Background; Multiple myeloma (MM) is an incurable plasma cell malignancy. Most investigators believe that progression and outcome in MM is secondary to specific genetic alterations of the malignant cells. Translocations at 14q32 are thought to be the genetic hallmark of MM. By conventional cytogenetic analysis (CC), others and Dr. Fonseca have determined that the presence of chromosomal abnormalities is associated with an adverse outcome. Structural abnormalities of the long arm of chromosomes 11 (mostly translocations), and 13 and the short arm of 17 have special prognostic significance. However, CC is fraught with many difficulties including inability to detect abnormalities in non-proliferating cells. Fluorescent in situ hybridization (FISH) can detect chromosomal abnormalities in interphase cells. The prognostic significance of FISH is not yet known. Preliminary data suggest that chromosomal abnormalities as detected by FISH are of significance as well. Understanding the genetic mechanisms of MM cell proliferation, disease progression and outcome is important to eventually overcoming the disease. Furthermore these abnormalities may identify biologically different subgroups of MM. Hypothesis: 1) Specific chromosomal structural and numerical abnormalities will have prognostic significance in patients with MM (overall survival and event free survival). 2) Translocations will result in gene overexpression as detected by RNA analysis (reverse transcriptase polymerase chain reaction, TR-PCR) and immunohistochemistry. 3) These chromosomal abnormalities will have correlations with known biological and prognostic factors. 4) Specific chromosomal abnormalities at two years after initiation of treatment may result in development of therapy-related myelodysplasia or acute leukemia (tMDS/AML). Objectives: 1) Determine the frequency and prognostic significance (overall survival and event free survival) of translocations between 14q32 and other donors chromosomes (11q13, 4q16.3, 16q23), deletions (13q and 17p13) and numerical chromosomal abnormalities (chromosomes 6, 7, 9, 11, 15,17). 2) Correlate the presence of specific chromosomal translocations with resulting gene overexpression by RT-PCR (cyclin D1, FGFR3, MMSET, and c-maf) and immunohistochemistry (cyclin D1 only). 3) Correlate chromosomal abnormalities with tumor biological markers (plasma cell labeling index, B-2 microglobulin, C-reactive protein, soluble IL-6 receptor, DNA content S-phase, DNA aneuploidy, and plasmablastic morphologic). 4) Assess for specific chromosomal abnormalities associated to myelodysphasia and therapy related leukemia and relate these findings to clinical development of tMDS/AML. Material and Methods; To detect chromosomal abnormalities he will perform dual-color FISH using locus-specific and chromosome-specific probes on archival samples of 250 patients collected for E9487 (associated ancillary laboratory trial to clinical trial E9486). To precisely identify monotypic plasma cells he will couple FISH with fluorescent staining for the cytoplasmic immunoglobulin. Additionally, he will do RT-PCR for RNA analysis and immunohistochemistry for protein overexpression (cyclin D1). He will perform biological correlations with other markers, and perform an overall survival and event free survival analysis according to the presence or absence of specific abnormalities. Variables will also be studied using a multiple-variable model to test them as independent predictors.
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