Summary

• The pharmacokinetics (PK) of CARVYKTI was assessed in 285 adult patients with relapsed/refractory multiple myeloma (RRMM) in CARTITUDE-1 and CARTITUDE-4 receiving a single infusion at a median dose of 0.71×10⁶ chimeric antigen receptor (CAR)+ viable T cells/kg (range, 0.41×10⁶ to 1.08×10⁶ cells/kg).¹
• Following a single infusion, CARVYKTI exhibited an initial expansion phase followed by a rapid decline and then a slower decline. However, high interindividual variability was observed.¹
• After a single infusion of CARVYKTI, expansion of CAR+ T cells coincided with decreases of serum soluble B-cell maturation antigen (sBCMA), serum M-protein, and/or free light chains. Across all patients, levels of interleukin (IL)-6, IL-10, interferon gamma (IFN-γ), and IL-2 receptor alpha (IL-2Rα) increased post-infusion and peaked at days 7-14. The serum levels of all cytokines generally returned to baseline levels within 2-3 months post-infusion.¹
• CARTITUDE-1 (MMY2001) was a phase 1b/2, open-label study that evaluated CARVYKTI in patients with RRMM who had previously received a proteasome inhibitor (PI), an immunomodulatory drug, and an anti-cluster of differentiation 38 (anti-CD38) antibody. The combined analysis from the phase 1b/2 portions of the CARTITUDE-1 study evaluated the efficacy and safety of CARVYKTI in 97 patients with RRMM.^2-4
  • Chang et al (2023)⁵ presented PK and pharmacodynamic (PD) profiles of CARVYKTI from 97 patients included in the CARTITUDE-1 study at a follow-up of approximately 24 months after the last patient dosed (LPD). Additionally, the analysis explored the exposureresponse relationship between CARVYKTI exposure and CAR-T cell neurotoxicity. Maximum observed concentration of CARVYKTI transgene (C_max) and time to peak peripheral expansion (T_max) were 48,692±27,174 copies/µg genomic deoxyribonucleic acid (gDNA) and 12.71 days (range, 8.73-329.77), respectively.
  • Montes de Oca et al (2023)⁶ presented the correlation of clinical response to
    CARVYKTI from the CARTITUDE-1 study at a median follow up of 33.4 months (range, 1.545.2). Prior to infusion, the CARVYKTI drug product exhibited an approximate central memory/effector memory T-cell ratio of 1:1, with median percentages of 33% and 37%, respectively. At T_max, CAR+CD8+ cells expanded preferentially (P=3.6×10^-24). C_max and persistence (time of last measurable concentration [T_last]) for CARVYKTI did not associate with best response or progression-free survival (PFS); however, longer PFS was observed in patients with a higher effector to target ratio.
  • Berdeja et al (2021)² reported the results from the CARTITUDE-1 study at a median follow-up of 12.4 months. The T_max of CAR+ T cells was 12.7 days (range, 8.754.6).
  • Singh et al (2020)⁷ presented the preliminary PK and PD analysis of CARVYKTI in patients from the phase 1b cohort of the CARTITUDE-1 study. The mean number of CAR transgene copies was 38,965 copies/μg gDNA at C_max. All patients reported a decline in serum sBCMA and M-protein levels after the administration of CARVYKTI.
  • Zudaire et al (2019)⁸ presented a translational analysis of PK and response data from the phase 1b cohort of the CARTITUDE-1 study. Best responses were independent of C_max and persistence of CAR+ T cells. The CD4:CD8 ratio in peripheral blood at C_max was positively correlated with that in bone marrow at day 28. Preferential expansion of CAR+ CD8 central memory T cells was observed at C_max.
  • A population-based cellular kinetic model was developed to characterize the CAR transgene levels following a single intravenous (IV) infusion of CARVYKTI in patients with RRMM who were enrolled in the CARTITUDE-1 study. The median number of total CAR+ viable T cells was 54.3×10⁶ (range, 23.5×10⁶-93.1×10⁶) in the total population (N=97). The median model-predicted C_max was 34,200 copies/µg gDNA (range, 5560-123,000).⁹
• CARTITUDE-2 (MMY2003) is an ongoing, phase 2, open-label, multicohort, single-arm, multicenter study evaluating the efficacy and safety of CARVYKTI in patients with multiple myeloma (MM) in various clinical settings.¹⁰ Janssen does not recommend the use of CARVYKTI in a manner that is inconsistent with the approved labeling.
  • Cohort A is evaluating the efficacy and safety of CARVYKTI in patients who had progressive MM after 1-3 prior lines of therapy (LOT) and were refractory to lenalidomide. The Cohort A initial subgroup analysis evaluated the efficacy and safety of CARVYKTI manufactured with the clinical trial process in 20 patients.¹¹
    • The peak expansion of CAR-T cells occurred on day 11 (range, 8.7-42.9) and the median persistence was 153 days (range, 57.1-336.8). A trend of increasing CD4/CD8 ratio associated with the severities of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) was observed.¹¹
