RNA Sequencing Finds Immune System Clues Long Before Patients Develop Multiple Myeloma

Patients who will go on to develop multiple myeloma (MM) experience a number of changes in their immune system long before their cancer becomes malignant, according to a new study.

The research, published in the journal Nature Center, could have implications for how the disease is detected and for how clinicians develop individualized treatment plans.

Investigators from the Dana-Farber Cancer Institute, the Broad Institute of Harvard and the Massachusetts Institute of Technology, and Massachusetts General Hospital collaborated on the study.

“Our results provide a comprehensive map of the immune changes that take place in pre-malignant myeloma,” said co-senior author Irene Ghobrial, MD, of DFCI and the Broad Institute, in a statement.

It is already known that patients with MM experience abnormalities in the plasma cells of their bone marrow prior to the onset of physical symptoms. Such phases are known as monoclonal gammography of unknown significance (MGUS) and smoldering multiple myeloma (SMM). However, Ghobrial and colleagues note that the presence of MGUS or SMM does not necessarily mean a patient will go on to develop MM. That poses a problem for clinicians, since it means they cannot begin treatment until more significant symptoms of MM appear.

Ghobrial and colleagues decided to find out what they could learn about the early stages of the disease by carrying out single-cell RNA sequencing, in which they scan the RNA of individual bone marrow cells from patients in the precursor stages, patients with full-blown MM, and healthy volunteers. The results show that specific markers are present even in the early stages of the disease.

During MGUS, Ghobrial and colleagues found patients had an increase in the number of natural killer cells (NK cells), which attack diseased cells. Patients with the highest volume of NK cells tended to have cells of the type that are drawn into the bone marrow as a result of signaling molecules, the authors said.

In SMM, RNA sequencing suggested some patients experience a loss of memory T cells. Those cells respond to threats like viruses and bacteria that the patient has already encountered. Ghobrial and colleagues say that means it’s possible the replenishment or reactivation of these memory T cells might be an effective therapy for some patients with SMM.

Lastly, the investigators found a dysregulation of certain monocytes, which would otherwise help fight off infected or cancerous cells. The result, they write, is a

weakened immune response to nascent cancer.

Nicholas Haradhvala, a graduate student in the Harvard Graduate Program in Biophysics, said the features they uncovered weren’t strictly tied to a particular phase. That means investigators might be able to identify combinations that put a patient at particular levels of risk.

“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,” he said.

The authors say they hope their research will lead to further, larger studies that could help elucidate such an axis.

Reference

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). doi: 10.1038/s43018-020-0053-3.