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August 2000 Volume 3, Issue 10:
Novel Horizons For The Treatment Of Myeloma
By William S. Dalton, Ph.D., M.D.
Bill Dalton discusses novel therapeutic approaches being developed to prevent or overcome these mechanisms of drug resistance
Effective therapy for the treatment of myeloma began in the early 1960’s with the discovery of melphalan (Alkeran®) and prednisone as effective therapy. During the past four decades, various combinations of chemotherapeutic drugs have been developed and proven to be effective in the treatment of myeloma. These combinations include agents such as Adriamycin, cyclophosphamide, vincristine and glucocorticoids, including prednisone and decadron. Although most patients respond to these chemotherapeutic drugs, essentially all patients eventually develop resistance to chemotherapy. Fortunately, basic research findings have begun to shed light on how myeloma cells become resistant to therapy and novel approaches are being developed to prevent or overcome these drug resistant mechanisms.

Today, at least three major ap-proaches are being investigated to improve therapy of myeloma patients. These include enhancing the effectiveness and reducing the side effects of currently available drugs, identifying new targets unique to the myeloma cell that control growth and survival of these cells, and enhancing the patient’s immune response against myeloma cells.

A major approach to overcoming clinical drug resistance is the use of very high doses of chemotherapy with or without total body irradiation. This form of high dose therapy is an effective means of improving responses and prolonging survival, but has significant side effects. Increasing the dose of drugs is known to eliminate more myeloma cells, but also damages more normal cells, especially bone marrow derived cells including white cells, red cells and platelets. Fortunately, patients may be rescued from this major side effect by using autologous bone marrow or peripheral blood stem cells following the administration of high dose therapy.

Another approach that ultimately may be more effective than high dose therapy is the development of drugs that target cellular pathways that regulate myeloma cell growth and survival. Developing drugs that target unique pathways in myeloma cells should allow clinicians an approach to eliminate myeloma cells but spare normal cells. For example, investigators at the Moffitt Cancer Center in Tampa, Florida recently discovered that a cellular pathway called the Jak2/Stat3 pathway prevented myeloma cell death by increasing the expression of an "anti-death" gene called Bcl-Xl. This Bcl-Xl gene prevents chemotherapy, radiation therapy, and maybe even immune therapy, from killing the myeloma cell. Basic research is now ongoing to develop means to interrupt the Jak2/Stat3 pathway in myeloma cells to improve therapeutic outcome.

A second example of a unique cellular pathway that may allow myeloma cells to survive and grow is the "Ras" pathway. The Ras gene is a cancer gene that is active in at least 40 to 50% of patients with myeloma. Laboratory studies have demonstrated that if the Ras pathway is inhibited by drugs called farnesytransferase inhibitors (FTIs), then cancer cells using this pathway may die. The FTI drugs may also be effective against other critical pathway molecules unique to the cancer cell and interruption of these critical pathways may prevent myeloma progression. Clinical studies are currently being planned to study the effectiveness of FTIs in myeloma patients.

Recent laboratory studies have also demonstrated that the bone marrow environment influences myeloma cell survival and growth. The bone marrow may influence myeloma cells by either making certain hormones (cytokines), or communicating with myeloma cells by direct cell contact. The major cytokine involved in myeloma progression is called interleukin-6 (IL-6). IL-6 is synthesized by bone marrow stromal cells and stimulates myeloma growth and survival. Basic science studies have also demonstrated that IL-6 may reduce the effectiveness of chemotherapeutic drugs. Inhibiting IL-6 production in the bone marrow or blocking the signaling pathways associated with IL-6 binding to myeloma cells may improve survival of myeloma patients and researchers are actively pursuing this possibility.

Another means by which the bone marrow environment influences myeloma cell survival is by direct cell contact. Our laboratory in Tampa, Florida recently reported that when myeloma cells are in direct contact with a particular bone marrow component called fibronectin, they are resistant to commonly used chemotherapy agents. This form of drug resistance is called "cell adhesion mediated drug resistance" (CAM-DR). Theoretically, disruption of myeloma cell adhesion to fibronectin (and possibly other bone marrow components) should enhance the effectiveness of chemotherapy and possibly other treatments. Investigators are now searching for agents that will disrupt adhesion and enhance the effectiveness of chemotherapy.

Basic research is uncovering unique properties of myeloma cells that will allow the development of novel therapeutic approaches to this disease. Understanding the biology of myeloma cells is the key to developing novel therapies to target myeloma cells and yet spare the normal cell. This specific targeting of the myeloma cell should enhance effectiveness and reduce side effects of myeloma therapy. Clinical studies are planned to identify potential drugs that will bring this promise to reality.

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