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.
• Cytokine release syndrome (CRS) has been reported as an adverse event (AE) in the CARTITUDE-1, CARTITUDE-2 and CARTITUDE-4 studies.^1-6
• 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.^1,2,7
  • At a median follow-up of 33.4 months, CRS of any grade had occurred in 95% of patients, with grade 3/4 CRS occurring in 4.1% of patients and grade 5 CRS occurring in 1 patient. The median duration of CRS was 4 days (interquartile range [IQR] 3-6). The median time to onset of CRS was 7 days (IQR 5-8 days), with 89% of patients experiencing CRS onset at day 4 or later. CRS resolved within 14 days of onset in 99% of patients.^1,7 No new events of CRS (no changes in the incidence, time to onset, or duration) have occurred since the median 12.4 month follow-up.^2,7
• CARTITUDE-2 (MMY2003) is a phase 2, multicohort, open-label study evaluating CARVYKTI in patients with multiple myeloma (MM) in various clinical settings.⁸ 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 LOT and were refractory to lenalidomide.^9-13
    • Initial Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with the clinical trial process in 20 patients.^9-12
      • At a median follow-up of 29.9 months, CRS of any grade occurred in 95% of patients (n=19), with grade 3/4 CRS occurring in 10% of patients (n=2). The median time to CRS onset was 7 days, with a median CRS duration of 3 days. CRS resolved in all patients.¹¹
    • Expansion Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with a commercial process in 23 patients.¹³
      • At a median follow-up of 15.6 months, CRS of any grade occurred in 100% of patients (n=23); no grade 3/4 CRS occurred. The median time to CRS onset was 8 days and recovery was 4 days.¹³
  • Cohort B is evaluating the efficacy and safety of CARVYKTI in 19 patients who had early relapse after initial MM therapy with a PI and an immunomodulatory drug.^4,11,14,15
    • At a median follow-up of 27.9 months, 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, with a median CRS duration of 4 days. CRS resolved in all patients.¹¹
  • Cohort C is evaluating the efficacy and safety of CARVYKTI in 20 patients with RRMM after a PI, an immunomodulatory drug, an anti-CD38 antibody and a non-cellular
    B-cell maturation antigen (BCMA)-directed therapy. Non-cellular BCMA-directed therapy included bispecific antibodies (BsAbs) and antibody-drug conjugates (ADC).^3,16
    • At a median follow-up of 18 months, CRS of any grade occurred in 60% of patients (n=12) overall with no grade 3/4 CRS reported. The median time to CRS onset was 7.5 days (range, 2-10) with a median duration of 5.5 days (range, 3-10). CRS resolved in all patients.³
  • 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).^5,17
    • At a median follow-up of 22.4 months, CRS of any grade occurred in 82.4% of patients (n=14) overall, with no grade 3/4 CRS reported. The median time to CRS onset was 8 days with a median duration of 2.5 days.¹⁷
• CARTITUDE-4 is a Phase 3, open-label, multicenter study evaluating CARVYKTI versus standard care regimens, DARZALEX FASPRO (daratumumab and hyaluronidase), pomalidomide, and dexamethasone (DPd) or pomalidomide, bortezomib, and dexamethasone (PVd), in patients with RRMM who received 1-3 prior LOT, including a proteasome inhibitor and an immunomodulatory drug, and are refractory to lenalidomide.^6,18
  • Chimeric antigen receptor (CAR)-T specific AEs were evaluated in the as-treated population which included patients who received CARVYKTI as study treatment (n=176).¹⁸
  • At a median follow up of 16.0 months, CRS of any grade occurred in 76.1% (n=134) of patients that received CARVYKTI as study treatment with grade 3/4 CRS occurring in 1.1% of patients (n=2). The median time to onset of CRS was 8 days with a median duration of 3 days. CRS resolved in all patients.¹⁸
  • 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.¹⁹
    • At a median follow-up of 15.9 months, among patients who received 1 prior LOT (N=68), CRS of any grade occurred in 64.7% of patients (n=44), with grade 3/4 CRS occurring in 1.5% of patients (n=1). Among patients who received 1 prior LOT and had functionally high-risk MM (N=40), CRS of any grade occurred in 62.5% of patients (n=25), with no grade 3/4 CRS reported.¹⁹

