Lipids Involved in Cause of Myeloma in One of Three Patients

Alexander M. Castellino, PhD

February 15, 2016

Why myeloma develops has been a mystery, but new research shows that lipids are involved, at least in about one-third of cases.

Researchers from the Yale Cancer Center report laboratory studies showing that chronic stimulation of the immune system by lipids made in the context of inflammation underlies the origins of at least one-third of all myeloma cases, and also in the origin of Gaucher's disease.

The finding was published in the February 11 issue of the New England Journal of Medicine.

The researchers show myeloma clonal immunoglobulin associated with transformed plasma cells was reactive against lysolipids, lysoglucosylceremide (LGL1) and lysophosphatidylcholine (LPC).

"Understanding the antigenic reactivity of clonal immunoglobulin not only has direct implications for antigenic origins of myeloma but may also lead to new strategies to prevent or treat clinical cancer by targeting the underlying antigen," the Yale researchers write in their discussion.

Medscape Medical News reached out to two myeloma experts not connected with this story for their comments.

"This work is very important as it gives us additional potential targets and strategies for prevention for patients with plasma cell disorders," Sagar Lonial, MD, told Medscape Medical News.

Dr Lonial is chair and professor of the Department of Hematology and Medical Oncology and chief medical office of the Winship Cancer Institute at the Emory University School of Medicine in Atlanta.

Paul G. Richardson, MD, R.J. Corman Professor at Harvard Medical School and the Dana-Farber Cancer Institute in Boston, told Medscape Medical News: "This is an elegant study and the preclinical work in the mouse model provides important clues to potentially translating these observations in the future, and is especially interesting given the links between myeloma, inflammation and metabolic disorders, including obesity."

The Study in Mice and "Men"

Senior author Madhav V. Dhodapkar, MBBS, who is the Arthur H. Bunker and Isabel Bunker Professor of Medicine and Immunobiology at the Yale Cancer Center in New Haven, Connecticut, explained to Medscape Medical News how the story started.

Patients with Gaucher's disease have an accumulation in lipids due to a glucocerebroside deficiency, which leads to increased levels of the LGL1, he indicated. With the advent of enzyme replacing therapies, these patients are living longer; however, longer survivals have been associated with myeloma being a common cancer seen in survivors of Gaucher's disease, he said.

"Gaucher's disease is a genetic clue linking lipids with myeloma," he told Medscape Medical News.

The researchers hypothesized that Gaucher's disease-associated gammopathy and sporadic monoclonal gammopathies seen in patients with smoldering myeloma or myeloma might be directly associated with lipids activating the immune system.

In this study, the researchers used tissue and blood samples from both mice and patients to show in several different ways that the immunoglobulins made by transformed plasma cells recognizes specific lipids.

Serum samples from patients were analyzed by means of serum protein electrophoresis, a diagnostic test used to identify monoclonal gammopathy of undetermined significance (MGUS). However, the researchers took this to the next level. They blotted this on a membrane, incubated with LGL1 or LPC, and showed that LGL1 and LPC recognized the immunoglobulins or the M spike on the membrane.

In addition, mice deficient in glucocerebroside (GBA1–/–) — the same enzyme deficient in patients with Gaucher's disease — produced antibodies against LGL1 when injected peritoneally with LGL1, but not when injected with saline.

An examination of germinal center B-cells in splenocytes from the enzyme-deficient mice showed a B-cell spike in animals primed with LGL1, but not in animals primed with saline. In another set of experiments, the researchers utilized lipid-coated beads to again show that the M spike recognized lipids.

Lysolipid reactivity was shown for all GBA1–/– mice, and also in patients with Gaucher's disease — in 78% of patients with monoclonal gammopathy and 91% with polyclonal gammopathy. In addition, lipid reactivity was also seen in 31% of patients with MGUS or asymptomatic myeloma and in 34% of patients with myeloma.

"Lysolipid reactivity was seen in one out of three patients with myeloma," Dr Dhodapkar told Medscape Medical News.

Significance of the Study

"The mystery in myeloma has always revolved around the M spike associated with the clonal expansion of transformed plasma cells," Dr Dhodapkar told Medscape Medical News.

 
If we know what the antibody recognizes, we would better understand how the cancer originates.
 

"If we know what the antibody recognizes, we would better understand how the cancer originates," he said. "In one-third of patients with myeloma, the trigger lies in bioactive lipids typically made in the context of inflammation," he added.

In explaining the significance of these observations, Dr Lonial told Medscape Medical News that this work provides a framework for possible pathogenesis and etiology of plasma cell disorders.

"What this work demonstrates is that for a significant fraction of patients, there is a lipid that is the potential target," he said, and "this may provide clues into why patients develop plasma cell disorders in the first place."

On the implications of the study, Dr Dhodapkar said: "Now that we know that lipid reactivity is relevant in some patients, we can now directly modify these lipids, pharmacologically or through dietary intervention, to test if it will lead to an altered natural history."

Dr Richardson indicated that even in myeloma patients the study suggests appropriate nonpharmacologic strategies that can be added to the clinical management of these patients.

"Although this study does not change the current management of patients with myeloma or smoldering myeloma, in a special setting of risk, there is an indication that lifestyle intervention through dietary changes may be the most rational steps to be incorporated into the clinical management of these patients," he told Medscape Medical News.

Dr Lonial indicated that more work is needed to understand these observations. "However, it could have implications for how we approach patients with MGUS or smoldering multiple myeloma, as it may provide nontreatment ways to try and prevent conversion from MGUS to myeloma," he said.

Before applying their findings to patients with myeloma, Dr Dhodapkar told Medscape Medical News that they will soon be evaluating whether eliglustat, a glucocerebroside synthase inhibitor that prevents the overproduction of LGL1, will modify the natural history of gammopathy in patients with Gaucher's disease — a genetically well-defined population.

This strategy has already been shown to work in mice. When GBA1–/– mice were fed a diet containing eliglustat, they showed an approximately 75% reduction in antibodies reactive to LGL1.

Although the implications for patients with multiple myeloma are not immediate, Dr Lonial indicated that, in future, it could have implications in a prevention strategy.

"It has been shown by others that obesity is a risk factor for developing multiple myeloma, and this helps to explain part of that connection," Dr Lonial told Medscape Medical News.

Dr Richardson agrees that there is a the link between obesity and the risk for myeloma, adding: "This study points to the metabolic basis of the epidemiology of myeloma."

"Metabolic pathways may explain progression of the disease," he added, and it would also help to explain why metformin, a drug used to treat diabetes and address glucose intolerance, has been shown to be beneficial when added to other medications used in the treatment of myeloma.

"The dysregulation of lysolipids has also been described in the context of obesity. The risk of myeloma has been shown to be higher among obese persons than among persons of normal weight," the researchers write.

"This work is very important, as it give us additional potential targets and strategies for prevention for patients with plasma cell disorders," Dr Lonial told Medscape Medical News. "It represents some of the best understanding between inflammation, lipids, and disease pathogenesis, and has great potential for helping us to better understand and eventually treat patients." he added.

Dr Dhodapkar goes further. "One of the potential insights from the discovery of inflammation-associated bioactive lysolipids as antigenic triggers is that it underscores the potential importance of chronic inflammation underlying this malignancy. The next big questions are what causes this inflammation and how to control it," he told Medscape Medical News.

Dr Lonial and Dr Richardson are paid consultants for several pharmaceutical companies, but none with relevance to this study. Coauthor Pramod Mistry, MD, from the Yale–New Haven Hospital, reports receiving funding from Genzyme.

N Engl J Med. 2016;374:555-561. Abstract

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