Abstract
Background: BCMA (TNFRSF17 or CD269) is a cell surface protein expressed on a subset of B cells and mature plasma cells. It is related to BAFF receptor, transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI). When engaged by their ligands APRIL and BAFF these three receptors induce B cell maturation and differentiation into plasma cells. BCMA (B cell Maturation Antigen) is also expressed in B cell lymphoma and plasma cell neoplasms including myeloma. Because of this restricted expression, it has emerged as a potential therapeutic target. A number of clinical trials using either chimeric antigen receptor T cells or antibody drug conjugates targeting BCMA have been initiated to treat plasma cell myeloma and B cell lymphomas. Although the expression of BCMA has been investigated in experimental models and cell lines, no clinical grade assays that can assess BCMA expression in routine clinical specimens, in particular, in decalcified formalin fixed paraffin embedded (FFPE) bone marrow biopsies, with high specificity and sensitivity have been established. Screening patients who may be appropraite candidates for BCMA targeted therapy is therfore challenging. Given the new therapies targeting BCMA, we developed and validated a clinical grade assay to assess BCMA expression on B and plasma cell malignancies on routine FFPE specimen in clinical practice.
Material and Methods: Total of 672 routine tissue and decalcified bone marrow biopsies were prospectively stained with anti-BCMA immunostain (Santa Cruz; Clone D6 Mouse Monoclonal Antibody) using standard methods. The cases included normal lymphoid tissues (n=45), B cell lymphoma (n=278), plasma cell neoplasms (multiple myeloma, n=162; plasmacytoma, n=13), other hematopoietic neoplasm and carcinomas (n=31 and 42, respectively). B cell lymphomas included low grade CLL/SLL, mantle cell lymphoma, marginal zone lymphoma and lymphoplasmacytic lymphoma and high grade lymphomas diffuse large B cell lymphoma (DLBCL), Burkitt and plasmablastic lymphoma. Sections from tonsils and reactive lymph nodes were used as a control. We developed a scoring system based on the predominant pattern (Golgi, membranous, Golgi and membranous), intensity (1+, 2+, 3+) and percentage (0-100%). We used >20% BCMA expression in the neoplastic cells as the positive cut off.
Results: In normal lymphoid tissues, BCMA expression was restricted to plasma cells and germinal center B cells. BCMA expression was not detected in other tissues (epithelium, T cells, dendritic cells and histiocytes/macrophages). BCMA showed a high level of expression in B cell lineage malignancies and plasma cell neoplasms. 97.1% cases of plasma cell neoplasms were positive for BCMA with predominant Golgi and membranous pattern and strong (3+) intensity. B cell neoplasms (DLBCL and low grade B lymphomas) predominately showed membranous pattern with 2-3+ staining intensity. High grade lymphomas (Burkitt and plamablastic lymphoma) showed strong (3+) intensity with both membranous and Golgi pattern. In DLBCL, both ABC and GCB subtypes expressed BCMA but there was no significant difference in the intensity and pattern of staining (ABC type=39.1% vs. GCB type=35.1%). Among follicular lymphomas no significant difference was observed between grade 1-2 and grade 3. Eight cases (87.5%) of Burkitt lymphoma and seven cases (100%) of plasmablastic lymphoma showed strong and diffuse BCMA expression (3+ intensity; membranous and Golgi pattern). T cell lymphoma, Hodgkin lymphoma and myeloid and lymphoblastic lymphoma/leukemia were negative for BCMA immunostain. The results are summarized in Table 1 and Figure 1.
Conclusion: This study shows broad expression of BCMA in a wide range of B and plasma cell neoplasms using a clinical grade assay, but not in normal tissues outside the lymphoid system or in other epithelial and hematopoietic neoplasms. BCMA expression is seen in many more B cell malignancies than previously recognized, including in a number of aggressive B cell neoplasms such as high grade B-cell lymphomas Burkitt and plasmablastic lymphomas. These findings suggest that the diseases that could be targeted by novel BCMA directed therapies are broader than previously realized. This assay will allow biomarker based selection of patients for BCMA targeted trials, and the semi-quantitative nature of the assay may allow the prediction of clinical outcomes for such therapies
Smith: Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: BCMA targeted CAR T cells, Research Funding. Dogan: Peer Review Institute: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Pharmaceuticals: Consultancy; Celgene: Consultancy.
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