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.^1,2,7

Study Design/Methods

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

• Per protocol, hospital stay was mandated for least 14 days post-infusion for the first
  6 patients within Phase 1b of the CARTITUDE-1 study. Subsequently, per Safety Evaluation Team recommendation, hospital stay guidance was decreased to at least
  10 days post-infusion.²²
• Body temperature was monitored twice daily for 28 days post CARVYKTI infusion.²³
• All patients were monitored and hospitalized for evaluation at the first sign of CRS.²³
• Cytokine profiling was conducted by collecting serum samples prior to lymphodepletion, prior to CARVYKTI infusion, 2 hours post-infusion on day 1, and on additional days (days 2, 3, 7, 10, 14, 21, 28, 42, 56, and 78) until day 100. Samples were also collected if CRS was reported or suspected in a patient.²³

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.²
• Prior to lymphodepletion, a total of 12 patients discontinued (progressive disease, n=2; withdrawal by subject, n=2; deaths, n=8). Prior to CARVYKTI infusion, 3 patients withdrew from treatment, and 1 patient died.²
• Patients received a median of 6 prior LOT, 88% of patients were triplerefractory, 42% of patients were penta-refractory, and 99% of patients were refractory to last LOT.^2,7

Safety - Adverse Events - CRS

• The incidence, timing/duration, and management of CRS are detailed in Table: CARTITUDE-1: CRS.
  • At a median follow-up of 33.4 months (range, 1.5-45.2), CRS had occurred in 95% of patients (92/97). Overall, 51% of patients (n=49) had grade 1 CRS and 39% of patients (n=38) had grade 2 CRS. Five CRS events were grade ≥3 (Grade 3/4, n=4; Grade 5, n=1).^1,7
  • Median time to CRS onset was 7 days (IQR 5-8 days), with 89% of patients experiencing CRS onset at day 4 or later, and 74% of patients experiencing CRS onset at day 6 or later.^1,21
  • Median duration of CRS was 4 days (IQR 3-6 days) and resolved in 91 (99%) patients within 14 days of onset.^1,21
• One death due to CRS/hemophagocytic lymphohistiocytosis occurred on Day 99 post CARVYKTI infusion.¹
• No new events of CRS (no changes in the incidence, time to onset, or duration) occurred since the median 12.4 month follow-up.²
• Anakinra was administered in patients for whom tocilizumab did not effectively manage CRS. ²⁴ Use of anakinra per study patient with CRS event is presented in Table: CARTITUDE-1: Use of Anakinra Per Study Patient with CRS Event.
  • A total of 18 patients received anakinra for CRS, typically within the first 48 hours of CRS onset (range, 0-6 days).²⁴
  • Subcutaneous injection of anakinra 100-200 mg was administered every 8-12 hours over a median of 2.5 days (range, 1-15 days).²⁴
  • CRS resolved after a median of 5 days (range, 2-10 days) in patients who received anakinra and tocilizumab, with (n=14) or without (n=4) steroids.²⁴
• CARVYKTI CAR+ T cells revealed maximum peripheral expansion at a median of 12.7 days (range 8.7-54.6 days).¹
• Interleukin (IL)-6, IL-10, and interferon (IFN)-gamma levels peaked at days 7-14 postCARVYKTI infusion.²³
  • CRS severity and supportive measures were associated with peak levels of IL-6, IL-10, and IFN-gamma. The results were similar for other cytokines (IL-2, IL-8, soluble IL-2Ra, and TNF-α).²³
• No association was observed between the severity of CRS and baseline or peak levels of C-reactive protein (CRP) or ferritin.²³
  • CRP and ferritin trends follow cytokine levels and can be useful for monitoring CRS.²³
• Incidence of CRS in key subgroups in CARTITUDE-1 (≥65 years of age, Black/African American, 3 and ≥4 prior LOT, triple-class refractory, penta-drug refractory, cytogenetic risk status, International Staging System (ISS) stage III disease at baseline, bone marrow plasma cell percentage at baseline (≤30%, >30 to <60%, and ≥60%), tumor BCMA expression at baseline (<median, ≥median), and presence of soft-tissue plasmacytomas (bone-based and extramedullary disease [EMD]) was consistent with the overall population.^2,25

