Abstract

T-cell–redirecting agents specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) are new agents with a novel mechanism of action. A better understanding of the most optimal sequence of all available drugs is needed to maximize patient survival and minimize toxicity. Sequencing should take into consideration the potential beneficial or harmful impact of drugs on the immune microenvironment, and how this will influence the efficacy of subsequent lines of therapy.

Keywords:T-cell redirecting therapy; Sequencing therapy; Bridging therapy; Holding therapy; CAR T-cells

Abbreviation: MM: multiple myeloma; TCRT: T-cell redirecting therapy; TCE: T-cell engager; BT: Bridging therapy; HT: holding therapy; LDC: lymphodepleting chemotherapy; bsAb: bispecific antibody; BCMA: B-cell maturation antigen; GRPC5D: G protein–coupled receptor class C group 5 member D; CRS: Cytokine Release Syndrome; TNFRSF17: TNF receptor superfamily member 17

Introduction

T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment landscape of relapsed/refractory multiple myeloma (MM) and shows promise in earlier lines of treatment. There are several available products targeting primarily B-cell maturation antigen (BCMA) and G protein–coupled receptor class C group 5 member D (GRPC5D) and several more are in development [1]. An understanding of the resistance mechanisms with TCRT will provide a background for sequencing therapy and combination approaches with TCE therapies in MM. In general, resistance is thought to occur as a result of a combination of tumor-, T-cell–, and microenvironment-related factors [2]. Variable factors including disease burden, targeted antigen density, mutation or shedding, T cell dysfunction as well as effector to target ratio (absolute T cell count to disease burden) contribute to the reduced response seen in some patients sequentially treated with TCRT both CAR T-cell and TCEs [1].

Mechanisms of relapse after cellular immunotherapy in MM

T-cell characteristics

Prior therapies can impair T cell quantitatively and qualitatively. For example, preexisting lymphopenia occuring when alkylators or bendamustine are used prior to apheresis. Both may preclude the successful manufacture of an autologous product and can also worsen CAR T-cell therapy outcomes. In addition, continuous activation of T-cells with TCEs results in increased expression of inhibitory receptors possibly contributing to impaired antitumor efficacy in ex vivo experiments [1]. Immunomodulatory drugs (lenalidomide and pomalidomide) and the newer cereblon modulators (iberdomide and mezigdomide) are attractive adjunctive agents to use in combination with bsAb or CAR T cells. They have been demonstrated to improve proliferation, activation, and differentiation of T cells, including in the tumor microenvironment (TME). Studies are currently ongoing to determine whether addition of these agents can increase the durability of response to TCE therapies [2].

Antigen escape and antigen loss

The emergence of tumors with low or negative BCMA antigen expression, in relapsed myeloma patients following CAR T-cell treatment is known as antigen escape [3]. Antigen loss is less established in MM. Case reports have described antigen loss due to mutations, deletions, splicing alterations, or more complex genetic alterations at the TNFRSF17 BCMA-encoding gene locus [2] for e.g., biallelic BCMA losses or monoallelic losses plus an extracellular mutation occur in approximately 40% of patients with BCMA-targeted therapy. Similarly, GPRC5D antigen loss was described in most patients with progression after GPRC5D CAR T-cell therapy. The emergence of several clones with either biallelic loss or monoallelic loss plus transmembrane or extracellular domain mutations occur much more frequently with selective GPRC5D-targeted TCE. Importantly, mutations in BCMA or GPRC5D extracellular domains following the binding of a given therapy do not necessary preclude the binding of a different agent targeting the same antigen [1].

CAR T-cell-mediated trogocytosis

This process involves the strip off of BCMA or other targeted antigens from the surface of malignant plasma cells through direct contact with lymphocytes. This phenomenon may contribute to reduced levels of target antigen available for CAR T-cell recognition and subsequent elimination [3].

CAR T-cell persistence

The lack of CAR T-cell persistence in the body limits their ability to provide sustained therapeutic effects. Various strategies, including genetic modifications and the use of co-stimulatory molecules are being tried to enhance the persistence of CAR T-cells and to improve treatment outcomes [3].

The tumor microenvironment

The immunosuppressive effects of the tumor microenvironment (TME) and malignant plasma cells within MM patients such as the presence of regulatory immune cells, immunosuppressive cytokines, and inhibitory immune checkpoints can impede CAR T-cell function and limit their ability to effectively eliminate malignant plasma cells [3].

