Multiple myeloma: increasing evidence for a multistep transformation process

Abstract

Multiple Myeloma (Mm) is a clonal B-cell neoplasm that affects terminally differentiated B cells (ie, plasma cells) and may proceed through different phases: an inactive phase in which tumor cells are nonproliferating mature plasma cells, an active phase with a small percentage (<1%) of proliferating plasmablastic cells, and a fulminant phase with the frequent occurrence of extramedullary proliferation and an increase in plasmablastic cells. During the past years, considerable progress has been made in identifying some of the critical components of neoplastic transformation in MM. This review intends to propose a model of a stepwise malignant transformation during MM pathogenesis. Both diagnostic and therapeutic implications of this model will be discussed.

Fig 1

Normal plasma cell development. Functional V(D)J rearrangements of IgH and IgL genes in pre-B cells in the BM generate an immature B cell that expresses a functional Ig on the cell surface, which then exits the BM as a virgin (mature) B cell, and homes to the secondary lymphoid tissues. Early in the immune response productive interaction with antigen stimulates formation of a lymphoblast which differentiates into a short-lived nonswitched (IgM), or switched (IgG, IgA, IgE, or IgD) PC. Later in the primary response or in a secondary response, the lymphoblast generated by productive interaction with antigen enters a germinal center, where it undergoes somatic hypermuation of its IgH and IgL genes, and antigen selection of cells with high affinity Ig receptor. A germinal center plasmablast that undergoes productive IgH switch recombination typically homes to the BM where it differentiates into a long-lived plasma cell (cf. myeloma cell).

Fig 2

Transmembrane signaling of IL-6, which is a major growth factor for MM. Binding of IL-6 to the α chain (gp80) of the IL-6 receptor (IL-6R) causes the formation of multimeric complexes composed of 2 IL-6R α chains, 2 β chains (IL-6Rβ or gp130), and 2 IL-6 molecules. Subsequently, tyrosine kinases (JAKs and Src kinases, in particular Hck) which are bound constitutively to the IL-6Rβ, become activated and (trans)phosphorylate the receptor. This creates specific docking sites for several signaling proteins including STAT1, STAT3, and Shc (?) on the IL-6Rβ, allowing further phosphorylation of these proteins by receptor-associated kinases. Activation of Shc recruits Grb2/Sos1 to the cell membrane. Sos1, a Ras-GDP/GTP exchange factor activates Ras; this activates a signaling cascade of several serine/threonine kinases including Raf-1, MKK, MAPK. Finally, MAPK phosphorylates substrates like c-Myc, c-Jun, c-Fos, RSK, and these events eventually enhance MM proliferation or prevent apoptosis. Upon phosphorylation, STAT1 and STAT3 form homodimers and heterodimers that are translocated to the nucleus and act as transcription factors for IL-6–induced promoters. Although the Ras-MAPK signaling cascade is believed to promote MM growth, no such function has yet been reported for the JAK-STAT pathway, believed to trigger rather metabolic events.

Fig 3

Progressive genetic events in MM. Although not every stage is discernible in each patient, there appears to be an ordered progression from a normal plasma cell; to MGUS where the cells are immortalized, but not transformed, and do not progressively accumulate or cause bone destruction; to intra-medullary myeloma, where the cells are confined to the BM micro-environment, accumulate and cause bone destruction; to extra-medullary myeloma, where the cells proliferate more rapidly and grow in the blood (plasma cell leukemia) or other extra-medullary sites; to a myeloma cell line, where the cells may be propagated in vitro. This model summarizes the possible timing of genetic events in relation to clinical progression. When the event may occur at a discrete time, we have indicated this with an arrow. When it is clearly associated with a defined clincal stage we have indicated this with a solid line. When the timing is unclear, we have used a dashed line. We suspect that the 14q32 translocation may be an early event, concordant with isotype switch recombination, so that it may precede MGUS. Some translocations [eg, t(11;14)] may lead more rapidly to fulminant disease. There is evidence of karyotypic instability in MGUS that continues throughout all stages of tumour progression. Monosomy 13 is present in intramedullary myeloma, independent of stage, but there is no evidence as to whether or not it is present in MGUS. Dysregulation of c-myc appears to be common, but the timing is unclear. In patients with ectopic FGFR3 expression caused by t(4;14), a mutation of FGFR3 could lead to ligand independence and clinical progression, as is suggested in one analyzed example. Mutations of N- and K-ras are not present in MGUS, but are present in intramedullary myeloma, with an increasing incidence as the disease progresses. Mutations of p53 are a late event associated with aggressive extra-medullary myeloma.