Immune System Alterations Occur Early on in the Development of Multiple Myeloma

^{By: Yvette C. Terrie, BS Pharm, RPh, Consultant Pharmacist}

In a recently published study in the journal Nature Center, researchers at Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and Massachusetts General Hospital (MGH) indicate that well before multiple myeloma becomes a malignant disease, the collection of immune system cells and signal carriers amid the tumor cells experiences dramatic shifts, with modifications in both the number and type of immune cells. This new study represents the first time that single-cell RNA sequencing—in which scientists collect individual cells from tissue and scan their RNA to ascertain which genes are active—has been employed to detect features of the immune microenvironment in myeloma precursor conditions. The researchers used single-cell RNA sequencing to map changes in immune microenvironment in myeloma precursor conditions.

Co-first author Oksana Zavidij, Ph.D., of Dana-Farber and the Broad Institute stated that,  "We wanted to understand the changes that occur in the microenvironment as the disease progresses from MGUS to SMM to overt myeloma, as compared to the bone marrow of healthy tissue donors. The approach could ultimately shed light on why some patients progress to myeloma while others don't and help us better target treatments to individual patients."

The study findings revealed that  key changes occurred early in the course of myeloma development:

• An upsurge in the number of natural killer (NK) cells—white blood cells that spring to attack foreign invaders and diseased cells—during monoclonal gammopathy of undetermined significance (MGUS). In patients with the highest volume of NK cells, the cells tended to be a type that is drawn into the bone marrow in response to signaling molecules.
• The loss, in SMM, of memory T cells—white blood cells that respond to previously encountered bacteria, viruses, and one's own abnormal cells. (The finding indicates that treatments that replenish or activate these cells could be useful in some patients.)
• A dysregulation of certain monocytes—large white blood cells that take on intruders. These monocytes normally display foreign or tumor proteins to T cells, which use that information to attack infected or cancerous cells. In myeloma precursor conditions, however, myeloma cells prevent these proteins from being presented, resulting in a tamped-down immune attack on the cancer.

Co-first author Nicholas Haradhvala, of the Broad Institute, MGH, and the Harvard Graduate Program in Biophysics stated, “These changes didn’t correspond to any particular precursor condition. They were found in different combinations in patients with MGUS and SMM, suggesting an axis upon which patients could be stratified for evaluation of individual-specific risk of progression and potential for early intervention.”

The authors noted that these results provide a comprehensive map of immune transformations at play over the evolution of premalignant MM, which will assist in the expansion of approaches for immune-based patient stratification. The authors also noted that the study findings are a step in the course of more personalized therapy of MM. Moreover, potential treatments may be tailored to the immune microenvironment of each patient’s disease – the specific constellation of immune cells in and around myeloma tissue.

Additionally, Irene Ghobrial, MD, of Dana-Farber, the Broad Institute noted, “Our results provide a comprehensive map of the immune changes that take place in pre-malignant myeloma. The discovery that the immune microenvironment is abnormal even at very early stages of the disease may suggest strategies for targeting myeloma before it becomes malignant.”

Gad Getz PhD of the Broad Institute and MGH noted, “Our findings have described the landscape of dysregulated immune system that can be used to follow up in much larger studies and build robust associations with patient risk and progression.”

Yvette C. Terrie, Consultant Pharmacist and Medical Writer and creator of A Pharmacist’s Perspective (https://apharmacistsperspective.blogspot.com/ ).

References

1. News Releases. Immune system changes occur early in the development of multiple myeloma, study finds. Dana Faber Cancer Institute website. https://www.dana-farber.org/newsroom/news-releases/2020/immune-system-changes-occur-early-in-development-of-multiple-myeloma--study-finds/ .  Published April 27, 2020. Accessed May 4, 2020.
2. Zavidij, O., Haradhvala, N.J., Mouhieddine, T.H. et al. Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma. Nat Cancer (2020).  Published April 27, 2020. https://doi.org/10.1038/s43018-020-0053-3.