Early Safety and Efficacy of CAR-T Cell Therapy in Precursor Myeloma: Results of the CAR-PRISM Study Using Ciltacabtagene Autoleucel in High-Risk Smoldering Myeloma

Speaker: Omar Nadeem, Dana-Farber Cancer Institute

Key Highlights       

CAR-T cell therapy has emerged as a transformative approach in multiple myeloma. Cilta-cel, an anti-BCMA CAR-T therapy, has shown significant efficacy in relapsed/refractory myeloma and recently demonstrated survival benefits in earlier treatment lines, as evidenced by the CARTITUDE-4 trial.

The CAR-PRISM study investigates cilta-cel’s application in high-risk SMM, leveraging the immune system’s superior fitness and lower tumor burden in early disease stages to achieve durable minimal residual disease (MRD) negativity and redefine treatment paradigms for SMM.

Study Design:

• Design:
  • Phase I safety run-in cohort of six patients treated with cilta-cel at 0.5×10⁶ or 0.75×10⁶ CAR-T cells/kg.
  • Endpoints included safety (primary), efficacy (MRD negativity, response rates, PFS), and adverse events (AEs).
• Eligibility: Patients with high-risk criteria per IMWG guidelines or cytogenetics, excluding active myeloma or >40% bone marrow plasmacytosis.

Efficacy Outcomes:

1. All six patients achieved complete responses (CRs) with MRD negativity (10⁻⁶ sensitivity).
2. Sustained MRD negativity reported, with three patients maintaining negativity at 1-year follow-up.
3. No biochemical or clinical progression noted.
4. CAR-T Cell Expansion
5. Successful CAR-T cell expansion in all patients, peaking at day 14.
6. Preferential expansion of CD4+ CAR-T cells compared to CD8+, differing from relapsed/refractory myeloma studies.

Safety Outcomes:

• No dose-limiting toxicities (DLTs).
• Cytokine Release Syndrome (CRS): Observed in all patients (grade ≤2), managed effectively with tocilizumab and dexamethasone.
• Other AEs: Grade 1 Bell’s palsy and grade 4 immune thrombocytopenia resolved without long-term effects. No grade ≥3 infections or secondary malignancies reported.

Conclusion:

Early CAR-PRISM results underscore cilta-cel’s safety and efficacy in high-risk SMM. With sustained MRD negativity and a "one-and-done" approach, cilta-cel could transform precursor myeloma treatment.

A Single-Centre, Single-Arm, Phase I Clinical Trial of Anti-BCMA/GPRC5D Bispecific CAR T-Cells in Patients with Refractory and Relapsed Multiple Myeloma with Extramedullary Disease

Speaker: Alex Chang, Shanghai YaKe Biotechnology Ltd.

Key Highlights

Study Design and Rationale:

Study Objective: Explore dual-targeting CAR-T cell therapy in a high-risk population with poor outcomes on current treatments.

Design:

• Participants: 8 RRMM patients with EMD.
• Regimen: Cyclophosphamide + fludarabine lymphodepletion followed by bispecific CAR-T infusion (1.0–1.5 × 10⁶ cells/kg).
• Endpoints:
  • Primary: Safety and overall response rate (ORR).
  • Secondary: CAR-T activity and MRD levels.

Patient Characteristics:

• Age Range: Median age 18–79 years.
• Treatment History: All had ≥3 prior therapies, including proteasome inhibitors, immunomodulators, and stem cell transplantation.
• Disease Type: One patient with primary EMD; others with secondary EMD.

Results:

Efficacy:

• ORR: 100%.
• 4 patients achieved complete response (CR).
• 1 patient had very good partial response (VGPR).
• 3 patients had partial response (PR) but progressed later.
• Survival: Median PFS and OS were not reached during the median follow-up of 6.08 months.

CAR-T Cell Activity:

• Peak Expansion: Median time: 13.5 days.
• Persistence: Median CAR-T persistence: 42.5 days.
• Cytokine Levels: High IL-6, CRP, and ferritin peaks observed around 9–11 days post-infusion.

