Winship Cancer Institute

Emory University School of Medicine

Multiple Myeloma is a cancer of the bone marrow that results in approximately 15,000 deaths per year in the United States.  The malignant cells are the plasma cells that are normally responsible for making the antibodies that provide protection against foreign invaders.  Myeloma cells keep many of the characteristics of normal plasma cells that contribute to the disease.  Plasma cells are long-lived cells that interact with other cells of the bone marrow and the cells that control bone density.  Plasma cells produce antibodies that are then distributed throughout the body via the bloodstream.  Myeloma cells are plasma cells that have acquired the ability to grow, therefore they begin to crowd out the other cells of the bone marrow resulting in anemia.  They effect the cells that produce and degrade bone resulting in weaker bones in many patients with myeloma.  It also can alter calcium levels in the blood.  Since the cells are growing they produce too much antibody.  This can result in kidney problems as the antibodies can effect the kidney’s ability to filter blood.

We have focused our research on many of the normal plasma cell features of myeloma cells as a potential means to treat this disease or to better understand why some therapies have activity in the treatment of myeloma.  We have shown that bortezomib (Velcade), a recently FDA-approved drug for the treatment of myeloma functions in part because it alters the myeloma plasma cell’s ability to cope with the large amount of antibody that the cell produces.  Not only does protein production result in cellular  stress, protein folding results in additional stress that the cell must cope with.  We reasoned that certain drugs that are regulated by similar processes as the way the cell deals with this type of stress might have activity in this disease.  We have focused on two arsenic-based compounds.  One has been FDA-approved for the treatment of a form of leukemia while the other is in clinical trials.

We are now focusing on the long-lived nature of these cells. This is part of the normal plasma cell biology and is controlled by proteins of the Bcl-2 family.  We are now targeting these proteins with a new drug called ABT-737 that is currently in clinical trials as well as a second form of the drug that can be taken orally.  By understanding how Bcl-2 proteins work in normal cells we believe we can predict sensitivity in of myeloma cells.  Finally, we are now also focusing on the unique aspect of myeloma biology, cell growth.  We have determined that a gene associated with cell growth, Myc is expressed at higher levels in myeloma cells compared to plasma cells and that inhibition of Myc in myeloma cell lines can result in cell death.  Therefore we will be determining why these cells are dependent on Myc.