Clinic Conversation of the Week: How to Talk With Patients About Second Primary Malignancies and T-Cell Lymphoma Risks After CAR T Therapy in Multiple Myeloma

Rahul Banerjee, MD, FACP: Welcome to this Clinic Conversation of the Week, a series where we explore how to discuss the latest groundbreaking research with our patients in clinic. My name is Rahul Banerjee. I’m an Assistant Professor of Medicine at the Fred Hutchinson Cancer Center in Seattle, Washington. Today, I’ll be discussing a piece by Dr. Karlo Perica and colleagues, entitled “CD4-Positive T-Cell Lymphoma Harboring a Chimeric Antigen Receptor Integration in TP53,” that was published in the New England Journal of Medicine in February 2025.

This is not a large prospective clinical trial; this is actually a case report. For a case report to get into a journal as prestigious as the New England Journal of Medicine, that tells you that it’s an important topic. In brief, it pertains to a topic that has been a huge issue for us in the CAR T and immunotherapy field—in myeloma, lymphoma, leukemia, etc—for the last couple of years. That’s this question of second primary malignancies or other cancers following CAR T therapy.

I think those second cancers can fall into two categories. There is the category of cancers that patients who have received CAR T may happen to get later in life. Second is the category of T-cell lymphoma—actual cancers of T cells that may or may not contain the actual gene put into them that was used during the CAR insertion process. Now that the FDA has a boxed warning in all CAR T therapy products across all malignancies, saying that patients may be at risk of a second cancer later in life, how do I talk about the topic with patients? For many of our patients, this is not new to them, right? Anyone who’s ever been on lenalidomide or had any kind of transplantation, they’ve been told about this topic before.

Here’s What I Say

I often start by discussing with patients that there is some element of immortal time bias, meaning that if you live long enough with your first cancer in remission, you are at risk of a second cancer developing that may or may not have happened anyways, or that may have happened as a result of the prior treatments you’ve been on. An example with CAR T therapy is the CARTITUDE-1 study of ciltacabtagene autoleucel (cilta-cel) in multiple myeloma. Patients, on average, had gotten six-plus prior lines of therapy. Of the 97 patients in that first trial, 10 of them went on to get myelodysplastic syndrome (MDS). Ten out of 97 seems like a huge number, and it is, but it’s worth noting that those patients, if they hadn’t gotten CAR T therapy, would have all died of myeloma. Many of them had gotten prior lenalidomide, prior transplants, etc.

So, if you imagine—and I have to use my hands for this—if you have patient number one who doesn’t get CAR T and dies of myeloma, and patient number two gets CAR T and lives on and later gets some other complication like MDS, the most important thing may still just be that they’re alive. It’s also worth noting in myeloma in particular, that even in the transplant setting, for patients who get second cancers after treatment for myeloma, the leading cause of death for them often is still the multiple myeloma.

I often tell patients that with CAR T therapy, there are some unknowns, as there are with any type of gene therapy. It is true that epidemiologically, patients who get CAR T appear to possibly, in some cases, have a slightly higher risk of second cancers than those who don’t. But again, the myeloma is a much bigger threat for them at this point in time. Two, if you live long enough with the myeloma remission, other complications may develop. That thinking and that framework, I think, is still very valid for most patients.

However, this past month in New England Journal of Medicine, they published a case of what we would argue would be the opposite of the gold standard—the worst standard of something that probably is truly a scenario where the presence and the process of CAR T therapy did lead to this patient developing a malignancy. In brief, this patient developed loose stools and diarrhea after receiving cilta-cel, which is a commercial CAR T therapy for multiple myeloma. We have published work through the US Myeloma Consortium about how diarrhea and loose stools after CAR T therapy can sometimes be enterocolitis. It can sometimes be a CAR T–driven process—not monoclonal, not neoplastic, not cancerous per se, but kind of a polyclonal infiltrate–causing problem.

Here though, they did sophisticated gene sequencing. This was work done by Dr. Perica and the senior author, Dr. Sham Mailankody, at Memorial Sloan Kettering Cancer Center in New York. They were able to identify that this was a monoclonal population of CAR T cells. Furthermore, the actual CAR—remember that CAR T cells require a CAR, a genetic sequence to be introduced into the T cells, typically with a viral vector—that viral vector had inserted into TP53, which is a tumor suppressor gene. By disrupting that, those cells automatically became destined to move towards cancer.

I think it’s a sobering case report, but an important one for our field to recognize. And I think it’s important to discuss with our patients that gene therapy does come with risks. Up until now, the risk of gene therapy leading to cancers was largely theoretical in the modern era. It happened a lot in the early days of gene therapy for severe combined immunodeficiency (SCID) research and so forth, but it hadn’t really happened in this kind of a smoking gun case until now. It’s still exceedingly rare. Thousands of patients have gotten CAR T therapy around the world and have not had this happen. The vast majority of my patients who’ve gotten CAR T are still doing excellently years later.

But I think this is important to bring up with patients, that it’s no longer a theoretical risk. It is a rare but reported risk here, so it’s a discussion to be had with them. Bottom line, I’ll tell you that since this second primary cancer warning has come out, every one of my patients has still, if they need CAR T therapy, favored going ahead with the CAR T therapy. The cancer at hand right now is a far bigger threat for the vast majority of patients than a theoretical cancer years later.

However, I think this is an important topic to bring up with them because for example, bispecific antibodies may not have this risk, and for some patients may be equally efficacious for them—especially a combination of teclistimab plus talquetamab in myeloma, as an example. I think this is also a good impetus to revisit the idea of allogeneic off-the-shelf CAR T cells. We used to do a lot of research with them, but there hasn’t been as much research with allogeneic CAR T cells in myeloma and lymphoma recently. I suspect that data like this may start to change things, because the idea is that if you can use healthy T cells and check where the gene is inserting with a fixed number of donors and a lot of good testing on it, that may lower the risk of this.

So, bottom line, how do I approach this discussion with patients? We’ve already been discussing the risk of second cancers with all of our patients receiving CAR T therapy. I think this is important because rather than describing it as a theoretical risk as I had been doing for the last year and a half now, we’ll describe it as a real documented, albeit quite rare, risk. Overall, the benefits of CAR T therapy absolutely outweigh the risks, particularly in the relapsed/refractory setting for patients with any kind of cancer. However, I do think we need better research to identify how to prevent this from happening with our autologous products or as we go to allogeneic CAR T cells—seeing how to make this not happen with them, period.

About Dr. Banerjee

Rahul Banerjee, MD, FACP, is an Assistant Professor in the Division of Medical Oncology at the University of Washington. He also holds a faculty appointment at the Fred Hutchinson Cancer Center in Seattle, Washington. Dr. Banerjee previously completed his Hematology/Oncology Fellowship and Advanced BMT/CAR-T Fellowship at the University of California, San Francisco. His clinical interests are in multiple myeloma, AL amyloidosis, and CAR T therapy. His research interests are in toxicity management, digital health, and the patient experience.