SUMMARY

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• Second Primary Malignancies (SPMs) have been reported in the CARTITUDE-1, CARTITUDE-2 and CARTITUDE-4 studies.^1-9
• 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-cluster of differentiation 38 (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.^1,3,4
  • At a median follow-up of 33.4 months (study closeout), a total of 26 SPMs were reported in 20 patients. Complete details are provided in Table: CARTITUDE-1: Second Primary Malignancies.⁴
    • At a median follow-up of 27.7 months, 16 patients had developed a total of 20 SPMs, all unrelated to CARVYKTI.³ Since the 27.7 month median follow-up, 4 new patients developed SPMs with 6 new cases reported.⁴
• CARTITUDE-2 (MMY2003) is a phase 2, multicohort, open-label study evaluating CARVYKTI in patients with multiple myeloma (MM) in various clinical settings.⁷ 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 (LOTs) and were refractory to lenalidomide.^5,8-11
    • Initial Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with the clinical trial process in 20 patients.^5,8,10,11
      • At a median follow-up of 29.9 months, SPM was reported in 1 patient (grade 3 mucoepidermoid carcinoma; not treatment related).⁵
    • Expansion Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with a commercial process in 23 patients.⁹
      • At a median follow-up of 15.6 months, SPMs were reported in 2 patients, which were not considered treatment-related per investigator assessment (basal cell carcinoma and cutaneous squamous cell carcinoma in 1 patient; myelodysplastic syndrome [MDS] in 1 patient).⁹
  • Cohort B 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 drug.⁵
    • At a median follow-up of 27.9 months, 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
  • Cohort D is evaluating the efficacy and safety of CARVYKTI with or without lenalidomide maintenance in 17 patients in patients who achieved less than complete response (CR) after frontline autologous stem cell transplantation (ASCT).^6,12
    • At a median follow-up of 22.4 months, SPM was reported in 1 patient (grade 3 MDS with an onset on day 353; not treatment related per investigator assessment).⁶
• CARTITUDE-4 (MMY3002) is a 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 MM after 1-3 prior LOT.^2,13
  • Adverse events (AEs) were evaluated in the safety population, which included all patients who received any part of study treatment (n=208 in both the CARVYKTI and standard care arms).²
    • At a median follow-up of 15.9 months, SPMs were reported in 9 patients (4.3%) and 14 patients (6.7%) in the CARVYKTI arm and standard care arm, respectively. Complete details are provided in Table: CARTITUDE-4: Second Primary Malignancies (Median Follow-up of 15.9 Months).^2,14
    • At a median follow-up of 33.6 months, SPMs were reported in 27 patients (13%) and 24 patients (11.5%) in the CARVYKTI arm and standard care arm, respectively. Complete details are provided in Table: CARTITUDE-4: Second Primary Malignancies (Median Follow-up of 33.6 Months).¹³
  • Subgroup Analysis in Patients with Functional High-Risk MM: efficacy and safety outcomes were evaluated in patients who received 1 prior LOT, including the subset of patients with functionally high-risk MM in the CARTITUDE-4 study.¹⁵
    • At a median follow-up of 15.9 months, SPMs occurred in 3 patients in the CARVYKTI arm, and in 2 patients in the standard care arm among those with 1 prior LOT; all occurred in patients with functionally high-risk MM (one patient in the CARVYKTI arm had peripheral T-cell lymphoma [TCL] unspecified).¹⁵
  • A case report provided details of a 51-year-old male patient enrolled in the CARTITUDE-4 study who developed a chimeric antigen receptor-positive (CAR+) TCL post CARVYKTI infusion.¹⁶

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 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.^1,3,4

Study Design/Methods

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

Results

Treatment Disposition, Patient Demographics, and Disease/Treatment Characteristics

• Overall, of the 113 patients enrolled/apheresed, 101 patients were lymphodepleted and 97 patients were treated with CARVYKTI in the combined phase 1b/2 study.³
• Prior to lymphodepletion, a total of 12 patients discontinued (progressive disease [PD], n=2; withdrawal by subject, n=2; deaths, n=8). Prior to CARVYKTI infusion, 3 patients withdrew from treatment, and 1 patient died.³
• Patients received a median of 6 prior LOTs, 88% of patients were triplerefractory, 42% of patients were penta-refractory, and 99% of patients were refractory to the last LOT.^3,4