Safety:

• CRS: All patients experienced low-grade cytokine release syndrome (CRS, grades 1–2).
• Neurotoxicity: One case of grade 2 neurotoxicity (ICANS).
• Off-Target Effects: No severe effects such as skin lesions or cerebellar toxicity.

Conclusion: This Phase I study underscores the potential of bispecific CAR-T cells targeting BCMA and GPRC5D in RRMM with EMD. Early data highlight robust efficacy and a favourable safety profile, making this a promising approach for high-risk patients.

CAR-T Cell Therapy in Advanced Myeloma with Extra-medullary Disease – an In-Vivo Imaging and Molecular Monitoring Study (CARAMEL): First Results of Cu-64 Radiolabelled Nanoparticle PET-CT and PET-MRI

Speaker: Simon Harrison, Peter MacCallum Cancer Centre

Key Highlights

Study Background and Methodology

Analysis from CARTITUDE-1 and CARTITUDE-4 demonstrated:

• Despite achieving 100% response rates, PFS and duration of response in high-risk EMD patients remain poor.
• The benefit magnitude, reflected in hazard ratios, was consistent with standard-risk patients, suggesting the need for innovative strategies to improve outcomes.

Understanding CAR-T cell bio-distribution and resistance mechanisms is vital to address these limitations:

• Technology: Iron nanoparticles with a silica shell covalently bonded to Cu-64, ensuring stability and preventing isotope leakage.
• Imaging Modality: PET-MRI enables high-resolution tracking of CAR-T cells' journey and interactions within the tumour microenvironment.

Study Design:

• Phase I, open-label, single-center trial.
• Primary goals: Assess feasibility and safety of imaging CAR-T cells.
• Patient Selection: Adults with PET-positive lesions (>1 cm) and manageable disease burden.

Procedure:

• 30% of thawed CAR-T cells labelled with Cu-64 and reinfused within 4 hours alongside 70% unlabelled cells.
• Imaging at 12-, 24-, and 48-hours post-infusion using PET-CT and PET-MRI.

Results:

• Response Rates: All patients responded, with some achieving complete metabolic response (CMR) in bone marrow and MRD-negative stringent CR, while the structural lesion responses varied, with incomplete resolution in one patient.
• Bio distribution: CAR-T cells consistently migrated to the liver, spleen, and bone marrow and showed limited penetration into extramedullary lesions in the early phase.
• Imaging Findings: High-resolution PET-MRI highlighted initial CAR-T clustering around lesions with limited infiltration into EMD and the Cu-64 biodistribution confirmed nanoparticle-labelling stability, with no isotope leakage.

Conclusion:

The CARAMEL study demonstrates the feasibility of Cu-64 radiolabeled nanoparticle imaging to track CAR-T cells in myeloma with EMD. Initial results reveal limited early infiltration into EMD lesions, suggesting micro-environmental barriers.

Efficacy of HBI0101, an Anti-BCMA Chimeric Antigen Receptor T-Cell (CART) for Relapsed/Refractory Multiple Myeloma

Speaker: Eyal Lebel, Hadassah Medical Centre, Jerusalem

Key Highlights

HBI0101, an academic anti-BCMA CAR-T therapy, was developed to overcome barriers of cost, production, and stringent eligibility associated with commercial CAR-T therapies. This study evaluated its efficacy, safety, and feasibility in a broader and frailer relapsed/refractory multiple myeloma (RRMM) patient population. The analysis included 96 patients treated with 800 million CAR-T cells.

Study Design:

• Population: Patients with R/R MM who had undergone at least three prior therapies, including a proteasome inhibitor, immunomodulator, and anti-CD38 antibody.
• Bridging therapy was administered to 35% of patients, predominantly in the frozen product cohort, using chemotherapy or radiation. Approximately half of the evaluable patients responded to bridging therapy, though the majority achieved only partial responses.
• Product Variants: Both fresh and cryopreserved CAR-T products were tested, with a transition to cryopreservation.

