At the forefront of multiple myeloma research are Teru Hideshima, MD, PhD, (front, left) and Ken Anderson, MD, along with colleagues (rear, left to right) Paul Richardson, MD, Constantine Mitsiades, MD, PhD, and Dharminder Chauhan, JD, PhD.
Not going solo
Multiple myeloma arises when bone marrow — the source of blood cells and key components of the immune system — becomes overcrowded with plasma cells, which produce disease-fighting antibodies; this leaves less room for healthy red and white blood cells and platelets. Precisely how the process begins is unclear, but once it's under way the myeloma cells are anything but independent actors. Fastening themselves to bone marrow tissue, they make the marrow an accomplice to their malignant lifestyle. They order the marrow to produce substances called cytokines, which help myeloma cells proliferate, and they build networks of blood vessels through the marrow to bring in nutrients.
"Binding to the bone marrow confers a significant survival advantage on myeloma cells," Anderson explains. "It provides them with access to cytokines and, partly as a result, they become resistant to a variety of medications." Though the interactions between myeloma cells and the bone marrow might seem a barrier to treatment, they're increasingly seen as therapeutic opportunities. "Each step in the process represents a potential weak link," he says, "where we can intervene to block myeloma cells' growth and survival."
It might seem unlikely that any single drug could interfere with the anchoring of myeloma cells to bone marrow and with the subsequent release of cytokines and growth of new blood vessels, but all these processes turn out to be interrelated. Attack one, and it is possible to hit two or even all three of them.
Anderson and colleagues in the Jerome Lipper Center for Multiple Myeloma at Dana-Farber have been leaders in developing and testing microenvironment-focused treatments for this illness. Each of the new generation of myeloma drugs approved by the U.S. Food and Drug Administration — lenalidomide, bortezomib, and thalidomide — was studied by researchers at the Lipper Center in the laboratory, in lab animals, and in clinical trials with human patients. (Thalidomide, which became notorious in the 1960s for causing birth defects when taken by pregnant women, has lately gained renewed life as an "antiangiogenic" agent, capable of cutting off tumors' blood supply.)
"These three drugs work by targeting the tumor cell directly, and by attacking extrinsic factors such as tumor cell binding and cytokine production," Anderson states. "Thalidomide and lenalidomide also boost the immune response to myeloma, activating cancer-fighting cells already in the microenvironment. These drugs, and others that are on the way, enable us to offer more effective treatments for multiple myeloma patients than ever before."
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