Prognostic value of early bone marrow MRD status in CAR-T therapy for myeloma

Bansal, Radhika; Baksh, Mizba; Larsen, Jeremy T.; Hathcock, Matthew; Dingli, David; Stewart, A. Keith; Kapoor, Prashant; Kourelis, Taxiarchis; Hayman, Suzanne R.; Warsame, Rahma; Fonseca, Rafaël; Bergsagel, P. Leif; Ailawadhi, Sikander; Kumar, Shaji; Lin, Yi

doi:10.1038/s41408-023-00820-y

Cited by 11 publications

(4 citation statements)

References 11 publications

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“…Accordingly, the presence of extramedullary disease after infusion with ide-cel was associated with inferior PFS in patients achieving undetectable MRD. These results confirm and expand the recent observations in patients treated with CAR T cells at the Mayo Clinic ( 17 ). Furthermore, it could help explain the cases in which the achievement of a transient MRD-negative status was followed by disease progression without ever attaining CR.…”

Section: Discussionsupporting

confidence: 91%

Time-Dependent Prognostic Value of Serological and Measurable Residual Disease Assessments after Idecabtagene Vicleucel

Manrique

Rytlewski

Campbell

et al. 2023

Blood Cancer Discovery

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The role of MRD in multiple myeloma patients treated with CAR T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) vs those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR vs <CR. Persistent MRD in the 10-6 logarithmic range and reappearance of normal plasma cells in MRD negative patients associated with inferior PFS. This study unveiled different prognostic implications of serological and MRD response dynamics after ide-cel and suggests potential value of studying the reappearance of normal plasma cells as a surrogate of loss of CAR T cell functionality.

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Section: Discussionsupporting

confidence: 91%

Time-Dependent Prognostic Value of Serological and Measurable Residual Disease Assessments after Idecabtagene Vicleucel

Manrique

Rytlewski

Campbell

et al. 2023

Blood Cancer Discovery

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“…This was sustained at 6 and 12 months, favorable in comparison with previous studies . Although bone marrow may still be hypocellular at the early time point after CAR T therapy, Lin Y et al recently reported that bone marrow MRD negative at month 1, regardless of cellularity status in bone marrow, correlated with CR/sCR response and prolonged PFS …”

Section: Discussionmentioning

confidence: 89%

“…11 Although bone marrow may still be hypocellular at the early time point after CAR T therapy, Lin Y et al recently reported that bone marrow MRD negative at month 1, regardless of cellularity status in bone marrow, correlated with CR/sCR response and prolonged PFS. 12 GC012F also showed a favorable safety profile without dose-limiting toxic effects. Cytopenia was the most common grade 3 or higher AE exhibiting a rapid recovery, faster than in the cohort of patients with RRMM.…”

Section: Discussionmentioning

confidence: 89%

B-Cell Maturation Antigen/CD19 Dual-Targeting Immunotherapy in Newly Diagnosed Multiple Myeloma

