The Significance Of MYC Activation In The Development Or Relapse Of Extramedullary Disease And Clinical Prognosis In Patients With Multiple Myeloma

Background and PurposeMultiple myeloma (MM) is a heterogeneous disorder characterized by clonal proliferation of malignant plasma cells, usually restricted to bone marrow. Extramedullary disease (EMD) may occur either at diagnosis (EMD1) or relapse (EMD2), which is associated with a poor prognosis, with a high mortality and a short suivival. The incidence is rising in recent years. Patients with EMD can’t get effective treatment although novel effective agents are available for myeloma treatment. Since the pathogenesis of is unclear and there is no sensitive indicators to identify these high-risk patients. It’s considered that deregulation of c-Myc and MYC gene rearrangement are associated with tumor progression. However the incidence and prognostic significance of MYC rearrangement are not definite in patients with MM. The main purposes of this study include:(1) To investigate the incidence, clinical features, cytogenetic abnormalities and prognosis of EMD so as to explore risk factors of EMD and possible effective treatment. (2) To reveal the correlation of MYC expression and clinical prognosis in MM. (3) To study cytogenetic aberrations including MYC relevant abnormalities in extramedullary plasmacytoma including EMD and solitary plasmacytoma (SP) to evaluate the significance of MYC expression in the development of extramedullary disease.MethodsThis study enrolled previously untreated MM patients in Peking Union Medical College Hospital from Jan 2008 to March 2014. Clinical data were retrospectively analyzed. Bone Marrow cell suspensions of MM patients were collected and interphase fluorescence in situ hybridization (iFISH) were applied to detect the incidence of MYC rearrangement in marrow plasma cells. Formalin-fixed and paraffin-embedded(FFPE) tumor tissues of these patients were also collected. Expression of c-MYC was examined by immunohistochemical staining on marrow tissue and extramedullary sections. In addition, FISH was pursued on pathological tissue of extramedullary plasmacytomas with a panel of probes to screen 1q21 gains,8p21 deletion, RBI deletion, D13S319 deletion, P53 deletion, IGH translocation and MYC rearrangement.Results1. The retrospective study enrolled a total of 261 MM patients including 54 patients with EMD. The incidence of EMD was 13.0% in newly diagnosed patients and 11.1% at relapse. Compared with nonEMD patients, IgD type (P=0.012), LDH elevation (P<0.001), 1q21 gain (P=0.003), P53 deletion (P=0.012), RBI deletion (P=0.020) were associated with the development of EMD. EMD group was associated with shorter overall survival (26 vs 41 months, P=0.008), especially EMD2, namely patients with extrameduallay relapse (15 vs 41 months, P<0.001). Bortezomib as induction therapy may overcome the poor prognosis of EMD with median OS 28m vs 39m in EMD and non-EMD respectively (P=0.237). While EMD patients receiving primary treatment without bortezomib had a significant worse OS compared with non-EMD patients (24m vs not reached with median follow up 25months, P=0.007)2. Bone marrow cell suspensions of 53 newly diagnosed MM and 17 relapsed MM patients were tested for iFISH analysis. The positive rates of MYC rearrangement in EMD1 and EMD2 were 22.6% and 29.5% respectively. The postive rate of MYC rearrangement in newly diagnosed non-EMD patients was significantly lower than that of EMD group (9.1 %vs 32.3%, P=0.047). Myc rearrangement was significantly correlated with 1q21 gains (P<0.001), P53 deletion (P=0.046), elevated LDH (P=0.037). Positive MYC rearrangement was associated with a poor prognosis compared with negative MYC expression (12m vs not reached with median follow up 31 months, P<0.001). Multivariate analysis revealed that MYC rearrangement was an independent risk factor of poor prognosis (P<0.001).3. FFPE tumor tissues of 24 EMD and 11 SP patients were selected for FISH analysis. The incidences of 1q21 gains (70.5% vs0%, P=0.001), MYC rearrangement (55.0% vs9.1%, P=0.024), RB1 deletion (66.7% vs20.0%, P=0.023), IGH translocation (62.5% vsl0.0%, P=0.014) were significantly higher in EMD patients than those of SP patients.4. Bone marrow biopsies of 54 newly diagnosed MM were evaluated by immunohistochemistry using anti-MYC antibody. Patients with EMD showed a significant stronger signal of nuclear MYC protein than that of nonEMD group (P= 0.032).Two SP patients with high nuclear MYC expression progressed to active MM in one to three years. Patients with MYC-positive ratio more than 30% showed a significant shorter overall survival compared with those with less than 30%(16m vs not reached with median follow up 31 months, P-0.006).ConclusionsThe development of EMD in MM patients is correlated with elevated LDH, P53 deletion and MYC rearrangement. EM involvement confers poor prognosis. Bortezomib containing primary treatment can partially overcome the poor prognosis of EMD. MYC rearrangement is associated with both extramedullary involvement and poor prognosis.