Heidi Lemmens

Interphase fluorescence in situ hybridization on selected plasma cells is superior in the detection of cytogenetic aberrations in plasma cell dyscrasia.

Interphase fluorescence in situ hybridization (FISH) detects nonrandom cytogenetic abnormalities in plasma cell (PC) dyscrasia according to PC burden. However, when performed on cultured whole bone marrow (BM), it often fails to detect these aberrations. We have compared this interphase FISH technique with FISH after PC purification or identification to detect recurrent aberrations. In this study, 235 BM samples were collected from patients with multiple myeloma (MM) or related PC disorders regardless of disease status. All samples were analyzed in parallel. Clonal abnormalities were detected in 34.9% of cultured samples compared with 71.0% PC selected samples (P < 0.001). Moreover, FISH on PCs allowed to detect more abnormalities per case (P < 0.001) and identified higher percentages of abnormal nuclei (P < 0.001). This study indicates that FISH on PCs is the preferred technique for routine cytogenetic investigation of MM.

RPL5 on 1p22.1 is recurrently deleted in multiple myeloma and its expression is linked to bortezomib response

Chromosomal region 1p22 is deleted in ⩾20% of multiple myeloma (MM) patients, suggesting the presence of an unidentified tumor suppressor. Using high-resolution genomic profiling, we delimit a 58 kb minimal deleted region (MDR) on 1p22.1 encompassing two genes: ectopic viral integration site 5 (EVI5) and ribosomal protein L5 (RPL5). Low mRNA expression of EVI5 and RPL5 was associated with worse survival in diagnostic cases. Patients with 1p22 deletion had lower mRNA expression of EVI5 and RPL5, however, 1p22 deletion status is a bad predictor of RPL5 expression in some cases, suggesting that other mechanisms downregulate RPL5 expression. Interestingly, RPL5 but not EVI5 mRNA levels were significantly lower in relapsed patients responding to bortezomib and; both in newly diagnosed and relapsed patients, bortezomib treatment could overcome their bad prognosis by raising their progression-free survival to equal that of patients with high RPL5 expression. In conclusion, our genetic data restrict the MDR on 1p22 to EVI5 and RPL5 and although the role of these genes in promoting MM progression remains to be determined, we identify RPL5 mRNA expression as a biomarker for initial response to bortezomib in relapsed patients and subsequent survival benefit after long-term treatment in newly diagnosed and relapsed patients.

MafB oncoprotein detected by immunohistochemistry as a highly sensitive and specific marker for the prognostic unfavorable t(14;20) (q32;q12) in multiple myeloma patients

MafB oncoprotein detected by immunohistochemistry as a highly sensitive and specific marker for the prognostic unfavorable t(14;20) (q32;q12) in multiple myeloma patients

The t(14;20)(q32;q12): a rare cytogenetic change in multiple myeloma associated with poor outcome

and concurrent sepsis causing diagnostic delay and significant morbidity. We believe that these predisposing events are common to all patients receiving high-dose chemotherapy for CNS lymphomas and that this complication is under-recognized. Evidence shows that cancer and its treatment is the leading case of WE in the paediatric population and that the diagnosis is commonly missed (Vasconcelos et al, 1999). We propose that prophylactic, parenteral thiamine should be administered to all patients receiving second-line anti-emetic therapy during high-dose chemotherapy for CNS malignancy.

A182 The t(14;20)(q32;q12): A Rare Cytogenetic Change in Multiple Myeloma (MM) Associated with Poor Outcome

monoclonal protein (M-protein). This report characterizes a unique presentation of multiple myeloma with monoclonal free truncated 3HC and free kappa light chains. A 34-year-old man presented with recurrent pneumonia with a mild anemia, neutropenia, proteinuria, an IgG M-protein of 23g/L with no associated light chain on immunofixation, a normal skeletal survey, and a bone marrow aspirate/trephine confirming myeloma. The patient was treated with cyclophosphamide, thalidomide and dexamethasone followed by a fully myeloablative sibling allogeneic peripheral blood stem cell transplantation and is in complete remission 19 months from presentation. Serum immunofixation identified an IgG M-protein (23g/L) shown to be 3 subclass. Western blot showed the 3HC was truncated with a large deletion. Kappa free light chains were elevated at 503.58 mg/L [3.30-19.4]. Urine immunofixation revealed separate HC and LC M-proteins. Western blot of the fractionated urine protein demonstrated different sized LC aggregates. Flow cytometry of the marrow aspirate revealed an unusual plasma cell phenotype: CD19, strong CD45, weak CD138, strong CD38, and negative for surface kappa, lambda, CD56, CD5, CD20, CD22, CD23, CD10, CD34. All plasma cells contained IgG heavy chain, 30% also contained kappa light chains. Immunophenotyping and immunohistochemistry confirmed a dual population with kappa producing and non-producing plasma cells. Cytogenetics and FISH were negative for the common myeloma abnormalities. This is the first description of multiple myeloma attributable to a clone of plasma cells that make truncated IgG heavy chain. This plasma cell dyscrasia is also unusual in that a subpopulation secrete large quantities of free light chain as well as truncated heavy chain. The clinical and immunologic findings are clearly different to typical findings in both 3HCD and Myeloma. The immunophenotype of the malignant plasma cells is unusual for myeloma. Other atypical features include young age at presentation, frank proteinuria, with a HC in the urine, but normal renal function and no radiologic or biochemical evidence of bone involvement. We propose that this unique myeloma has distinct immunologic and clinical features.