Patient Characteristics:

• High-risk cytogenetics in 44% (77% including 1q gain).
• 25% had extramedullary disease.
• 85% were triple-refractory; 34% were penta-refractory.
• Nearly 50% would not qualify for registrational CAR-T trials.

Results:

Efficacy

• ORR: 92%.
• Stringent Complete Response (sCR): 64%.
• MRD Negativity: 74%.
• Median PFS: 13.5 months.
• Median OS: Not reached.
• Fresh and frozen products showed comparable efficacy, with a trend favouring frozen CAR-T likely due to bridging therapy.

Safety

1. Hematological Toxicity:
   1. Grade ≥3 anemia (66%), thrombocytopenia (43%), neutropenia (99%).
   2. Persistent cytopenias were rare.
2. Infections: Occurred in 53%, with 13% being grade ≥3.
3. CRS:
   1. Occurred in 95% of patients, with 16% grade 3.
   2. No grade 4/5 CRS or severe neurotoxicity (ICANS).
4. Tocilizumab was used in 90% of cases.

Subgroup Insights:

High-risk cytogenetics, extramedullary disease, and effector memory cell-enriched CAR-T products correlated with shorter PFS. Patients excluded from registrational trials had worse outcomes compared to eligible patients.

AL Amyloidosis Subgroup:

The study included 16 AL amyloidosis patients who achieved a 94% ORR with manageable toxicity, even in frail individuals with multi-organ involvement. Results were published in the Journal of Clinical Oncology (JCO).

Conclusion:

HBI0101 demonstrated high efficacy and manageable safety in a real-world, high-risk myeloma population. This academic CAR-T therapy provides a viable, accessible alternative to commercial CAR-T products, potentially transforming the treatment landscape for RRMM.

Phase 2 Registrational Study of Anitocabtagene Autoleucel for the Treatment of Patients with Relapsed and/or Refractory Multiple Myeloma: Preliminary Results from the IMMagine-1 Trial

Speaker: Ciara Freeman, Moffit Cancer Centre, Tampa

Key Highlights

Anitocabtagene Autoleucel (Anito-cel) utilizes a synthetic D-domain binding region designed for enhanced transduction efficiency, stable expression, and reduced tonic signaling, potentially increasing efficacy while minimizing inflammation. The trial aims to assess Anito-cel’s safety and efficacy in heavily pre-treated relapsed/refractory multiple myeloma (R/R MM) patients.

Patient Population:

1. Eligibility: Triple-class exposed patients with ≥3 prior therapies, including a proteasome inhibitor, immunomodulator, and anti-CD38 antibody, and refractory to their most recent treatment.
2. Enrolment: 129 patients leukapheresed; 117 received CAR-T infusion.
3. Baseline Features:
   1. Median age: 65 years (12% aged >75).
   2. High-risk cytogenetics: 38%; extramedullary disease: 15%.
   3. Triple-refractory majority; 43% penta-refractory.
   4. Outpatient administration: 8%.

Efficacy Results: Follow-Up: Median of 9.5 months.

• ORR: 97%; CR or better: 62%.
• MRD Negativity: Achieved by 93% of evaluable patients at 10^-5 sensitivity within a median of 1 month.
• PFS: 6-month estimate: 93.3%; 12-month estimate: 78.5%.

• OS: Median not reached.

Safety Profile:

1. CRS:
   1. Any-grade: 83%; no CRS in 17%.
   2. Grade ≥2 CRS: Low incidence; median onset: 4 days; resolved by day 14.
2. Neurotoxicity (ICANS):
   1. Incidence: 9%; median onset: 7 days; all resolved within 4 days before discharge.
   2. No delayed or non-ICANS neurotoxicities observed.
3. Adverse Events:
   1. Grade ≥3 cytopenias: Common.
   2. Grade ≥3 infections: 10%.
   3. Three deaths: Grade 5 CRS (n=1), HLH with retroperitoneal hemorrhage (n=1), invasive fungal infection (n=1).

