P-003: Determinants of response to anti-CD38 and Bispecific combination therapy in patients with relapsed/refractory Multiple Myeloma

Introduction: The TRiMM2 study is an ongoing phase 1b study which combines anti-CD38 therapy with Bispecific antibody (BiAb) therapy. BiAb therapy has yielded response rates of over 70% in relapsed/refractory multiple myeloma (RRMM) patients, however a subset of patients do not maintain a durable response. Identifying predictive markers and the immune dynamics associated with treatment response and durability is an unmet need. Here, we investigated the immune profiles of MM patients receiving BiAb in combination with anti-CD38 therapy and analyzed their correlation with treatment outcomes.

Methods: We identified 27 RRMM patients enrolled in the TRiMM2 clinical trial that received BiAb in combination with anti-CD38 therapy. One third of patients (n=9) were on doublet therapy of BiAb and anti-CD38 therapy only while 67% patients (n=18) had the addition of Pomalidomide to theBiAb and anti-CD38 backbone. Of the 27 patients, 5 received Anti-BCMA BiAb and 22 received Anti-GPRC5D BiAb therapy. Prior to BiAb therapy, 52% of patients had progressed on previous T cell directed therapy (BiAb n= 6, or anti-BCMA CAR-T n=8) and 48% had progressed on other salvage therapies (n=13). Immune profiling was performed by high-dimensional spectral flow, focusing on T cell exhaustion, activation, and senescence markers. Patients were categorized based on their progression-free survival (PFS) duration with patients divided into < 6 months PFS and >6 months PFS groups.

Results: We profiled T cells in peripheral blood mononuclear cells (PBMCs), prior to initiation and during BiAb therapy. Patients with shorter PFS had higher presence of checkpoint inhibitors prior to the start of therapy. Specifically, these patients had a higher presence of PD1+CD8+ T cells (p=0.02) and TIGIT+ CD8+ T cells (p=0.04). Shorter PFS patients had more senescent CD4+ T cells co-expressing CD57+ and TIGIT compared to those with more durable responses (p=0.04). During BiAb therapy, patients with shorter PFS had a significant decrease in their white blood cell and lymphocyte counts not seen in responders (p< 0.01). Patients with greater PFS had a significant shift to an effector memory phenotype in both CD4+ and CD8+ T cells (p< 0.001) during therapy. In addition, these patients also showed a significant increase of activation markers on CD8+ and CD4+ T cells (p< 0.01) that was not present in patients with shorter PFS (p=0.23). Frequency of Tregs were significantly lowered during therapy in patients that had a durable response (p=0.017) that was not seen in patients that progressed within 6 months.

Conclusions: Our findings show that the state of T cells at baseline impacts the outcomes of BiAb therapy in RRMM patients. Patients with PFS of less than 6 months had an increase of checkpoint inhibitors on CD8+ T cells prior to treatment. During treatment, patients with a durable response had a decrease in Treg population and increased CD8+ and CD4+ T cell activation.