  • Cohort B is evaluating the efficacy and safety of CARVYKTI in 19 patients who had early relapse after initial therapy with a PI and an immunomodulatory drug.^12,13
    • The peak expansion of CAR-T cells occurred on day 13 (range, 9.8-14.8); median persistence was 76 days (range, 26.9-273.1). CD4/CD8 ratio was not associated with the severities of CRS and ICANS.^12,13
  • Cohort C is evaluating the efficacy and safety of CARVYKTI in 20 patients with RRMM after receiving a PI, an immunomodulatory drug, an anti-CD38 antibody, and a noncellular B-cell maturation antigen (BCMA)-directed therapy. Noncellular BCMA-directed therapy included bispecific monoclonal antibodies (BsAbs) or antibody-drug conjugates (ADCs) as monotherapy or combination LOT.^10,14,15
    • After infusion, an initial expansion phase of the CAR transgene, with a T_max of approximately 15 days (range, 9-41), followed by a rapid decline phase and then a slower decline over months was observed. The median time to the last measurable CAR transgene was approximately 127 days (range, 15-213).¹⁴
    • At a median follow-up of 18 months, central memory CAR+ T cells were dominant in both CD4+ and CD8+ T-cell compartments at T_max in the ADCexposed and BsAb-exposed groups.¹⁶
  • Cohort D is evaluating the efficacy and safety of CARVYKTI with or without lenalidomide maintenance in 17 patients with RRMM who achieved less than complete response (<CR) after frontline autologous stem cell transplantation (ASCT).^10,17,18
    • At a median follow-up of 22.4 months (range, 4.7-39.3), both CAR+ CD4 and CAR+ CD8 T cell expansion was observed after infusion; however, CAR+ CD8 T cells expanded more than CAR+ CD4 T cells in blood. CAR+ CD4:CD8 T-cell ratios were lower in blood at ~T_max than in drug product (P<0.005).¹⁷
  • Wu et al (2024)¹⁹ presented cellular kinetics, PD, and immunogenicity of CARVYKTI for CARTITUDE-2 Cohorts A, B, and C to study CARVYKTI in vivo expansion and its relationships with clinical factors in various MM populations. Cohorts A, B, and C showed similar cellular kinetic profiles, with an initial expansion phase followed by a rapid and then slower decline over months. High interindividual variability of CARVYKTI exposure was noted. The median T_max ranged from 11 to 15 days. A higher mean C_max was observed in Cohorts A and B with a lower C_max noted in Cohort C; area under the curve in the first 28 days following CARVYKTI administration (AUC_0-28d) was comparable across the 3 cohorts. The overall incidence of treatment-emergent antidrug antibodies (ADAs) to CARVYKTI was 25.0% for Cohorts A and C and 42% for Cohort B.
• CARTITUDE-4 (MMY3002) is a phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI vs standard care (physician's choice of pomalidomide, bortezomib, and dexamethasone [PVd] or DARZALEX FASPRO^® [daratumumab and hyaluronidase], pomalidomide, and dexamethasone [DPd]) in adult patients with lenalidomide-refractory MM after 1-3 prior LOT.^20,21
  • The PK of CARVYKTI was assessed in the 176 patients who received CARVYKTI as study treatment. CD3+ CAR+ T cells reached a mean ± standard deviation C_max of 1451±6169 cells/µL at a median of 13 days. Mean AUC_0-28d of CD3+ CAR+ T cells in the blood was 11,710±56,994. Both CAR+ CD4 and CD8 T cells expanded after infusion (greater expansion was observed with CAR+ CD8 T cells). Central memory CAR+ T cells were dominant in both CD4+and CD8+ T-cell compartments at T_max.^20,22
  • Costa et al (2024)²³ presented the efficacy and safety outcomes in patients who received 1 prior LOT, including the subset of patients with functionally high-risk MM, in the CARTITUDE-4 study. Preferential CD8+ CAR+ T-cell expansion and dominant central memory phenotypes were comparable between patients with 1 prior LOT with and without functionally high-risk MM status. Patients with 1 prior LOT showed similar peak expansion of CAR-T cells and baseline sBCMA levels with and without a functionally high-risk MM status.
• van de Donk et al (2023)²⁴ presented the clinical presentation and management of cranial nerve palsy (CNP) in patients treated with CARVYKTI in the CARTITUDE-1; CARTITUDE-2 Cohorts A, B, and C; and CARTITUDE-4 study. A total of 16/176 patients experienced CNP in the CARTITUDE-4 study. In patients with and without CNP, T cells with a central memory phenotype were dominant in the CD4 and CD8 CAR+ T compartments at T_max. Patients with CNP had significantly higher CAR+ T-cell C_max and exposure (mean area under the curve till CNP onset) than those without CNP (P<0.001 for both). Patients with vs without CNP had significantly higher C_max of IL-10 and higher exposure levels up to CNP onset of IL-10 and IL-2Rα. Patients with CNP tended to have higher peak IL-6 and IL-2Rα levels and higher exposure levels of IL-6.

