Phase 1 study combining elotuzumab with autologous stem cell transplant and lenalidomide for multiple myeloma

Abstract

Background: Autologous stem cell transplantation (ASCT) after induction therapy improves disease-free survival for patients with multiple myeloma (MM). While the goal of ASCT is to render a minimal disease state, it is also associated with eradication of immunosuppressive cells, and we hypothesize that early introduction of immunotherapy post-ASCT may provide a window of opportunity to boost treatment efficacy.

Methods: We conducted a phase 1 clinical trial to investigate the application of autologous lymphocyte infusion and anti-SLAMF7 monoclonal antibody, elotuzumab, after ASCT in patients with newly diagnosed MM previously treated with induction therapy. In addition to CD34+ stem cells, peripheral blood mononuclear cells were harvested prior to transplant and infused on day 3 after stem cell infusion to accelerate immune reconstitution and provide autologous natural killer (NK) cells that are essential to the mechanism of elotuzumab. Elotuzumab was administered starting on day 4 and then every 28 days after until 1 year post-ASCT. Cycles 4-12 were administered with standard-of-care lenalidomide maintenance.

Results: All subjects were evaluated for safety, and 13 of 15 subjects completed the treatment protocol. At 1 year post-ASCT, the disease status of enrolled subjects was as follows: five stringent complete responses, one complete response, six very good partial responses, one partial response, and two progressive diseases. The treatment plan was well tolerated, with most grade 3 and 4 AEs being expected hematologic toxicities associated with ASCT. Correlative analysis of the immune microenvironment demonstrated a trend toward reduced regulatory T cells during the first 3 months post-transplant followed by an increase in NK cells and monocytes in patients achieving a complete remission.

Conclusions: This phase 1 clinical trial demonstrates that early introduction of immunotherapy after ASCT is well tolerated and shows promising disease control in patients with MM, accompanied by favorable changes in the immune microenvironment.

Trial registration number: NCT02655458.

Keywords: hematologic neoplasms; immunotherapy; transplantation immunology; tumor microenvironment.

Figure 1

Study design and correlative analyses. Created with BioRender.com. BMMC, bone marrow mononuclear cell; PBMC, peripheral blood mononuclear cell; TCRß, T cell receptor beta. CyTOF, cytometry by time-of-flight.

Figure 2

Depth of treatment response. Kaplan-Meier survival curve of progression-free survival (A) and overall survival (B) for the entire study cohort (n=15). (C) Overall response rate by IMWG response criteria. (D) Change in MM disease biomarkers at diagnosis, screening, day 90, and day 365. CR, complete response; PD, progressive disease; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.

Figure 3

Bone marrow immune composition among study participants at screening, day 90, and day 365. Volcano plots showing differentially abundant immune cells from the comparison of patients achieving ≥CR to ≤VGPR at screening, day 90, and day 365. CR, complete response; VGPR, very good partial response.

Figure 4

Differential expression analysis of cytometry by time-of-flight markers by cell type. (A) Dots are shown if Wilcoxon rank-sum test p<0.05 and log2(fold change) <0.3 or <−0.3. Blue denotes markers with increased expression in patients achieving ≥CR, while red indicates markers with decreased expression in patients achieving ≤VGPR. (B) Percentage of plasma cells and normalized programmed death-ligand 1 (PD-L1) expression on plasmablasts across all time points. (C) Percentage of cells expressing SLAMF7 by cell type. CR, complete response; VGPR, very good partial response.

Figure 5

Bone marrow immune secretory protein composition among study participants at screening, day 90, and day 365. (A) Heatmap of Olink normalized protein expression (NPX) among patients achieving ≥CR and ≤VGPR. (B) Volcano plots showing differentially abundant proteins from a comparison of patients achieving ≥CR to ≤VGPR at screening and day 365. Proteins with Wilcoxon rank-sum p<0.1 and log₂(fold change) >0.1 or <−0.1 are highlighted in red. CR, complete response; GZMB, granzyme B; KLRD1, killer cell lectin-like receptor D1; NOS3, nitric oxide synthase 3; VGPR, very good partial response

Figure 6

Peripheral blood T cell receptor beta (TCRβ) dynamics among study participants at screening and day 365. (A) Bhattacharyya coefficient comparing the TCRβ repertoire similarity per patient between screening and day 365 time points. A higher value indicates a greater number of shared TCRβ sequences between time points. (B) Gini coefficient comparing the diversity of the TCRβ repertoire at screening and day 365. A lower value indicates greater diversity of TCRβ sequences. (C) The percentage of TCRβ sequences that are significantly expanding or contracting per patient between screening and day 365. CR, complete response; VGPR, very good partial response.