Distinguishing Early and Late-Presenting CAR T Toxicities

Chimeric antigen receptor (CAR) T-cell therapy is being employed in a wider range of patients with multiple myeloma at an earlier phase of treatment. While early toxicities from CAR T-cell therapies are managed in an academic center, it is important for all treating oncologists to familiarize themselves with long-term toxicities including cytopenias, infections, and the risks of second malignancies. At a recent virtual Case-Based Roundtable meeting, Jorge Monge, MD, assistant professor of medicine in the division of hematology at the University of Colorado, spoke to oncologists in Colorado and neighboring states about the adverse events (AEs) reported in the CARTITUDE-4 trial (NCT04181827) and discussed how to counsel and support patients with multiple myeloma.

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Targeted Oncology: What toxicities of special concern were reported in the phase 3 CARTITUDE-4 trial?

Jorge Monge, MD: On the update, we've seen that cytokine release syndrome [CRS] occurred in 76% of patients, mostly grade 1 and 2, all of them resolved.¹ The neurotoxicity occurred in about 20% of cases. But immune effector cell–associated neurotoxicity syndrome was only in 4.5% and none of them were grade 3 or 4. The rest are the ones that we call delayed neurotoxicities, and this includes cranial nerve palsies, peripheral neuropathy and the MNTs [movement and neurocognitive treatment-emergent adverse events] or Parkinsonism and Guillain-Barré syndrome. One patient that got any grade MNT, but one patient is too many, and a lot of them will get very put off by that kind of AE.

Could the higher rate of MNTs in the prior CARTITUDE-1 trial (NCT03548207) be due to using CAR T-cells later in the disease course?

Absolutely, it is much easier to control [disease earlier]. Remember, on CARTITUDE-1 the only thing we had to debulk the patients with was [DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin)], and DCEP on the eighth line of therapy only lasts for a couple of weeks. You'll get a response, but the tumor comes right back up, and you might not get the amount of time needed for the CAR T to be manufactured. Then you have to decide, do we do another cycle, or do we go straight into it, and that's the tough part.

What late-appearing toxicities reported in CARTITUDE-4 should be considered?

Another of the AEs we're very cognizant about are second primary malignancies. Cutaneous/noninvasive ones don't scare me as much because you can send them to dermatology and they take care of it with some Mohs [surgery], and that's it. The numbers are very similar between [ciltacabtagene autoleucel (cilta-cel; Carvykti) and standard of care], 7% and 7% [Table 1²].

For noncutaneous/invasive, there were very similar rates, 3% and 3.8% [respectively]. The ones that we need to see a little bit more frequently are the hematologic ones. Once you've seen one of those peripheral T-cell lymphomas, you've seen too many. It's not that the standard-of-care arm doesn't have them. It can also be that it was too early for them to have it, because 1% or 0.5% [rate] on an arm who…received transplant and lenalidomide is not the expected [rate].

But this is a randomized trial, so these signals are to be taken seriously. These are 7 patients with hematologic malignancies vs 1 patient on the standard-of-care arm. However, there were 50 patients who died after getting cilta-cel vs 82 patients who died after getting standard of care. There might be 6 more deaths due to hematologic malignancies, but there are 32 more deaths on the standard of care, 30 more deaths based on progressive disease. That is what I counsel my patients on. Even though they are all very scared about the second primary malignancies, this is something that helps them decide one way or the other.

How significant is the hematotoxicity with cilta-cel?

Another one of the late toxicities is what we call immune effector cell–associated hematotoxicity. These patients are all going to become neutropenic, thrombocytopenic, and anemic after we give them fludarabine and cyclophosphamide as lymphodepleting chemotherapy, but you expect the majority to recover quite quickly. There are still a quarter of the patients who have grade 3 to 4 hematotoxicities 30 days out, and about 10% at 60 days out [Table 2³]. It can become a little bit tough to manage.

I am using a lot more growth factor support now. I've gotten very lucky with approval processes to give granulocyte colony-stimulating factor (G-CSF), darbopoetin, and even thrombopoietin agonists like romiplostin, and those have been able to decrease the transfusion requirements of my patients. Of course, if the patient is younger, maybe there are cells left in the freezer, and then we give them the so-called stem cell boost. There are very good data published that can help get those insurance approvals.^4,5

Are there any specific precautions if we have to give the transfusions?

