Computer Model Shows How BCMA Mutations Repond to Immunotherapies

Mutations in the protein BCMA in multiple myeloma patients could impact the effectiveness of two popular immunotherapy drugs, according to new research by Pfizer scientists presented at the 22nd International Myeloma Society Annual Meeting.¹

The researchers used computer modeling to show how BCMA mutations R27P, S30del, P33S, and P34del, typically found in a small percentage of myeloma patients, impact the effectiveness of elranatamab and teclistamab. Both drugs work by attaching to the BCMA protein on the cancer cells, so mutations in BCMA carries implications for patient response to these drugs.

Metholology and Results

Researchers used AlphaFold modeling to predict how the drugs would bind to the different BCMA mutations tested. They then created lab-grown human cells with either normal or mutated BCMA proteins and tested the computer-generated hypotheses using surface plasmon resonance (SPR) to measure flow cytometry.

According to their findings, of the four mutations tested, only one mutation, P33S, had no impact on the efficacy of either drug. The S30del mutation "severely diminished" the effectiveness of teclistamab but had minimal impact on elranatamab. Both drugs, though, had reduced efficacy against the R27P and P24del mutations due to structural changes that impacted the drugs' ability to bind to the proteins.¹

While clinical studies are needed to confirm these results, the modeling provides possible hypotheses for any such future studies and provide possible guidance for health care providers in choosing drugs for their patients based on BCMA mutations.

REFERENCES

1. Josic M, Scheibold R, Chu T, et al. Differential impact of BCMA (TNFRSF17) extracellular domain mutations on in vitro potency of elranatamab versus teclistamab. Abstracts of the 22nd International Myeloma Society Annual Meeting. Abstract PA-037.