Summary

• CARTITUDE-1 (MMY2001) was a phase 1b/2, open-label, single-arm, multicenter study that evaluated CARVYKTI in patients with relapsed/refractory multiple myeloma (RRMM) who had previously received a proteasome inhibitor (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.^1-4
  • Bridging therapy was a short-term treatment with a previously used agent resulting in at least stable disease (SD).¹
  • Bridging therapy (anti-plasma cell directed treatment between apheresis and the first dose of the conditioning/lymphodepletion regimen) was allowed when clinically indicated (i.e., to maintain disease stability while waiting for manufacturing of CARVYKTI). Additional cycles of bridging therapy could be considered based on patient’s clinical status and timing of availability of CARVYKTI.³
  • Patients were not permitted to receive CARVYKTI infusion if they had complete response (CR) after bridging therapy.³
  • Overall, 75% of patients (n=73) received bridging therapies (systemic corticosteroids, antineoplastic agents, or immunosuppressants) between apheresis and CARVYKTI infusion.¹
    • During the period of bridging therapy prior to the start of lymphodepleting chemotherapy, 52% of patients (n=38) had an increase or no change in M-protein and/or serum-free light chains (sFLC), 45% of patients (n=33) had a decrease (with no patient achieving CR) and 3% of patients (n=2) were not evaluable at baseline.^1,3
  • Based on CARTITUDE-1 data, patient management strategies in patients with ≥2 risk factors for movement and neurocognitive treatment-emergent adverse events (MNTs)/parkinsonism, including enhanced bridging therapy, were implemented across the CARVYKTI development program to prevent or reduce the incidence and severity of neurological adverse events (AEs)/parkinsonism (CARTITUDE-2 and subsequent studies).^1,2,5
• CARTITUDE-4 (MMY3002) is an ongoing, phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI versus 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 multiple myeloma (MM) after 1-3 prior lines of therapy (LOT).⁶
  • After undergoing apheresis, patients in the CARVYKTI arm received ≥1 cycle of bridging therapy (physicians’ choice) with PVd or DPd (number of cycles was based on clinical status and CARVYKTI manufacturing time).⁶
  • All 208 patients randomized to the CARVYKTI arm received bridging therapy with either DPd (n=182) or PVd (n=26). A total of 176 patients (84.6%) received CARVYKTI as study treatment (as-treated population). In the as-treated population, 21.6% of patients received 1 bridging therapy cycle, 58.5% of patients received 2 bridging therapy cycles, and 19.9% of patients received 3–6 bridging therapy cycles.^6,7
• A post hoc analysis evaluated the efficacy of CARVYKTI by the response to bridging therapy in patients who received CARVYKTI as study treatment in CARTITUDE-4. At a median follow-up of 15.9 months, the median progression-free survival (PFS) was not reached (95% confidence interval [CI], not estimable [NE]-NE) in patients with ≥25% tumor burden reduction vs. 19.2 months (95% CI, 15.8-NE) in patients with <25% decrease in tumor burden (hazard ratio [HR], 0.32; 95% CI, 0.16-0.66).⁸

PRODUCT LABELING

• 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.

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 antiCD38 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.^1-4

Study Design/Methods

• The study design is presented in Figure: CARTITUDE-1 Study Design.
• Bridging therapy (anti-plasma cell directed treatment between apheresis and the first dose of the conditioning/lymphodepletion regimen) was allowed when clinically indicated (ie, to maintain disease stability while waiting for manufacturing of CARVYKTI).³
  • Bridging therapy as originally defined allowed for short-term treatment with a previously used agent resulting in at least SD.¹
  • Additional cycles of bridging therapy could be considered based on patient’s clinical status and timing of availability of CARVYKTI.³
  • Patients were not permitted to receive CARVYKTI infusion if they had CR after bridging therapy.³
• Based on CARTITUDE-1 data, patient management strategies in patients with ≥2 risk factors for MNTs/parkinsonism, including enhanced bridging therapy, were implemented across the CARVYKTI development program to prevent or reduce the incidence and severity of neurological AEs/parkinsonism (CARTITUDE-2 and subsequent studies).^1,2,6
  • Enhanced bridging therapy was not implemented in CARTITUDE-1. It was implemented in CARTITUDE-2 and subsequent studies in the CARTITUDE program.^1,2,5
  • Enhanced bridging therapy may have included therapies that a patient was not previously exposed to.⁵
    • To reduce baseline tumor burden before CARVYKTI infusion, enhanced bridging therapy included fewer restrictions per protocol on the investigator’s choice of bridging therapy (including duration).⁵

Results

Treatment Disposition and Disease/Treatment Characteristics

• Overall, 75% of patients (n=73) received bridging therapies (systemic corticosteroids, antineoplastic agents, or immunosuppressants) between apheresis and CARVYKTI infusion. See Table: CARTITUDE-1: Bridging Therapies for a complete listing of therapies.¹
• During the period of bridging therapy prior to the start of lymphodepleting chemotherapy, 52% of patients (n=38) had an increase or no change in M-protein and/or sFLCs, 45% of patients (n=33) had a decrease (with no patient achieving CR) and 3% of patients (n=2) were not evaluable at baseline.^1,3

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 versus standard care (physician's choice of PVd or DPd) in adult patients with lenalidomide-refractory MM after 1-3 prior LOT.⁶

