Assistant Professor The University of Texas MD Anderson Cancer Center Houston, Texas, United States
Introduction: Smoldering multiple myeloma is a heterogeneous disease in which patients with high-risk (HRSMM) stratification have high rates of progression to MM, making them suitable candidates for early intervention. Isatuximab, a selective anti-CD38 monoclonal antibody, is currently approved in two combination regimens for relapsed and/or refractory myeloma where, it improved progression free survival over standard of care. Here, we aimed to investigate the impact of single agent Isatuximab in the bone marrow immune microenvironment of HRSMM patients.
Methods: Patients with HRSMM (based on immunoparesis and ≥95% immunophenotypically abnormal marrow plasma cells) treated in stage 1 of the ISAMAR study with isatuximab monotherapy (NCT02960555) with available formalin-fixed paraffin embedded tissue (FFPE) bone marrow biopsies were included in the study. A previously optimized and validated multiplex immunofluorescence (mIF) panel was developed to assess plasma cells (CD138), macrophages (CD68), immune checkpoints (PD-1, PD-L1), and subsets of T-cells (CD3, CD8, Foxp3, CD45RO). The slides were imaged using Vectra Polaris system (Akoya Biosciences, Marlborough, MA) and the whole tissue was selected for the analysis, and data was consolidated using Spotfire software. Differences in cell densities among different treatment time points: baseline, post-cycle 6 (pC6), post-cycle 18 (pC18), and end of treatment/post-cycle 30 (EOT) were evaluated with Kruskal-Wallis test using SAS Enterprise Guide 7.1.
Results: Eighteen of 24 patients had available samples. Most patients were female (11/18, 61%), white (16/18, 88%) and had kappa light chain restriction (16/18, 88%). After a median follow-up of 40 months (range: 11-56 months), two patients had complete response, thirteen partial response and two had stable disease. Two patients died of other causes. Efficacy and toxicity were previously reported (Blood (2019) 134 (Supplement_1): 3116.). Sixty samples with a median area of 1.85 mm2/case and a median number of 8947 cells/case were analyzed by mIF. When comparing different time points of treatment, cases pC6 and EOT had a had a significantly lower cell density of total CD138+ cells (p= 0.0002), though the residual plasma cells had significantly higher staining for CD138+/PD-L1+ (p < 0.0001). Also, there were higher levels of total CD3+ (p < 0.0001), CD3+/PD-1+ (p < 0.0001), CD3+/CD8+ (p < 0.0001), CD3+/Foxp3+/CD8- (p= 0.018), CD3+/CD45RO+ (p < 0.0001), CD3+/CD45RO+/CD8+ (p < 0.0001), CD3+/CD45RO+/CD8- (p=0.0002), and CD68+/PD-L1+ (p < 0.0001). Interestingly, among the patients with partial response only, except for CD3+/Foxp3+/CD8-, pC6 and EOT time points also showed the same statistically significant differences in the immune populations.
Conclusions: Isatuximab promotes significant immune activation in the bone marrow of patients with HRSMM, characterized by upregulation of different subsets of T-cells, and PD-L1+ plasma cells and macrophages.
