Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy

Abstract

Recently, we have described the biological correlations associated with the main translocations involving the 14q32 chromosomal region, that is, t(14q32), in patients with multiple myeloma (MM). We have now extended the analysis to the prognostic value of these chromosomal rearrangements in 168 consecutive patients with newly diagnosed MM receiving intensive chemotherapy within clinical trials of the Intergroupe Francophone du Myelome (IFM). Patients with t(4;14) displayed a poor outcome (short event-free survival and short overall survival), whereas those with t(11;14) displayed long survival. On the other hand, patients with neither t(4;14) nor t(11;14) presented an intermediate outcome. Importantly, chromosome 13 abnormalities (C13As) significantly influence the prognosis of this latter group. In contrast, C13As affected the outcome of the other patients to a much lesser extent, either because of an almost constant association (in the t(4;14) group) or because of a lack of any significant prognostic impact (in the t(11;14) group; only one event occurred in the 10 patients with t(11;14) and C13As). Considering that t(4;14) and t(11;14) (1) are the only (so far recognized) true, recurrent t(14q32)'s, (2) are linked to specific immunoglobulin isotypes, and (3) display specific outcomes, they represent distinct entities corresponding to a specific oncogenesis and prognosis. These data emphasized the interest in analyzing these two translocations by fluorescence in situ hybridization in prospective therapeutic trials in order to consider these translocations as distinct entities. IntroductionChromosomal abnormalities represent the main prognostic parameter in several hematological malignancies, especially acute leukemias. Such a prognostic value is less evident in other hematological neoplasms, either because of a lower proliferative index (preventing the obtaining of clonal metaphases) or because of technical reasons (difficulties in harvesting tumor cells, such as in lymph nodes). However, with the development of techniques circumventing the nonproliferative pitfall, and especially interphase fluorescence in situ hybridization (FISH) technologies, it is now possible to target some specific recurrent chromosomal changes to assess their potential impact on either response to therapy or survival. Recently, a nice application of this approach has been demonstrated in chronic lymphocytic leukemia. Whereas chromosomal abnormalities are usually observed in fewer than 50% of the patients by means of conventional cytogenetics, a systematic interphase FISH analysis identified chromosomal changes in up to 85% of the patients. 1 Moreover, this study demonstrated the high prognostic significance of these abnormalities for patients' survival.Multiple myeloma (MM) is characterized by a low proliferative index (labeling index lower than 1%). This low proliferative capability is correlated with a low cytogenetic informative capability. A systematic literature survey was done to an informative capability of between 30% and 50% o...

Mutually Exclusive Cyclin-Dependent Kinase 4/Cyclin D1 and Cyclin-Dependent Kinase 6/Cyclin D2 Pairing Inactivates Retinoblastoma Protein and Promotes Cell Cycle Dysregulation in Multiple Myeloma

“…Translocation of the cyclin D1 gene to the immunoglobulin heavy chain locus t (11:14) and overexpression of cyclin D1 RNA have been implicated in cell cycle dysregulation in multiple myeloma (14,15,17,18). Paradoxically, cyclin D1 overexpression has also been linked to a more favorable prognosis in multiple myeloma (22)(23)(24), calling into question the precise role of cyclin D1 overexpression in multiple myeloma. We showed by sequential analysis of bone marrow biopsies (5-26) that cyclin D1 expression did not vary during the clinical course of 21 patients (Fig.…”

“…However, there has been no functional evidence to support this concept. Moreover, elevation of cyclin D1 RNA has been paradoxically linked to a more favorable prognosis in multiple myeloma (22)(23)(24). The mechanism that underlies cell cycle dysregulation in multiple myeloma, therefore, remains undefined.…”

RHAMM expression and isoform balance predict aggressive disease and poor survival in multiple myeloma

“…32 At present, standard prognostic factors in MM are not particularly useful for determining the best treatment for each patient. Newer, molecular prognostic factors, such as RHAMM, t(4;14) 6 , and other IgH translocations, 34,35 are exciting not just for their prognostic value but because their associations with survival are also linked to a biologically plausible reasoning behind the observed association. It is hoped that such molecular epidemiologic studies as this one will be more clinically useful than older studies of prognosis by helping us to understand the biology of myeloma, and more particularly by identifying novel targets for therapy.…”

Impact of early relapse after auto-SCT for multiple myeloma

“…Identification of genetic abnormalities such as t(4:14), t(14:16), p53 (17p-) abnormalities, chromosome 13 abnormalities on conventional cytogenetics clearly predict for poor outcome in the majority of patients with these abnormalities. 15,[23][24][25][26] In addition, a host of other high risk features have been identified in myeloma including presence of proliferating myeloma cells as measured by labeling index, higher International Staging System stage, plasmablastic morphology and high LDH among others. 17,24,[27][28][29][30] Previous studies have demonstrated poor survival among patients with some of these poor genetic risk factors undergoing SCT whereas others have suggested a reduced impact of these markers in the absence of an elevated b 2 M. 31 Although recognition of some of these high risk features may dissuade patients and physicians from proceeding to auto-SCT, many patients without these abnormalities have myeloma that relapse shortly after SCT.…”