Safety - Adverse Events - Second Primary Malignancies

• At a median follow-up of 33.4 months (range, 1.5-4.2; study closeout), a total of 26 SPMs were reported in 20 patients. Complete details are provided in Table: CARTITUDE-1: Second Primary Malignancies.⁴
  • At a median follow-up of 27.7 months, 16 patients had developed a total of 20 SPMs, all unrelated to CARVYKTI.³
    • Hematologic malignancies occurred in 9 patients; 1 low-grade B-cell lymphoma, 6 MDS (1 case was fatal), 3 fatal acute myelogenous leukemia (AML; 1 patient had both MDS and fatal AML).³
    • A total of 6 non-melanoma skin cancers occurred; squamous cell carcinoma occurred in 4 patients (basal cell carcinoma also occurred in 1 of the patients) and 1 patient had basal cell carcinoma that was present before CARVYKTI infusion.^3,19
    • Malignant melanoma, adenocarcinoma, and myxofibrosarcoma occurred in 1 patient each. Prostate cancer occurred in 1 patient (patient also had squamous cell carcinoma and AML reported above).³
  • Since the 27.7 month median follow-up, 4 new patients developed SPMs, with 6 new cases reported including basal cell carcinoma (n=2) and 1 case each of MDS, B-cell lymphoma, melanoma, and prostate cancer.⁴

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.⁷

• Cohort A is evaluating the efficacy and safety of CARVYKTI in patients who had progressive MM after 1-3 prior LOTs and were refractory to lenalidomide.^5,8-11
  • Initial Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with the clinical trial process in 20 patients.^5,8,10,11
  • Expansion Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with a commercial process in 23 patients.⁹
• Cohort B 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 drug.⁵
  • 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.⁵
• Cohort D is evaluating the efficacy and safety of CARVYKTI with or without lenalidomide maintenance in 17 patients who achieved <CR after frontline ASCT.⁶

Study Design/Methods

• Key eligibility criteria for Cohort A: adult patients with progressive MM after 13 prior LOTs, including a PI and an immunomodulatory drug, who were lenalidomide refractory, had no prior exposure to B-cell maturation antigen (BCMA)-targeting agents or CAR T-cell therapy directed at any target, and had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤1.⁷
• Key eligibility criteria for Cohort B: adult patients who received 1 prior LOT including a PI and an immunomodulatory agent, had disease progression per International Myeloma Working Group (IMWG) criteria ≤12 months after ASCT or ≤12 months from the start of anti-MM therapy (for patients who did not receive ASCT), had no prior exposure to BCMAtargeting agents or CAR T-cell therapy directed at any target, and had an ECOG PS of ≤1.⁷
• Key eligibility criteria for Cohort D: adult patients with a history of 4-8 cycles of initial therapy, including induction, high-dose therapy, and ASCT with or without consolidation; overall best response <CR; no prior exposure to BCMA-targeting agents and CAR T-cell therapy directed at any target; and ECOG PS ≤1.^6,12
• Dosing: patients received a single infusion of CARVYKTI at a target dose of 0.75x10⁶ viable CAR+ T cells/kg (target range, 0.5-1.0x10⁶) 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).^5-9,12,20
• Primary endpoint: minimal residual disease (MRD) negativity at the 10^-5 sensitivity level as assessed by next-generation sequencing (clonoSEQ^®) or next-generation flow.^5-9,12,20
• Key secondary endpoints: overall response rate per IMWG criteria, duration of response, time to response, time and duration of MRD negativity, and incidence and severity of AEs.^5-9,12,20

Results

Treatment Disposition, Patient Demographics, and Disease/Treatment Characteristics

Cohort A

• Initial Subgroup: Overall, 20 patients were enrolled, lymphodepleted, and treated with CARVYKTI manufactured with the clinical trial process.^5,8,10,11
  • Patients received a median of 2 prior LOTs (range, 1-3); 95% of patients were refractory to their last LOT.⁵
• Expansion Subgroup: Overall, 24 patients were enrolled and 23 patients were treated with CARVYKTI manufactured with a commercial process.⁹
  • Patients received a median of 3 prior LOTs (range, 1-3); 95.7% of patients were refractory to their last LOT.⁹

