SUMMARY  

• CARVYKTI is not approved by the regulatory agencies for use in early relapse MM. Janssen does not recommend the use of CARVYKTI in a manner that is inconsistent with the approved labeling.
• CARTITUDE-2 is an ongoing, phase 2, multicohort, open-label study evaluating CARVYKTI in patients with multiple myeloma (MM) in various clinical settings. Cohort B is evaluating the efficacy and safety of CARVYKTI in 19 patients with MM who had early relapse after initial therapy with a proteasome inhibitor (PI) and an immunomodulatory drug. One patient was treated in an outpatient setting to evaluate the suitability of outpatient administration for CARVYKTI.^1-5
• Efficacy outcomes are presented in Table: CARTITUDE-2 Cohort B: Efficacy - Response.
  • At a median follow-up of 27.9 months (range, 5.2-32.1), a total of 15 patients had minimal residual disease (MRD)-evaluable samples at the 10^-5 threshold; 93.3% of patients were MRD negative (primary endpoint).⁵
• The most common hematologic adverse events (AEs) (≥20%) of any grade were neutropenia (94.7%), anemia (57.9%), thrombocytopenia (57.9%), lymphopenia (47.4%), and leukopenia (31.6%). Grade 3/4 hematologic AEs included neutropenia (89.5%), anemia (47.4%), lymphopenia (47.4%), leukopenia (31.6%) and thrombocytopenia (26.3%).^3,5
• Second primary malignancies (SPMs) were reported in 2 patients (grade 2 prostate cancer; not treatment related and grade 4 choroid melanoma; not treatment related; n=1 each).⁵
• Cytokine release syndrome (CRS) of any grade occurred in 84.2% of patients (n=16); with grade 3/4 CRS occurring in 5.3% of patients (n=1). The median time to CRS onset was 8 days (range, 5-11) with a median duration of 4 days. CRS resolved in all patients at the time of data cut-off.^4,5
• Total chimeric antigen receptor T (CAR-T) cell neurotoxicity of any grade occurred in 31.6% of patients (n=6) with grade 3/4 events occurring in 5.3% of patients (n=1).⁵
  • One patient experienced grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) with a median time to onset of 11 days and a median duration of 4 days. At the time of data cut-off, all ICANS cases had resolved.^3,5
  • Other neurotoxicities of any grade occurred in 5 patients (26.3%) with 1 patient (5.3%) experiencing a grade 3/4 event. The median time to onset of other neurotoxicities was 22 days with a median duration of 128 days. Other neurotoxicity cases resolved in 3/5 patients.⁵
    • One patient experienced grade 3/4 movement and neurocognitive treatment-related adverse events (MNTs)/parkinsonism. Patient management strategies implemented across the CARTITUDE program have reduced the incidence of parkinsonism.⁵
• A total of 4 deaths have occurred after CARVYKTI infusion. The reasons for death were progressive disease (n=3) and cardiac arrest (n=1; not treatment related).⁵

Clinical Data

CARTITUDE-2 (MMY2003; clinicaltrials.gov identifier: NCT04133636) is an ongoing, phase 2, multicohort, open-label study evaluating CARVYKTI in patients with MM in various clinical settings.^1-5

• Cohort B of the CARTITUDE-2 study is evaluating the efficacy and safety of CARVYKTI in 19 patients with MM who had early relapse after initial therapy with a PI and an immunomodulatory agent. Suitability of outpatient administration for CARVYKTI is also being explored.^1-5
  • Early relapse was defined as progression within 12 months after autologous stem cell transplant (ASCT) or from start of anti-MM therapy for patients who have not had an ASCT.^1-4

Study Design/Methods

• The study design is presented in the Figure: CARTITUDE-2 (Cohort B) Study Design.

• Per protocol, bone marrow aspirate samples for MRD evaluation were collected at time of suspected complete response (CR)/stringent complete response(sCR); for all dosed patients at months 2, 6, 12, 18, and 24 and yearly thereafter for patients in CR/sCR.⁵

Results

Patient Demographics and Disease/Treatment Characteristics

• Overall, 19 patients were lymphodepleted and treated with CARVYKTI in Cohort B of the CARTITUDE2 study. Patient details are presented in Table: CARTITUDE-2 (Cohort B): Demographics and Disease Characteristics.^4,5
• Median follow-up at data cut-off was 27.9 months (range, 5.2-32.1).⁵
• One patient was treated in an outpatient setting to evaluate the suitability of outpatient administration for CARVYKTI.⁴

Efficacy

• To date, Cohort B has been evaluated for response in 19 patients at a median follow-up of 10.6 months (range, 4.1-17.4), 13.4 months (range, 5.2-21.7), 18.0 months
  (range, 5.2-26.3) and 27.9 months (range, 5.2-32.1) respectively. Efficacy outcomes are presented in Table: CARTITUDE-2 Cohort B: Efficacy - Response.^1,3-5
  • At a median follow-up of 27.9 months, ORR was 100%; a total of 73.7% of patients achieved a sCR and 89.5% of patients achieved ≥CR.⁵
  • Overall, 15 patients had with MRD-evaluable samples at the 10^-5 threshold; 93.3 % of patients (n=14) were MRD negative (primary endpoint).⁵
    • A total of 13 patients had samples evaluable for sustained MRD-negativity at both 6 months and 12-months. Sustained MRD-negativity at the 10^-5 threshold for ≥6 months was reported in 10 patients (76.9%) and sustained MRD-negativity for ≥12 months was reported in 8 patients (61.5%).⁵
    • MRD-negative CR/sCR was achieved in 68.4% of patients (13/19).⁵
  • The PFS rates (95% CI) at 18 months and 24 months were 83% (95% CI, 55.9-94.3) and 73.3% (47.2-87.9) respectively.^4,5
  • OS rates (95% CI) at 18-months and 24 months were 83% (95% CI, 55.7-94.2) and 84.2% (58.7-94.6) respectively.^4,5
  • The 24-month DOR rate was 70.5% (95% CI, 42.5-86.7).⁵