PRODUCT LABELING

Prescribing Information

• CARVYKTI (ciltacabtagene autoleucel) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/CARVYKTI-pi.pdf.
• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf.

Pharmacokinetics

The PK of CARVYKTI was assessed in 285 adult patients with RRMM in CARTITUDE-1 and CARTITUDE-4 receiving a single infusion at a median dose of 0.71×10⁶ CAR+ viable T cells/kg (range, 0.41×10⁶ to 1.08×10⁶ cells/kg).¹

Following a single infusion, CARVYKTI exhibited an initial expansion phase followed by a rapid decline and then a slower decline. However, high interindividual variability was observed. Specific PK parameters can be found in Table: Pharmacokinetic Parameters of CARVYKTI in Patients With MM.¹

After the cell expansion, the persistence phase of CARVYKTI was observed for all patients. At the time of analysis in the CARTITUDE-1 (n=65) and CARTITUDE-4 (n=87) studies, the median time for CAR transgene levels in peripheral blood to return to the pre-dose baseline level was approximately 100 days (range, 28-365 days) and 109 days (range, 29-366 days) post-infusion respectively.¹

Detectable CARVYKTI exposures in the bone marrow indicate a distribution of CARVYKTI from systemic circulation to the bone marrow. Similar to blood transgene levels, bone marrow transgene levels declined over time and exhibited high interindividual variability. Patients with higher CAR-T cell expansion tended to have higher rates of CRS. Some patients required tocilizumab, corticosteroids, and anakinra for the management of CRS. CARVYKTI continues to expand and persist following the administration of tocilizumab, corticosteroids, and anakinra. In CARTITUDE-1, CARVYKTI median C_max and AUC_0-28d in patients treated with tocilizumab (n=68) for CRS were 168% and 209% of those in patients (n=29) who did not receive tocilizumab for CRS, respectively. The median C_max and AUC_028d of CARVYKTI in patients who received corticosteroids (n=21) for CRS were 186% and 307% of those in patients who did not receive corticosteroids (n=76) for CRS, respectively. In addition, the median C_max and AUC_0-28d of CARVYKTI in patients who received anakinra (n=18) for CRS were 139% and 232% of those in patients who did not receive anakinra (n=79) for CRS, respectively.¹

In CARTITUDE-4, the results related to tocilizumab and corticosteroid were consistent with CARTITUDE-1.¹

Specific Populations

The PK of CARVYKTI (C_max and AUC_0-28d) were not impacted by age (27-78 years), gender, body weight, race, mild hepatic dysfunction ([total bilirubin ≤ upper limit of normal {ULN} and aspartate aminotransferase > ULN] or [ULN < total bilirubin ≤1.5 times ULN]), mild renal dysfunction (60 mL/min ≤ creatinine clearance [CrCL] <90 mL/min), or moderate renal dysfunction (30 mL/min ≤ CrCL <60 mL/min). Formal renal and hepatic impairment studies of CARVYKTI were not conducted.¹

Pharmacodynamics

After a single infusion of CARVYKTI, expansion of CAR+ T cells coincided with decreases of serum sBCMA, serum M-protein, and/or free light chains. Across all patients, levels of IL-6, IL-10, IFN-γ, and IL-2Rα increased post-infusion and peaked at days 7-14. The serum levels of all cytokines generally returned to baseline levels within 2-3 months post-infusion.¹

Clinical Data - Cartitude-1 - Phase 1B/2 STUDY

CARTITUDE-1 (MMY2001; clinicaltrials.gov identifier: NCT03548207) was a phase 1b/2, open-label, single-arm, multicenter study that evaluated the safety and efficacy of CARVYKTI in patients with RRMM who had previously received a PI, an immunomodulatory drug, and an anti-CD38 antibody. The combined analysis from the phase 1b/2 portions of the CARTITUDE-1 study evaluated the safety and efficacy of CARVYKTI in 97 patients with RRMM.^2,3

Study Design/Methods

• The study design is presented in Figure: CARTITUDE-1 Study Design.

Chang et al (2023)⁵ presented PK and PD profiles of CARVYKTI from the CARTITUDE-1 study. Additionally, the analysis explored the exposureresponse relationship between
CARVYKTI exposure and CAR-T cell neurotoxicity, including ICANS, other neurotoxicities, and movement and neurocognitive treatment-emergent adverse events (MNTs).

Study Design/Methods

• PK was evaluated by measuring the CAR transgene copies/μg gDNA in blood using quantitative polymerase chain reaction (qPCR).
• PD was evaluated by measuring the sBCMA in serum using a ligand binding assay.
• Exposureresponse analyses were performed on the basis of the data extracted from 97 patients with approximately 24 months of follow-up after the LPD.

Results

• Overall, 97 patients received a single infusion of CARVYKTI at a target dose of 0.75×10⁶ CAR+ viable T cells/kg (range, 0.5-1.0×10⁶).

