ASSESSMENT OF THE ROLE OF CLONOGENIC B-LYMPHOCYTES IN THE PATHOGENESIS OF MULTIPLE-MYELOMA

The identifiable neoplastic cell in multiple myeloma is the plasma cel l, which usually synthesizes and secretes a monoclonal immunoglobulin. However, there exists the possibility that the neoplastic event has o ccurred in a less mature clonally-related cell, such as a B lymphocyte , prior to Ig class switching. Since the presence of such a clonogenic cell could influence design of therapy, particularly with monoclonal antibodies, we have used the analysis of tumour-related V-H genes to a pproach this question. Cloning and sequencing of PCR products from V-H genes of tumour cells obtained from 4/4 patients with myeloma reveale d significant mutation of the genes as compared to germ line sequences . In all cases the mutations were scattered throughout the variable re gion, with a pattern which did not indicate a role for antigen in sele ction. Importantly for therapy, multiple V-H sequences from all patien ts were completely homogeneous, with no intraclonal variation. These f indings indicate that, although IgM-positive clonogenic cells may exis t, it is unlikely that they are involved in continuous maintenance of the malignant isotype-switched cell population. One possibility is tha t the B-cell progenitor population has to undergo further chromosomal changes to generate the malignant cell, and that this occurs at a more mature stage; in this case, antibody therapy should he aimed primaril y at the more differentiated cells.