Recent advances in our understanding of the cellular and molecular derangements involved in multiple myeloma are beginning to be translated into novel therapeutic approaches. Growth factors, specifically interleukin-6, appear to be critical for disease progression, and interruption of autocrine and paracrine loops has been achieved, with resultant inhibition of myeloma cell growth. Oncogenes, tumor-suppressor genes, and cell-survival genes have all been found to be dysregulated in some myeloma patients. The implications of acquisition of the multidrug resistance phenotype are just beginning to be understood. High-dose therapeutic regimens with bone marrow or peripheral stem-cell rescue are being studied in an attempt to produce a cure. Autologous marrow and peripheral blood stem-cell transplantation are better suited to the older myeloma patient population than is allogeneic marrow transplantation, and have also yielded promising results.
Myeloma is a neoplastic disease of cells in the B-lymphocyte lineage, with a peak incidence in individuals 70 to 80 years old. Although the median age at diagnosis is 70 years , it is not uncommon for the disease to be diagnosed in much younger patients. An estimated 13,500 new cases of multiple myeloma were diagnosed in the United States in 1992. Little improvement in 5-year survival rates has occurred since the mid-1970s.
Myeloma has a distinct racial distribution, with incidence and death rates in American blacks nearly double those in whites . In fact, myeloma represents the most common (30%) of all lymphoreticular malignancies in the American black population .
The etiology of myeloma has remained obscure. Hereditary factors, radiation exposure, agricultural exposure, and antigenic stimulation have all been implicated to some extent. Support for the theory of antigenic stimulation has come from the discovery that some myeloma paraproteins show antibody activity against specific antigens . Also supporting this theory is the fact that, in murine models, the ability to induce peritoneal plasmacytomas is vastly reduced when the mice are raised in a germ-free environment .
Recent research has begun to elucidate the cellular and molecular derangements involved in the pathogenesis of multiple myeloma. These advances, in turn, have suggested novel approaches to treatment.
Renewable "Stem-Cell" Compartment
Although the terminally differentiated B-lymphocyte, the plasma cell, is the morphologically identifiable cell in myeloma, it represents the end-stage, nonproliferating cell compartment. It has been well documented that there are also monoclonal, early-stage B-cells circulating in the peripheral blood, and that these cells bear the same unique idiotype (clonally rearranged immunoglobulin genes) as the malignant plasma cells . Accumulating evidence suggests that the clonal B-cells may represent the renewable "stem-cell" compartment in myeloma.
Myeloma tumor cells have been well characterized by extensive phenotypic analysis. The cells in the circulating "stem-cell" pool express the B-cell markers CD19, CD20, and CD24. They also express the pre-B-cell markers CD10 (CALLA) and CD9 (an activated lymphocyte marker), as well as the plasma cell marker PCA-1. A subset express CD5 (an activation marker expressed on T-cells). This profile is consistent with differentiating, late-stage B-cells.
Aside from the fact that they are monoclonal, these "stem cells" differ from normal B-cells in that they express adhesion molecules, as well as other molecules known to play a role in cell motility, extravasation, and invasion, such as CD11b. These data are consistent with the hypothesis that myeloma originates with the transformation of a B-cell precursor in an extramedullary site, with subsequent migration of late-stage B-cells through the peripheral blood to the bone marrow, where the terminal stages of maturation to the plasma cell occur. The bone marrow microenvironment, with its collection of stromal cells, extracellular matrix glycoproteins, and many cytokines, is apparently very conducive for the maturation of malignant B-cells to plasma cells, leading to further disease expansion and progression.
Assays have been developed that take advantage of the fact that the "stem-cell" compartment in myeloma is identifiable by the unique immunoglobulin gene rearrangement of the malignant clone. Bird et al described their findings using a polymerase chain reaction (PCR)-based technique that employs consensus primers to amplify the rearranged locus of the immunoglobulin heavy-chain gene . They followed six myeloma patients in clinical complete remission after allogeneic bone marrow transplantation.
All patients were PCR positive within the first year after bone marrow transplantation. One patient became PCR negative at 1 year after transplantation, and two others at 2 and 4.5 years post-transplantation, respectively. These investigators concluded that PCR positivity up to 1 year after marrow transplantation is common, and is not necessarily predictive of relapse.
The significance of residual clonally rearranged cells is not completely understood at this time. Elucidation of this phenomenon will require further study of more cases with longer follow-up. The goal of such efforts is to identify patients who may benefit from additional therapeutic intervention after bone marrow transplantation.
There appear to be both qualitative and quantitative abnormalities in immunoregulatory T-cells in myeloma patients. The ratio of CD4 to CD8 cells is decreased on presentation and continues to decline with disease progression. T-cells with membrane receptors specific for both the idiotype and isotype of the immunoglobulin have been found in myeloma patients. These T-cells can bind to and suppress human myeloma cell lines in vitro.
Sensitive molecular techniques have revealed clonal T-cell populations in myeloma patients . However, the relevance of these clonal T-cells is unknown.
Recently, Massaia et al demonstrated anti-plasma-cell activity in bone marrow mononuclear cells from myeloma patients stimulated with the anti-CD3 monoclonal antibody OKT3 . A greater understanding of the role of immunoregulatory cells in myeloma should set the stage for targeted therapeutic interventions.
Dysregulation of Interleukin-6
The progression of myeloma depends greatly on growth factors, specifically, interleukin-6 (IL-6). In murine model systems, dysregulated IL-6 production can lead to various plasma-cell proliferative disorders, including plasmacytomas and Castleman's disease .
An overproduction of IL-6 is found in 37% of myeloma patients at diagnosis, and is associated with a poor prognosis.11 Initial work suggested that IL-6 was an autocrine growth factor, produced by the myeloma tumor cells themselves . However, more recent data suggest that marrow stromal overproduction of IL-6 is more important in myeloma .
The study of critical paracrine and autocrine loops in disease progression can help identify targets for novel therapeutic approaches. A recent case report from France described a patient with refractory myeloma in whom monoclonal anti-IL-6 antibodies produced an impressive, albeit transitory, response .
It has also been demonstrated that IL-6 antisense oligonucleotides can inhibit the growth of human myeloma cell lines . Very recent work has shown that gamma-interferon can inhibit several IL-6-dependent biologic processes by downregulating IL-6 receptor expression, and can completely inhibit four human myeloma cell lines that are dependent on exogenous IL-6 for growth .
Isolated monoclonal gammopathy, the so-called monoclonal gammopathy of undetermined significance (MGUS), is a preneoplastic syndrome that has been extensively studied. However, because of the asymptomatic nature of MGUS, it is unknown whether this syndrome always precedes myeloma. Natural history studies by Kyle have demonstrated that after a median follow-up of 22 years, approximately 25% of patients with MGUS will develop myeloma, amyloidosis, or another lymphoproliferative disease .
Extramedullary plasmacytomas and solitary plasmacytomas of bone are two other syndromes that have the propensity to develop into myeloma. The further study of preneoplastic lesions should help elucidate factors necessary for tumor progression, as well as potential targets for intervention.
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