The Approved Medication That Boosts CAR-T Giving It a Longer Life 

A study recently published in Blood suggests that an approved myeloma therapy, carfilzomib, may help restore the effectiveness of BCMA-targeted CAR T therapy

Researchers at the Technical University of Munich have identified a new mechanism by which multiple myeloma cells evade CAR T-cell therapy. The discovery sheds light on why CAR T-cell therapy sometimes stops working and offers a hopeful path toward more personalized and durable treatment approaches.

Why does CAR T-cell therapy stop working in multiple myeloma?

Chimeric antigen receptor (CAR) T-cell therapy is a type of immunotherapy that uses a patient’s own immune cells. These T cells are collected, genetically modified in a laboratory to recognize cancer cells, and then infused back into the body to attack the disease.

In multiple myeloma, CAR T-cells are designed to target BCMA (B-cell maturation antigen), a protein found on malignant plasma cells. While this therapy can lead to deep remissions, most people eventually relapse.

Until now, one explanation for relapse has been that myeloma cells genetically lose BCMA. However, this accounts for only a small percentage of cases. Many patients relapse even though BCMA has not been permanently deleted.

What causes BCMA to disappear from the myeloma cell’s surface? 

The research team uncovered a previously unknown mechanism that causes BCMA to disappear from the surface of myeloma cells.

They found that BCMA is rapidly broken down by a system inside cells called the ubiquitin-proteasome system (UPS). The UPS acts like a recycling center, tagging proteins for destruction. This process directly affects BCMA at the cell surface, a phenomenon not previously described.

When BCMA is removed from the cell surface, CAR T cells can no longer “see” or recognize the cancer. Under the selective pressure of therapy, myeloma cells with low BCMA levels survive and grow, leading to relapse.

How does carfilzomib help restore BCMA?

Carfilzomib (Kyprolis) is a proteasome inhibitor approved to treat multiple myeloma. Proteasome inhibitors block the protein-recycling machinery inside cancer cells.

In the laboratory, carfilzomib significantly increased BCMA levels on myeloma cells. This happened in both:

• Cells that were sensitive to proteasome inhibitors
• Cells that were resistant to proteasome inhibitors

Carfilzomib prevented BCMA from being degraded, allowing it to remain on the cell surface. As a result, CAR T cells were better able to recognize and destroy myeloma cells. 

Does carfilzomib perform as well in people as it does in the lab? 

To explore whether this strategy could work in real-world patients, researchers treated 10 people whose BCMA CAR T therapy had stopped working.

All patients received carfilzomib after relapse. The results were encouraging:

• BCMA expression increased in all 10 patients.
• Six patients had detectable CAR T cells still present in their body.
• Among those six, CAR T activity was restored in several patients, leading to clinical responses.
• Importantly, when patients were treated with carfilzomib alongside CAR-T, it did not increase toxicity.

Patients who no longer had enough CAR T cells circulating did not experience the same benefit. This suggests that carfilzomib may “reawaken” existing CAR T cells, but it cannot replace them.

Conclusions 

Although the results are encouraging,  larger clinical trials will be needed to determine which patients are most likely to benefit.

This research provides two major insights:

• It reveals a new biological weakness in multiple myeloma. BCMA can also be temporarily suppressed by protein degradation. That means resistance may be reversible.
• The importance of repurposing an already approved drug to strengthen immunotherapy. Instead of developing entirely new treatments, researchers may strategically combine existing therapies to improve outcomes.
• Finding that similar mechanisms could affect other immunotherapy targets, opening the door to broader applications.

More studies like this show us the future of precision medicine

Multiple myeloma treatment has evolved dramatically over the past decade. From proteasome inhibitors to immunomodulatory drugs, monoclonal antibodies, and CAR T-cell therapies, options continue to expand.

This new research highlights an important shift: rather than treating all relapses the same way, scientists are learning to identify specific biological mechanisms and directly target them.

By understanding how therapies stop working, doctors may be able to:

• Restore sensitivity to previous treatments.
• Reduce unnecessary exposure to ineffective drugs.
• Limit side effects by using more targeted combinations.
• Design smarter, personalized treatment plans.

The more precisely we can identify a cancer cell’s specific weakness, the less we need to rely on broadly toxic approaches.

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Sources: 

• Boosting CAR T-cell efficacy by blocking proteasomal degradation of membrane antigens

• Established cancer drug gives multiple myeloma immunotherapy new lease of life