Conclusion:

Anito-cel demonstrates a robust ORR of 97%, high MRD negativity (93%), and manageable toxicity in heavily pre-treated R/R MM patients. These promising results underscore its potential as a transformative therapy, warranting further investigation in randomized trials.

Ciltacabtagene Autoleucel (Cilta-cel) Vs Standard of Care (SoC) in Patients with Lenalidomide (Len)-Refractory Multiple Myeloma (MM) after 1–3 Lines of Therapy: Minimal Residual Disease (MRD) Negativity in the Phase 3 CARTITUDE-4 Trial

Speaker: Rakesh Popat, University College London Hospitals

Key Highlights

CARTITUDE-4 trial evaluated the efficacy of ciltacabtagene autoleucel (Cilta-cel), a BCMA-directed CAR-T therapy, compared to standard-of-care (SoC) regimens in patients with lenalidomide-refractory multiple myeloma (MM) after 1–3 prior lines of therapy.

The study highlighted a significant advantage of Cilta-cel in achieving MRD negativity and sustaining PFS and OS.

Study Design and Population:

• Design: Randomized, multicenter phase 3 trial comparing Cilta-cel to SoC (pomalidomide-bortezomib-dexamethasone or daratumumab-pomalidomide-dexamethasone).
• Patients: 419 with lenalidomide-refractory MM (1–3 prior therapies), randomized to Cilta-cel (n=208) or SoC.

Efficacy Results:

1. MRD Negativity:
   1. At 10^-5 Sensitivity: 62% (Cilta-cel) vs 18.5% (SoC) in intent-to-treat population.
   2. Among MRD-evaluable patients: 89% (Cilta-cel) vs 38% (SoC).
2. Rapid and Deep MRD Negativity with Cilta-cel:
   1. 69% achieved MRD negativity by day 56 post-infusion, rising to 86% at 6 months.
   2. Most MRD-negative responses reached the 10^-6 threshold, underscoring the depth of response.
3. Sustained MRD Negativity:
   1. Achieved in 51% (Cilta-cel) vs 16% (SoC) for ≥12 months.
   2. Strong correlation with prolonged PFS and OS.
4. Survival Outcomes:
   1. PFS: 30-month PFS: 93.2% (MRD-negative Cilta-cel) vs 46.8% (MRD-positive or unevaluable).
   2. OS: 30-month OS: 97.3% (MRD-negative Cilta-cel) vs 65% (MRD-positive).
   3. Median PFS and OS were not reached for Cilta-cel-treated patients.

Subgroup Analysis: Cilta-cel demonstrated consistent MRD-negativity benefits across high-risk subgroups:

• ISS Stage 3.
• High tumor burden.
• High-risk cytogenetics.
• Refractory to ≥2 drug classes.
• Correlates of MRD Negativity

Enhanced Immune Fitness: Higher CD4+ naive T-cells and lower effector memory T-cells at apheresis in MRD-negative patients.

Reduced Inflammatory Markers:

• Lower cytokine levels pre-infusion in MRD-negative responders.
• Improved CAR-T Expansion:
• Greater CAR-T cell expansion in MRD-negative vs MRD-positive patients.

Comparison to CARTITUDE-1:

1. Higher MRD-Negativity Rates in CARTITUDE-4 (Earlier-Line Therapy) vs CARTITUDE-1 (Relapsed/Refractory Disease):
   1. At 10^-5: 89% vs 68%.
   2. At 10^-6: 86% vs 58%.
2. Better 30-month PFS and OS Outcomes in CARTITUDE-4:
3. OS: 84% (CARTITUDE-4) vs 68% (CARTITUDE-1).

Conclusion:

Cilta-cel significantly outperformed SoC in achieving rapid, deep, and sustained MRD negativity, translating into superior PFS and OS outcomes. Sustained MRD negativity was a key predictor of long-term survival, reinforcing its prognostic value. These results position Cilta-cel as a highly effective therapy in earlier lines of treatment for lenalidomide-refractory MM. Further investigation into long-term outcomes and operational cure potential is warranted.

ASH Annual Meeting and Exposition, 7-10 December 2024, San Diego, California