Study Design/Methods

• The study design is presented in Figure: CARTITUDE-4 Study Design.
• Patients were randomized 1:1 into one of two arms to receive standard care (PVd or DPd) or CARVYKTI.⁶
• CARVYKTI arm: After undergoing apheresis, patients in the CARVYKTI arm received ≥1 cycle of bridging therapy (physicians’ choice) with PVd or DPd (number of cycles was based on clinical status and CARVYKTI manufacturing time).⁶
  • PVd as bridging therapy was administered as 21-day cycles of pomalidomide 4 mg orally (PO) daily for 14 days; bortezomib 1.3 mg/m² subcutaneously (SC) on bridging days 1, 4, 8 and 11 and dexamethasone 20 mg PO on bridging days 1, 2, 4, 5, 8, 9, 11, and 12.^6,11
  • DPd as bridging therapy was administered as 28-day cycles of DARZALEX FASPRO 1800 mg SC weekly on days 1, 8, 15, and 22; pomalidomide 4 mg PO for 21 days and dexamethasone 40 mg PO or IV on bridging days 1, 8, 15, and 22 or split over 2 days (two-20 mg doses).^6,11
  • Physicians’ choice of PVd or DPd was based on the patient’s prior anti-myeloma therapy.¹²
  • Prior to initiating the lymphodepletion regimen, patients had to have a washout period which occurred from the last dose of bridging therapy. Cycles beyond bridging cycle 1 could be truncated to allow for adequate washout and minimize time off therapy.¹²
  • Patients who had confirmed disease progression during bridging therapy or lymphodepletion were assessed as having a progression event. Subsequent therapy with CARVYKTI could be administered at investigator discretion.⁶

Results

Treatment Disposition and Disease/Treatment Characteristics

• Overall, 419 patients were randomized to receive CARVYKTI (n=208) or standard care (n=211; DPd [n=183] or PVd [n=28]).⁶
  • All 208 patients randomized to the CARVYKTI arm received bridging therapy with either DPd (n=182) or PVd (n=26). A total of 176 patients (84.6%) received CARVYKTI as study treatment (as-treated population). In the as-treated population, 21.6% of patients received 1 bridging therapy cycle, 58.5% of patients received 2 bridging therapy cycles, and 19.9% of patients received 3-6 bridging therapy cycles.^6,7

clinical data - CARTITUDE-4 - Post Hoc Analysis

• A post hoc analysis evaluated the efficacy of CARVYKTI by response to bridging therapy in patients who received CARVYKTI as study treatment in CARTITUDE-4.⁸

Study Design/Methods

• The study design is presented in Figure: CARTITUDE-4 Study Design.
• PFS was measured from randomization and evaluated from baseline to the start of lymphodepletion in patients with ≥25% tumor burden reduction vs <25% (defined as <25% decrease, no change, or an increase in tumor burden). Overall, 2 patients were not evaluable.⁸
• Tumor burden change was measured by determining the difference between paraprotein at baseline and at lymphodepletion for each patient.⁸
• The in vivo effector-to-target (E:T) ratio was derived from peak chimeric antigen receptor-T (CAR-T) cell expansion, which was assessed by flow cytometry and normalized to pre-infusion serum soluble B-cell maturation antigen (sBCMA) levels.⁸

Results

Treatment Disposition and Disease/Treatment Characteristics

• A total of 176 patients received CARVYKTI as study treatment and all patients received bridging therapy with either DPd (n=158) or PVd (n=18).⁸
• During the period of bridging therapy, 148 patients (84%) had ≥25% tumor burden reduction, and 28 patients (16%) had <25% decrease.⁸
• Patient baseline details are presented in Table: CARTITUDE-4 Post Hoc Analysis: Baseline Disease Characteristics Based on Tumor Burden Decrease (CARVYKTI Arm).⁸

Efficacy by Response to Bridging Therapy

• At a median follow-up of 15.9 months, the median PFS was not reached (95% CI, NE-NE) in patients with ≥25% tumor burden reduction vs. 19.2 months (95% CI, 15.8-NE) in patients with <25% decrease in tumor burden (HR, 0.32; 95% CI, 0.16-0.66). See Figure: PFS by Tumor Burden Change of ≥25% Between Baseline and Start of Lymphodepletion.⁸
  • The estimated 15-month PFS rates were 87.5% (95% CI, 80.6-92.1) and 74.0% (95% CI, 52.9-86.7) in patients with ≥25% and <25% tumor burden reduction, respectively.⁸

Biomarker Correlates of Response to Bridging Therapy and Post CARVYKTI Outcomes

• Among patients with biomarker data, patients with ≥25% decrease in tumor burden showed a comparable CAR-T peak expansion in the blood (C_max), lower sBCMA levels pre-infusion, and a higher in vivo E:T ratio vs patients with <25% decrease in tumor burden.⁸ See Figure: Cmax (A), sBCMA (B), and E:T Ratio (C) by Response to Bridging Therapy in Patients with ≥25% Tumor Reduction.⁸
  • The median (interquartile range [IQR]) C_max was 479.5 (811.8) cells/mL vs 508 (1353.8) cells/mL in patients with ≥25% and <25% tumor burden reduction, respectively.⁸
  • The median (IQR) pre-infusion sBCMA was 6.2 (14.6) mg/mL vs 64.0 (216.5) mg/mL in patients with ≥25% and <25% tumor burden reduction, respectively.⁸
  • The median (IQR) normalized C_max was 62.6 (139.2) cells/mL vs 5.4 (62.3) cells/mL in patients with ≥25% and <25% tumor burden reduction, respectively.⁸
  • Lower pre-infusion sBCMA levels were observed in patients with greater tumor burden reduction; no correlation with C_max was noted.⁸
  • Patients with effective bridging therapy had a higher E:T ratio (adjusted for baseline tumor burden variations).⁸
• Patients with higher E:T ratios showed improvement in PFS.⁸
  • C_max was similar in the subgroups of patients with both higher and lower tumor burden.⁸

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 30 September 2024.