Belantamab Mafodotin Exhibits No Evidence Of Immune Cell Impairment

Topic: Myeloma and other monoclonal gammopathies — Biology & translational research

Background:Belantamab mafodotin (belamaf) is a B-cell maturation antigen (BCMA) targeted antibody-drug-conjugatewith mechanisms of action against multiple myeloma (MM) cells including antibody-dependent cellularcytotoxicity and phagocytosis, and immunogenic cell death. Commonly in MM, immune dysfunction resultsfrom the bone marrow microenvironment: exhausted T cell populations may affect responses to bispecificantibodies1 and bispecifics may lead to T cell exhaustion.2 Previous work suggests belamaf may not impair T ornatural killer (NK) cell function, which could have important implications on treatment sequencing in MMand/or using combinations of anti-BCMA therapies and other agents that rely on unimpaired T cell function forefficacy.

Aims:This post-hoc analysis aimed to determine the impact of belamaf (±nirogacestat, a gamma secretase inhibitorthat inhibits cleavage of membrane-bound BCMA) on immune cell populations including peripheral T and NKcell phenotypes in patients with relapsed/refractory MM(RRMM).

Methods:Samples were collected in the randomized, Phase 1/2, open-label, platform design DREAMM-5 study ofbelamaf in novel combinations and as monotherapy in patients with RRMM. DREAMM-5 Substudy 3 evaluatesbelamaf IV at variable doses and schedules in combination with nirogacestat 100 mg BID. Multicolor flowcytometric analysis of T and NK cells in peripheral blood of patients treated with combination therapy wasperformed. Phenotypes were evaluated using markers including the exhaustion marker programmed cell deathprotein-1 (PD-1), the coinhibitory marker TIGIT, and the activation markers Granzyme B (GZMB) and CD107a.Cell cycling capacity was assessed by Ki67 expression. Additionally, neutrophil-to-lymphocyte ratio and totallymphocyte counts were analyzed via complete blood count and differential counts in patients treated withmonotherapy or combination therapy. Data analysis was post-hoc.

Results:Immune cell subtypes and phenotypes were characterized using multiple cell surface markers. CD4+/CD8+ Tcells and NK cells from patients treated with belamaf 1 mg/kg or 1.4 mg/kg (Cycle 1 Q4W, Cycle 2+ Q8W)+nirogacestat showed no increase in expression from baseline in exhaustion marker PD-1 or coinhibitorymarker TIGIT, and cell cycling capacity was maintained as demonstrated by detectable Ki67 expression on allthree cell types over time. Furthermore, retention of immune cell activity was observed, as evidenced by theexpression of GZMB and CD107a on CD4+/CD8+ T cells and on NK cells.Analysis of patients treated with a combination of belamaf 0.95 mg/kg Q3W +nirogacestat or belamaf 2.5mg/kg Q3W monotherapy showed no meaningful change from baseline in lymphocyte count or neutrophil-to-lymphocyte ratio, with immune cell profiles remaining similar and consistent over time.

Summary/Conclusion:Belamaf had no negative impact on immune cell populations and did not, unlike bispecific antibodies2, lead toexhaustion of circulating immune cells, with evidence that immune cells maintained their activation, cyclingcapacity, and overall frequency with belamaf (±nirogacestat). These results provide a foundation for theongoing optimization of therapy sequencing, ensuring maximized patient benefits in MM where immunedysfunction is prevalent.1Friedrich et al. Cancer Cell;2023:41:711–7252Philipp et al. Blood;2022:140(10)1104–1118

Funding: GSK (Study 208887, NCT04126200). Drug linker technology licensed from Seagen Inc.; monoclonalantibody produced using POTELLIGENT Technology licensed from BioWa. Nirogacestat provided under clinicalcollaboration agreement with SpringWorks Therapeutics, Inc.

Keywords: Natural killer, B-cell maturation antigen, Multiple myeloma, T cel

https://clin.larvol.com/abstract-detail/EHA 2024/70979582