Nivolumab May Restore T-Cell Fitness Following CAR T-Cell Therapy in Patients With Multiple Myeloma

Treatment with nivolumab (Opvido; Bristol Myers Squibb) after chimeric antigen receptor (CAR) T-cell therapy may restore T-cell fitness in patients with relapsed, refractory multiple myeloma (RRMM), according to a study published in Blood Advances. These findings build on emerging understandings of the intersection between cellular therapies and immunotherapies in the treatment of hematologic malignancies.¹

Visualization of a CAR T-cell | Image Credit: © DruZhi Art - stock.adobe.com

MM is the second most common hematologic malignancy, characterized by the overproduction of B lymphocytes, leading to renal failure, brittle bones, and other health complications. MM remains incurable, and all patients will eventually relapse with each successive line of therapy. The development of novel agents such as immunotherapies and CAR T-cell therapy has revolutionized the treatment paradigm for this disease and greatly improved outcomes for patients, but barriers remain. MM is a very heterogeneous disease, making it difficult to treat and underscoring the need for dynamic, multi-pronged approaches to treatment regimens.

A common complication associated with CAR T-cell therapies is T-cell exhaustion, which can greatly undermine treatment responses and outcomes. T-cell exhaustion is a physiological process and regulatory mechanism that limits excessive T-cell responses, which can cause damage to surrounding cells and tissues, and it is a major cause of failure for even the most promising therapies. When T-cells are overly activated, it greatly reduces their proliferative capacity, metabolic fitness, and cytokine production.²

In an effort to restore T-cell function in patients with RRMM, researchers evaluated the use of nivolumab, a PD-1 inhibitor, as a salvage therapy following CAR T-cell therapy. They hypothesized that post–CAR T treatment with the nivolumab may restore sensitivity to CAR T therapies and that the clinical response to nivolumab is dependent on the condition of a patient’s non-modified T-cells, non-CAR T-cells.¹

The researchers included a total of 4 patients who were treated with idecabtagene vicleucel (Abecma, ide-cel; Celgene Corporation) in the phase 1 CRB401 trial (NCT02658929). They received a combination of nivolumab, lenalidomide or pomalidomide, and dexamethasone upon relapse to the first or second ide-cel infusion. The end points of the study included progression-free survival (PFS), overall survival (OS), median time-to-next treatment (TTNT), and response (partial response [PR], stable disease [SD], or progressive disease [PD]).^1,3

The median PFS was 10.4 months (range: 3.0-13.8 months), with an OS of 21.5 months (range: 16.0-34.6 months) and a TTNT of 3.6 months (range: 0.4-8.0 months). Of the participants, 2 patients had PD following nivolumab-based salvage therapy, one achieved a PR, and the final had SD.¹

The researchers sought to understand the underlying reason for the differing responses through use of single-cell RNA sequencing and found that nivolumab’s effectiveness was highly dependent on the fitness of the preexisting T-cell microenvironment. According to the study data, the patient with a hyporesponsive T-cell state prior to treatment with nivolumab experienced a clinical response, whereas another patient with intact T-cell fitness did not experience any clinical benefit.¹

The study suggests PD-1 inhibition could be a viable strategy to resensitize CAR-T–refractory patients with RRMM, but only in a well-selected subgroup. The authors point to the real-time profiling of T-cell activation states in non-CAR T-cells to guide treatment decisions. They also note that checkpoint inhibition may be more effective as a consolidation therapy rather than a salvage approach.¹

These findings highlight the need for a precision-based approach to integrating checkpoint inhibition with CAR T therapy, ensuring its use aligns with the patient’s immune landscape for optimal benefit.

REFERENCES

1. Waldschmidt J, Sotudeh N, Arora S, et al. Nivolumab to restore T-cell fitness in CAR-T refractory multiple myeloma. Blood Adv. February 28, 2025. doi: 10.1182/bloodadvances.2024015285

2. Overcoming treatment challenges in multiple myeloma: bispecific antibodies and CAR T-cell therapy. Pharmacy Times. September 27, 2025. https://www.pharmacytimes.com/view/overcoming-treatment-challenges-in-multiple-myeloma-bispecific-antibodies-and-car-t-cell-therapy

3. Study of bb2121 in multiple myeloma. Updated January 23, 2023. Accessed April 2, 2025. https://clinicaltrials.gov/study/NCT02658929