Translocation t(14;16) in IgM multiple myeloma (2011)

IgM multiple myeloma (MM) is rare and poorly characterized disorder. It is estimated to account for approximately 0·3% of all cases of myeloma and a recent report has confirmed, at least in the context of high-dose therapy, an inferior clinical outcome (Morris et al, 2010). Avet-Loiseau et al (2003) were the first to evaluate the cytogenetic features of IgM MM and demonstrated the t(11;14) in seven of eight cases (88%) suggesting that this may be a defining feature of the disease. The present report details the clinical and laboratory features of a patient with IgM MM in whom a t(14;16) was demonstrable by fluorescence in situ hybridization (FISH). We believe this to be the first reported case of this translocation in IgM MM. A 64-year-old female patient presented in December 2008 with anaemia (haemoglobin 93 g/l) and an IgM kappa paraprotein of 48 g/l. The bone marrow was diffusely replaced by large atypical plasma cells showing strong uniform expression of CD138 and IRF4/MUM1 and cytoplasmic IgM kappa. There was no evidence of a surface Ig+ CD20+ B-cell component either by flow cytometry or immunohistochemistry and a diagnosis of IgM MM was suspected. This was confirmed by the demonstration of an aberrant plasma cell immunophenotype – CD19- CD56- CD27-. There was however no evidence of CD20 or cyclin D1 protein expression. FISH studies were performed using the following probe combinations – LSI IGH@ dual colour breakapart, LSI 13q14.3/LSI 13q34, LSI IGH@/LSI CCND1, LSI IGH@/LSI FGFR3 and LSI IGH@/LSI MAF (all Abbott Molecular Inc., Des Plaines, IL, USA). These demonstrated that the majority of cells were characterized by monosomy 13 and IGH@/MAF fusion signals. There was no evidence of IGH@/CCND1 or IGH@/FGFR3 fusions and a diagnosis of IgM MM with a t(14;16) and monosomy 13 was therefore made. The patient was initially treated with four cycles of cyclophosphamide, thalidomide and dexamethasone (CTD), achieving a partial response, and subsequently proceeded to consolidation with high-dose melphalan (HDM) with stem cell support. The formal day 100 assessment demonstrated a very good partial response but minimal residual disease was demonstrated by flow cytometry as neoplastic plasma cells comprised 0·35% of bone marrow leucocytes. Unfortunately the patient showed evidence of disease progression in April 2010 (10 months post HDM) and was consequently treated with bortezomib and dexamethasone again achieving a partial response. This response was unfortunately short lived (approximately 3 months) and the patient is currently receiving lenalidomide and dexamethasone. There is very limited published cytogenetic data in IgM MM. In the first published series Avet-Loiseau et al (2003) demonstrated the t(11;14) in seven of eight cases (88%) suggesting that it a may be disease defining. Subsequent studies have however reported a lower incidence. We demonstrated the t(11;14) in 5/8 (63%) (Feyler et al, 2007); Schuster et al (2010) demonstrated it in 6/16 (38%) and Willenbacher et al (2008) failed to demonstrate it in two additional cases. In addition to the t(11;14), standard class-switched myeloma may also be characterized by other translocations involving the IGH@ at 14q32, namely the t(4;14), t(14;16) and t(14;20) and in this context they are associated with an adverse outcome (Munshi et al, 2011). We have previously reported a patient with a t(4;14) (Ackroyd et al, 2005) and believe this current report to be the first reported case of t(14;16) in IgM MM. This case was also characterized by deletion of chromosome 13 and this, in common with standard myeloma appears to be a common abnormality in IgM MM with an overall incidence of 56% in our series (five of nine evaluable cases; Feyler et al, 2007). It is clear therefore that although the incidence of the t(11;14) is typically higher in IgM MM it cannot be regarded as a defining feature. Other IGH@ translocations do occur but it remains to be seen whether these translocations have a similar prognostic impact in IgM MM as they do in standard class-switched MM.