CAR-T Cell Myeloma,Has the Mission of CAR-T Cell Therapy for Multiple Myeloma Been Accomplished?

CAR-T Cell Myeloma,Has the Mission of CAR-T Cell Therapy for Multiple Myeloma Been Accomplished?

CAR-T Therapy for Multiple Myeloma

BCMA CAR-T cell therapy is an innovative approach for the treatment of multiple myeloma. In a recent “Blood Spotlight” article published in Blood, the authors reviewed relevant clinical and preclinical data supporting the incorporation of CAR-T cells into frontline therapy and their use prior to T-cell engager antibodies.

Furthermore, the authors believe that the desire to cure multiple myeloma with (BCMA) CAR-T cells may be realized through genomic and phenotypic analysis to assess BCMA expression, steady improvement in early diagnosis and management of adverse effects, and the development of rapid, scalable CAR-T cell production (improving accessibility).

Blood Spotlight

Blood Spotlight

Real-World Data of BCMA CAR-T

The approval of two BCMA CAR-T cell products, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), marks the entry of cellular immunotherapy into a new era for multiple myeloma (MM). In addition to their pivotal studies, an increasing amount of long-term clinical follow-up data, related studies, and real-world evidence have provided a broader perspective and highlighted the tremendous therapeutic potential and current limitations of BCMA CAR-T cell therapy in multiple myeloma (Table 1).

Real-World Data of BCMA CAR-T

The approval of the two BCMA CAR-T cell products, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), marks the entry of cellular immunotherapy into a new era for multiple myeloma (MM). In addition to their pivotal studies, an increasing amount of long-term clinical follow-up data, related studies, and real-world evidence have provided a broader perspective and highlighted the tremendous therapeutic potential and current limitations of BCMA CAR-T cell therapy in multiple myeloma (Table 1).

Potential and Limitations of BCMA CAR-T Cell Therapy for Multiple Myeloma

Potential and Limitations of BCMA CAR-T Cell Therapy for Multiple Myeloma

A key question currently is the optimal sequencing of CAR-T cell therapy and other anti-multiple myeloma treatments, particularly T-cell bispecific antibodies (BsAbs), with the aim of maximizing therapeutic effect, which requires T cells to be not terminally exhausted and multiple myeloma cells to be unedited (minimizing or loosening target antigen expression).

Preliminary results indicate that patients previously treated with anti-BCMA BsAbs (N=7) who received cilta-cel had an ORR of 57.1% and a PFS of 5.3 months, while BCMA treatment-naive patients had an ORR of 98% and a median PFS not reached. A retrospective real-world study from the United States included 196 patients who received ide-cel as a single agent; these patients were heavily pretreated, with only a few meeting the eligibility criteria of the pivotal KarMMa study. The progression-free survival (PFS) was 8.5 months, compared to 11.3 months in the pivotal KarMMa study (optimal dosing cohort), with a non-relapse mortality rate of 5%. In a multivariate analysis, prior BCMA-targeted therapy (especially BsAbs) was associated with poorer outcomes with BCMA CAR-T cell therapy (median PFS 3.2 vs. 9 months). These data suggest that prior exposure to BCMA-targeting agents (BsAbs teclistamab or elranatamab) adversely impacts the efficacy of BCMA CAR-T cells, and the sequencing of BsAbs followed by CAR-T cell therapy is suboptimal. On the other hand, considering the small number of patients, the use of BsAbs post-CAR-T cell therapy only modestly reduced the ORR.

Patient Selection for BCMA CAR-T Cell Therapy

Given the availability of BsAbs and their relative ease of access, patient and product selection for CAR-T cell therapy remains challenging, but there have been several recent reports on this topic. One example is frailty, which does not preclude CAR-T cell therapy if organ function is preserved. In fact, several ongoing studies are evaluating BCMA CAR-T cells in patients ineligible for autologous transplantation (e.g., CARTITUDE-5, NCT04923893); a recent study even demonstrated the feasibility of CAR-T cell therapy in patients on hemodialysis. However, high-risk features such as an R-ISS score of 3 and extramedullary disease remain poor prognostic factors for CAR-T cell therapy in multiple myeloma, and therefore highly proliferative relapsed/refractory multiple myeloma (RRMM) patients may not be good candidates for CAR-T cell therapy without effective bridging and/or debulking treatment, especially when the vein-to-vein (i.e., leukapheresis-to-CAR-T cell infusion) time exceeds 6-8 weeks, making disease control challenging in these patients. Additionally, notable are the further compounding issues of manufacturing failure rates and non-conforming CAR-T cell products. Next-generation CAR-T cell production platforms with ultra-short ex vivo culture and non-viral fresh-in/fresh-out manufacturing can achieve vein-to-vein times of 2-3 weeks or shorter, and clinical data on these “rapid” CAR-T cell products are eagerly awaited (NCT05172596, NCT04935580, NCT04394650, NCT04499339). Allogeneic CAR-T cells can be provided as an off-the-shelf product, but their efficacy in early clinical trials has been quite disappointing and inferior to autologous CAR-T cells, likely due to immunogenicity from HLA mismatches and genotoxicity from gene editing.

