High Expression of MUM1/IRF4 mRNA Is Associated with a Shorter Overall Survival in Patients with Multiple Myeloma.

MUM1 (multiple myeloma oncogene 1)/IRF4 (interferon regulatory factor 4) has been shown to be expressed by neoplastic B-cells and to be closely linked to poor survival in large B-cell lymphomas. Information on a possible expression of MUM1 in myeloma cells and on a possible role as prognostic marker has not been presented up to now. Hence, we aimed to analyse these issues in a cohort of well characterized patients with multiple myeloma.

Fifty-three patients with multiple myeloma, median age 70 years, were enrolled. Nine presented with Durie Salmon stage I, 6 had stage II, and 38 stage III. Forty-five were newly diagnosed and 8 pretreated (median number of treatment lines: 2). MUM1 mRNA expression was analysed by real time PCR in freshly isolated unsorted as well as CD 138 enriched myeloma cells and controls. Survival was calculated using the Kaplan-Meier product limit method. For multivariate analyses the Cox proportional hazards method was used.

MUM1 mRNA levels were detected in all 53 unsorted myeloma samples with a distribution range covering 3 orders of magnitude (0.35 to 261.38-fold, median: 10.5 relative to normal blood=1). MUM1 RNA expression was validated in CD138 enriched myeloma cells (N=10). A strong but heterogeneous expression was found in the CD 138 positive cell fraction while low expression was found in the remaining CD138 negative cell fraction.

When patients were divided regarding the magnitude of MUM1 expression by using a cut off level of 13 (relative to the level detected in normal blood) 32 were found with low and 21 with high MUM1 expression. Median survival was significantly shorter in patients with high MUM1 expression compared to low expressers (45 months, vs. 58 months, p =8x10⁻⁵, Hazard Ratio 9.65). Among the following parameters: ß2-microglobulin (>5mg/ml), CRP, albumin, creatinine, M-component, and bone marrow plasma cell infiltration tested, only increased MUM1 expression (p = 0.00088), high ß2-microglobulin (>5mg/ml, p = 9x10⁻⁴), creatinine (p <0.0095), and CRP (p = 0.091) were found to be significantly associated with short survival in univariate analysis. Cox multivariate analysis revealed only high MUM1 (p= 0.0036) and high ß2-microglobulin (p = 0.0039) independently associated with short survival. The 12 patients who presented with both negative prognostic factors (ß2-microglobulin >5mg/ml and MUM1 expression >13) had very short survival (median: 3 months). In contrast median survival was 58 months in the 41 patients with none or only one adverse prognostic factor (p = 6.71 x 10⁻¹¹).

In conclusion, high MUM1 RNA expression in myeloma cells was found in 40% of patients. High MUM1 RNA expression strongly correlated with poor survival both in univariate and in multivariate analysis. The latter analysis revealed MUM1 RNA expression together with high ß2-microglobulin levels as only parameters independently predicting for poor outcome.