Cohort B

• Overall, 19 patients were lymphodepleted and treated with CARVYKTI in Cohort B of the CARTITUDE-2 study.²⁰
• Patients received a median of 1 prior LOT (range, 1-1); 78.9% of patients were refractory to their last LOT.^5,20

Cohort D

• Overall, 17 patients were treated with CARVYKTI in Cohort D of the CARTITUDE-2 study.⁶
• In total, all 17 patients had prior ASCT and were previously exposed to PI and immunomodulatory drug; 17.6% of patients had received prior anti-CD38 monoclonal antibody therapy.⁶

Safety - Adverse Events - Second Primary Malignancies - Cohort A

• Initial Subgroup: At a median follow-up of 29.9 months (range, 3.3-35.6), SPM was reported in 1 patient (grade 3 mucoepidermoid carcinoma; not treatment related).⁵
• Expansion Subgroup: At a median follow-up of 15.6 months (range, 1.0-29.2), SPMs were reported in 2 patients, which were not considered treatment-related per investigator assessment.⁹
  • Basal cell carcinoma and cutaneous squamous cell carcinoma were observed in 1 patient.⁹
  • On day 842 after CARVYKTI infusion, one patient was diagnosed with MDS, which later transformed to acute myeloid leukemia.⁹

Safety - Adverse Events - Second Primary Malignancies - Cohort B

• At a median follow-up of 27.9 months (range, 5.2-32.1), 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

Safety - Adverse Events - Second Primary Malignancies - Cohort D

• At a median follow-up of 22.4 months (range, 4.7-39.3), SPM was reported in 1 patient (grade 3 MDS with an onset on day 353; not treatment related per investigator assessment).⁶

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 LOTs.²

Study Design/Methods

• The study design is shown in Figure: CARTITUDE-4 Study Design.

Results

Treatment Disposition, Patient Demographics, 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]).²
  • 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).²
    • Prior to receipt of CARVYKTI, 32 patients discontinued study treatment mainly due to disease progression (n=30) or death (n=2) during bridging therapy or lymphodepletion. Of these, 20 patients received subsequent therapy with CARVYKTI.²
  • A total of 208 patients (98.6%) were dosed with standard care.²
    • Treatment discontinuation was reported in 131 standard care patients (63.0%), mostly due to disease progression (56.3%).²
• High-risk cytogenetics were present in 59.4% of CARVYKTI patients and 62.9% of standard care patients. The median prior LOT in both the CARVYKTI and standard care arms were 2 (range, 1-3).^2,22

Safety - Adverse Events - Second Primary Malignancies

• AEs were evaluated in the safety population which included all patients who received any part of study treatment (n=208 in both the CARVYKTI and standard care arms).²

Median Follow-up of 15.9 Months

• At the data cut-off date of November 1, 2022, 143 CARVYKTI patients were ongoing in the post-treatment phase and 77 patients were ongoing on standard care therapy.²
• At a median follow-up of 15.9 months (range, 0.1-27.3), SPMs were reported in 9 patients (4.3%) and 14 patients (6.7%) in the CARVYKTI arm and standard care arm, respectively. Complete details are provided in Table: CARTITUDE-4: Second Primary Malignancies (Median Follow-up of 15.9 Months).¹⁴

Median Follow-up of 33.6 Months

• At the data cut-off date of May 1, 2024, 117 CARVYKTI patients were ongoing in the post-treatment phase and 43 patients were ongoing on standard care therapy.¹³
• At a median follow-up of 33.6 months (range, 0.1-45.0), SPMs were reported in 27 patients (13%) and 24 patients (11.5%) in the CARVYKTI arm and standard care arm, respectively. Complete details are provided in Table: CARTITUDE-4: Second Primary Malignancies (Median Follow-up of 33.6 Months).¹³

CARTITUDE-4 Subgroup Analysis in Patients with Functional High-Risk MM

• Efficacy and safety outcomes were evaluated in patients who received 1 prior LOT, including the subset of patients with functionally high-risk MM, in the CARTITUDE-4 study.¹⁵

