Nivolumab-Based Salvage Therapy to Restore T Cell Fitness in Penta-Refractory Multiple Myeloma with Relapse to Anti-BCMA CAR T Cell Therapy

Background: Idecabtagene Vicleucel (ide-cel) is the first FDA-approved BCMA-directed CAR T cell therapy for the treatment of relapsed/refractory multiple myeloma (RRMM). Despite remarkable activity of 85% objective response rate and a progression-free survival (PFS) of 11.8 months reported in the CRB-401 trial (NCT02658929), most responses to ide-cel are not durable, and nearly all patients (pts) eventually relapse, even those achieving MRD-negative complete remission (CR). Factors associated with clinical relapse to ide-cel include BCMA loss, lack of CAR T persistence, T-cell exhaustion and PD-1/ PD-L1 impaired T-cell fitness. Here, we report clinical data and correlative findings for 4 pts who were salvaged with a nivolumab (anti-PD1)- based triplet therapy at the time of clinical relapse to first or second ide-cel infusion. Methods: Four pts with penta-refractory RRMM were treated as part of the CRB-401 phase 1 study as previously reported (Raje et al.N Engl J Med.2019;380:1726-37). All pts received nivolumab along with lenalidomide-dexamethasone (Nivo-Rd) or pomalidomide-dexamethasone (Nivo-Pd) at the time of relapse to ide-cel. CD3+ T cells (n=1,047) were isolated from the peripheral blood of 2 of these pts and full-length single-cell RNA sequencing (scRNA-seq) was conducted before and upon treatment with Nivo-Rd/-Pd. Response rates were assessed as per IMWG criteria. Results: The median age of pts was 48.5 years (range 37-56). Two out of 4 pts had cytogenetic high-risk MM and all pts were penta-refractory at the time of CRB-401 study inclusion. The median PFS and OS after first ide-cel infusion were 10.4 (range 3.0-13.8) months and 21.5 (range 16.0-34.6) months, respectively. Three pts received a second ide-cel infusion, whereof only 1 pt achieved a partial response (PR) at a PFS of 5.2 months. Two pts each were treated with Nivo-Rd and Nivo-Pd respectively at the time of progression to ide-cel. Responses to anti-PD1- based therapy varied markedly with 1 PR, 1 stable disease (SD) and 2 progressive disease (PD) as per IMWG criteria. The median PFS to nivolumab-based salvage therapy was 3.6 (range 0.4-8.1) months. Interestingly, pts MM1 and MM2 both had a CR to first ide-cel infusion (PFS 13.8 and 11.9 months, respectively), but while both pts did not respond to second CAR T cell infusion, the benefit from anti-PD1 treatment differed markedly in both pts. MM1 reached a PR and PFS of 105 days. In contrast, MM2 experienced immediate PD and succumbed to his disease 3.0 months later. Profiling of CD3+ T cells from MM1 and MM2 by scRNA-seq revealed rapid cellular state changes in response to PD1 inhibition. PAGODA2 clustering and t-Stochastic Neighbor Embedding (t-SNE) visualization revealed 3 distinct clusters, segregating to an individual pre-anti-PD1 cluster for MM1 and MM2 each and a shared post-anti-PD1 cluster comprising CD3+ T cells from both pts. The pre-anti-PD1 cluster for MM1 contained CD3+ T-cells with a memory T cell- like phenotype (IL7Rhigh, CD62Lhigh) and decreased expression of markers correlating with T-cell fitness (GNLY, PRF1, NKG7, GZMH,LY6C, KLRG1). This phenotype could be rescued, and T-cell fitness could be restored by Nivo-Pd treatment, potentially contributing to the clinical response observed in MM1. Opposingly, the pre-anti-PD1 cluster for MM2 showed intact T-cell fitness with low expression of T-cell exhaustion markers. No clinical benefit to Nivo-Rd was noted in this pt. Conclusions: Checkpoint inhibition and IMiD therapy can induce clinical responses at the time of relapse to first or second CAR T infusion. Efficacy however seems to depend on impaired T-cell fitness as premise for PD1 inhibition to re-induce clinical responses in selected pts.