Multiple myeloma is a multistep malignancy, starting with an indolent phase (monoclonal gammopathy of unknown significance [MGUS] or smoldering myeloma), progressing to overt myeloma (which is typically restricted to the bone marrow), and terminating with an aggressive transformation (typically associated with a high lactate dehydrogenase [LDH] level, high plasma cell labeling index, plasmablastic morphology, and multiple cytogenetic abnormalities, including deletion of chromosome 13). In the terminal phase, the disease has extramedullary manifestations, sometimes including disease of the central nervous system.
Timing of Treatment
In the second phase, the myeloma cells are entirely dependent on the microenvironment for their survival and growth, and their resistance to chemotherapy is an epigenetic phenomenon. In the terminal phase, the myeloma cells have become independent of the microenvironment, and drug resistance is based on acquired genetic changes. This stage of the disease is completely refractory to chemotherapy. Although responses can be seen, they are short-lived.
It is essential to treat myeloma patients in the second phase of the disease, after minimal and preferentially rotating standard chemotherapy (to avoid induction of drug resistance), with high-dose chemotherapy to overcome the epigenetically induced drug resistance. It should be noted that the epigenetic mechanisms of drug resistance of plasma cells and myeloma cells are similar to those observed with hematopoietic stem cells, and just as conventional chemotherapy will not destroy all stem cells, it will not eradicate all myeloma cells.
Autologous vs Allogeneic Transplants
The best treatment results in myeloma are obtained with tandem transplants, as evidenced by the significantly improved long-term outcome reported in patients undergoing such treatment in a University of Arkansas study, and by preliminary reports of the randomized IFM-94 study.[1,2] Our Total Therapy I study shows an overall 10-year survival of 45% in an absence of cytogenetic abnormalities, and a continuous complete remission (CR) rate of 60% in patients achieving a CR posttransplantation. It will be very difficult to improve on these results with any alternative treatment approach, including allotransplantation, because of its excessive first-year treatment-related mortality.
In contrast, the survival rate with tandem autologous transplants at 10 years for patients with cytogenetic abnormalities is less than 20%. It is in these patients that the role of allotransplantation needs to be explored, because they are virtually incurable with high-dose chemotherapy but respond well to a graft-vs-myeloma effect.