Qiang,

Lu,

Jia

et al. 2024

JAMA Oncol

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ImportancePatients with high-risk newly diagnosed multiple myeloma (NDMM) often have poor outcomes with standard treatments, necessitating novel effective frontline therapies to enhance clinical outcomes. GC012F, a B-cell maturation antigen/CD19 dual-targeting chimeric antigen receptor (CAR) T-cell therapy, has been developed on the novel FasTCAR platform. Notably, its use as a frontline therapy for patients with high-risk NDMM who are eligible for transplant has not been thoroughly explored.ObjectiveTo examine the safety, pharmacokinetics, and patient health and survival outcomes associated with GC012F in individuals with NDMM.Design, Setting, and ParticipantsPatients were enrolled in this single-arm, open-label phase 1 cohort study between June 28, 2021, and June 1, 2023 (the data cutoff date). All patients included in this study were treated at a single center, Shanghai Changzheng Hospital. The patients in the efficacy evaluation were followed up for a minimum period of 3 months.InterventionPatients underwent 2 cycles of induction therapy, followed by GC012F infusion (at 1 × 105 cells/kg, 2 × 105 cells/kg, or 3 × 105 cells/kg).Main Outcomes and MeasuresThe primary goals were to assess the safety, efficacy, and pharmacokinetics of GC012F at various dose levels.ResultsOf 22 patients receiving GC012F treatment, 6 experienced mild to moderate cytokine release syndrome (grade 1-2) and none experienced neurotoxic effects. Nineteen patients were included in the efficacy evaluation, and all 19 patients showed stringent complete responses and achieved minimal residual disease negativity. The treatment’s effectiveness was consistent across different dose levels. GC012F demonstrated a rapid response, with a median time to first stringent complete response of 84 days (range, 26-267 days) and achieving minimal residual disease negativity within 28 days (range, 23-135 days). The CAR T-cell expansion was robust, with a median peak copy number of 60 652 copies/μg genomic DNA (range, 8754-331 159 copies/μg genomic DNA), and the median time to median peak copy number was 10 days (range, 9-14 days).Conclusions and RelevanceThe findings of this single-arm, open-label phase 1 cohort study suggest that GC012F may be a safe treatment associated with positive health and survival outcomes for patients with high-risk NDMM eligible for transplant. Owing to the small sample size, further studies with larger cohorts and longer follow-up durations are needed.

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“…According to a previous study, early MRD positivity likely predicts impending clinical relapse. 25 In our phase I clinical trials of CAR-T-cell treatment of the seven RRMM patients, the overall response rate (ORR) was 85.7% (6/7), and included four patients with an sCR, one patient with a CR, one patient with a PR and one patient with SD. Durable responses were found in four patients at the time of last follow-up, and disease relapse was detected in one patient at 19.2 months (figure 6G).…”

Section: Pd-1 Kd Bcma Car-t Cells Exhibited Comparable Tolerability A...mentioning

confidence: 99%

PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion

Ouyang,

Jin,

et al. 2024

J Immunother Cancer

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BackgroundDespite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects and dysfunctions of CAR-T cells have limited the efficacy and clinical application of this promising approach.MethodsIn this study, we incorporated a short hairpin RNA cassette targeting PD-1 into a BCMA-CAR with an OX-40 costimulatory domain. The transduced PD-1KDBCMA CAR-T cells were evaluated for surface CAR expression, T-cell proliferation, cytotoxicity, cytokine production, and subsets when they were exposed to a single or repetitive antigen stimulation. Safety and efficacy were initially observed in a phase I clinical trial for RRMM patients.ResultsCompared with parental BCMA CAR-T cells, PD-1KDBCMA CAR-T cell therapy showed reduced T-cell exhaustion and increased percentage of memory T cells in vitro. Better antitumor activity in vivo was also observed in PD-1KDBCMA CAR-T group. In the phase I clinical trial of the CAR-T cell therapy for seven RRMM patients, safety and efficacy were initially observed in all seven patients, including four patients (4/7, 57.1%) with at least one extramedullary site and four patients (4/7, 57.1%) with high-risk cytogenetics. The overall response rate was 85.7% (6/7). Four patients had a stringent complete response (sCR), one patient had a CR, one patient had a partial response, and one patient had stable disease. Safety profile was also observed in these patients, with an incidence of manageable mild to moderate cytokine release syndrome and without the occurrence of neurological toxicity.ConclusionsOur study demonstrates a design concept of CAR-T cells independent of antigen specificity and provides an alternative approach for improving the efficacy of CAR-T cell therapy.

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Prognostic value of early bone marrow MRD status in CAR-T therapy for myeloma

Cited by 11 publications

References 11 publications

Time-Dependent Prognostic Value of Serological and Measurable Residual Disease Assessments after Idecabtagene Vicleucel

Time-Dependent Prognostic Value of Serological and Measurable Residual Disease Assessments after Idecabtagene Vicleucel

B-Cell Maturation Antigen/CD19 Dual-Targeting Immunotherapy in Newly Diagnosed Multiple Myeloma

PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion

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