Elotuzumab-Iberdomide-Dexamethasone Combination Therapy Activates T and NK Cells within the Immune Microenvironment of Multiple Myeloma Patients

Background

Elotuzumab, a monoclonal antibody targeting SLAMF7 on multiple myeloma (MM) cells, augments immune-mediated cytotoxicity through the direct activation of NK cells. Addition of Elotuzumab to immunomodulatory drugs (IMiDs) has been shown to improve progression-free survival of MM patients compared to IMiDs alone. We have recently described the immune-stimulatory effects of cereblon E3 ligase modulators (CELMoDs) on the tumour microenvironment (Oekelen et al, Cell Reports Medicine 2024, Chen et al ASH 2023). Here, we report the detailed peripheral blood (PB) and bone marrow (BM) immunophenotypic characteristics of relapsed refractory (RR) MM patients treated as part of the phase 1 Elotuzumab-Iberdomide-Dexamethasone (Elo-Iber-Dex) clinical trial.

Methods

We characterized paired screening and treatment (C2D15) CD138-negative samples from bone marrow (n=5) and peripheral blood (n=6) of 6 RRMM patients treated with Elo-Iber-Dex as part of the phase 1 clinical trial (NCT05560399), using a custom-designed immune-focused spectral flow cytometry panel. As part of the trial, patients received Elotuzumab 10mg/kg weekly for cycles 1-2 then 20mg/kg 4-weekly, Iberdomide 1.0mg-1.3mg once daily for 21 days per 28-day cycle, and Dexamethasone 40mg once weekly. Immune population frequencies are reported as median percentage of the parent population.

Results

The median age of our cohort was 68 years (range 53 to 76 years) and median number of prior therapy lines was 3 (range 2 to 6). Two patients were classified as high-risk by ISS and cytogenetics at diagnosis. Of the 6 treated patients thus far, partial response (PR) or better was achieved in 3 patients (complete response (CR), n=1; very good partial response (VGPR), n=1; PR, n=1).

Most peripheral blood (PB) and bone marrow (BM) immune population frequencies, including, overall monocyte, T cell and NK cell populations remained stable on treatment. Similar to previous CELMoD studies, a trend toward increased activated immune cell populations was seen, with HLADR-positive CD4 T cell populations increasing from 6.36% to 14.6% (p=0.031) in PB and 6.22% to 14.9% (p=0.31) in BM. Compared to baseline, a noticeable increase in effector memory (CD45RA-CCR7-) CD8 T cells was seen on treatment, from 33.2% to 79.3% (p=0.094) in PB and 32.2% to 56% (p=0.31) in BM. Furthermore, an increase in Ki67-positive NK cells from 3.06% to 17.6% (p=0.094) in PB and 13% to 31.5% (p=0.062) in BM was observed. CD16-bright CD56-dim cytotoxic NK cells also increased on treatment from 19.6% to 61% (p=0.094) in PB and 42.2% to 58% (p=0.31) in BM, whilst CD16-positive CD56-negative NK cells significantly reduced from 58.4% to 7.53% in PB (p=0.031) and 16.7% to 2.26% in BM (p=0.12). The proportion of cytotoxic NK cells that were Ki67-positive also increased from 3.5% to 7.94% (p=0.31) in PB and 5.78% to 26.2% (p=0.062) in BM.

Patients who received Daratumumab (n=4) as part of their latest line of therapy had a lower proportion of CD16-bright CD56-dim cytotoxic NK cells (18.5%) in PB at baseline compared to patients (n=2) who had not recently receive an anti-CD38 monoclonal antibody (47.7%). On treatment, a near two-fold increase in the proportion of cytotoxic NK cells in PB was seen in both groups (18.5% to 45.2% Daratumumab, 47.7% to 88.6% no Daratumumab), suggesting Elo-Iber-Dex is, to some degree, able to augment NK cell activity in the context of recent anti-CD38 therapy.

Conclusion

Albeit with a small sample size, our initial immunophenotypic analyses demonstrate trends of T and NK cell activation in both PB and BM of MM patients treated with Elo-Iber-Dex. Of note, an increase in activated CD4 T cell populations, effector memory CD8 T cell populations and CD16-bright cytotoxic NK cell populations was observed on treatment, concordant with the known immune-stimulatory effects of both Elotuzumab and Iberdomide. Further functional studies are required to elucidate the possible synergistic effects on T and NK cell activation that may occur with combined CELMoD and SLAMF7 monoclonal antibody treatment.

Amatangelo:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Nevers:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Sun:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pierceall:Bristol Myers Squibb: Ended employment in the past 24 months. Kappes:GRAIL, Inc.: Research Funding. Jagannath:Janssen, BMS, Caribou, Legend Biotech, Regeneron, Takeda, Sanofi, Posieda Therapeutics, GRAIL: Consultancy; IMS and SOHO: Membership on an entity's Board of Directors or advisory committees. Rodriguez:Amgen, BMS, Janssen, Karyopharm, Sanofi, Artiva: Consultancy; BMS, Janssen, Sanofi, Artiva: Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, BMS, Teneobio: Research Funding.