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.⁸

• 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.^9-13
  • Initial Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with the clinical trial process in 20 patients.^9-12
  • Expansion Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with a commercial process in 23 patients.¹³
• Cohort B is evaluating the efficacy and safety of CARVYKTI in 19 patients who had progressive MM and an early relapse after initial therapy with a PI and an immunomodulatory drug.^4,11,14,15
  • 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.^4,11,14,15
• Cohort C is evaluating the efficacy and safety of CARVYKTI in 20 patients with RRMM after a PI, an immunomodulatory drug, an anti-CD38 antibody and a non-cellular BCMA-directed therapy. Non-cellular BCMA-directed therapy included BsAbs and ADCs.^3,16
• Cohort D is evaluating the efficacy and safety of CARVYKTI with or without lenalidomide maintenance in 17 patients who achieved <CR after frontline ASCT.^5,17

Study Design/Methods

• Key eligibility criteria for Cohort A: adult patients with progressive MM after 1-3 prior LOT including a PI and an immunomodulatory drug; lenalidomide refractory; no prior exposure to BCMA-targeting agents; Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1.^8,11
• Key eligibility criteria for Cohort B: adult patients who received 1 prior LOT including a PI and an immunomodulatory drug; disease progression per International Myeloma Working Group (IMWG) criteria ≤12 months after treatment with ASCT or ≤12 months from the start of anti-myeloma therapy for patients who have not had an ASCT; no prior exposure to BCMA-targeting agents or CAR-T therapy directed at any target; ECOG PS ≤1.⁸
• Key eligibility criteria for Cohort C: adult patients previously treated with a PI, an immunomodulatory drug, an anti-CD38 antibody, and a non-cellular BCMA-directed therapy (ADC or BsAb as monotherapy or combination); diagnosis of MM per IMWG criteria and evidence of progressive MM within 12 months of last LOT, or within 6 months of prior therapy and refractory to their most recent line of treatment; measurable disease at baseline; ECOG PS ≤1; BCMA expression was not required for eligibility.^8,16
• 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 therapy directed at any target; and ECOG PS ≤1.^5,17
• Dosing: patients received a single infusion of CARVYKTI at a target dose of 0.75×10⁶ 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).^{3-5,8,10,11,17}
• Primary endpoint: minimal residual disease (MRD) negativity at the 10^-5 sensitivity level as assessed by next-generation sequencing (clonoSEQ^®) or next-generation flow.^{3-5,8,10,11,17,27}
• Key secondary endpoints: overall response rate (ORR) per IMWG criteria, duration of response, time to response, time and duration of MRD negativity, and incidence and severity of AEs.^{3-5,8,10,11,17}

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.^9-12
  • Patients received a median of 2 prior LOTs (range, 1-3); 95% of patients were refractory to their last LOT.¹¹
• Expansion Subgroup: Overall, 24 patients were enrolled and 23 patients were treated with CARVYKTI manufactured with a commercial process.¹³
  • Patients received a median of 3 prior LOTs (range, 1-3); 95.7% of patients were refractory to their last LOT.¹³

Cohort B

• Overall, 19 patients were enrolled, lymphodepleted and treated with CARVYKTI in Cohort B of the CARTITUDE-2 study.¹¹
• Patients received a median of 1 prior LOT (range, 1-1); 78.9% of patients were refractory to their last LOT.¹¹

Cohort C

• Overall, 24 patients were enrolled/apheresed and 20 patients (7 patients in BsAb-exposed group and 13 patients in the ADC-exposed group) were treated with
  CARVYKTI in Cohort C of the CARTITUDE2 study.³
• Patients received a median of 8 prior LOTs (range, 4-13); 90% of patients were anti-BCMA refractory and 95% of patients were refractory to their last LOT. In total, 30% of patients (n=6) received anti-BCMA as their last line of treatment (n=4 ADC-exposed; n=2 BsAb-exposed).^3,16

