Why Multiple Myeloma Can Return After CAR T-Cell Therapy

At the 2026 COMy (Controversies in Multiple Myeloma) Conference, Dr. Carlos Fernández de Larrea presented on resistance to CAR T-cell therapy. CAR-T therapy is a treatment that re-engineers a patient's own T cells to recognize and attack the cancer cells. After CAR T-cell therapy, many patients experience a complete response, and the cancer is controlled for long periods of time. But most patients eventually see their myeloma return for reasons that differ from patient to patient.

What is CAR T-cell therapy in multiple myeloma?

Multiple myeloma is a cancer of plasma cells in the bone marrow. Most CAR T-cell therapies used in myeloma today target a protein called BCMA (B-cell maturation antigen). This protein sits on the surface of myeloma cells and gives the engineered T cells something to recognize.

Dr. Fernández de Larrea explained that even though CAR T-cell therapy has shown remarkable results in heavily pretreated patients, many still relapse. Resistance to the therapy can come from different places: 

• The T cells used to make the product.
• The bone marrow environment where the CAR T cells must work.
• The biology of the myeloma itself.

Which factors can affect CAR-T outcomes?

Certain characteristics are linked to less favorable outcomes after CAR T-cell therapy. According to Dr. Fernández de Larrea, these include:

• Plasma cell leukemia. This is an aggressive form of myeloma in which cancer cells circulate in the blood.
• Extramedullary disease. This is myeloma that has spread outside the bone marrow into soft tissues.
• High-risk cytogenetics. These are specific genetic changes in the myeloma cells associated with poorer prognosis.

Even with effective CAR T-cell therapy, patients with these features still tend to do somewhat worse than those without them.

What happens to BCMA after CAR T?

One of the clearest findings Dr. Fernández de Larrea presented involves what happens to BCMA itself. When researchers compared BCMA levels on myeloma cells before treatment and at the time of relapse, they saw a significant drop in BCMA expression.

True BCMA-negative relapse, where the cancer has lost the target entirely, is uncommon. It only occurs in only about 5% to 7% of cases, but even a partial reduction in BCMA can blunt how well the CAR T cells work.

The presenter also discussed soluble BCMA, which is BCMA released from cell surfaces into the bloodstream. Soluble BCMA can be found in variable concentrations in patients. Higher levels have been linked to more toxicity (tolerance and adverse events) and shorter survival.

Another important factor is prior exposure to BCMA-targeted therapies. Patients previously treated with antibodies that bind BCMA, such as belantamab, tend to have significantly weaker responses to BCMA-directed CAR T-cell therapy afterward. The theory is that BCMA protein floating in the blood “soaks up" the drug before it reaches the cancer.

What new approaches are being studied?

To address these problems, researchers are exploring CAR T-cell therapies that target different proteins on myeloma cells. One promising target is GPRC5D. This receptor is highly expressed on myeloma cells in nearly all patients with multiple myeloma. Importantly, the activity of GPRC5D-directed therapy does not appear to be reduced by previous treatment with belantamab.

Researchers are also studying other molecules as targets, both alone and in combinations that aim to hit several antigens at once. This is so the cancer cannot easily escape by losing just one. Gamma secretase inhibitors are another area of interest. In models, using these drugs for longer periods of time helped prevent the loss of BCMA from the surface of myeloma cells, which could improve CAR T-cell effectiveness.

Why the quality of T cells matters

Beyond the target itself, the quality of the T cells used to manufacture the CAR T-cell product also makes a difference. T cells in earlier stages of development, known as naive and memory T cells, multiply into much larger numbers inside the body and produce stronger responses. Exhausted T cells, on the other hand, do not multiply as well, so the CAR-T cells run out faster and don’t work as well.

Dr. Fernández de Larrea pointed to ongoing work in his own lab and elsewhere on modifying T cells to keep them in a more memory-like state. One strategy involves blocking PD-L1. This is a molecule cancer cells use to stop the immune system from attacking. The manufacturing process used to produce CAR T cells is another factor that influences how well the final product works.

The role of the tumor environment

The tumor environment is another major piece of the puzzle, particularly in extramedullary disease. Dr. Fernández de Larrea described it as a different ecosystem, one where T-cell exhaustion is higher, immune cells have trouble reaching the tumor, and CAR T-cell activity is limited.

This helps explain why patients with extramedullary or paraskeletal disease often relapse again in those same areas. Paraskeletal disease is myeloma growing alongside the bones.

New generations of CAR T cells

Researchers are also engineering new generations of CAR T cells designed to overcome these obstacles. Dr. Fernández de Larrea shared one example from his group in which they changed the transmembrane domain. This is the part of the engineered receptor that crosses through the cell membrane. Changing this reduced toxicity while keeping target recognition on the cell surface similar. In mouse models, this change translated into a survival advantage.

"We are living exciting times," Dr. Fernández de Larrea said, noting that CAR T-cell therapy has shown clear and remarkable efficacy in heavily pretreated myeloma. Still, many patients relapse, and the field has much to explore. He emphasized that improving the quality of CAR T cells and addressing the tissue environment where they will incorporate will be crucial for making this therapy last longer for more patients with multiple myeloma.

Key takeaway

CAR T-cell therapy has been a real breakthrough for people living with multiple myeloma, helping many achieve deep responses even after other treatments have stopped working. Still, the myeloma often finds a way to come back, and Dr. Fernández de Larrea's talk helped explain why. Sometimes the target on the myeloma cells (BCMA) fades after treatment, sometimes the T cells themselves run out of steam, and sometimes the environment around the tumor makes it hard for CAR T cells to do their job. 

The encouraging news is that researchers are actively working on each of these challenges, exploring new targets like GPRC5D, smarter ways to build CAR T cells, and strategies to help them last longer. The goal, as he put it, is to keep moving toward longer-lasting responses for more patients.

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