The International consensus recommendations for the optimal sequential use of immunotherapy agents in the treatment of MM [1]

Nine consensus recommendations have been published in 2025 for the optimal sequential use of immunotherapy agents in MM treatment. This Guidelines summary covers the following: when to proceed with T-cell redirecting therapy (TCRT), washout periods between treatments, when bridging therapy (BT) might be required, and treatment options for patients whose MM is progressing rapidly or despite therapy [1].

Recommendation 1

No concerns are recommended about proceeding with TCRT in patients receiving a corticosteroid, immunomodulatory drug (IMiD), a proteasome inhibitor (PI), (naked) monoclonal antibody, or any combination of these drug classes as most recent line of therapy. A washout period of 2 weeks is recommended between the last dose of conventional agent and apheresis of mononuclear cells when they are used as “holding therapy, HT” before T-cell collection for CAR T-cell manufacturing. Also, a 2-week washout for these agents is recommended before the first dose of TCE [1].

Explanation

PIs, alkylating drugs, and steroids reduce the number and function of T cells and also reduce the fitness of T cells in the apheresis product. These agents potentially reduce the activity and impair the efficacy of subsequent therapy with T-cell– engaging bispecific antibodies [4].

Recommendation 2

Avoid mononuclear cells collection for CAR T-cell manufacturing in patients receiving a TCE, if feasible. If this sequence is the best option for the patient, a minimum washout period of 4-weeks is recommended between the last dose of the TCE and apheresis collection. As an alternative, consider collection of T-cell prior to TCE initiation if possible [1].

Explanation

HT is MM treatment given prior to apheresis. TCEs should be avoided as HT if possible, regardless of target for two reasons. First, TCEs (particularly in the initial 1-2 cycles) can lead to profound lymphopenia due to trafficking into the bone marrow and other sites of MM. Second, continuous TCE exposure can lead to T-cell dysfunction. Patients proceeding with CAR T-cell therapy immediately after TCE have higher risk of manufacturing failure and less durable responses when compared to non-TCE-treated patients. A minimum of 4-week treatment-free intervals washout period is suggested for TCE regardless of TCE target to allow for recovery of T-cell number and function before apheresis [1].

Recommendation 3

Avoid the use of high-dose alkylators and bendamustine in patients for whom the next therapy is likely to be CAR T-cell and/ or a TCE [1].

Explanation

Both high-dose alkylators and bendamustine are associated with lymphopenia when used prior to apheresis. Bendamustine should be avoided prior to TCRT regardless of the intervening time given evidence from several studies on lymphoma demonstrating its long-term detrimental impact on T-cells [1].

Recommendation 4

BT is strongly considered after apheresis for CAR T-cell manufacturing in patients with high disease burden or at risk of developing morbidity from MM during the 4-6 weeks of manufacturing. The ideal BT will contain agent(s) without known resistance to patient’s myeloma, be short, with low risk of prolonged cytopenias or infection [1].

Explanation

Autologous CAR T-cell therapy often encounters a delay of multiple weeks between the time of apheresis to lymphodepleting chemotherapy (LDC) and subsequent infusion of CAR T-cells (“vein to vein” time) and even more between the decision to pursue CAR T-cell therapy and infusion (“brain to vein” time). This delay can allow for uncontrolled tumor progression [1]. BT is a plasma cell-directed therapy administered during the manufacturing period of CAR T-cells to allow their safe administration and disease control [1]. BT has to be differentiated from LDC which is a very standardized therapy, typically consisted of fludarabine and cyclophosphamide combination given immediately prior to CAR T-cell infusion to induce significant lymphopenia and create an optimal cytokine milieu that favors CAR T-cell expansion and persistence [1].

