Winship researchers identify immune clues that could personalize multiple myeloma treatment

Researchers at Winship Cancer Institute of Emory University helped lead a landmark, multi-institutional study published in Nature Cancer that created the largest-ever single-cell immune atlas of bone marrow in patients with multiple myeloma. The findings reveal that the state of a patient’s immune system at diagnosis, in addition to the genetics of their tumor, can predict how their disease will progress and respond to treatment.

“For decades, research in multiple myeloma has focused primarily on the malignant plasma cells themselves,” says Manoj Bhasin, PhD, MS, cancer immunology researcher at Winship Cancer Institute of Emory University and co-senior and co-corresponding author of the study. “By profiling more than a million single cells, we showed that the immune system plays a broad, treatment-independent role in myeloma progression and outcomes.”

The study analyzed nearly 1.5 million immune and bone-marrow cells from 337 newly diagnosed patients in the Multiple Myeloma Research Foundation (MMRF) CoMMpass study, using advanced single-cell RNA-sequencing technology. The Immune Atlas is a detailed, single-cell map of immune cells in the bone marrow that shows how different immune cell types interact with cancer cells and how those patterns vary across patients. This approach enabled investigators to examine how individual immune-cell types communicate with tumor cells and influence disease course. Winship scientists co-led the study design and data analysis, performing single-cell assays and integrating the resulting data into a national Immune Atlas built with collaborators from Mount Sinai Health System, Washington University in St. Louis, Beth Israel Deaconess Medical Center, Mayo Clinic, and the MMRF.

“The scale and maturity of the MMRF’s CoMMpass study and the breadth of this multi-center collaboration highlight the importance of building ‘big science’ teams,” says George Mulligan, PhD, chief scientific officer at the MMRF. “This atlas is the result of more than a decade of investment in data, samples and partnerships, and it will accelerate discoveries across the multiple myeloma field.”

“Emory researchers played a central role in the study design, performing single-cell assays, and leading the analysis to explore how the immune landscape shapes outcomes,” says Bhasin, Professor in the Departments of Pediatrics and Biomedical Informatics at Emory University School of Medicine, director, Single Cell Biology Program at Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, and co-director of the Atlanta Single Cell Omics and Analytics Initiative.

The atlas showed that patients who relapsed early had signs of immune aging even before beginning treatment. Their bone marrow contained large numbers of exhausted CD8 T cells and fewer of the fresh T cells that help the body respond to new challenges. The study also identified distinct immune patterns within certain high-risk genetic groups. For example, patients with a 17p13 deletion had heightened interferon activity, while those with t(4;14) or 1q21 gain had reduced interferon signaling and more evidence of immune exhaustion.

“These findings highlight that immune dysregulation, rather than tumor genetics alone, can shape disease risk, influence therapy response and ultimately determine patient prognosis,” Bhasin explains.

By integrating immune profiles with tumor genetics, the team significantly improved the ability to predict progression-free survival. Patients with “immunosenescent” or inflamed bone-marrow signatures had poor outcomes even when their tumor genetics appeared favorable. “Including immune data creates a more comprehensive and accurate risk model, potentially leading to a new generation of prognostic scores,” Bhasin adds.

The study also highlighted specific immune pathways that may guide future treatment strategies. In some high-risk groups, briefly stimulating a part of the immune system called the interferon pathway, using medicines already used in treating myeloma, could help strengthen the body’s ability to fight the cancer. In other patients, where this pathway is constantly switched on and causing immune fatigue, drugs known as immune checkpoint inhibitors may help reset T-cell function.

Another pathway, known as APRIL–BCMA, involves signals from certain immune cells that can help myeloma cells survive. Targeting this interaction could make existing BCMA-directed therapies even more effective and reduce the support the tumor receives from its surroundings.

“Targeting pathways such as interferon and APRIL–BCMA could help disrupt tumor-supportive interactions and guide the next wave of combination immunotherapies,” Bhasin says.

Sagar Lonial, MD, FACP, FASCO, chief medical officer of Winship Cancer Institute, professor and chair, Department of Hematology and Medical Oncology, Emory University School of Medicine, and member of the MMRF Scientific Advisory Board, says the research adds an important dimension to how clinicians understand and treat multiple myeloma. “This research helps us understand why two patients with the same tumor genetics can have very different outcomes,” Lonial says. “By accounting for the immune environment, we may one day tailor myeloma therapy more precisely and intervene earlier for those at highest risk.”

The project, designed and funded by the MMRF, drew on 12 years of patient data and biospecimens, making it one of the most comprehensive resources of its kind. The immune atlas is expected to spark new lines of research and accelerate translational efforts across the field.

“By mapping tumor-immune interactions at single-cell resolution, we can identify shared or cancer-specific immune dysfunctions and design targeted therapies accordingly,” notes Bhasin.

The study was supported by the Immune Atlas Consortium, collaborating institutions and the MMRF, with additional fellowship support from the Myeloma Solutions Fund for analysts and student researchers involved in the project. “We are grateful to Immune Atlas Consortium members and collaborators, the MMRF, and the Bhasin Lab members for their dedication and contributions to this work,” Bhasin adds.

Related research by members of the same multi-institutional collaboration was recently published in Blood Cancer Discovery, examining how tumor and immune cells change over time during treatment in patients with multiple myeloma. Together, the studies highlight how both baseline immune health and immune evolution can influence disease outcomes.