FURTHER PROGRESS IN THE TREATMENT OF MYELOMAWILL ONLY BE MADE IF WE HAVE A BETTER UNDERSTANDINGOF THE MYELOMA POPULAT<strong>ION</strong> THAT SURVIVES EVEN THEMOST INTENSIVE TREATMENT STRATEGIES.oncologistics volume 7, issue 1 - spr<strong>in</strong>g <strong>2008</strong> 42
oncologistics a better treatment of myelomaAutologous stem cell transplantation representsa major step forward <strong>in</strong> the treatment of myeloma.While most transplant protocols <strong>in</strong> myeloma call forone round of high-dose chemotherapy and no furthertreatment thereafter, we now know that a more <strong>in</strong>tensiveapproach <strong>in</strong>clud<strong>in</strong>g <strong>in</strong>duction therapy, two cycles of highdose chemotherapy coupled with an autologous stemcell transplant, consolidation therapy, and two yearsof ma<strong>in</strong>tenance therapy is more effective. This is thelesson we have learned as a result of our Total Therapystudies, which consistently have delivered the besttreatment results for newly diagnosed myeloma patients.Further improvements will come, for the most part, froma better understand<strong>in</strong>g of myeloma biology and also,to a lesser extent, from some tweak<strong>in</strong>g of the TotalTherapy approach to decrease toxicity and further<strong>in</strong>crease survival.Multiple myeloma (MM) is a differentiated clonal B-celltumor, consist<strong>in</strong>g <strong>in</strong> the early stages of the disease ofslowly proliferat<strong>in</strong>g malignant plasma cells (myelomacells). It is the second most common hematologicmalignancy after non-Hodgk<strong>in</strong> lymphoma. Normalplasma cells are very hardy cells and usually the onlytype of cell to survive the effects of myelosuppressivechemotherapy and radiation. The clonal plasma cellshave abnormal cytogenetics even at the stage ofmonoclonal gammopathy of undeterm<strong>in</strong>ed signifi cance.Before it transforms to an aggressive disease—whichis typically associated with extramedullary disease,immature morphology of the myeloma cells, rapidproliferation, and <strong>in</strong>crease <strong>in</strong> LDH—the disease isentirely bone marrow stroma-dependent and, therefore,conta<strong>in</strong>ed with<strong>in</strong> the active hematopoietic bone marrow,although breakout lesions from the bone can be seen.The myeloma cell displays on its membrane a multitudeof receptors, the ligands of which are present <strong>in</strong> themicro-environment. B<strong>in</strong>d<strong>in</strong>g of these receptors by theirligands promotes growth and survival of the myelomacells and also results <strong>in</strong> the secretion by the plasma cellsof angiogenic factors. In addition to support<strong>in</strong>g growthand survival, the micro-environment also places most ofmyeloma cells <strong>in</strong> a deep G1 phase by up-regulation ofp21 and p27. Cells <strong>in</strong> the G1 phase of the cell cycle arevery poor targets for conventional dose chemotherapy.It is very likely that <strong>in</strong> myeloma, just as many othercancers, a cancer stem cell population exists. It isestimated that one <strong>in</strong> 10,000 to one <strong>in</strong> 20,000 malignantcells is a cancer stem cell. Based on the extensivesomatic mutations <strong>in</strong> the complementarity regions ofthe gene cod<strong>in</strong>g for the heavy cha<strong>in</strong>, it is very likely thatthis cancer stem cell arises from a B-cell that has hadextensive exposure to antigen <strong>in</strong> the germ<strong>in</strong>al centerand therefore most likely is either a memory B-cell ora plasmablast. If there is <strong>in</strong>deed a myeloma stem cell,such a cell will have many characteristics <strong>in</strong> commonwith a hematopoietic stem cell <strong>in</strong> that it is resistant toconventional doses of chemotherapy and that highdoses of chemotherapy will be necessary, which can atleast eradicate hematopoietic stem cells and thereforesuch therapy will require stem cell support. The agentsmost toxic to hematopoietic stem cells are alkylators,such as melphalan, busulfan, and BCNU, agents foundto be very effective <strong>in</strong> myeloma, while other alkylators,such as cyclophosphamide and plat<strong>in</strong>um compoundsWORKING TOWARD A BETTERUNDERSTANDING AND A BETTERTREATMENT OF MYELOMAby: Guido Tricot, M.D., Ph.D.oncologistics 43
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