Cyclin D1 overexpression is a favorable prognostic variable for newly diagnosed multiple myeloma patients treated with high-dose chemotherapy and single or double autologous transplantation

Abstract

We used a sensitive real-time reverse transcription-polymerase chain reaction assay to quantify cyclin D1 mRNA levels in bone marrow samples collected at diagnosis from 74 newly diagnosed multiple myeloma (MM) patients who were randomized to undergo either single or double autologous peripheral blood stem cell transplantation as part of first-line therapy for their malignancy. In 46 cases, fluorescence in situ hybridization (FISH) analysis and/or conventional cytogenetics were performed to detect chromosome 11 abnormalities. Patients with the t(11;14) or trisomy 11 significantly overexpressed cyclin D1 (P < .0001) in comparison with patients without 11q abnormalities, who had cyclin D1 mRNA levels similar to healthy donors. Overall, 32 (43%) of 74 patients showed cyclin D1 overexpression. No difference was found between cyclin D1-positive (group A) and cyclin D1-negative (group B) patients with respect to presenting clinical and laboratory characteristics, including chromosome 13 abnormalities, as well as to response to therapy and overall survival, both of which were calculated on an intent-to-treat basis. Patients who overexpressed cyclin D1 had significantly longer duration of remission in comparison with patients who did not (41 vs 26 months, respectively; P ‫؍‬ .02). As a result, median event-free survival (EFS) was longer in group A than in group B (33 vs 24 months, respectively; P ‫؍‬ .055). We concluded that cyclin D1 overexpression is closely associated with 11q abnormalities and identifies a subset of MM patients who are more likely to have prolonged duration of remission and EFS following autologous transplantation. (Blood. 2003;102:1588-1594)

The enigmatic role of cyclin D1 in multiple myeloma

“…Indeed, MM patients with the t(11;14) or a chromosome 11 trisomy, i.e., all expressing cyclin D1, show better overall survival, better response to intensive chemotherapy and longer duration of remission after autologous transplantations (Table II). [33][34][35][36][37] Those observations are in good correlation with a lower proliferative index of cyclin D1-expressing MM cells.…”

“…Indeed, MM patients with the t(11;14) or a chromosome 11 trisomy, i.e., all expressing cyclin D1, show better overall survival, better response to intensive chemotherapy and longer duration of remission after autologous transplantations (Table II). [33][34][35][36][37] Those observations are in good correlation with a lower proliferative index of cyclin D1-expressing MM cells.Indeed, the proliferative activity measurement, assessed using BrdU labeling index, indicates that patients with t(11;14), i.e., expressing cyclin D1, have a lower proliferative index than the others. 37,38 The speculation that overexpression of cyclin D1 triggers MM cell proliferation is not supported by those clinical data.…”

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.…”

Genetic heterogeneity in multiple myeloma

“…Interestingly, recent reports have shown that patients with trisomy 11 displayed a high expression of cyclin D1, with levels close to those observed in the cases with t (11;14). 43,44 Since chromosome 11 is one of the most often gained chromosomes in hyperdiploidy, these data raise the question of the prognostic role of cyclin D1 expression in hyperdiploid cases.…”