Pharmacokinetics

• After a single infusion, CARVYKTI showed an initial expansion phase, followed by a rapid decline, succeeded by a slower decline, demonstrating transgene persistence over the course of several months. See Figure: Mean Blood Concentration-Time Curves of CARVYKTI Transgene in CARTITUDE-1.
• CARVYKTI transgene PK are presented in Table: Transgene PK Parameters in CARTITUDE-1.
• There was no clear CARVYKTI dose-exposure (AUC_0-28d) relationship.

Pharmacodynamics

• For all 97 patients, the mean sBCMA reached nadir levels around lower limit of quantification (LLOQ) between days 78 and 100 after a single infusion.
  • Following the decline, sBCMA concentrations increased from the nadir in some patients but remained lower than baseline levels.

ExposureResponse Analyses

• There was no association between the total administered dose of CARVYKTI and the occurrence of ICANS and other neurotoxicities.
• Apparent higher median CAR-transgene PK metrics (C_max and AUC_0-28d) was observed in patients with CAR-T cell neurotoxicity vs those without neurotoxicity adverse events (AEs) for all-grade ICANS events and all-grade other neurotoxicities.
• The association between exposure and neurotoxicity AEs was not clear due to wide overlapping ranges of PK transgene levels and high interindividual variability.

Montes de Oca et al (2023)⁶ presented the correlation of clinical response to CARVYKTI from the CARTITUDE-1 study at the ~3-year follow-up.

Study Design/Methods

• Drug product, samples of baseline and post-infusion whole blood and bone marrow were analyzed via flow cytometry, Meso Scale Discovery immunoassays, Cellular Indexing of Transcriptomes and Epitopes by Sequencing, and T-cell receptor sequencing.
• Correlative analyses were performed with best confirmed response and PFS at ~3-year follow-up.

Results

• At a data cutoff of October 14, 2022, and median follow-up of 33.4 months (range,
  1.5-45.2), 97 patients were treated with CARVYKTI.

Pharmacokinetics

• The median proportion of CAR+ T cells in the drug product was 16% (range, 5-32).
• Prior to infusion, the CARVYKTI drug product exhibited an approximate central memory/effector memory T-cell ratio of 1:1, with median percentages of 33% and 37%, respectively.
  • Following infusion, a significant enrichment in central memory T-cells was observed at T_max.
• At T_max, CAR+CD8+ cells expanded preferentially (P=3.6×10^-24); CAR+CD4+ T cells (central memory T-cell median, 95% [range, 62-99.5]) and CAR+CD8+ T cells (central memory T-cell median, 96% [range, 33-99.7]) had a predominantly central memory phenotype. See Figure: CAR+ T-cell Characterization at T_max in CARTITUDE-1.
• CAR+ T-cell expansion and persistence were variable.
• CARVYKTI peak expansion (C_max) and persistence (T_last) were not associated with best response or PFS. See Figure: CAR-T cells C_max by Best Response in CARTITUDE-1. Longer PFS was observed in patients with a higher effector to target ratio. See Figure: PFS by CAR+ T cell to sBCMA Ratio in CARTITUDE1.

Pharmacodynamics

• Baseline expression of BCMA and sBCMA levels in plasma cells were not significantly associated with best response; however, higher baseline sBCMA levels prior to infusion was associated with shorter PFS (P=0.0098).
• In patients with plasmacytomas vs those without plasmacytomas, the 2-year PFS rate was 47% vs 66% (P=0.042).
  • In patients with high- vs standard-risk cytogenetics, the 2-year PFS rate was 48% vs 67%
  • In patients with bone marrow plasma cells ≥60% vs >30% to <60% vs ≤30%, the 2-year PFS rate was 52% vs 59% vs 69%, respectively.

Berdeja et al (2021)² reported results from the CARTITUDE-1 study at a median follow-up of 12.4 months (interquartile range, 10.6-15.2).

Results

• Overall, 113 patients enrolled/apheresed and 97 patients were treated with CARVYKTI.

Pharmacokinetics

• Median T_max of CAR+ T cells was 12.7 days (range, 8.7-54.6).
• Most patients who had 6 months of follow-up had CARVYKTI CAR transgene concentration below the level of quantification (<50 CAR gene copies per µg gDNA) in peripheral blood.
• Expansion and persistence of CAR+ T cells in peripheral blood at the 12.4-month followup are shown in Figure: Expansion and Persistence of CAR+ T cells in Peripheral Blood in CARTITUDE-1 (12.4-Month Follow-up).

Singh et al (2020)⁷ presented the preliminary PK and PD analysis of CARVYKTI in patients from the phase 1b cohort of the CARTITUDE-1 study.

Results

• All 29 enrolled patients received study treatment, 10 of whom had detectable peripheral CAR transgene levels and CAR+ T cells at a 6-month follow-up.

Pharmacokinetics

• Median T_max of CAR+ T cells was approximately 13 days (range, 7.7-20.0) after infusion. PK parameters from evaluable patients (n=29) are summarized in Table:
  PK Parameters in CARTITUDE-1.
• C_max did not appear to be associated with observed best response at data cutoff.