Acute and Chronic Toxicities of BCMA CAR-T Cell Therapy

As the number of patients receiving BCMA CAR-T cell therapy increases, more insights into acute and chronic toxicities and their clinical management strategies have been derived. Cytokine release syndrome (CRS) occurs in up to 80%, but has lost its “fear factor” as refined diagnostic and treatment strategies have been established, and experience accumulates, especially in “high-volume” CAR-T cell centers. Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially life-threatening complication following BCMA CAR-T cell therapy if not adequately managed, with rapidly rising ferritin being a key laboratory finding. Sarcoidosis-like flare-up is another rare CRS-related disorder. A common challenge after BCMA CAR-T cell therapy in multiple myeloma is infection, as myeloma patients are susceptible to infections due to disease-related immunosuppression; furthermore, the pre-conditioning lymphodepletion prior to CAR-T cell infusion, on-target off-tumor recognition of B cells and plasma cells during CRS, and marrow inflammation further compound the quantitative and qualitative deficits in the immune system.

At ASH 2022, Shambavi et al. reported that over one-third of patients failed to recover serum IgM, peripheral blood T cells, and B cells 2 years after CAR-T cell therapy, even in those achieving complete remission from multiple myeloma. Vaccination prior to CAR-T cell therapy and intravenous immunoglobulin replacement therapy aid in preventing infections.

The most troublesome side effect following BCMA CAR-T cell therapy is multi-lineage cytopenias. In many patients, the cytopenias follow a biphasic pattern, with an initial nadir shortly after CAR-T cell infusion (primarily due to lymphodepletion), and a second nadir around 1 month after CAR-T cell infusion (primarily due to on-target reactivity and inflammation). As a result, some patients remain transfusion-dependent or experience severe infections, negating the benefits of the treatment-free interval for multiple myeloma. Recently, Rejeski et al. introduced the CAR-HEMATOTOX scoring system to assess the risk of prolonged severe neutropenia and severe infections in RRMM patients receiving BCMA CAR-T cell therapy. In addition to growth factor support, the value of autologous stem cell boost should be evaluated in patients with prolonged cytopenias.

The mechanism underlying neurotoxicity following BCMA-targeted immunotherapy remains poorly understood. In contrast to CD19 CAR-T cells, immune effector cell-associated neurotoxicity syndrome (ICANS) is uncommon after BCMA CAR-T cell therapy. However, in patients receiving BCMA CAR-T cells, the overall incidence of various neurological adverse events is around 20%, including headache, tremor, mild aphasia, mental status changes with impaired attention and confusion, neglect syndromes, and somnolence; less common are life-threatening cranial neuropathies such as Guillain-Barré syndrome and Bell’s palsy.

A perplexing side effect is the movement and neurocognitive therapy-associated adverse events (MNT) occurring in approximately 5% of patients receiving cilta-cel. A recent case study reported low BCMA expression in the basal ganglia and caudate nucleus of a patient who developed Parkinsonism-like symptoms and ultimately died. Patients with high tumor burden and early neurotoxicity are at risk for developing MNT at later time points. In clinical practice, effective bridging therapy, vigilant monitoring and treatment of CRS and neurological symptoms, and lowering myeloma burden have significantly reduced the incidence of late neurotoxicity. A recent case report suggests that cyclophosphamide may be an effective treatment for MNT. Overall, the non-relapse mortality rate in clinical trials of BCMA CAR-T cell therapy is below 5%, and 5-9% in real-world studies, no higher than conventional chemotherapy in late-stage RRMM.

