OA-09: Combination of forimtamig with standard of care improves depth and duration of response in preclinical models of multiple myeloma

Introduction: Forimtamig (forimtamig) is a 2:1 GPRC5D T cell bispecific antibody with high clinical response rates of > 60% in relapsed or refractory multiple myeloma (MM) patients. .

Methods: Here, we highlight the therapeutic potential of combining forimtamig with standard of care (SoC) agents in MM using clinically relevant ex vivo and in vivo models of myeloma

Results: We combined forimtamig with carfilzomib, daratumumab and/or pomalidomide in bone marrow aspirate samples from MM patients. Tumor lysis increased 2-fold from 40% to 80% when forimtamig was combined with daratumumab or with daratumumab and pomalidomide while combination with pomalidomide or carfilzomib showed no further increase in response. Antitumor effects were associated with increase of CD69 and PD-1 on CD8+ T cells and secretion of IFNg, MIP1a and granzyme A. Activation of CD8+ TILs was increased in combination with pomalidomide as shown by a 4-fold increased cytokine release and elevated surface expression of CD137 and CD25 compared to forimtamig alone. Forimtamig induced activation of NK cells, as measured by CD25 and CD107a expression which was increased 3-fold in combination with daratumumab and increased further for the triple combination with pomalidomide. A combination with carfilzomib did not change the activation status of autologous TILs or NK cells.
Next, we explored any effect of SoC combinations on depth and durability of response in tumor-bearing humanized mice using a fixed duration schedule. Combination with pomalidomide resulted in faster onset of regressions in 20% of mice and increased tumor cell lysis (65% vs 45%) at the end of cycle 1 (C1). However, the progression free survival (PFS) rate of 53% achieved by forimtamig monotherapy at 3 weeks after last dosing was not improved overall. Although daratumumab combination had no impact on the depth of early responses, the PFS rate increased by 10%. carfilzomib induced rapid onset of regressions in 70% of mice in C1 and showed the highest PFS rate of 70%. To test potential effects of SoC combinations on cytokine release syndrome (CRS), we measured cytokine levels in serum of mice 48h after treatment initiation. In line with our ex vivo results, pomalidomide combination further increased serum levels of IFNg, IL2 and TNFa compared to forimtamig alone while daratumumab induced only a moderate increase of TNFa. In contrast, we observed a slight decrease in cytokine release in combination with carfilzomib.

Conclusions: Synergistic anti-tumoral and NK stimulatory effects suggest a benefit of daratumumab combination in patients with high tumor burden and high risk of developing CRS. Broad immunomodulatory effects of pomalidomide could help sustain T cell responses in patients but may increase the risk of CRS. Considering the importance of balancing CRS and efficacy, carfilzomib was identified as another promising combination partner for forimtamig.