KAPPA MYELOMA ANTIGEN (KMA) AND LAMBDA MYELOMA ANTIGEN (LMA) ARE EXPRESSED ON B CELL MALIGNANCIES AND ARE PROMISING NOVEL TARGETS ON MALIGNANT PLASMA CELLS

Abstract

Introduction: The kappa myeloma antigen (KMA) and the lambda myeloma antigen (LMA) are found on the surface of malignant plasma cells (PCs) in multiple myeloma (MM), other plasma cell dyscrasia patient bone marrow (BM) samples, human myeloma cell lines and in patient BM samples from plasmacytomas, lymphoplasmacytoid and B cell lymphoproliferative disorders (BLPD). KMA and LMA are not present on normal B cells in BM but are found on occasional mononuclear cells in tonsillar tissue and secondary mucosal lymphoid tissue. KappaMab is a therapeutic antibody that specifically targets KMA and a phase IIb study in combination with lenalidomide and dexamethasone has recently been completed. In early clinical trials, KappaMab was shown to have an excellent safety profile, with low-grade infusion-related reactions and no haematological toxicities. Two human therapeutic LambdaMabs (10B3 and 7F11) bind specifically to LMA expressed only on malignant cells in lambda restricted B cell diseases. Here we compare the expression of KMA and LMA to that of BCMA in MGUS, newly diagnosed MM and relapsed, refractory (RRMM) myeloma BM samples. We describe the difference in phenotype between KMA and LMA expressing malignant PCs and their enrichment in RRMM compared to early disease stages. Methods: Patient BM samples (κ = 70 and λ = 40) were analysed using multiparametric FCM immunophenotyping with APC labelled LambdaMab (10B3) and KappaMab Fab’2 fragments, CD38, CD138, CD269 (BCMA), CD319 (SLAM F7), CD56 and CD45 monoclonal antibodies. PCs were identified by initial gating using CD38 and CD138. LMA and KMA expression was determined and compared with the other cell markers. Results: KMA was expressed on the majority of kappa restricted BM PCs from MGUS through to RRMM, on lymphoplasmacytoid cells in 2 out of 3 BM samples and in all 4 plasmacytoma BM samples. LMA was expressed on the surface of BM PCs in lambda restricted MGUS through to RRMM and in all 4 AL amyloidosis BM samples. KMA and LMA antigen densities were both higher than BCMA in the RRMM population: KMA mean 1899 (range 468–7943) versus BCMA mean 1426 (range 350-2630) and LMA mean 2439 (range 263–6664) versus BCMA mean 817 (range 537–1065) molecules of PE/cell. Conclusions: Although there are smaller numbers of samples from other B cell malignancies such as lymphoplasmacytoid, amyloidosis and BLPDs, we have demonstrated that KMA or LMA are expressed on malignant BM PCs. In the myeloma cases, the antigen density of both KMA and LMA was increased compared to BCMA on RRMM BM PCs, which suggests a clonal advantage of KMA and LMA expressing plasma cells that are resistant to standard of care treatments. These data suggest that KappaMab and LambdaMabs have therapeutic potential in RRMM where the combination of high antigen density and restriction of the target antigen to the malignant subpopulation of PCs may confer clinical benefit by retaining normal plasma cells following treatment. Keywords: Immunotherapy, Multiple Myeloma Conflicts of interests pertinent to the abstract D. Gottlieb Consultant or advisory role David sits on the Scientific Advisory Board for HaemaLogiX Ltd. R. Dunn Employment or leadership position: Employee at HaemaLogiX Ltd. Stock ownership: Yes