Pharmacodynamics

• All patients showed similar kinetics of decline in serum sBCMA levels upon CAR-T cell expansion, suggesting CAR-T cell-mediated PD activity.
• At a median follow-up of 11.5 months (range, 3-17), all patients achieved a reduction in M-protein levels.

Zudaire et al (2019)⁸ presented a translational analysis of PK and response data from the phase 1b cohort of the CARTITUDE-1 study.

Results

• Data from 29 patients with a median follow-up of 6 months (range, 3-14) were included.

Pharmacokinetics

• At C_max, the median number of CAR transgene copies was 38,282 copies/μg gDNA (range, 9574-83,603).
  • Median CAR+ CD3 T-cell count was 647 cells/μL (range, 26-3458).
  • Median percentage of CAR+ CD3 T cells among total T cells was 68% (range, 20%-87%).
• The number of CAR+ T cells/μL was below the limit of quantification (2 cells/μL) in 18 of 28 patients at a 3-month follow-up.
• Expansion and persistence of CAR+ T cells was not associated with best response.
• An initial median CD4:CD8 ratio of 1.54 in the drug product during administration was associated with post-expansion median CD4:CD8 ratios of 0.33in peripheral blood at C_max and 0.4 in bone marrow at day 28. The CD4:CD8 ratio in peripheral blood at C_max was positively correlated with that in bone marrow at day 28.
• Preferential expansion of CAR+ CD8 central memory T cells was observed at C_max.

Population-Based PK Model From the CARTITUDE-1 Study

Wu et al (2022)⁹ developed a population-based cellular kinetic model to characterize the CAR transgene levels following a single IV infusion of CARVYKTI in adult patients with RRMM who were enrolled in the CARTITUDE-1 study.

Study Design/Methods

• The CAR transgene levels in the blood were measured by qPCR.

Results

• The population analysis dataset included 1306 CARVYKTI transgene levels from all 97 patients enrolled in the CARTITUDE-1 study.
• The median of the last PK-assessment timepoints was 11.7 months (range, 1.2-23.4).

Pharmacokinetics

• After a single IV infusion, CARVYKTI exhibited an initial expansion phase followed by a rapid decline and then a slower decline with persistence over months. High
  inter-individual variability was reported.
• The number of total CAR+ viable T cells are summarized in Table: Total CAR+ Viable T cells in CARTITUDE-1.
• Model-predicted exposure metrics of CARVYKTI are described in Table: Model-Predicted PK Parameters in CARTITUDE-1.
• A covariate analysis revealed no statistically significant effect of the analyzed product-, patient-, and disease-related covariates on the PK of CARVYKTI.

CLINICAL DATA - cartitude-2 - PHASE 2 STUDY

CARTITUDE-2 (MMY2003; clinicaltrials.gov identifier: NCT04133636) is an ongoing, phase 2, open-label, multicohort, single-arm, multicenter study evaluating the efficacy and safety of CARVYKTI in patients with MM in various clinical settings.¹⁰

• Cohort A is evaluating the efficacy and safety of CARVYKTI in patients who had progressive MM after 1-3 prior LOT and were refractory to lenalidomide. The Cohort A initial subgroup analysis evaluated the efficacy and safety of CARVYKTI manufactured with the clinical trial process in 20 patients.¹¹
• Cohort B is evaluating the efficacy and safety of CARVYKTI in 19 patients who had early relapse after initial therapy with a PI and an immunomodulatory drug.^12,13
  • Early relapse was defined as progression within 12 months after ASCT or from start of anti-MM therapy for patients who have not had an ASCT.^10,12,13
• Cohort C is evaluating the efficacy and safety of CARVYKTI in 20 patients with RRMM after receiving a PI, an immunomodulatory drug, an anti-CD38 antibody, and a noncellular BCMA-directed therapy. Noncellular BCMA-directed therapy included BsAbs or ADCs as monotherapy or combination LOT.^10,14-16
• Cohort D is evaluating the efficacy and safety of CARVYKTI with or without lenalidomide maintenance in 17 patients with RRMM who achieved <CR after frontline ASCT.^17,18

