Multiple myeloma- The Causes

Multiple myeloma, also known as plasma cell myeloma or Kahler’s disease, is a types of abnormal growth of plasma cells collected in the bone marrow where they grow and multiple to interfere with the production of normal blood cells. Paraprotein, an abnormal antibody produced by the plasma cell myeloma not only can causes kidney problem but also interference with the Roche automated total bilirubin assay by precipitate formation of that can lead to clinical confusion, according to the study by the Harvard Medical School, Boston(1). Other study indicated that the production of paraproteins caused spurious results on individual analytes including total bilirubin (TBIL), direct bilirubin (DBIL), or HDL-cholesterol (HDL-C)(b). there is also a report of a 50 years old
chloride resistant metabolic alkalosis in a patient with hypercalcemia related to Multiple Myeloma (MM)(c).
 
A. Causes
1. Monoclonal gammopathy of undetermined significance (MGUS)
Monoclonal gammopathy of undetermined significance (MGUS) has been associated with an increased risk of smoldering multiple myeloma (SMM. Strong evidence showed that multiple myeloma is consistently preceded by a precursor state at the molecular level, there is urgent need to better understand mechanisms that regulate transformation from precursor to full-blown multiple myeloma(7).
2. Genetic abnormalities 
a. Dysregulation of c-myc Gene
Dysregulation of c-myc by translocation to the switch regions of the IgH locus occurs in most murine plasmacytomas. Translocations involving 14q32 have been reported in 20-40% of abnormal karyotypes from human multiple myeloma (MM), and involve a variety of loci(8).
b. Gene (IgH)
Chromosome translocations involving the immunoglobulin heavy chain gene (IgH) on 14q32 are a seminal event in the pathogenesis of many B-cell malignancies. According to the study by the New York Presbyterian Hospital-Weill Medical College of Cornell University, , Recurrent Ig translocations identify at least three distinct molecular subtypes of myeloma(9).
c. Chromosome translocations
(11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), and 16q23 (c-maf))
Four chromosomal partners appear to account for the majority of primary IgH translocations: 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), and 16q23 (c-maf).  They are mediated primarily by errors in IgH switch recombination and less often by errors in somatic hypermutation, with the former dissociating the intronic and 3′ enhancer(s), so that potential oncogenes can be dysregulated on each derivative chromosome (e.g., FGFR3 on der14 and MMSET on der4). Secondary translocations, which sometimes do not involve Ig loci, are more complex, and are not mediated by errors in B cell specific DNA modification mechanisms(10).
d. Cytogenetic alteration and/or hyperdiploidy
At diagnosis, 96% of cases with multiple myeloma versus 77% of monoclonal gammopathy of undetermined significance cases showed at least one cytogenetic alteration and/or hyperdiploidy(11).
3. Etc.
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(a) http://www.ncbi.nlm.nih.gov/pubmed/12521367
(b) http://www.ncbi.nlm.nih.gov/pubmed/18251580
(c) http://www.ncbi.nlm.nih.gov/pubmed/22073517 
(7) http://www.ncbi.nlm.nih.gov/pubmed/21411440 
(8) http://www.ncbi.nlm.nih.gov/pubmed/9308253
(9) http://www.ncbi.nlm.nih.gov/pubmed/10707795
(10) http://www.ncbi.nlm.nih.gov/pubmed/11607813 
(11) http://www.ncbi.nlm.nih.gov/pubmed/22929983