Study Identifies Mechanisms of Resistance to Immunotherapy for Multiple Myeloma

A study published in Nature Medicine explored potential mechanisms of treatment resistance in patients with multiple myeloma following immunotherapies targeting B cell maturation antigen (BCMA) or G-protein-coupled receptor family C group 5 member D (GPRC5D).¹ Investigators found that myeloma cells may lose or change the targets and subsequently go undetected by these therapies, suggesting that screening for such changes regularly could help guide treatment.

Illustration of T cells | Image credit: Sebastian - stock.adobe.com

“Despite promising results obtained by using novel immunotherapeutic approaches, every multiple myeloma patient relapses at some point. We wanted to understand why this happens in order to prevent disease relapse and develop better treatments for our patients,” Nizar Bahlis, MD, associate professor at the Cumming School of Medicine (CSM) and senior author of the paper, said in a press release.²

To assess tumor-intrinsic factors that may contribute to antigen escape, a known mechanism of resistance to immunotherapy, researchers analyzed tumor samples from 30 patients treated with anti-BCMA and/or anti-GPRC5D chimeric antigen receptor (CAR) T-cell therapy or bispecific T-cell engager (TCE) therapy, which target BCMA or GPRC5D expressed on the surface of cells. Combined bulk and single-cell whole-genome sequencing and copy number variation analysis was done to determine the factors potentially leading to antigen escape.

“We found that the tumor cells escape the reach of immunotherapy by losing or changing these targets (BCMA, GPRC5D) on their surface,” Holly Lee, MD, hematologist, PhD student, and first author of the paper, said.² “When this happens, the tumor becomes invisible to the targeted therapy, like a strong signal that suddenly disappears from a radar screen.”

Specifically, sequencing revealed that multiple myeloma relapse following TCE or CAR T-cell therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss in 2 cases.¹

In 5 cases, despite BCMA protein expression on the surface, the investigators found that newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the effects of BCMA-targeting TCE therapy. They noted that functional epitope loss secondary to nontruncating mutation and in-frame deletions in the extracellular domain of BCMA is a previously unrecognized mechanism of resistance, to their knowledge.

In 4 cases, multiple myeloma that relapsed following anti-GPRC5D TCE therapy showed biallelic mutations of GPRC5D; this included 2 instances of convergent evolution where multiple subclones lost GPRC5D through somatic events.

The rate of BCMA mutational events was higher following anti-BCMA TCE than has been seen previously, the authors noted, and diverse mechanisms contributed to antigen loss in these cases. Six of 14 patients in the study who experienced disease progression following BCMA-targeted TCE showed mutational events in TNFRSF17 (42.8%), while biallelic loss of TNFRSF17 at relapse was rare after CAR T-cell therapy (6%).

Notably, BCMA extracellular domain mutant subclones were not seen in samples taken prior to therapy in index patients, emphasizing the importance of repeated sampling and analysis to inform treatment.

“We have noticed that the tumor can also change and mutate, altering the target recognized by these therapies, making the tumor cells unrecognizable to the therapies,” co-senior author Paola Neri, MD, PhD, oncologist TBCC, Alberta Health Services, said in a statement.² “Therefore, screening for these changes is key. If you know that the tumor mutations are present, you can consider different targets or other therapeutic options, personalizing the treatment for our myeloma patients.”

The researchers concluded that emerging BCMA mutations after BCMA-targeted CAR T-cell therapy and TCE are an important mechanism of resistance to multiple myeloma treatment, although they were previously considered rare.

“Our results suggest the importance of periodically profiling myeloma cells throughout a patient’s treatment course, ideally every three months. This proactive approach would enable us to adapt the treatment strategy in response to any tumor mutations that may arise,” Bahlis said.² “As more immunotherapies are being developed, it is critical to understand which ones will work the best and in which scenario.”

References

1. Lee H, Ahn S, Maity R, et al. Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma. Nat Med. Nat Med. 2023;29(9):2295-2306. doi:10.1038/s41591-023-02491-5

2. UCalgary and AHS researchers discover how multiple myeloma cells become resistant to immunotherapy. News release. University of Calgary. October 23, 2023. Accessed October 30, 2023. ttps://cumming.ucalgary.ca/news/ucalgary-and-ahs-researchers-discover-how-multiple-myeloma-cells-become-resistant-immunotherapy