Lipids, Inflammation Linked to Multiple Myeloma Origins

Madhav Dhodapkar, MD

Inflammation and chronic stimulation of the immune system by lipids may trigger multiple myeloma in approximately one-third of all cases, according to early research from Yale Cancer Center published in The New England Journal of Medicine.¹

Using tissue and blood samples from humans and mice with Gaucher disease, an inherited lipid storage disorder, researchers found that gammopathy is triggered by specific lipids, and that the antibodies made by tumor cells in patients with myeloma are directed against such lipids. Monoclonal gammopathy is a precursor to myeloma.

The new findings build on prior research, which demonstrated that patients with Gaucher disease have a significantly increased risk for developing myeloma. The researchers also discovered a subset of lipid-reactive immune cells, called type 2 NKT-TFH, that promotes the development of plasma cells.

OncLive: Why is this study significant?

OncLive spoke with lead study author, Madhav Dhodapkar, MBBS, professor of Medicine and professor of Immunobiology, chief of the Section of Hematology, Department of Internal Medicine, clinical research program leader of the Hematology Program at Yale Cancer Center. In his interview, Dhodapkar explains the potential impact this research may have on multiple myeloma prevention and what next steps are needed.Dhodapkar: We are still early in this research, but what the study showed is that specific lipids that are involved in inflammation could be important triggers for the development of monoclonal gammopathies in myeloma. Understanding these initial triggers could help us design preventive approaches and define populations that may be at risk.

The patient population that we began with in the study was a group of patients with Gaucher disease who actually do have an increase in lipids and inflammation, and a higher risk of developing myeloma. However, high levels of lipids and inflammation could be a broader risk factor, even in patients who don’t have Gaucher disease.

How could these findings impact how patients are treated?

What are the next steps planned in this research?

What this study basically does is provide a link between lipids as a potential target or as a potential trigger, if you will, for the activation of the immune system. The kinds of lipids that are involved in these processes seem to be linked to chronic inflammation. Now, we need to better understand how chronic inflammation may underline these sorts of conditions.There are many potential approaches that could evolve out of this. They all need to be tested in the clinic to prove it. Medications that lower the levels of those lipids could be available pharmacologically. In principle, levels of lipids and inflammation could be altered by even simple measures like lifestyle changes. Obviously, one needs to prove that doing those sorts of lifestyle changes actually does have a favorable impact. This all needs to be studied, and we need to understand it better in the context of clinical studies. However, this study set us up for the next generation of studies.In patients with Gaucher disease who have an increase in gammopathies, we already know which drug actually reduces lipids in that setting. We are going to do a small clinical study to actually ask the question, “If you give patients this class of drugs, will that lead to a reduction in gammopathies in that population?”

Is this research mostly focused around prevention of disease or could it be applicable to treatment of myeloma?

Why do you think myeloma research is so important?

Then, we need to ask that same question in context of the non-Gaucher patients. What kinds of lipids are involved in those specific cases and, if you lower them, would that lead non-Gaucher patients to have a lower risk of myeloma?Honestly, I don’t think we know the answer to that question, because we don’t know yet whether, when myeloma is already developed, to what degree it is dependent on stimulation of that underlying antigen. That is an unanswered question. The more direct implication is more for prevention at this point, although the question regarding therapy needs to be explored.Myeloma makes up about 10% of all blood cancers. We still lose a lot of patients in this country with myeloma, around 13,000 to 14,000 cases a year, so it’s a significant component of cancer related mortality.

We have made a lot of progress in terms of several new drugs that have been approved for therapy of myeloma over the last decade. However, there is a significant unmet need for newer approaches, not just to actually achieve durable responses and responses that equate to a cure, but also to try to prevent the disease in the first place. We have a lot to do.

Nair S, Branagan AR, Liu J, et al. Clonal immunoglobulin against lysolipids in the origin of myeloma. N Eng J Med. 2016;374:555-561.