint was safety, obviously, because [with] nivolumab, there are 2 sets of toxicities here. Nivolumab may have the classic toxicities of checkpoint inhibitors. For example, it can cause autoimmune conditions like dermatitis or thyroid issues or liver problems. But on top of that, we had a big concern that if [we] turn the T cells back on again, [we] can turn them too on and trigger some of these issues like cytokine release syndrome and neurotoxicity, [which] can be very distressing for patients.

Can you summarize your findings?

In a nutshell, I think nivolumab works for a minority of patients; we just cannot figure out who they are. Am I putting a rosy spin on that slightly? I would say that it was not the panacea that we were hoping for it to be. We were hoping to see a high response or waking up the T cells and so forth. In lymphoma, we had a 1-patient response, and that is similar to what other studies have shown. In the myeloma cohort, 2 patients responded, about a 22% response rate. That is still better descriptively [than] some of the nivolumab studies that had been done in myeloma previously. [It is] hard to say whether there is something unique about the study. We are still running a lot of correlatives to find out. For the 9 patients with myeloma with no response to nivolumab, [we] knew quickly. Within a month, it was like the myeloma brushed off the nivolumab entirely. The T cells, if they were waking up for the patients who did respond, [did so] [rapidly]. [When nivolumab worked,] that worked dramatically.

What I do not know as of today is: Is it because nivolumab woke up the T cells? Is it because the nivolumab directly attacked or helped the native T cells besides the CAR T cells to attack the myeloma or both? Hopefully by this time next year, we will have that answer. It is surprisingly difficult, surprising to me maybe [but] not surprising to my colleagues in the lab, how tricky this is to actually suss out those 2 potential causes of responses, so we will see. Further study is needed.

Even though the findings are inconclusive, are there any takeaways for a community oncologist?

We were using nivolumab, which is FDA-approved in a non-FDA-approved indication. My first word of caution would be not to do that in the community, because even though you could try to get it off-label, I always say our study where we did have it in an investigational trial, the FDA cleared the protocol. [It is] probably not worth it [in the community].

I think the bigger realization from our study is that we do not really know why CAR T stopped working in myeloma. I think the main takeaway for [doctors] in the community is that when this happens, most of these patients already have someone at an academic center whom they are kind of comanaging the patient with. But what I would say is, taking this study into account and taking some of the other studies that have been discussed here, is that if CAR T fails, if you have a relapse afterwards, or patients refractory to CAR T therapy, bispecific [antibodies] are1promising arena. There was an oral abstract presented showing thatfor patients who had relapsed after [idecabtagenevicleucel (ide-cel; Abecma)], going to bispecific antibodies seemed to do better for them than others. [There are] limitations there because that was historical [data]. We did not have all the bispecificsthat we do [now].

Now, the other thing is that you do not need to go to something new and shiny like nivolumab or to bispecific antibodies. The old drugs might work just fine. I think the bottom line of what I would say is that if your patient is relapsing after CAR T therapy, talk to 1 of us [at an academic center] and we are happy to help. If it has been years since [the patient] has gotten daratumumab [Darzalex], isatuximab [Sarclisa], even pomalidomide [Pomalyst],there is a good chance that recycling those old therapies 2 or 3 years later might have, maybe not the best response, but a pretty good response and worth trying.