After apheresis, TCE therapy is reasonable and attractive novel BT prior to BCMA CAR T-cell particularly if targeting a different antigen than CAR T-cell [1]. A BCMA directed TCE as BT may raise the risk of decreased efficacy while using a GPRC5D-targeted TCE can bypass this risk by targeting a different antigen with potential to eradicate disease clones which may be BCMA-low or -null, but still express GPRC5D [1]. Given its safety and efficacy, an anti- CD38 mAb-based combination remains the preferred strategy in patients who do not have triple-class refractory disease or have anti-CD38 naïve or sensitive disease [1]. Daratumumab reduces CD38 expression on T cells. Daratumumab rapidly downregulates CD38 on T cells, through the trogocytic transfer of CD38/daratumumab complexes from T cells to monocytes and granulocytes. It eliminates CD38+ regulatory T cells and myeloid-derived suppressor cells, and promotes T-cell expansion and increases their functional activity. Preclinical studies have shown that prior daratumumab treatment enhances the efficacy of BCMA-targeting T-cell engaging bispecific antibodies by virtue of its immunomodulatory effects [4].

Recommendation 5

Assuming equal access, it is recommended to pursue TCRT in patients who are reasonable candidates to both BCMA-targeted antibody-drug conjugate (ADC) and BCMA-targeted TCRT. TCRT is given first for its higher activity and lower efficacy after prior BCMA targeted ADC (1).

Recommendation 6

Assuming equal access, it is recommended to pursue CAR T-cell therapy in patients who are reasonable candidates to both BCMA CAR T-cell and TCE. This recommendation considers more robust data supporting the activity of TCEs upon progression after CAR T-cell therapy and also the extended treatment-free interval post-CAR-T that is typically associated with more salvage options at the time of progression. However, data on the use of combination therapies with TCE and sequential therapy with different antigen target evolves (for example talquetamab followed by cilta-cel), this will need to be revisited, especially in specific populations [1].

Explanation

The pace of disease is one of the primary determinants of choosing between a CAR T-cell and a TCE in a given patient.

Recommendation 7

Proceed with TCE due to their faster access in patients with rapidly progressing disease and unlikely to transit through apheresis and bridging without disease related morbidity [1].

Explanation

MM patients with fulminant disease progression are either unable to get CAR T-cell infusion or will have more complications during CAR T-cell treatment. CAR T-cell infusion in patients with rapidly progressive disease may experience worsening cytopenia, progressive organ dysfunction and decline in functional status while CAR T-cell infusion in the setting of high disease burden could be particularly associated with higher grade and severity of cytokine release syndrome (CRS) and neurotoxicity [1].

Recommendation 8

Both BCMA-targeted and GPRC5D-targeted immunotherapy are safe and active in patients with prior BCMA-targeted CAR T-cell therapy. Responses to BCMA-targeting therapies post BCMA-targeted CAR T-cell therapy are likely to be less frequent and durable than in patients who are not previously treated with BCMA-targeted CAR T-cell therapy [1].

Explanation

The sequential use of therapies targeting the same antigen can potentially predispose patients to inferior outcomes with the second therapy [1].

Recommendation 9

There are limited data on the feasibility and efficacy of BCMA targeted therapy of a different modality upon disease progression on BCMA-targeted TCE at the approved dose intensities until progression. Outcomes after lower dose intensity or fixed duration of therapy are unknown. Therapy with different mechanisms of action or immunotherapy targeting a different antigen is recommended for patients progressing while receiving or shortly after receiving BCMA-targeting TCE [1].

Conclusion

More information is needed on the impact of reducing tumor burden prior to T-cell–redirecting therapy (optimizing effectorto- target ratio). The development of rapid manufacturing and allogeneic platforms may ultimately obviate the need for BT. More information is also needed about the best treatment strategy for patients relapsing after BCMA-targeted therapy and how effective is sequencing of agents that target BCMA versus using immunotherapies targeting other tumor antigens such as GPRC5D?.

References

 

1. Costa LJ, Banerjee R, Mian H, Weisel K, Bal S, et al. (2025) International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma. Leukemia 39(3): 543-554.
2. Mohan M, Oekelen OV, Akhtar OS, Cohen A, Parekh S () Charting the Course: Sequencing immunotherapy for multiple myeloma. Am Soc Clin Oncol Educ Book 44(3): e432204.
3. Sheykhhasan M, Ahmadieh-Yazdi A, Vicidomini R, Poondla N, Tanzadehpanah H, Dirbaziyan A, et al. (2024) CAR T therapies in multiple myeloma: unleashing the future. Cancer Gene Therapy 31(5): 667-686.
4. Niels WCJ (2020) van de Donk.Sequencing multiple myeloma therapies with and after antibody therapies. Hematology Am Soc Hematol Educ Program 2020(1): 248-258.

 

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