It helps if they are CMV [cytomegalovirus]-negative, but it's not a patient with allogeneic transplant. You can use the same kind of precautions you use for the autologous stem cell patients, who are not always CMV negative. Most of the transfusions end up being leuko-reduced, and that usually takes care of that. [Being] irradiated is important.

What vaccination schedule do you give these patients, and can it include live attenuated vaccines?

I would urge physicians to point that question to the person who gave the patient the CAR T. In my center, we vaccinate the patients with the same schedule as we vaccinate autologous stem cell transplant patients, and it depends on the patient's immunologic status at the 2-year mark whether I would recommend or not giving them MMR [measles, mumps, rubella]. I have 1 patient who is living in New Mexico and was especially concerned about MMR because of an outbreak...in a city next to them, and I did give them the MMR vaccine. They did not get a disease. But I wouldn't do a blanket statement to overrule every single cellular therapy center.

I start at 6 months with Haemophilus influenzae type B vaccine, [pneumococcal conjugate vaccine], tetanus, diphtheria, pertussis, and then I make sure that they've received the shingles vaccine after a year and a half and then consider the MMR especially on seronegative patients at the 2-year mark. If they have recovered, we do a lot of lymphocyte subsets. So if their CD4 count is back up and running, then I'm completely OK vaccinating them.

We recommend either valacyclovir or acyclovir for at least 1 year post CAR T, levofloxacin 500 mg until at least the neutropenia has resolved and I am no longer using any G-CSF to support it. I give my patients trimethoprim/sulfamethoxazole [Bactrim] until at least 6 months, and only if the CD4 count has recovered to above 200/mm³. I give everybody primary intravenous immunoglobulin replacement if their IgG is less than 400 mg/dL and G-CSF used to keep their absolute neutrophil count above 1000/μL.

Are there still barriers to accessing CAR T-cell therapy?

Recently, the FDA gave new advice regarding the REMS [Risk Evaluation and Management Strategy] requirements,⁶ and that might be something to look at and discuss with your CAR T-cell referring center, because there have been some adjustments to the requirements that the center has for the amount of minutes, miles, and days that you needed to be around the center [From the Data⁶]. There have been some big changes on both the B-cell maturation antigen CAR Ts and on the CD19 CAR Ts for those who also treat patients with lymphoma. I invite you to [review] the FDA’s new REMS advice. But a patient who is living alone is [still] challenging. We’ve been able to sometimes get help when the caregiver needed to go to work and couldn’t be there 24/7, and we were able to get some grants to give 12-hour support with a home health aide. But I know that that doesn’t fix everything for everybody.

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DISCLOSURES: Monge previously reported consulting fees with Janssen.

_REFERENCES:

_{1. Sidiqi MH, Corradini P, Purtill D, et al. Efficacy and safety in patients with lenalidomide-refractory multiple myeloma after 1-3 prior lines who received a single infusion of ciltacabtagene autoleucel as study treatment in the phase 3 CARTITUDE-4 trial. Blood. 2023;142(suppl 1):4866. doi:10.1182/blood-2023-178778}

_{2. Mateos MV, San-Miguel J, Dhakal B, et al. Overall survival (OS) with ciltacabtagene autoleucel (cilta-cel) versus standard of care (SoC) in lenalidomide (len)-refractory multiple myeloma (MM): phase 3 CARTITUDE-4 study update. Clin Lymphoma Myeloma Leuk. 2024;24(suppl_2):S290. doi:10.1016/S2152-2650(24)02346-2}

_{3. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379}

_{4. Wesson W, Ahmed N, Davis JA, et al. Use of eltrombopag for post-CAR T cytopenias: a multi-institutional experience. Blood. 2023;142(suppl 1):2136. doi:10.1182/blood-2023-181283}

<sub>5. Lin Y, Qiu L, Usmani S, et al; International Myeloma Working Group. Consensus guidelines and recommendations for the management and response assessment of chimeric antigen receptor T-cell therapy in clinical practice for relapsed and refractory multiple myeloma: a report from the International Myeloma Working Group Immunotherapy Committee. Lancet Oncol. 2024;25(8):e374-e387. doi:10.1016/S1470-2045(24)00094-9
6. FDA eliminates Risk Evaluation and Mitigation Strategies (REMS) for autologous chimeric antigen receptor CAR T cell immunotherapies. News release. FDA. June 27, 2025. Accessed August 6, 2025. https://tinyurl.com/bp5pxxks</sub>