Immune cell atlas may improve survival predictions, guide treatment decisions in multiple myeloma

A new study maps the immune cell landscape of bone marrow in patients with multiple myeloma, a rare cancer that develops in the plasma cells of the bone marrow and has no cure. This large immune cell atlas, which includes robust patient outcome data, provides unparalleled new insights into how the immune system interacts with cancerous plasma cells and can be used to determine how aggressive a patient's multiple myeloma is likely to be. The knowledge may improve survival predictions, guide treatment decisions and help in the development of new immune-based therapies for patients with multiple myeloma.

Co-led by researchers at Washington University School of Medicine in St. Louis in collaboration with the Multiple Myeloma Research Foundation (MMRF) and other leading institutions across the country, the study appears Jan. 9 in the journal Nature Cancer.

"It is time for a better understanding of the immune system in multiple myeloma," said WashU Medicine co-senior author Li Ding, PhD, the David English Smith Professor of Medicine and a research member of Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine. "In addition to targeting the cancerous plasma cells directly, we also want new and better ways to activate the immune system to attack the malignant cells. This large-scale immune cell atlas will serve as a critical resource to investigators studying multiple myeloma and working to develop better therapies."

While considered a rare cancer, multiple myeloma is the second most common blood cancer after leukemia, accounting for about 15%-20% of new blood cancer diagnoses in the U.S. annually. Plasma cells are white blood cells in the bone marrow. When they grow out of control, they crowd out healthy blood cells. About 60% of patients are still living five years after diagnosis.

Many new treatment options have emerged for multiple myeloma in recent years that can extend survival for many patients, sometimes for more than a decade. Even so, the disease almost always returns after periods of remission, emphasizing the need for new and better options.

Several of the newest therapies for multiple myeloma are immune system-based, including CAR-T cells and what are known as bispecific antibodies. But researchers suspect there may yet be untapped opportunities for immune-based treatments for multiple myeloma, and the immune cell atlas is a new tool to harness in pursuit of such therapies.

This immune atlas provides a roadmap for the next generation of myeloma care. As immunotherapies like CAR-T cells and bispecific antibodies become central to treatment, understanding the immune context in which they operate is essential. Clinically, this work lays the foundation for immune-informed risk stratification and rational development of new therapies that not only target the tumor but also restore effective anti-myeloma immunity."

Ravi Vij, MD, the Jeffrey S. and Prue H. Gershman Distinguished Professor of Medicine, coauthor and WashU Medicine oncologist 

Vij treats patients with multiple myeloma and other blood cancers at Siteman Cancer Center.

A cell-by-cell catalog of multiple myeloma

The research team performed a rigorous and cutting-edge genetic analysis called single-cell RNA sequencing of almost 1.4 million individual plasma and immune cells in bone marrow sampled from 337 newly diagnosed multiple myeloma patients. This type of analysis can reveal how individual immune cells may function - or become dysfunctional - in the context of multiple myeloma.

The data describe patients enrolled in MMRF's CoMMpass Study, which is the first large-scale, long-running study of patients with multiple myeloma focused on analyzing disease progression and treatment response based on the genomic and molecular profiles of the patients. WashU Medicine is one of multiple sites participating in the CoMMpass Study.

The investigators found that patients with certain types of immune cells in their bone marrow at diagnosis were more likely than others to relapse quickly, meaning their cancer returned soon after a first round of treatment. The researchers identified signaling patterns between the cancer cells and immune cells that drive inflammation, which might be boosting the cancer's growth in patients with aggressive disease.

The team also identified a type of T cell that had stopped working as expected and, rather than attacking the tumor as it should, acted to suppress immune activity against the cancer. Together, these findings could help make prognosis more accurate and aid in selecting the best therapies.

"This immune atlas represents the power of collaborative science," said co-senior author and MMRF Chief Scientific Officer George Mulligan, PhD. "The MMRF's CoMMpass Study, combined with the expertise from investigators at WashU Medicine and leading institutions across the country, has created an unprecedented resource that will accelerate discovery and improve outcomes for myeloma patients."

Importantly, the researchers showed that knowledge of the immune environment in a patient's bone marrow could improve upon current methods for predicting which patients are most likely to experience an aggressive course of the disease and have shortened survival. Such predictions can help guide treatment decisions in terms of matching the intensity of the treatment with the aggressiveness of the cancer.

Current methods for determining whether a patient has high-risk multiple myeloma versus standard risk rely on knowing the genetic features of the cancer cells combined with clinical aspects of the patient's health. The new study found that adding an immune component to this analysis would likely improve the accuracy of the categorization.

"More work is needed to develop specific immune-based blood tests, for example, that clinicians could order to better identify the aggressiveness of a particular case of multiple myeloma and help them select the best treatments for that patient," Ding said. "This immune cell atlas fills a gap in knowledge that is needed to develop these types of new clinical tools."

The MMRF designed and funded this research, which involved collaboration among the Georgia Institute of Technology, Emory University, Harvard Medical School and the Icahn School of Medicine at Mount Sinai.