P-064: Heterogeneity of bone marrow biopsy and bone marrow aspirate (BMA) in patients with heavily pretreated relapsed/refractory Multiple Myeloma (RRMM)

Background Despite new regimens approved for RRMM, patients still relapse, and new therapies are needed. T-cell directed therapies that target bone marrow plasma cells (BMPCs), including CD3 bispecific antibodies, have shown promise for the treatment of RRMM. REGN5458, a B-cell maturation antigen (BCMA) xCD3 bispecific antibody, demonstrated an acceptable safety and tolerability profile with early, deep, and durable efficacy in heavily pretreated and triple refractory patients with RRMM [1]. Aim To elucidate disease aspects amenable to T-cell-directed therapies targeting plasma cells, such as REGN5458, we characterized the plasma and immune composition of baseline BMA and core biopsies from patients with RRMM, and evaluated relationships between bone marrow profile, secretory measures of disease, and response. Methods Patients with progressive RRMM (triple refractory or intolerant to prior lines of systemic therapy, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody), were treated with REGN5458 (NCT03761108). Matched BMA and biopsy samples obtained at screening were analyzed by multiplex immunohistochemistry (IHC, N=48) and multiparameter flow cytometry (N=81). Cell numbers and phenotypes were correlated to secretory measures of disease, including serum M-protein, immunoglobulin-free light chain (FLC) assays and R-ISS staging. Results Biopsy analysis revealed a variable BMPC burden in RRMM patients. Median percentage of BMPCs by CD138 IHC was 22.5% (range 1–95%). There was no correlation between BMPC burden and serum M-protein levels, but a modest correlation between BMPC burden and serum FLC (rho=0.66; p=0.01). The majority of CD138 biopsy BMPCs in RRMM patients expressed BCMA by IHC; levels varied between patients (median BCMA+ H scores: 45 and 200 for membrane and cytoplasmic staining). BCMA IHC expression was not associated with IMWG response to REGN5458,1 and did not correlate with soluble BCMA levels at study initiation. BMA analysis by flow cytometry revealed variable levels of abnormal BMPCs in patients with RRMM (median: 2.2% [range 0–68.7%]). BCMA expression was variable in all BMPCs; 53.1% of patients had higher BCMA staining intensity relative to CD38: ratios ranged from 1.2–6.6. Frequency of CD3+ T-cells in CD45+ BMA from RRMM patients ranged from 1.0–63.5%. Preliminary analysis suggests a higher frequency of T cells in R-ISS stage I compared to stage II. T-cell subset distribution in BMA from patients with RRMM reflected low CD8 TCM (5.0%) and predominantly TEM (37.0%) and TEMRA (41.0%). Conclusions Analyses of matched BMA and biopsy samples from heavily pretreated RRMM patients, reveal that most BMPC express BCMA, though soluble vs membrane-bound BCMA levels are heterogenous. Diversity in immune and plasma cell markers and subsets is also observed. Ongoing analyses include correlations of plasma and immune cell profile with response to T-cell-targeting therapies such as REGN5458.