Emerging Challenges:Relapse after BCMA CAR-T Cell Therapy in the Later Lines

BCMA CAR-T cell therapy is the most potent anti-myeloma therapy introduced into the clinic to date, yet most patients eventually relapse, with the myeloma cells frequently acquiring changes in target antigen expression upon relapse. CAR-T cells and BsAbs targeting alternative antigens (such as GPRC5D, FcRH5, and SLAMF7) have shown promising preclinical and early clinical activity as salvage therapies. MCARH109 is an anti-GPRC5D CAR-T cell product that achieved an ORR of approximately 70% in RRMM patients, regardless of prior BCMA therapy exposure.

BCMA downregulation and loss is a key mechanism by which myeloma evades selective pressure from CAR-T cells and BsAbs. There are numerous genomic aberrations leading to BCMA deficiency, such as homozygous deletions, frameshifts, and mutations, as well as single nucleotide variants (SNVs) disrupting the binding epitopes for teclistamab and elranatamab, with one such SNV detected as a clonal variant in a primary refractory ide-cel patient. Similarly, antigen loss appears to be a common resistance mechanism after GPRC5D-CAR-T cell therapy and BsAbs. A systematic analysis of antigen loss frequencies for candidate myeloma target antigens is currently lacking. Another focus of current research is to determine the antigen density thresholds required for recognition and elimination of myeloma cells by different CAR-T cell products and BsAbs. Previous reports have demonstrated that for optimized CD19 CARs, this threshold can be in the range of a few hundred CD19 molecules, and relevant clinical data support the notion that CD19 expression above a certain threshold correlates with an increased likelihood of achieving and maintaining lymphoma remissions. Therefore, the application of novel diagnostic tools (such as whole-genome sequencing and single-molecule sensitive microscopy) to the clinical pathology evaluation of myeloma should aid in patient stratification and monitoring.

Elucidating other mechanisms of response and relapse can inform the refinement of CAR-T cells and BsAbs and their optimal clinical deployment. Lin et al. reported correlative data from the Karmamultiple myeloma study, highlighting greater CAR-T cell expansion in responders compared to non-responders. Interestingly, a higher proportion of naïve and early memory CD4 T cells in the leukapheresis material correlated with CAR-T cell expansion and response. These data encourage efforts to enhance CAR-T cell fitness, such as through the expression of transcription factors supporting engraftment, in vivo expansion, and longevity. The myeloma microenvironment also impacts T cell trafficking and infiltration into plasma cell tumors, with Robinson et al. revealing intra- and inter-lesional heterogeneity in myeloma, with the coexistence of T cell-rich and T cell-excluded microregions potentially regulated by chemokine signaling and CD2-CD58 interactions. Recently described alterations in T cell repertoire and macrophage content within intramedullary lesions have further reinforced the interest in modulating the myeloma microenvironment to favor CAR-T cell performance.

New Opportunities:Deploying CAR-T Cells for Myeloma Cure in Earlier Lines?

Two randomized studies have reported outcomes of BCMA CAR-T cell therapy versus standard-of-care in earlier treatment lines. The Karmamultiple myeloma-3 study randomized daratumumab-refractory RRMM patients (mostly also IMiD-refractory) who had received 2-4 prior lines to ide-cel or standard-of-care. With a median follow-up of 18.6 months, the median PFS in the ide-cel arm was 13.3 months versus 4.4 months in the standard-of-care arm. In CARTITUDE-4, lenalidomide-refractory multiple myeloma patients who had received 1-3 prior lines were randomized to cilta-cel or standard-of-care. With a median follow-up of 15.9 months, the median PFS was not reached in the cilta-cel arm versus 11.8 months in the standard-of-care arm. Thus, it can be confidently stated that BCMA CAR-T cell therapy should and will become a new backbone of frontline myeloma therapy, with the potential to cure a substantial proportion of patients (Figure 1). Several clinical trials evaluating BCMA CAR-T cells and BsAbs in the frontline setting are currently ongoing, addressing questions around induction (e.g., NCT05695508), consolidation (e.g., NCT05257083), and maintenance (NCT05243797) in the frontline.

A major outstanding goal remains to expand and facilitate patient access to CAR-T cell therapy. At the time of writing, ide-cel is available and reimbursed in 5 countries (US, France, Switzerland, Japan, Germany), while cilta-cel is reimbursed in only 2 countries (US, Germany). Advances in scalable, automated, non-viral manufacturing will further increase product availability, while point-of-care manufacturing is another key lever for shortening vein-to-vein time, reducing costs, and engaging clinical trial sites in the workflow and value stream. Finally, revisiting one-time reimbursement schemes in favor of baseline payment plus performance-based installments would aid payer acceptance and enable patient access in the white spaces on the CAR-T cell world map.

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