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August 2000 Volume 3, Issue 10:
New Insights And Future Directions
By Kenneth C. Anderson, M.D.
Ken Anderson discusses the need for new therapies based upon a better understanding of how myeloma cells grow
Although multiple myeloma is sensitive to chemotherapy and radiation therapy, long term survival without symptoms or signs of myeloma is unusual and few, if any, patients have been cured. Therefore, new therapies based upon a better understanding of how myeloma cells grow are urgently needed. Advances in three areas of research now provide the framework for related novel therapies for myeloma.

Myeloma cells grow and survive in the bone marrow where they adhere to the normal bone marrow cells and proteins. This binding of tumor cells assures their localization in an environment where they can grow and survive, and furthermore makes them resistant to chemotherapy. Drugs which inhibit myeloma cell binding to bone marrow cells can restore the ability of chemotherapy to kill myeloma cells. Potent aminobisphosphonates, which are currently used in myeloma to delay bone disease, also may act by inhibiting the ability of myeloma cells to adhere to bone marrow. When myeloma cells adhere in the bone marrow, factors which augment tumor cell growth and survival are also produced (i.e. interleukin-6). Proteosome inhibitors are newly available drugs which not only directly kill myeloma cells, but also are able to decrease tumor cell binding in the bone marrow and interleukin-6 production. Moreover, these new drugs kill even those myeloma cells which are bound to bone marrow and protected against chemotherapy. Other factors are produced in excess by tumor and bone marrow cells in myeloma which change the marrow environment. One such factor is vascular endothelial growth factor, which both augments tumor cell growth and increases formation of new blood vessels in the marrow to supply myeloma cells with needed nutrients. Drugs are now available which inhibit this new blood vessel formation, such as angiogenesis inhibitors and thalidomide, and also target cells. More potent analogues of thalidomide directly kill tumor cells, alter the interaction of myeloma and bone marrow cells, overcome resistance of myeloma cells to chemotherapy, and stimulate the patient's own immune response against their myeloma cells. These and other agents therefore offer great potential to improve the outcome of treatment, since they both directly kill myeloma cells and in addition act to change the bone marrow in ways which further inhibit the ability of the myeloma cell to grow and survive.

The second area of great promise is derived from an increased understanding of the circuits within the myeloma cell which allow the tumor cell to grow and survive without the controls which exist in normal cells. Novel drugs can either be circuit-breakers, which inhibit myeloma cell growth circuits, or circuit-makers, which trigger the circuits in myeloma cells leading to their death. These designer drugs are undergoing laboratory testing and should be available for clinical evaluation soon.

The third area of high promise is the development of immune-based treatments, either vaccinations or adoptive therapies. Vaccines against myeloma are designed to stimulate the patient's own immune system to recognize and reject the myeloma cells as foreign invaders. These vaccines stimulate the patient's immune system to recognize proteins which are either unique to each patient with myeloma or proteins which are shared by many patients. Additional vaccines are designed to stimulate a patient's immune defense system to recognize the entire myeloma cell as foreign and reject it. Besides vaccines, it is now possible to remove immune T cells from patients or their siblings and educate them in the laboratory to recognize and kill myeloma cells. These educated T cells can then be transfused to patients as another way to generate an immune response against myeloma cells. These immune-based approaches offer the opportunity to selectively and very efficiently target myeloma cells without the adverse side effects related to the harm done to normal cells which accompanies chemotherapy.

In summary, multiple new treatment approaches will kill the tumor cell directly and target the bone marrow microenvironment; target the abnormal growth and survival circuits in myeloma cells; and stimulate immune responses against myeloma. These new treatments will not only be more effective, but also have fewer side effects than currently available therapies. They offer great potential to improve the quality of life and survival of patients with myeloma.

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