Pharmacodynamic Signatures and Correlatives of Response in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Talquetamab or Teclistamab Plus Daratumumab and Pomalidomide

Introduction: First-in-class bispecific antibodies (BsAbs) like talquetamab (tal; targeting G protein-coupled receptor class C group 5 member D) have shown deep, durable responses in RRMM. Targeting multiple epitopes with combination therapies may enhance antimyeloma activity. The anti-CD38 monoclonal antibody daratumumab (D) and immunomodulatory drugs (IMiDs) such as pomalidomide (P) are known to augment T-cell activity. D exhibits direct antitumor cytotoxicity, increases T-cell recruitment, and depletes CD38 immunoregulatory cells; P upregulates CD38 expression and increases natural killer (NK)-cell activity. We assessed immunologic pharmacodynamic profiles, correlatives of response, and associations with outcomes in patients (pts) treated with tal-DP from TRIMM-2 (NCT04108195) to better understand the potential of this regimen. Methods: Eligible pts had ≥3 prior lines of therapy, including a proteasome inhibitor (PI) and IMiD, or were double refractory to a PI and IMiD. Pts received tal 0.4 mg/kg weekly (QW) or 0.8 mg/kg biweekly (Q2W) with step-up dosing and approved schedules of D 1800 mg and P 2 mg. Peripheral blood samples collected at baseline (BL) and on treatment were analyzed by flow cytometry. Max-fold change was calculated per pt using the highest fold change relative to BL or cycle (C) 2 day 1 (when P was added to tal-D). Correlations with progression-free survival (PFS), duration of response (DOR), and best response groups (complete response [CR]/stringent CR [sCR], partial response [PR]/very good PR [VGPR], and stable disease [SD]/progressive disease [PD]) were performed. Results: Samples from 77 pts in TRIMM-2 were analyzed (tal QW, n=18; tal Q2W, n=59; CR/sCR, n=37; VGPR/PR, n=24; and SD/PD, n=6). Tal-D showed complementary pharmacodynamic effects, including T-cell margination, increased absolute T-cell recovery, expanded effector memory, and decreased naive-CD8 T cells during the first C, which were enhanced after addition of P in C2. While D treatment led to an initial reduction in CD38+ CD8 T cells, addition of tal transiently induced activation of this subset despite concurrent D dosing. After P administration, reinduction of CD38 on CD8 T cells was observed, indicating T-cell restimulation. D reduced immunosuppressive CD38+ regulatory T cells (Tregs), and addition of P rescued NK cells reduced by D. A subgroup analysis showed a pronounced impact of tal-DP on pts with prior BsAb exposure. Although a more dysfunctional, exhausted T-cell phenotype at BL was identified in these pts, tal-DP led to greater CD8 T-cell expansion, NK-cell recovery, CD38+ T-cell activation, and reduction of CD38+ Tregs vs pts without prior BsAb exposure. BL response signatures showed higher CD8 T-cell counts and lower expression of T-cell activation/coinhibitory receptor expression on CD8 T cells (CD38, PD-1/LAG-3, and PD-1/TIM-3) in pts with deeper responses that also demonstrated trends associated with improved PFS and DOR. Longitudinal correlative analyses showed greater, earlier recovery of absolute CD8 T cells in deeper responders to tal-DP that correlated with longer PFS and DOR, particularly following addition of P. NK-cell reduction was comparable across all response groups after tal-D; however, pts with deep responses exhibited NK-cell recovery after P was added, which was not evident in pts with less deep or no responses. Although D addition initially reduced CD38+ CD8 T cells, pts with deeper responses showed greater induction of CD38+ CD8 T-cell activation after addition of tal, which was sustained following P administration; in contrast, nonresponding pts displayed a shorter reactivation of CD38 T cells after P. Higher max-fold change in absolute NK-cell counts and CD38+ CD8 T cells showed trends toward improved PFS and DOR, notably in C2 after the addition of P. Finally, less persistent expression of coinhibitory receptors on CD8 T cells was observed in pts with deep responses, while a reduction in CD38+ Tregs was seen in all pts with tal-DP. Preliminary results with teclistamab (tec)-DP show comparable results to tal-DP, and further analyses are ongoing. Conclusions: Tal-DP exhibits a deep, long-term impact on efficacy through complementary mechanisms of action and may be especially beneficial in pts with prior BsAb exposure, who typically have unfavorable BL immune profiles. Ongoing analyses of tec-DP from MajesTEC-2 (NCT04722146) will be presented.