The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models

Abstract

We investigated here the novel immunomodulation and anti–multiple myeloma (MM) function of T cells engaged by the bispecific T-cell engager molecule AMG 701, and further examined the impact of AMG 701 in combination with immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide). AMG 701 potently induced T-cell–dependent cellular cytotoxicity (TDCC) against MM cells expressing B-cell maturation antigen, including autologous cells from patients with relapsed and refractory MM (RRMM) (half maximal effective concentration, <46.6 pM). Besides inducing T-cell proliferation and cytolytic activity, AMG 701 also promoted differentiation of patient T cells to central memory, effector memory, and stem cell–like memory (scm) phenotypes, more so in CD8 vs CD4 T subsets, resulting in increased CD8/CD4 ratios in 7-day ex vivo cocultures. IMiDs and AMG 701 synergistically induced TDCC against MM cell lines and autologous RRMM patient cells, even in the presence of immunosuppressive bone marrow stromal cells or osteoclasts. IMiDs further upregulated AMG 701–induced patient T-cell differentiation toward memory phenotypes, associated with increased CD8/CD4 ratios, increased Tscm, and decreased interleukin 10–positive T and T regulatory cells (CD25highFOXP3high), which may downregulate T effector cells. Importantly, the combination of AMG 701 with lenalidomide induced sustained inhibition of MM cell growth in SCID mice reconstituted with human T cells; tumor regrowth was eventually observed in cohorts treated with either agent alone (P < .001). These results strongly support AMG 701 clinical studies as monotherapy in patients with RRMM (NCT03287908) and the combination with IMiDs to improve patient outcomes in MM.

Harnessing the Immune System Against Multiple Myeloma: Challenges and Opportunities

“…Specifically, AMG 701 holds an extended half-life in vivo and mediates T-cell dependent cellular cytotoxicity (TDCC) of BCMA positive MM cells and is currently under clinical investigation (NCT03287908). We have also shown that MM cytotoxicity can be augmented at lower effector: tumor cell ratios when low doses of AMG 701 are combined with lenalidomide or pomalidomide, suggesting a favorable therapeutic index ( 70 ). Although early results look promising and both ADC and Bites approaches have the advantage for “off the shelf” availability, longer follow-up in larger studies is needed to assess their clinical efficacy and toxicity.…”

Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies

“…The combination therapy with PD-1 blockers resulted in synthetic effects [ 109 ]. Immunomodulatory imide drugs including lenalidomide and pomalidomide could make AMG 701 more potent in xenograft models [ 110 ]. Phase I clinical trials of AMG 701 in patients with R/R MM are being conducted.…”

Boosting Immunity against Multiple Myeloma

“…This BiTE has an extended half-life and has showed strong encouraging results [ 100 ]. A trial is currently recruiting RR MM patients to receive this therapy either as monotherapy or in combination with IMIDs (e.g., pomalidomide) and with or without dexamethasone (NCT03287908) [ 101 ]. BI 836909 is another T cell engager that has demonstrated successful in vivo anti-myeloma activity [ 102 ].…”