A flurry of new research on the bone marrow microenvironment of myeloma cells is leading to a better understanding of the mechanism of action of myeloma treatments, as well as the biology of disease progression. The findings, experts say, are informing the development of novel therapies and could possibly enhance the benefits of existing treatments.
“Myeloma has been kind of a black box in that drug applications were in many cases preceding our knowledge of what was going on in the microenvironment,” said Tyler Moser-Katz, a PhD student at Emory University and lead author of a recent article that reviewed the latest research on the role of the microenvironment in myeloma cell progression.1
Myeloma cells have many “allies” within the bone marrow, as the authors noted, including bone marrow stromal cells that bind to myeloma cells and support their growth and drug resistance. At the same time, the immune cells in the microenvironment, particularly T cells and natural killer (NK) cells, can reign in myeloma cells but become suppressed and dysregulated during disease progression. Many of the myeloma drugs that have been around for decades, as well as new therapies in development, aim “to mobilize immune cells to counter the malignant cells,” Moser-Katz noted.
The importance of targeting the immunosuppressive microenvironment was hinted at when the U.S. Food and Drug Administration (FDA) approved the first immunomodulatory drug (IMID), thalidomide, for myeloma in 1998. Even though IMIDs are now a major drug class for myeloma treatment that includes lenalidomide and pomalidomide, “at the time when we were using these IMIDs, we had no idea how they worked,” said Noopur Raje, MD, director of the Center for Multiple Myeloma at Massachusetts General Hospital and a professor of medicine at Harvard Medical School in Boston.
Since then, research on the microenvironment has shed light on the mechanism of IMIDs to activate T cells and NK cells. Although the early studies provided a much less detailed picture of the microenvironment, “putting it all under one umbrella of the bone marrow stromal cells,” Dr Raje said, researchers during the past few years have been dissecting and studying the various compartments of the microenvironment, such as immune cells and the adipogenic compartment, which are the focus of Dr Raje’s lab.
Understanding the role of the microenvironment is especially important because myeloma progression and treatment response do not seem to be driven by genetic changes, as years of work sequencing plasma cells has revealed, said Flavia Pichiorri, PhD, MS, scientist and leader of the Multiple Myeloma Disease Team at the Judy and Bernard Briskin Center for Multiple Myeloma Research at City of Hope Comprehensive Cancer Center in Duarte, California. “Microenvironment [research] in the last few years is answering many more questions than the plasma cells answered in the last 30 years,” noted Dr Pichiorri, who is also an associate professor in the Department of Hematologic Malignancies Translational Science at City of Hope.
In addition to elucidating mechanisms of therapeutic action and disease progression, the recent microenvironment insights are opening up new ways of looking at how to combine treatments to achieve the greatest clinical benefit, Dr Pichiorri explained.