Results

Treatment Disposition, Patient Demographics, and Disease/Treatment Characteristics

• A total of 136 patients received 1 prior LOT in the CARTITUDE-4 study.¹⁵
  • In the CARVYKTI arm, 68 patients underwent apheresis/bridging therapy; 40 patients had functionally high-risk MM. Of the 68 patients, 60 patients received CARVYKTI as study treatment; 35 patients had functionally high-risk MM.¹⁵
  • A total of 68 patients received standard care; 39 of these patients had functionally high-risk MM.¹⁵
  • Functionally high-risk MM defined as PD ≤18 months after receiving ASCT or the start of initial frontline therapy in patients with no ASCT.¹⁵

Safety - Adverse Events - Second Primary Malignancies

• At a median follow-up of 15.9 months (range, 0.1-28.3), SPMs occurred in 3 patients in the CARVYKTI arm, and in 2 patients in the standard care arm among those with 1 prior LOT; all occurred in patients with functionally high-risk MM (one patient in the CARVYKTI arm had peripheral TCL unspecified).¹⁵

Case Report: CAR+ TCL Post CARVYKTI in CARTITUDE-4

A case report provided details of a 51-year-old male patient enrolled in the CARTITUDE-4 study who developed a CAR+ TCL post CARVYKTI infusion.¹⁶

Methods

• The presence of CAR+ cells in lymph node biopsy (LNB) was assessed by quantitative polymerase chain reaction (qPCR), immunohistochemistry (IHC) and in situ hybridization (ISH).¹⁶
• Additional analyses conducted included: whole genome sequencing (WGS), transcriptome sequencing, whole exome sequencing (WES), genome-wide CAR integration and T-cell receptor (TCR) sequencing.¹⁶

Results

• On day 14, CAR+ T cells peaked in the blood (77 cells/uL).¹⁶
• On day 92, CAR+ T cells in the blood decreased (3 cells/µL). At this time, the patient achieved a stringent CR and MRD negativity at a sensitivity of 10^-5.¹⁶
• At 5 months post-infusion, the patient was diagnosed with TCL based on facial lesion biopsy (biopsy showed an infiltrate of atypical T cells positive for CD2 and CD3 but negative for CD4, CD8, CD7, CD56, ALK, EBER-ISH, TdT, CD30, and cytotoxic T-cell markers). qPCR and ISH/IHC revealed 90-100% of LNB cells to be CAR+.¹⁶
• On day 162, CAR+ T cells re-expanded in the blood (378 cells/uL); independent of BCMA antigen.¹⁶
• CAR integration analysis of LNB revealed a dominant insertion into the 3′ untranslated region (UTR) of PBX2 (91.1% of total reads from all integration sites). TCR sequencing of the LNB showed a monoclonal sequence in 91% of all T cells. An analysis of the drug product showed the same unique TCR sequence from the monoclone at low frequency.¹⁶
• WGS in the LNB showed low overall mutational burden (1.26 mutations/megabase), with total of 37 coding and 3286 non-coding variants (including 2 predicted loss-of-function TET2 mutations, a PTPRB truncation, and a focal duplication involving the 5′ UTR to intron 16 of NFKB2.¹⁶
• WES of the LNB indicated a heterozygous, likely clonal TET2 mutation (p.H1416R) which was not due to CAR insertion.¹⁶
• The presence of a heterozygous JAK3 variant (p.V7221) was detected in germline samples; however, no abnormalities were observed in targeted sequencing (0.5% sensitivity) of stored CD34+ cells and bone marrow aspirate that had been collected from the patient 2 years earlier.¹⁶
• The patient was treated with CHOEP-21 (cyclophosphamide-doxorubicin-vincristine-prednisone-etoposide) for the TCL and achieved metabolic CR. Relapse was reported after treatment was stopped. Subsequent treatment included gemcitabine-dexamethasone-cisplatinalemtuzumab, followed by consolidation with fludarabine plus melphalan and matched allogeneic stem cell transplant. Within 3 months, the patient relapsed with cutaneous disease.¹⁶

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.