Cyclin D1 Immunohistochemistry Identifies a Subset of Plasma Cell Myeloma with Superior Overall Survival.

The expression of Cyclin D1 is dysregulated in approximately half of cases of plasma cell myeloma due to translocations, aneusomy, or other abnormalities. Recent studies using quantitative mRNA analysis have suggested that increased Cyclin D1 mRNA expression is associated with a favorable prognosis. Previous attempts to examine the significance of cyclin D1 protein expression by immunohistochemistry have been hampered by the use of antibodies with weak staining and high background. In this study, we employ a newly available, commercial antibody that gives superior staining in B5 fixed tissues. We performed immunohistochemistry for Cyclin D1 on bone marrow core biopsies from a series of 44 newly diagnosed plasma cell myeloma patients who were uniformly treated on a Phase II study of rituxan, melphalan and prednisone. 22 patients (50%) were positive for Cyclin D1, defined as any plasma cells with positive nuclear staining. Cyclin D1 positive and negative cases displayed no significant differences in the initial levels of β₂m (3.6±0.5 mg/L vs. 3.5±0.5 mg/L, p=0.860), number of bone marrow plasma cells (63±5.5% vs. 47±6.2%, p=0.063), or proportion of cases classified as SWOG stage 3-4 (2 of 22 (9%) vs. 5 of 22 (23%), p=0.412). The cyclin D1 positive cases displayed a superior overall survival with an estimated 3-year survival of 95% for Cyclin D1 positive cases versus 56% for Cyclin D1 negative cases (p=0.032). The cyclin D1 positive cases also displayed a trend towards better progression-free survival (median progression free survival of 15.7 months for Cyclin D1 positive versus 12.8 months for Cyclin D1 negative, p=0.13). In a Cox proportional hazards regression model, used to compare the effect of Cyclin D1 protein expression on overall survival time while adjusting for stage, the Cyclin D1 positive patients continued to show a strong trend to better overall survival (p=0.062). This study demonstrates that cyclin D1 immunohistochemistry, which could be readily performed in most pathology laboratories, is capable of identifying a subset of plasma cell myeloma with a favorable survival. Additional studies are ongoing to determine if these results can be generalized to other forms of therapy. If confirmed, routine cyclin D1 immunohistochemistry at the time of diagnosis may offer important prognostic information that could identify lower risk patients for whom less intensive therapies might be appropriate.