Groundbreaking New MMRF-Led Studies Shed Light on Immune System’s Role in Multiple Myeloma

Scientists have long studied myeloma cells’ genetic features to better understand how the disease behaves in patients. But much less is known about the role the immune system plays. Now, new research from the Multiple Myeloma Research Foundation (MMRF) and its partners offers groundbreaking insights on this complex and important relationship—work that is a major advancement in our understanding of the disease and patient outcomes.

This research—a paper published today in Nature Cancer and another published last month in Blood Cancer Discovery—is the result of a years-long collaborative project called the Immune Atlas. The MMRF launched this initiative in 2019 with five leading academic medical centers: Emory University, Beth Israel Deaconess, Washington University School of Medicine in St. Louis, Icahn School of Medicine at Mount Sinai, and the Mayo Clinic.

Crucially, these two publications demonstrate the unique role that the MMRF plays in driving collaborative science. These reports also represent the first of many forthcoming insights as investigators continue to analyze this invaluable dataset.

Here, the MMRF highlights the major findings, how the MMRF’s forethought drove these discoveries, and what’s to come.

Highlights from Nature Cancer

Investigators involved in today’s Nature Cancer paper created an unprecedented map of the environment around myeloma cells by using sophisticated single-cell sequencing technology to analyze millions of individual immune cells.

To better understand how the immune system behaves in myeloma, the team studied bone marrow samples from 337 newly diagnosed patients who enrolled in the MMRF’s CoMMpass Study. Researchers carefully measured the types and amounts of different immune cells and compared these patterns across patients. Then they linked this information to how each person’s disease progressed and their survival after treatment. This allowed them to see which immune system features related to faster or slower disease progression.

“This is the most robust characterization of the immune system in newly diagnosed multiple myeloma patients and a major advancement in our understanding of the disease,” said the MMRF’s Chief Scientific Officer George Mulligan, PhD.

Importantly, this study showed that immune information can be combined with what we already know about the genetics of myeloma tumor cells to better define the biology of aggressive cases. For example, in patients whose disease progressed quickly despite low-risk tumor genetics (or slowly despite high-risk genetics) immune differences may help explain this unpredictable clinical outcome. These include loss or accumulation of certain T cells that led to an immunosuppressed state, and certain gene expression changes within immune cells.

While this work does not yet allow clinicians to make personalized treatment decisions, it demonstrates the potential value of immune information for future care. It also sets the stage for further research on immune function in myeloma patients treated with recently approved immune therapies.  Further, this unique dataset from 337 patients will be shared on Virtual Lab, the MMRF’s data platform, enabling additional researchers across the globe to test new immune related ideas more quickly.

Highlights from Blood Cancer Discovery

The Blood Cancer Discovery paper, published on December 9, provides another example of the power of the MMRF’s large datasets. Using the Atlas’ immune and clinical data, investigators focused on the 102 patients who donated multiple bone marrow samples during their myeloma journey, including when they were first diagnosed, after they had responded to treatment, and after disease relapse (when the myeloma returned after a response).

By following these patients and collecting this unprecedented data, the team made several critical discoveries to describe specific immune system changes in these patients over time:

• Patients who had longer remissions after stem cell transplant had more B-cells (a type of immune cell) that were “naïve,” meaning that they hadn’t been exposed to myeloma cells before.
• When patients had high levels of inflammation, their immune system had a harder time forming a lasting “memory.”
• In about 40 percent of patients, myeloma cells activated the expression of genes encoding certain “cancer-testis antigens” not normally part of risk models.

Overall, this paper revealed that the immune system’s ability to recover after treatment strongly predicts how long patients will stay in remission. Measuring immune health after treatment may eventually help doctors identify patients who are at a high risk of relapse and then optimize their treatment. This study also opens the door for further research into targets for immunotherapy and other strategies to strengthen patients’ immune systems.

Expanding the Power of MMRF’s Data and Network

The MMRF Immune Atlas data that powered this research was born out of the MMRF’s seminal CoMMpass Study, the largest, most detailed myeloma dataset available today. This collection of patient data and clinical outcomes, tumor genomics, clinical samples, and Immune Atlas data is publicly available to the scientific community and continues to generate new insights. Immune Atlas data provides a foundation for additional immune-related research by this MMRF Atlas team and researchers worldwide. This dataset, by virtue of size, multi-center origin, and MMRF’s commitment to rapid data sharing, will facilitate a variety of new insights.

The MMRF’s broad network of partners made the Immune Atlas possible. By initiating, funding, and leading new concepts—and then actively collaborating with five leading medical centers to advance data generation and analysis—the MMRF and its partners created a shared immune resource that no institution could have developed alone.

“Since multiple myeloma is highly complex and varies from patient to patient, creating an atlas that reflects the heterogeneity of the disease required a large number of CoMMpass patients and investigators at five centers working together,” Mulligan said. “The MMRF is grateful to our institutional partners and the many patients who joined this research. These reports represent years of work and are the perfect example of the kind of highly collaborative, data-driven research that will propel the field’s next breakthroughs and, ultimately, improve outcomes for patients.”