P-381: Mezigdomide (CC-92480) activates innate and adaptive immune populations in the bone marrow microenvironment of heavily pre-treated multiple myeloma patients

Introduction: Mezigdomide (MEZI) is a novel cereblon E3 ligase modulator (CELMoD) that induces potent degradation of aiolos and ikaros. MEZI plus dexamethasone (MEZI+DEX) has demonstrated promising clinical efficacy in triple-class refractory multiple myeloma (MM) patients (pts) with ≥3 prior lines of therapy in the phase 1/2 study, CC-92480-MM-001. We report results from high-resolution mass-cytometry immune profiling of sequentially collected bone marrow (BM) samples from MM pts before and during MEZI+DEX treatment from part 1 and 2 of this study.

Methods: A CyTOF panel of 39 markers was used for in-depth immune-phenotyping of paired longitudinal BM aspirates from MEZI+DEX-treated MM pts at baseline and mid cycle 2 or 3 of treatment. Approximately 3.6 million cells were analyzed from 38 pts dosed with 0.8-1mg of MEZI for 14 or more days of a 28-day cycle. Detailed analyses of B, T and NK cell populations were conducted using both manual hierarchical gating and a computational R workflow.

Results: Significant changes within the BM tumour microenvironment (TME) were seen with MEZI+DEX treatment. Compared with baseline samples, on-treatment samples showed an increase in total NK (median 10.7% vs 16.5%, p=0.034) and NKT cells (median 7.6% vs 13.8%, p < 0.001). CD4 and CD8 effector memory (CCR7-CD45RA-) T cells increased on treatment (CD4 median 58.2% vs 73.9%, p < 0.001; and CD8 median 51.2% vs 71.1% p < 0.0001) with concurrent reductions in CD4 and CD8 central memory (CCR7+CD45RA-), naïve (CCR7+CD45RA+) and TEMRA (CD45RA+CCR7-) populations. Activated populations of T and NK cells also expanded on treatment. HLADR+ CD4 and CD8 T cells both increased more than three-fold (p < 0.0001), and significant increases in HLADR+ NK cells (median: 11.7% vs 17.9%, p=0.02) and ICOS+ CD4 T cells (median: 8.6% vs 14.1%, p< 0.001) were observed. Concurrently, T and NK cells showed a considerable reduction in the proportion of cells expressing the inhibitory markers KLRG1 (CD4 median 23.8% vs 15.8%, p=0.0016; CD8 median: 52.6% vs 41.0%, p=0.0013; NK median: 19.2% vs 14.9%, p=0.043) and TIGIT (CD8 median: 25.8% vs 8.2%, p< 0.0001; NK median: 18.1% vs 5.6%, p< 0.0001). Similar immune activation was observed regardless of number of prior lines of therapy and in pts refractory to pomalidomide or daratumumab.

Conclusions: MEZI+DEX significantly activates NK and T cells in the BM TME of heavily pre-treated triple-class refractory MM pts, suggesting an important immunomodulatory mechanism of action. Marked reduction of inhibitory markers, such as KLRG1 and TIGIT, was observed in T cells and NK cells suggesting a potential role for MEZI+DEX in addressing immune cell exhaustion and promoting transition to a cytotoxic TME phenotype. While further studies are required to interrogate the role of these activated immune populations in the clearance of MM cells, this data supports the potential of MEZI+DEX to enhance the activity of other immune redirecting therapies for the treatment of MM.