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Immune Cell Shifts Mark Microenvironments of Precursor Cases Progressing to Multiple Myeloma

NEW YORK – New research suggests immune microenvironment changes can contribute to early-stage multiple myeloma, appearing in precursor conditions that precede the blood cancer. 

As they reported in Nature Cancer on Monday, researchers at the Dana-Farber Cancer Institute, Harvard Medical School, the Broad Institute, and elsewhere did cell sorting and single-cell RNA sequencing on some 19,000 cells from bone marrow samples from seven newly diagnosed multiple myeloma patients; 11 individuals with high- or low-risk "smoldering" multiple myeloma involving some altered plasma cells; and five individuals with a condition known as monoclonal gammopathy of unknown significance (MGUS) that sometimes progresses to multiple myeloma.

"Our results provide a comprehensive map of the immune changes that take place in pre-malignant myeloma," co-senior and co-corresponding author Irene Ghobrial, a medical oncology researcher affiliated with the Dana-Farber, Harvard, and the Broad, said in a statement. "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."

The team's analyses uncovered expression-based clusters representing nine types of immune cells including CD16+ or CD14+ monocytes, natural killer cells, B cells, and T cells. In the early stages of multiple myeloma, for example, the single-cell transcriptome data pointed to an uptick in natural killer cell representation in the immune microenvironment, together with chemokine receptor expression changes.

The researchers also picked up other immune changes, from a decline in certain memory cytotoxic T cells and enhanced interferon signaling by multiple immune cell types to altered regulation of monocyte immune cells with effects on T cell activity. They went on to confirm some of the immune microenvironment changes in mouse models of early multiple myeloma, in vitro cell line experiments, and phenotyping profiles for bone marrow samples from more than a dozen individuals with or without multiple myeloma or a precursor condition.

"We demonstrate the critical importance of memory T cells for [multiple myeloma] immunosurveillance," the authors wrote, noting that, among other things, multiple myeloma cells "lead to loss of antigen presentation, inducing a T cell suppressive phenotype in monocytes."

Even so, co-first author Nicholas Haradhvala, a researcher affiliated with the Broad, Mass General, and the Harvard Biophysics graduate program, noted in a statement that such immune shifts were not specific to a given precursor condition, but did turn up "in different combinations" in MGUS and smoldering multiple myeloma, "suggesting an axis upon which patients could be stratified for evaluation of individual-specific risk of progression and potential for early intervention."

Though the immune changes appeared to be somewhat heterogeneous, the authors reasoned that they may offer insights into multiple myeloma development and progression. Such insights may go beyond what can be learned from looking at chromosomal alterations and other genomic features in multiple myelomas, which may overlap with those already present in precursor conditions such as MGUS or in smoldering multiple myeloma.

"These results provide a comprehensive map of immune changes at play over the evolution of premalignant [multiple myeloma], which will help develop strategies for immune-based patient stratification," the authors reported, noting that it is currently difficult to know whether cases will progress to full-blown multiple myeloma and to treat those appropriately at an early stage.