Study Design/Methods

• Key eligibility criteria for Cohort A: adult patients with progressive MM after 13 prior LOT, including a PI and an immunomodulatory drug, who were lenalidomide refractory, had no prior exposure to BCMA-targeting drugs or CAR-T cell therapy directed at any target, and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤1.¹⁰
• Key eligibility criteria for Cohort B: adult patients who received 1 prior LOT including a PI and an immunomodulatory drug, had disease progression per International Myeloma Working Group (IMWG) criteria ≤12 months after ASCT or ≤12 months from the start of antimyeloma therapy (for patients who did not receive ASCT), had no prior exposure to BCMAtargeting drugs or CAR-T cell therapy directed at any target, and had an ECOG PS of ≤1.¹⁰
• Key eligibility criteria for Cohort C: adult patients who were previously treated with a PI, an immunomodulatory drug, an anti-CD38 antibody, and a noncellular BCMAdirected therapy (ADC or BsAb as monotherapy or combination therapy), having a diagnosis of MM per IMWG criteria and evidence of progressive MM ≤12 months of last LOT or ≤6 months of prior therapy and refractory to their most recent LOT, with measurable disease at baseline and an ECOG PS of ≤1. BCMA expression was not required for eligibility.^10,14,16
• Key eligibility criteria for Cohort D: adult patients with a history of 4 to 8 total cycles of initial therapy, including induction, high-dose chemotherapy, and ASCT with or without consolidation; overall best response <3; had no prior exposure to BCMAtargeting drugs or CAR-T cell therapy directed at any target; and had an ECOG PS of ≤1.^10,17,18
• Dosing: patients received a single infusion of CARVYKTI at a target dose of 0.75×10⁶ viable CAR+ T cells/kg (target range, 0.5-1.0×10⁶) 5-7 days after the start of lymphodepletion/conditioning regimen (cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² daily for 3 days on days -5 to -3).^10,13-15
• Primary endpoint: percentage of patients with minimal residual disease (MRD) negativity at the 10^-5 sensitivity level defined by IMWG criteria (assessed by nextgeneration sequencing or next-generation flow).^10-15,28
• Key secondary endpoints: overall response rate (ORR) per the IMWG response criteria, duration of response, time and duration of MRD-negativity, time to response, and incidence and severity of AEs.^10-15,28
  • Additional Cohort C analysis: in the T-cell phenotype analyses, markers included CD45RO/CD27. The memory T-cell phenotype-specific marker CD27 replaced a previously used CC-chemokine receptor 7 T-cell marker.¹⁶
    • Central memory cells: CD45RO⁺/CD27⁺
    • Effector memory cells: CD45RO⁺/CD27^-
    • Naïve T cells: CD45RO^-/CD27⁺
    • Terminally differentiated effector memory (TEMRA) T cells: CD45RO^-/CD27^-

Results

Pharmacokinetics and Pharmacodynamics - Cohort A

• Peak expansion of CAR+ T cells occurred on day 11 (range, 8.7-42.9). The median persistence was 153 days (range, 57.1-336.8).¹¹
• The levels of IL-6, IFN-γ, IL-2Rα, and IL-10 increased after infusion and peaked at days 7-14. The levels returned to baseline within 2-3 months after infusion.¹¹
• Higher cytokine levels were associated with higher CRS severity with similar profiles for levels of IFN-γ, IL-2Rα and IL-10.¹¹
• A trend of increasing CD4/CD8 ratio being associated with increasing severities of CRS and ICANS was observed.¹¹

Pharmacokinetics and Pharmacodynamics - Cohort B

• Peak expansion of CAR+ T cells occurred on day 13 (range, 9.8-14.8). The median persistence was 76 days (range, 26.9-273.1).¹³
• Levels of IL-6, IFN-γ, IL-2Rα, and IL-10 increased after infusion and peaked at days
  7-14. The levels returned to baseline within 2-3 months after infusion.¹²
• Higher IL-6 levels were associated with higher CRS severity with similar profiles for levels of IFN-γ, IL-2Rα and IL-10.¹²
• CD4/CD8 ratio was not associated with the severity of CRS and ICANS.¹²
• CD4/CD8 CAR+ T-cell ratio was stable around 1:1 after CARVYKTI infusion.¹³

Pharmacokinetics and Pharmacodynamics - Cohort C

• The PK of CARVYKTI was characterized by CAR transgene levels and CAR+ T cells in peripheral blood and bone marrow.¹⁴
• After infusion, there was an initial expansion phase of the CAR transgene, with time to maximum concentration around 15 days (range, 9-41), followed by a rapid decline phase and then a slower decline over months. The median time to the last measurable CAR transgene was approximately 127 days (range, 15-213).¹⁴
• CAR transgene exposure parameters including C_max and AUC_0-28d showed slightly higher mean values in the BsAb group compared with the ADC group. Similar observations were noted when measuring CAR+ T cells in the blood.¹⁴
• Prior to CARVYKTI infusion, the mean serum BCMA level at baseline was 211 µg/L (range, 0.4-943) and 203 µg/L (range, 1.3-541) for the ADC and BsAb group, respectively. Serum BCMA decreased after CARVYKTI infusion, with mean serum concentrations reaching nadir levels near the LLOQ around day 100.^14,15
  • All patients with progressive disease in the study (n=9: ADC group, n=7; BsAb group, n=2) had serum BCMA levels at the time of progression similar to baseline levels prior to CARVYKTI treatment. No correlation was identified between baseline BCMA and clinical response.¹⁴
• At baseline, 3 patients in the ADC group (23%) were positive for ADAs. There was no increase in ADAs observed during follow-up. No patients in the BsAb group were positive for ADAs at baseline or during follow-up.¹⁴

CD4+ and CD8+ T-cell Phenotypes

• At a median follow-up of 18 months, central memory CAR+ T cells were dominant in both CD4+ and CD8+ T-cell compartments at T_max in the ADCexposed and BsAbexposed groups.¹⁶
  • At apheresis, the majority of CD4+ T cells included central memory cells, and CD8+ T cells included a significant amount of central memory cells, stem cell-like memory cells, and TEMRA cells.¹⁶
    • T-cell phenotypes were similar in patients with prior ADC vs prior BsAb exposure.

