The role of cytogenetics in myeloma

Multiple myeloma is a slowly proliferating disease of ‘mature B cells’, involving mainly the bone marrow. Active myeloma is often preceded by an indolent phase of monoclonal gammopathy of undetermined significance or smoldering myeloma. Although patients at this stage do not require therapy, genetically, the plasma cells are already very abnormal with the large majority of such patients having an aneuploid DNA content and abnormal cytogenetics by fluorescence in situ hybridization (FISH), including deletion of chromosome 13, t(11;14), t(4;14), t(6;14), t(14;16) and t(14;20), although the latter three translocations are uncommon. In patients with active myeloma, more than 90% have abnormal cytogenetics by FISH if tested for hyperdiploidy and for the common translocations involving 14q32. In contrast, using metaphase cytogenetics, only one-third of patients will show an abnormal karyotype, which is usually complex and on an average 11 chromosomes are involved. The other two-thirds will have normal metaphase cytogenetics. These normal metaphases are not derived from the myeloma cells, but from the remaining normal hematopoietic cells. The reason for failure to have informative mitoses is the low proliferative capacity of the myeloma cells. It is the failure to obtain informative cytogenetics in the majority of patients that has led to a shift away from metaphase cytogenetics to interphase FISH. Deletion of chromosome 13 and hypodiploidy by metaphase cytogenetics are associated with a poor outcome. Based on these findings, it has been assumed that deletion of chromosome 13 by FISH would have a similar poor prognosis as the metaphase abnormality. In fact, in the IFM 99 study, poor prognosis was defined as a combination of deletion 13 by FISH and elevated B2 microglobulin level. Unfortunately, mixing results of metaphase cytogenetics with those obtained by FISH has resulted in confusion and statements that deletion of chromosome 13 (as determined by FISH) was not a poor prognostic factor. Patients with inferior outcome as analyzed by FISH were those with t(4;14), t(14;16) and gene deletion of p53. Also, it was claimed that on metaphase cytogenetics not deletion 13, but hypodiploidy was associated with poor outcome. It is clear that often there is an association between hypodiploidy and deletion of chromosome 13. However, our work has shown that both hypodiploidy without deletion of chromosome 13 and deletion of chromosome 13 without hypodiploidy are associated with a poor prognosis. When analyzing outcome of patients with or without FISH deletion 13, those with deletion 13 (approximately 50% of all patients) as a group have an inferior outcome (Figure 1), but if we divide patients with deletion 13 by FISH into those with normal versus abnormal metaphase karyotypes, it becomes evident that the inferior prognosis of patients with FISH deletion 13 is entirely due to the one-third of those patients (17% of the overall patient population) with abnormal metaphase cytogenetics, whereas those with normal metaphase cytogenetics and deletion 13 by FISH have an outcome similar to those without FISH deletion 13 (Figure 2). In the context of the ongoing confusion of the prognostic value of metaphase versus FISH cytogenetics, the paper in this issue by Laura Chiecchio et al. is very relevant. The authors compared results obtained by FISH, not only for deletion of chromosome 13, but also for hyperdiploidy, p53, t(14;16), t(14;20), t(6;14) and t(4;14), with those obtained by metaphase cytogenetics. This was a large multicenter study including 794 patients, with 78% of these patients studied at the time of diagnosis. A weakness of the study is that the treatment approach was not uniform and that it is unknown whether the knowledge of cytogenetic results had an impact on the type of therapy given to patients. In addition, the median follow-up was a short 22 months. Their findings confirm our data that abnormal metaphase cytogenetics are associated with a poor outcome and that patients with FISH deletion 13 but without abnormal metaphase cytogenetics had similar outcomes to those with no