Study Identifies Why Multiple Myeloma May Return After Immunotherapy

Multiple myeloma research led by researchers at the University of Calgary identified how tumor cells adapt after immunotherapy, potentially helping explain why patients with cancer may relapse and informing future personalized treatment strategies.

Why do patients with multiple myeloma relapse after immunotherapy?

An international study published in Nature Medicine examined why patients with multiple myeloma experience relapse after receiving immunotherapy. By analyzing tumor cells from patients with cancer across North America, Europe and Asia, investigators found that cancer cells can adapt in several ways to resist treatment, highlighting the need for more personalized approaches to care.

The research focused on patients with cancer who had previously received a bispecific T-cell engager, a type of immunotherapy that helps the immune system recognize and attack multiple myeloma cells by targeting a protein called GPRC5D on the surface of tumor cells. Despite initial responses, some patients experienced disease recurrence, prompting researchers to investigate the underlying causes.

Tumor adaptation drives treatment resistance in multiple myeloma

Researchers found that tumor cells in multiple myeloma are highly adaptable under treatment pressure. According to study findings, approximately 60% to 70% of patients with cancer who relapsed did so because of changes in the GPRC5D protein on the tumor cells. These changes allowed the cancer cells to evade detection and attack by the immune system, reducing the effectiveness of the therapy over time.

“Multiple myeloma tumor cells are highly adaptable under therapeutic pressure,” said Dr. Holly Lee, clinical assistant professor at the Cumming School of Medicine and first author of the study, in a news release detailing the findings. “A treatment could be incredibly effective, bringing disease bulk down from about 100% to about 1% to 2% — but all it took was that 1% to 2% of the cells that were left to adapt and cause this relapse in patients.”

The study also showed that tumor cells developed resistance through multiple biological pathways, not just a single mechanism. This variability helps explain why patients with cancer can have very different outcomes, even when receiving the same treatment. Some patients remain in remission for four or five years, while others experience relapse within six months.

Researchers emphasized that understanding these adaptive changes may help guide the development of next-generation therapies designed to anticipate and overcome resistance. These findings may also extend beyond multiple myeloma, as similar mechanisms could apply to other cancers.

Study examined global patient data after bispecific immunotherapy

The study was led by Lee alongside project leads Dr. Paola Neri and Dr. Nizar Bahlis. Investigators evaluated tumor samples from patients with cancer who relapsed after receiving bispecific T-cell engager therapy targeting GPRC5D.

Researchers noted that identifying patterns of tumor adaptation required broad data sharing, as the true incidence of these biological changes was previously unknown.

“The true incidence of this type of biological adaptation in GPRC5D was unknown in the field. In order to generate enough data to support the research, it required a collaborative effort,” Lee said.

Researchers indicated that future efforts will focus on integrating more targeted screening into clinical practice with faster turnaround times, allowing clinicians to better tailor treatment strategies for patients in real time.

References

1. “International study led by UCalgary explores why multiple myeloma patients often relapse after immunotherapy by Dr. Holly Lee, et al., Nature Medicine.”

For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here.