Safety

• At a median follow-up of 10.6 months, the most common AEs (≥20%, any grade) were: headache (32%), pyrexia (32%), asthenia (26%), back pain (21%) and myalgia (21%).¹
• At the 27.9-month median follow-up, treatment-emergent AEs of any grade were reported in 100% of patients (n=19) with grade 3/4 events reported in 94.8% of patients (n=18). Serious treatment-emergent AEs of any grade were reported in 36.8% of patients (n=7).⁵
• The most common (all grade) hematologic AEs occurring in ≥20% of patients at a median follow-up of 27.9 months are noted in Table: CARTITUDE-2 (Cohort B): Hematologic Adverse Events (≥20% Any Grade).⁵
  • The incidence of initial grade 3/4 cytopenia not recovered to grade ≤2 by day 60 was 16% for thrombocytopenia, and 11% for lymphopenia/neutropenia (reported at the 18-month median follow-up).⁴
• SPMs were reported in 2 patients (grade 2 prostate cancer; not treatment related and grade 4 choroid melanoma; not treatment related; n=1 each).⁵
• A total of 4 deaths occurred due to progressive disease (2 of the 3 patients who died had high-risk cytogenetic profiles; none had extramedullary disease) and cardiac arrest (n=1; not treatment related).^4,5
• The 1 patient who was administered CARVYKTI in an outpatient setting had a manageable safety profile.¹

Cytokine Release Syndrome

• The incidence, timing/duration, and management of CRS are detailed in Table: CARTITUDE-2 (Cohort B): CRS.
  • CRS of any grade occurred in 84.2% of patients (n=16) with grade 3/4 CRS occurring in 5.3% of patients (n=1). The median time to CRS onset was 8 days (range, 5-11) with a median duration of 4 days. At the time of data cut-off, all CRS cases had resolved.^4,5

Neurotoxicity

• The incidence of neurotoxicity is detailed in Table: CARTITUDE-2 (Cohort B): Neurotoxicities.
  • Total CAR-T cell neurotoxicity of any grade occurred in 31.6% of patients (n=6) and grade 3/4 events occurred in 5.3% of patients (n=1).⁵
  • One patient experienced grade 1 ICANS. The time to onset was 11 days with a duration of 4 days. No patients experienced grade 3/4 ICANS. At the time of data cut-off, all ICANS cases had resolved.⁵
  • Other neurotoxicities of any grade occurred in 5 patients (26.3%); 1 case each of MNT (not resolved), hypoesthesia (not resolved), sensory loss (resolved), facial paralysis (resolved), and personality change (resolved). The median time to onset of other neurotoxicities was 22 days with a median duration of 128 days. Other neurotoxicity cases resolved in 3/5 patients.⁵
  • At a clinical cut-off date of April 12, 2023, grade 2 cranial nerve palsy (CNP) occurred in 1 patient (5.3%) which presented as facial nerve palsy, ie, involving cranial nerve VII. The CNP resolved in this patient.⁶
  • One patient (male, age 44) developed grade 3 MNTs/parkinsonism, with a median time to onset of 38 days after CARVYKTI infusion.^1,4,5,7
    • The patient had associated risk factors for MNTs (high baseline tumor burden (95% plasma cells in bone marrow biopsy at lymphodepletion [M-protein from 5.0 g/dL at screening to 6.1 g/dL at lymphodepletion chemotherapy]), worsening burden despite bridging therapy, grade 4 CRS, high CAR-T cell expansion and persistence).⁵
    • One of the first signs of MNTs in this patient was micrographia, with subsequent development of variable and wide-ranging neurotoxic symptoms, including bradykinesia, rigidity, bradyphrenia, flat effect, apathy, gait disorder, and cognitive impairment.^4,7
    • At data cut-off, the event was not recovered/resolved. The patient died due to cardiac arrest on day 749 post CARVYKTI.⁵
  • Since implementation, patient management strategies across the CARTITUDE program have reduced the incidence of MNTs/parkinsonism.⁴
    • Preventative measures, monitoring and management strategies included enhanced bridging therapy to reduce tumor burden, early and aggressive supportive care including steroids for any grade treatment of CRS and ICANS and tocilizumab for any-grade ICANS with concurrent CRS, handwriting assessments using a novel handwriting tool for early detection of neurotoxicity symptoms, and extended monitoring beyond the first 100 days post- CARVYKTI infusion (up to
      1 year).^4,7

Pharmacokinetics

CAR+ T Cell Expansion, Persistence and Cytokines

• 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).⁴
• Levels of interleukin-6 (IL-6), interferon gamma (IFN-gamma), IL-2Rα, and IL-10 increased post infusion and peaked at days 7-14. Return to baseline levels occurred within 2-3 months post infusion.³

Cytokines and cluster of differentiation (CD4/CD8) ratio with respect to CRS and ICANS

• Higher IL-6 levels were associated with CRS severity with similar profiles for levels of IFN-gamma, IL-2Ra and IL-10.³
• CD4/CD8 ratio was not associated with CRS and ICANs severity.³

CD4/CD8 CAR+ T cell ratio

• CD4/CD8 CAR+ T cells ratio was stable around 1:1 post CARVYKTI infusion.⁴

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 04 November 2024.