Pharmacokinetics and Pharmacodynamics - Cohort D

• CAR-T cell expansion profile at a median follow-up of 22.4 months (range, 4.7-39.3) is presented in Table: CARTITUDE-2 (Cohort D): CAR-T Cell Expansion Profile.¹⁷
• Both CAR+ CD4 and CAR+ CD8 T cells expanded after infusion.¹⁷
  • CAR+ CD8 T cells expanded more than CAR+ CD4 T cells in blood. See Figure: CARTITUDE-2 (Cohort D): CAR+ CD4 and CAR+ CD8 T-cell Levels.
• CAR+ CD4:CD8 T-cell ratios were lower in blood at ~T_max than in drug product (P<0.005). See Figure: CARTITUDE-2 (Cohort D): CAR+ CD4:CD8 T-cell Ratio.¹⁷

Clinical Pharmacological Characterization of CARVYKTI in CARTITUDE2

Wu et al (2024)¹⁹ presented cellular kinetics, PD, and immunogenicity data from CARTITUDE-2 Cohorts A, B, and C, evaluating CARVYKTI in vivo expansion and its relationships with clinical factors in various MM populations.

Study Design/Methods

• Cellular kinetics was evaluated in Cohorts A (first 20 patients who received CARVYKTI treated via the clinical trial process), B, and C by measuring CAR transgene copy levels and CAR⁺CD3⁺ cell levels in blood after a single infusion of 0.75 ×10⁶ CAR-positive viable T cells/kg (range, 0.5-1.0).
• For PD evaluation, sBCMA levels in serum were measured using a ligand binding assay.
• Serum samples were analyzed for antibodies binding to CARVYKTI (ie, ADAs).

Results

Pharmacokinetics

• CARVYKTI PK measurements, using transgene and cellular levels, were consistent.
• Cohorts A, B, and C showed similar cellular kinetic profiles, with an initial expansion phase followed by a rapid and then slower decline over months. High interindividual variability was noted. See Figure: Mean (+SD) Blood CARVYKTI CAR Transgene Levels vs Time Profile.
• A higher mean C_max was observed in Cohorts A and B with a lower C_max noted in Cohort C; AUC_0-28d was comparable across the 3 cohorts.
• Among Cohorts A, B, and C, median T_max ranged from 11 to 15 days, and the median time to reach below quantification levels (T_bql) was similar, ranging from 125 to 157 days. See Table: Pharmacokinetic Parameters of CARVYKTI Transgene Levels in Blood Following a Single Infusion of CARVYKTI.
• No clear dose-exposure relationship was seen across the 3 cohorts.

Pharmacodynamics

• CAR-positive T-cell expansion and persistence coincided with a reduction in sBCMA levels after a single CARVYKTI infusion.
• Mean sBCMA levels reached their nadir (LLOQ <0.250 μg/L) on day 56 for Cohort A and on day 100 for Cohorts B and C. sBCMA levels gradually increased in some patients; most patients maintained sBCMA levels significantly lower than baseline for up to 1 year after infusion.

Immunogenicity

• The overall incidence of treatment-emergent ADAs to CARVYKTI was 25.0% for Cohorts A and C and 42% for Cohort B.
• Median ADA onset ranged from 57 to 186 days across the 3 cohorts.
• Similar cellular kinetics was observed between ADA-positive and ADA-negative patients across all cohorts.
• The observed median ADA onset (57-186 days) occurred much later than the reported median T_max (approximately 14 days).
• No apparent impact of ADAs was observed on the CARVYKTI cellular kinetic parameters (C_max and AUC_0-28d).

CLINICAL DATA - cartitude-4 - PHASE 3 STUDY

CARTITUDE-4 (MMY3002; clinicaltrials.gov identifier: NCT04181827) is an ongoing, phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI vs standard care (physician's choice of PVd or DPd) in adult patients with lenalidomide-refractory MM after 1-3 prior LOT.²⁰

Additionally, the CAR-T cell PK and phenotypes results, sBCMA levels, and correlates of response and relapse from the CARTITUDE-4 study were also reported.²²

Study Design/Methods

• The study design is shown in Figure: CARTITUDE-4 Study Design.
• CAR+ T-cell levels in blood were evaluated for PK using samples collected on day 1 pre-infusion, and then evaluated on days 3, 7, 10, 14, 28, 56, 84, and 112, every
  8 weeks for up to 1 year starting on day 140, and at disease progression or end of study.²⁹

