THE MALIGNANT HIERARCHY IN MULTIPLE MYELOMA: RELATIONSHIPS BETWEEN MALIGNANT CELLS AND BONE DISEASE

Multiple myeloma (MM) is an incurable cancer of the bone marrow (BM), with survival of 3–4 years. MM accounts for 1% of all cancers, and 19% of deaths from hematological malignancies. It is characterized by monoclonal immunoglobulin (mIg) in the blood, lytic bone lesions, and monoclonal plasma cells in the BM. These plasma cells are responsible for most symptoms of MM, but considerable work confirms that the MM clone also includes earlier stage B lymphocytes. The MM clone is characterized by an immunoglobulin variable region gene rearrangement (IgH VDJ), termed “clonotypic”. The IgH VDJ rearrangement that defines the MM clone in each patient is unique, thus providing an unequivocal molecular signature for MM cells regardless of, for example, genetic abnormalities, phenotype, morphology or physical location. Although the phenotypic properties of the MM clone are altered as the disease progresses and genetic heterogeneity increases, the clonotypic IgH VDJ signature remains constant, exhibiting rigid intraclonal homogeneity of sequence (1–3). With the exception of plasma cells, the distribution of the myeloma clone in situ, and its relationship to bone lesions within the BM is largely unknown. Because it is at best difficult, and at worst impossible to morphologically or phenotypically distinguish the earlier stage members of the MM clone from normal B lineage cells, detection of the IgH VDJ MM signature is essential as the distinguishing characteristic of individual MM cells participating in the apparently synergistic relationship between bone and malignancy.