Interactions Between Tumor Genes, Microenvironment Impact Treatment Response in Multiple Myeloma

This article was originally published by Pharmacy Times^®. This version has been lightly edited.

A recent study published in Nature Cancer showed that distinct genomic drivers in multiple myeloma may affect clinical outcomes. Researchers also identified factors associated with sustained minimal residual disease negativity.¹

Investigators at the University of Miami Miller School of Medicine found that the interactions between tumor cells and immune components of the microenvironment can influence treatment responses and outcomes in patients who are newly diagnosed with multiple myeloma and undergoing combination treatments that include targeted immunotherapy. Although immunotherapies targeting the molecule CD38 are particularly effective in improving survival rates, multiple myeloma either continues to respond properly, or progresses prematurely in 30% to 50% of newly diagnosed patients.²

Harmful changes that occur in the genetic makeup of tumor cells are sometimes driven by the tumors themselves; however, others may occur as immunotherapies change the treatment landscape, which creates a moving target for researchers. Newly diagnosed patients are often treated with therapies that influence the immune microenvironment.

“Since the introduction of advanced, targeted immunotherapy regimens, there has been a pressing need to better understand the tumor genomic and immune interactions that drive resistance to combination treatment approaches,” said Carl Ola Landgren, MD, hematologist/oncologist, chief of the Division of Myeloma, and director of the Myeloma Institute at Sylvester, in a press release.² “This study adds significant information that will result in better clinical trials and more effective therapies for patients with high-risk disease.”

In this study, researchers collected bone marrow samples from 49 enrolled patients who had received a combination drug therapy that included daratumumab, a CD38-targeting monoclonal antibody. Whole genome sequencing was performed to look for chromosomal changes in tumor cells that could increase the risk for treatment resistance. In addition, single-cell RNA sequencing was performed to analyze tumor microenvironments.

The investigators identified specific gene mutations and changes—including high APOBEC mutational activity, IKZF3 and RPL5 deletions, and chromosome 8q gain—that influenced clinical outcomes.¹ Further, they described immune-related factors and events that predict sustained treatment effects with prolonged survival.

“We found that stronger treatment responses and prolonged progression-free survival were driven by a complex interplay between tumor genomic features and immune microenvironment changes,” said Francesco Maura, MD, assistant professor and co-principal investigator of the Myeloma Computational and Translational Laboratory.² “Interestingly, we found that with the introduction of immunotherapy, some historically important genomic prognostic factors lost some of their power to predict outcome and a number of genomic drivers and microenvironmental features emerged as being of importance.”

Reference

1. Maura F, Boyle EM, Coffey D, et al. Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens. Nat Cancer. Published online November 9, 2023. doi:10.1038/s43018-023-00657-1

2. Sylvester research shows how interactions between tumor genes and microenvironment influence treatment response in multiple myeloma. News release. University of Miami Miller School of Medicine. November 9, 2023. Accessed November 9, 2023. https://www.eurekalert.org/news-releases/1007448