Genome Sequencing Identifies Factors That Cause Resistance in Multiple Myeloma T Cell Therapies

Study suggests the problem is more common than previously thought

PHOENIX, AZ. — Aug 31, 2023 — Among the newest types of treatments for multiple myeloma are T cell immunotherapies that target specific tumor proteins. Although the therapies have shown promise, patients can relapse if mutated versions of the proteins—which can’t be targeted by the T cells—become more prevalent in a tumor.

This phenomenon was thought to be relatively rare in multiple myeloma, but a new study in Nature Medicine led by Nizar J Bahlis, MD, of the Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada, has found several kinds of these mutations in whole genomes sequenced from 30 patients previously exposed to these therapies.

In fact, up to 65% of relapsing multiple myeloma patients could be affected by mutations that impact targeted T cell treatments, according to the study authors, including researchers from the Translational Genomics Research Institute (TGen), part of City of Hope, and City of Hope, one of the largest cancer research and treatment organizations in the United States.

“The thought has been that it’s pretty rare for patients to lose the target antigens, but this study shows the target is just not there or in some cases the target is there but mutated, so one drug might work but another one doesn’t,” said Amrita Krishnan, M.D., Director of the Judy and Bernard Briskin Center for Multiple Myeloma Research at City of Hope, and a co-author on the paper.

The findings could help clinicians and patients choose from among a variety of T cell therapies for multiple myeloma to find treatments that best match a patient’s available tumor targets. Two new treatments—elranatamab (Elrexfio™) and talquetamab (Talvey™) were approved by the U.S. Food and Drug Administration in August 2023 to complement three existing therapies approved in the last two years.

According to Jonathan Keats, Ph.D., Director of Bioinformatics at TGen, Scientific Director of the Judy and Bernard Briskin Center for Multiple Myeloma Research at City of Hope, and a co-author on the paper, the currently approved T cell therapies target either B cell maturation antigen (BCMA) or the GPRC5D protein on the surface of tumor cells. Previous research showed that some patients progressing on BCMA directed therapies had lost the target gene, but this study shows many patients lack a copy of the gene for one of these proteins (about 3% of patients for BCMA and about 15% for GPRC5D) when they are first diagnosed.

“This study has uncovered a variety of other ways that these two proteins can be mutated, including ways that help the tumor “escape” targeting by the therapy,” said Keats.

Along with new mutations in BCMA, the study for the first time identified mutations in GPRC5D that lead to patient relapse.

“These findings, in particular the mutations that block one drug from binding but not others, shows how important precision medicine approaches will be for myeloma patients in the future” said Bahlis, the paper’s senior author.

As more T cell therapies are approved that target these targets and others, results from whole genome sequencing will become crucial in determining which drug to use and in which order. In keeping with its mission to translate genomic findings into clinical practice, TGen will open a clinical lab in 2024 that provides whole genome sequencing results for acute myeloid leukemia and multiple myeloma patients within 48 hours.

“This kind of study highlights a group of myeloma patients who could benefit from those rapid test results,” said Keats. “Rapid sequencing will, in the near future, provide patients access to information that will help guide their day-to-day clinical care.”

Keats’ research is supported by the Judy and Bernard Briskin Center for Multiple Myeloma Research at City of Hope, the Multiple Myeloma Research Foundation, and the City of Hope Comprehensive Cancer Center NCI Core Grant (P30 CA 033572).

Written by Becky Ham /TGen


Posted in AZBio News.