Researchers Identify an Underlying Cause of Some Myelomas Associated With Gaucher Disease

Researchers have uncovered the mechanism that causes about one-third of myeloma cases associated with Gaucher disease, showing that myeloma cells target certain lipids that are elevated in the blood of a subset of patients.

Researchers at Yale University School of Medicine in New Haven, Connecticut, have uncovered a mechanism that may cause certain cases of myeloma associated with Gaucher disease, finding that myeloma cells target certain lipids that are elevated in the blood. The results are published in the New England Journal of Medicine.

Madhav Dhodapkar, MBBS, professor of medicine and immunobiology and chief of hematology at the Yale Cancer Center, and colleagues found that constant stimulation of the immune system by certain types of lipids during inflammation causes these myeloma cases.

Plasma cells normally make a spectrum of different antibodies that fight infection but uncontrolled growth of these immune cells can lead to anemia, kidney issues, myeloma, and also Gaucher disease, a group of disorders that affect enzymes in the body that break down macromolecules including lipids. Patients with Gaucher disease, which in the general population occurs in 1 out of every 50,000 to 100,000 people, are also at higher risk of developing myeloma.

The results, according to the authors, could lead to strategies to treat or prevent tumor development by targeting the antigens responsible for the chronic stimulation of plasma cells.

“These studies set the stage for newer approaches to lower the levels of these lipids in patients with Gaucher disease and others with precursors for myeloma,” Dhodapkar said in a statement. “Potentially, this could be achieved with drugs or lifestyle changes to reduce the levels of lipids to lower the risk of cancer.”

Because the presence of certain lipids have been found to be associated with Gaucher disease, myeloma, and mouse models of myeloma, Dhodapkar and coauthors first tested whether plasma cells in Gaucher disease patients are reactive against certain lipids, present at higher levels in the blood of patients. They showed that the presence of a specific lipid, called lyso-glucosylceramide (LGL1), resulted in high plasma cell reactivity in blood samples from Gaucher disease patients, but not in healthy donor samples.

The same B-cell reactivity against LGL1 was also seen in 33% (22 of 66) of blood samples from patients with multiple myeloma associated with Gaucher disease. “In contrast,” the authors wrote, “no reactivity was observed in patients with polyclonal gammopathy that was not associated with Gaucher’s disease.”

The new findings also point to the importance of the link between lysolipids-natural cell products formed by the hydrolysis of phospholipids-and obesity. Lysolipids have been shown to be dysregulated in people with obesity, and the risk of myeloma is higher among obese individuals, according to epidemiological studies. There is also animal study evidence that diet-induced obesity in mice can lead to a myeloma-like condition in mice.

Large cohort studies are needed to understand whether changing levels of these lipids could potentially thwart the development of myeloma and other plasma cell proliferation disorders.