Nivolumab Shows Marginal ORR Following CAR T Failure in MM, NHL

Treatment with nivolumab (Opdivo) had limited benefit in patients with multiple myeloma (MM) or non-Hodkin lymphoma (NHL) whose disease progressed following chimeric antigen receptor (CAR) T-cell therapy, according to a phase 2 study (NCT04205409) whose results were published in Blood Immunology & Cellular Therapy.¹

The trial failed to meet its primary end point of overall response rate (ORR) in 20 enrolled patients, leading investigators to not continue investigation of this approach. However, in the 2 patients with MM who did have a response, the durations of response (DOR) were over 18 months, suggesting checkpoint inhibition could improve outcomes through its effect on endogenous T cells.

Study Design and Efficacy

This single-center, open-label phase 2 trial enrolled 20 patients, 11 with MM and 9 with NHL, who had autologous CAR T therapy as their most recent line of treatment. Patients received the PD-1 inhibitor nivolumab at 480 mg intravenously every 28 days until disease progression or intolerable toxicity. Key secondary end points included DOR and safety.

The study resulted in an ORR of only 15% across the entire cohort. When broken down by disease type, the ORR was 18% (n = 2/11) for MM and 11% (n = 1/9) for NHL. For the 17 nonresponders, progressive disease occurred rapidly, at a median of 0.9 months following nivolumab initiation.

Durable Responses in Myeloma

Despite the low ORR, the findings in the myeloma cohort were notable for the durability of the responses. The 2 responding patients with MM achieved remarkably sustained responses lasting 18.9 and 18.3 months. In contrast, the single responder in the NHL group had a DOR of only 1.6 months.

The investigators described one of the patients with relapsed MM (patient MM02) who had 7 prior lines of therapy and was treated with nivolumab 18.1 months after receiving orvacabtagene autoleucel, an investigational CAR T-cell therapy targeting BCMA. The patient had full resolution of an 8.6-cm hypermetabolic extramedullary plasmacytoma within the renal collecting duct system and achieved a complete response (CR) but withdrew from the study due to an unrelated diagnosis of myelodysplastic syndrome.

Biological Correlates and the Role of Endogenous T Cells

A critical component of this study was the longitudinal analysis of T-cell dynamics. Preclinical data suggested nivolumab’s PD-1 blockade could improve the effector function of CAR T cells, but previous studies of this type have been retrospective and largely unsuccessful. Nivolumab’s activation of the endogenous T cells could also drive response.

At the time of nivolumab initiation, circulating CAR T cells were detectable in only 30% of patients and their frequency did not increase following treatment. Detectable CAR T cells were present in only 1 of the 3 responding patients, and these CAR T cells demonstrated a terminally exhausted phenotype and did not show expansion despite a high baseline PD-1 expression.

However, Ki-67 expression in endogenous T cells indicated activation and proliferation that peaked at approximately 7 days after initiation of nivolumab, independent of clinical response. These findings suggest that the durable responses seen in the MM cohort were driven by the activation of endogenous T cells rather than the reinvigoration of the CAR T product.

Safety Profile

Prior retrospective data with nivolumab did not report safety results, making this a valuable result from this trial. Nivolumab was generally well tolerated in this heavily pretreated population. No cases of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome were reported. Grade 3 or higher adverse events (AEs) were reported in 55%, but AEs attributed to nivolumab occurred in 15% of patients (n = 3) and none were grade 3 or higher. One of the patients with MM who had a response reported grade 2 thyroiditis and grade 1 rash after 8 and 12 months of therapy, respectively, and a patient with MM had a grade 2 infusion reaction and another with NHL had a grade 2 rash. Serious adverse events occurred in 25% of patients, including 3 cases of bacterial sepsis, though these were generally deemed unrelated to the study drug.

Clinical Implications for Oncologists

The 15% ORR and lack of effect on CAR T persistence provide prospective supporting evidence for the overall poor outcomes previously seen retrospectively with PD-1 inhibition after CAR T failure. However, the responders the myeloma group highlight a potential therapeutic window. The study authors suggest that better biomarkers are needed to identify this small subset of patients who may benefit. In the only other known prospective trial of nivolumab monotherapy in MM, it yielded poor outcomes,² but the investigators suggested that “it is also biologically plausible that nivolumab is more effective specifically in the setting of antecedent CAR T therapy.”¹

An ongoing phase 2 trial (NCT06523621) is investigating nivolumab in the setting of sub-CR responses to idecabtagene vicleucel (ide-cel; Abecma) in MM and is incorporating longitudinal correlative assessments of both CAR-transduced and endogenous T cells. The investigators suggested that this will allow for prospective evaluation of PD-1 blockade’s benefit via activation of endogenous T cells.

_REFERENCES

_{1. Banerjee R, Simon S, Voutsinas JM, et al. Nivolumab following CAR-T failure in multiple myeloma and non-Hodgkin lymphoma: results of a phase 2 study. Blood ICT. 2026;2(1):100022. doi:10.1016/j.bict.2025.100022.}

_{2. Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib Study. J Clin Oncol. 2016;34(23):2698-2704. doi:10.1200/JCO.2015.65.9789}