Novel Antigens LMA and Kma Are Expressed on Malignant Bone Marrow Plasma Cells from Patients with Relapsed Refractory Multiple Myeloma and Plasma Cell Dyscrasias

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Introduction Previous studies have identified the lambda myeloma antigen (LMA) and kappa myeloma antigen (KMA) on the surface of malignant plasma cells in myeloma patient bone marrow samples, human myeloma cell lines and other plasma cell dyscrasias1-3. LMA and KMA are not present on normal B cells and are found on occasional mononuclear cells in tonsillar tissue and secondary mucosal lymphoid tissue. Targeting KMA and LMA through cellular and other immunological therapies has the potential advantage of leaving a population of normal plasma cells untouched and minimising the risk of serious post-treatment infection. Characteristics of the antibodies called KappaMab and LambdaMabs (10B3 and 7F11) that bind to specific conformational epitopes in the constant regions of these surface-bound light chains have been described in clinical trials and in vitro experiments1, 2, 4-6. Here, we present data on a larger series of patients with plasma cell dyscrasias, demonstrating the expression of LMA on plasma cells from patients in whom myeloma evolves from monoclonal gammopathy of unknown significance (MGUS). We also describe the difference in phenotype between LMA and KMA expressing malignant plasma cells and the frequent expression of KMA in relapsed refractory myeloma patient (RRMM) samples. Methods Patient BM samples (κ=49 and λ=31) 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. Plasma cells were identified as previously described by initial gating using CD38 and CD138. LMA and KMA expression was determined and compared with the other cell markers. Results Nine of 12 (75%) newly diagnosed λ-type patients with MGUS or SMM expressed LMA on the surface of BM plasma cells. Longitudinal data from two patients was available. One patient showed LMA expression and antigen density increasing on the surface of bone marrow plasma cells during progression from MGUS (2020) to smoldering myeloma (SMM) (2022) (% of plasma cells positive for LMA rose from 61% to 92%, antigen density increased from 532 to 5164 molecules of PE/cell). In a second individual, LMA expression and antigen density increased on bone marrow plasma cells during progression from SMM (2020) to myeloma (2022) (% of plasma cells positive for LMA rose from 94% to 100%, antigen density increased from 3981 to 8941 molecules of PE/cell). KMA expression continued to be observed on plasma cells in 4 of 6 patients after autologous stem cell transplant. KMA was expressed in 86% of patients with ĸRRMM (n=14). LMA expression was observed in 2 of 4 patients with λRRMM. Both KMA and LMA antigen densities were higher than BCMA in the RRMM population (KMA mean 1802, range 468-7943 vs BCMA mean 1306, range 350-2630 molecules of PE/cell), (LMA mean 2439, range 263-6664 vs BCMA mean 817, range 537-1065 molecules of PE/cell). Conclusions In an enlarged cohort of patients with myeloma, we have confirmed that KMA and LMA are expressed at all stages of disease. Our data examining longitudinal expression in individual patients suggests that expression of LMA on BM plasma cells increases from MGUS to MM. The majority of patients with relapsed refractory kappa myeloma expressed KMA. Further data is required to confirm LMA expression in this population. The antigen density of both LMA and KMA is higher than BCMA on RRMM BM plasma cells. KMA and LMA expression is independent of serum Ig and FLC levels and % marrow plasma cells. These data show that KappaMab and LambdaMab have therapeutic potential in the treatment of myeloma patients, especially in the setting of relapsed refractory disease where the combination of high antigen density and restriction of the target antigen to the malignant subpopulation of plasma cells will confer valuable clinical benefit.