While CAR T-cell therapy is a revolutionary treatment for multiple myeloma, managing its complex side effects is crucial for patient safety and success. In a comprehensive overview at the International Myeloma Society 2025 conference, Dr. Benjamin Puliafito detailed the latest understanding and management strategies for three major concerns: 

• Infections

• Neurological toxicities of secondary cancers.

Across all CAR-T trials, infections are responsible for 50% of all non-relapse deaths. When an infection appears after CAR-T therapy is also important to consider. For example, bacterial infections are most common during the first 30 days. After 30 days, viral infections become the primary threat.

The first 100 days post-infusion are crucial and require close monitoring because people are more prone to infections during that time due to low blood counts. After this point, the risk tends to level off, unlike with bispecific antibodies, where infection risk continues to climb over time.

To address this issue, Dr. Puliafito addressed that not only antiviral medications and vaccinations are necessary, but also Intravenous Immunoglobulin (IVIG), a key component of infection prevention. IVIG should be started within the first month and continued monthly for at least six months to help prevent viral infections. 

Beyond ICANS: Understanding delayed neurotoxicity

Beyond the well-known neurotoxicity called ICANS, a different set of neurological side effects can emerge, often weeks or months after infusion. These "non-ICANS neurotoxicities" can be distressing for patients and include facial paralysis (cranial nerve palsy) and severe movement disorders that resemble Parkinson's disease.

A clear risk factor for these toxicities is a high tumor burden at the time of CAR-T infusion, which can lead to an overly aggressive expansion of the CAR-T cells. This is why effective bridging therapy is so important.

A simple blood test called absolute lymphocyte count (ALC) has emerged as a powerful predictor. Studies show that a peak ALC above 3,000 massively increases the risk of developing these neurological problems. This raises a critical question for the future: can doctors proactively treat a rapidly rising ALC with a short course of steroids to prevent these toxicities before they start?

When these severe neurotoxicities do occur, they are often resistant to standard steroid treatment. Different cancer centers are pioneering new approaches. New ways to prevent neurotoxicity after CAR-T therapy are being explored, for example cyclophosphamide has shown to reduce the non-ICANS neurotoxicities after CAR-T. Another therapeutic approach is to directly administer chemotherapy into the cerebrospinal fluid (intrathecal), to reduce parkinson-like movement side effects and other neurological symptoms. These are not perfect solutions, highlighting the urgent need for better management strategies.

Putting the risk of secondary cancers in perspective

There is a small risk of developing a new cancer after CAR T-cell therapy. Although this is rare, there are two common types of cancer to look out for:

1. Therapy-Related Myeloid Neoplasms (t-MN): These are blood disorders like MDS and AML that are a known risk from prior myeloma treatments. Large randomized trials and real-world data show a low risk of around 1%. However, long-term follow-up is still needed.

2. CAR-Positive T-Cell Lymphomas: This is a new and very rare cancer where the CAR T-cells themselves become malignant. Though incredibly rare, doctors should be suspicious if a patient develops unusual symptoms like severe diarrhea or new skin lesions. A biopsy is essential to make the diagnosis.

Dr. Puliafito emphasized the need for advanced genomic sequencing of the abnormal cells of the secondary cancer to find its specific weaknesses. This can lead to highly personalized treatments, such as using a JAK inhibitor for a JAK-STAT mutation or an anti-CCR4 antibody for a tumor overexpressing CCR4.

Ultimately, the journey with CAR T-cell therapy is one of balancing immense promise with significant, manageable risks. The field is rapidly learning how to predict, prevent, and treat these complex side effects. Through proactive infection control, vigilant monitoring for neurological changes, and a clear-eyed understanding of long-term risks, clinicians are continually making this powerful therapy safer. As CAR-T moves into earlier lines of treatment, this focus on safety and supportive care will become even more critical to ensuring the best possible outcomes for patients.