Results

Pharmacokinetics

• CARVYKTI PK were assessed in the 176 patients who received CARVYKTI as study treatment.²⁰
• Patients received a median of 53.1×10⁶ CAR+ viable T cells (range, 22.7106.5×10⁶).^20,22
• CD3+ CAR+ T cells reached C_max of 1451 cells/µL at a median of 13 days. Additional PK parameters are shown in Table: PK Parameters in CARTITUDE-4.^20,22
• Both CAR+ CD4 and CD8 T cells expanded after infusion (greater expansion was observed with CAR+ CD8 T cells).²²
  • CAR+ CD4:CD8 T-cell ratios were lower in blood at ~T_max than in the drug product (P<0.0001; See Figure: CAR+ CD4 and CD8 T-cell Levels in CARTITUDE-4).
• Central memory CAR+ T cells with a central memory phenotype were dominant in both CD4+and CD8+ T-cell compartments at T_max.²²
• CAR+ T-cell peak expansion and exposure can be seen in Figure: CAR+ T-cell Peak Expansion and Exposure in CARTITUDE-4.²²
• Maximum CAR+ T-cell expansion and exposure appeared comparable in patients with
  ≥CR and ≤very good partial response (VGPR); however, the analyses were limited by the ORR and ≥CR rate.²²
• In patients with progressive disease vs patients with no progressive disease, CAR+
  T-cell expansion (C_max; median, 243 vs 510 cells/μL) and exposure (AUC_0-28d; median, 1998.5 vs 4509.9 cells×day/μL) were comparable.²²
• sBCMA levels decreased in all patients, with a median time to undetectability of 56 days.²²
  • After an initial decrease, the sBCMA levels increased in patients who had progressive disease after CARVYKTI infusion.
  • As sBCMA levels increased, CAR+ T-cell reappearance or re-expansion was not observed.

Costa et al (2024)²³ presented efficacy and safety outcomes in patients who received 1 prior LOT, including the subset of patients with functionally high-risk MM, in the CARTITUDE-4 study.

Results

Patient Demographics and Disease/Treatment Characteristics

• A total of 136 patients received 1 prior LOT in the CARTITUDE-4 study.
  • In the CARVYKTI arm, 68 patients underwent apheresis/bridging therapy; 40 patients had functionally high-risk MM.  Of the 68 patients, 60 received CARVYKTI as study treatment; 35 patients had functionally high-risk MM.
  • A total of 68 patients received standard care; 39 of these patients had functionally high-risk MM.
  • Functionally high-risk MM defined as progressive disease ≤18 months after receiving ASCT or the start of initial frontline therapy in patients with no ASCT.

Pharmacokinetics

• Preferential CD8+ CAR+ T-cell expansion and dominant central memory phenotypes were comparable between patients with 1 prior LOT with and without functionally high-risk MM status.
  • In patients with 1 prior LOT, with and without a functionally high-risk MM status, CAR+ CD4:CD8 T-cell ratios were notably reduced in blood at near T_max compared with the levels in the drug product. See Figure: CARTITUDE-4: CAR+ CD4:CD8 T-cell Ratios in Patients With 1 Prior LOT With and Without Functionally High-Risk MM Status.
  • Central memory T-cell phenotypes were dominant in CD4+ and CD8+ CAR+ compartments at T_max in patients with 1 prior LOT with and without functionally high-risk MM status.
• Patients with 1 prior LOT showed similar peak expansion of CAR-T cells and baseline sBCMA levels with and without a functionally high-risk MM status. See Figure: CARTITUDE-4: CAR-T Peak Expansion and Baseline sBCMA in Patients With 1 Prior LOT With and Without Functionally High-Risk MM Status.

Clinical Experience With CNP in CARTITUDE-1, CARTITUDE-2, and CARTITUDE-4

van de Donk et al (2023)²⁴ presented the clinical presentation and management of CNP in patients treated with CARVYKTI in the CARTITUDE-1; CARTITUDE-2 Cohorts A, B, and C; and CARTITUDE-4 study.

Study Design/Methods

• Peripheral blood levels of CARVYKTI and CAR+ T cells with memory phenotypes were assessed by flow cytometry.
• Serum cytokine levels were measured by multiplex sandwich immunoassays (Meso Scale Discovery platform).

Results

• In the CARTITUDE-4 study, a total of 16/176 patients experienced CNP at a clinical data cutoff of November 1, 2022.

T-cell and Cytokine Analyses

• In patients with and without CNP, the differentiation pattern of memory T cells from apheresis to T_max was comparable.
  • At T_max, T cells with a central memory phenotype were dominant in the CD4 and CD8 CAR+ T compartments for patients with and without CNP.
• Patients with CNP had significantly higher CAR+ T-cell peak expansion (C_max, P=0.00049) and exposure levels (CNP onset, P=1.9×10^-5) than those without CNP (P<0.001 for both).
• Patients with vs without CNP had significantly higher C_max of IL-10 and higher exposure levels up to CNP onset of IL-10 and IL-2Rα. See Figure: Peak and AUC Levels of Serum Inflammatory Markers in CARTITUDE-4.
• Patients with CNP tended to have higher peak IL-6 and IL-2Rα levels and higher exposure levels of IL-6.
• No difference was observed between the groups in peak or exposure levels of IFN-y.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 14 October 2024.