RRMM and Post-BCMA Treated Subjects from the CC-220-MM-001 Study Show Increased Genomic Aberrations Associated with High-Risk and Significant Dysfunction in CD4+ T-Cell Compartment Compared to NDMM Subjects

Introduction Outcomes for patients with multiple myeloma (MM) have improved significantly through development of novel therapeutics, including immunomodulatory agents (IMiDs ®), proteasome inhibitors, anti-CD38 monoclonal antibodies and new BMCA targeting T-cell redirecting therapies. While most MM patients respond well to initial therapy, over time their disease relapses, requiring several subsequent lines of treatment. However, how patient tumors and immune profiles evolve over lines of treatment and how this may impact the efficacy of subsequent treatment regimens remains poorly understood. CC-220-MM-001 is a multicohort, phase 1/2 trial (NCT02773030) studying the efficacy of iberdomide (CC-220; a cereblon [CRBN] E3 ligase modulator) as monotherapy, and in combination with other treatments in subjects with newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM), including patients who have received prior BCMA targeting agents. This study allows uniform comparison of immune and tumor biomarkers across these clinical patient segments. Methods Baseline samples collected in the CC-220-MM-001 study prior to iberdomide treatment included peripheral blood for immunophenotyping, bone marrow biopsies for immunohistochemistry and CD138+ enriched bone marrow aspirates for genomic analysis. Biomarkers were evaluated for differences between NDMM subjects and subjects refractory to IMiD agents, proteasome inhibitors, anti-CD38 antibodies, and BCMA targeting CAR-T and T-cell engager therapies. Results Analysis of immune profiles showed NDMM subjects had a less immunodeficient profile compared to RRMM subjects, particularly in the CD4+ compartment, with significantly more total and naïve CD4+ T-cells (p30% T-cells expressing activation markers (HLA-DR+ and ICOS+) and exhibiting a memory phenotype (CD45RO+). In contrast, a low proportion of pre-treatment T-cells were observed to be in a proliferative state (Ki-67+; median 6.2