Cohort D

• Overall, 17 patients were treated with CARVYKTI in Cohort D of the CARTITUDE-2 study.¹⁷
• 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.¹⁷

Safety - Adverse Events - CRS - Cohort A

• Initial Subgroup: The incidence and timing/duration of CRS are summarized in Table: CARTITUDE-2 (Cohort A) Initial Subgroup: CRS.¹¹
  • At a median follow-up of 29.9 months (range, 3.3-35.6), any grade CRS occurred in 95% (n=19) of patients. Grade 3/4 CRS occurred in 10% (n=2) of patients.The median time to onset of CRS was 7 days, with a median CRS duration of 3 days. At the time of data cutoff, CRS had resolved in all 19 patients.¹¹
• Expansion Subgroup: At a median follow-up of 15.6 months (range, 1.0-29.2), CRS of any grade occurred in 100% of patients (n=23); no grade 3/4 CRS occurred.The median time to CRS onset was 8 days and recovery was 4 days.¹³

Safety - Adverse Events - CRS - Cohort B

• The incidence and timing/duration of CRS are detailed in Table: CARTITUDE-2 (Cohort B): CRS.¹¹
• At a median follow-up of 27.9 months (range, 5.2-32.1), any grade CRS occurred in 84.2% (n=16) of patients. Grade 3/4 CRS occurred in 5.3% (n=1) of patients.¹¹
• At the time of data cutoff, CRS had resolved in all 16 patients.¹¹

Safety - Adverse Events - CRS - Cohort C

• The incidence, timing/duration, and management of CRS are detailed in Table: CARTITUDE-2 (Cohort C): CRS.³
• At a median follow-up of 18 months (range, 0.622.7), CRS occurred in 60% of patients (n=12) overall, with 6 patients in each of the ADC-exposed and BsAb-exposed groups.^3,16
• The median time to onset of CRS was 7.5 days (range, 2-10) with a median duration of 5.5 days (range, 3-10).³
• All patients who experienced CRS received ≥1 treatment (tocilizumab n=9; anakinra n=3, corticosteroids n=6).³
• CRS resolved in all patients at the time of data cut-off.^3,16

Safety - Adverse Events - CRS - Cohort D

• At a median follow-up of 22.4 months (range, 4.7-39.3), CRS occurred in 82.4% of patients overall (n=14). The incidence, timing/duration of CRS is detailed in Table: CARTITUDE-2 (Cohort D): CRS.¹⁷

clinical data - CARTITUDE-4 - PHASE 3 STUDY

CARTITUDE-4 (MMY3001; NCT04181827) is a Phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI versus standard care (physician's choice of DPd or PVd) in adult patients with lenalidomide-refractory MM after 1-3 prior LOT.^6,18

Study Design/Methods

• Treatment arms: Randomized 1:1 to receive either CARVYKTI or standard care (DPd or PVd)
• Key eligibility criteria
  • Received 1-3 prior lines of therapy including a PI and an immunomodulatory drug
  • Refractory to lenalidomide
  • No prior exposure to CAR-T or BCMA targeting therapy
• Primary endpoint: Progression-free survival (PFS)

Safety - Adverse Events - CRS

• CAR-T specific AEs were evaluated in patients treated with CARVYKTI as study treatment (as-treated population; n=176).^18,28
  • At a median follow-up of 16.0 months (range, 3.8-27.3), CRS occurred in 76.1% (n=134) of patients in the as-treated population receiving CARVYKTI.
    • Most of the CRS events were grade 1 or grade 2 (52.8% vs 22.2%, respectively) with grade 3 events occurring in 1.1% of patients. CRS resolved in all patients.
    • The median time to onset of CRS was 8 days (range, 1-23), with a median CRS duration of 3 days (range, 1-17).
    • Supportive treatments (n=131) included: tocilizumab (n=71), oxygen therapy (n=17), corticosteroids (n=8), and vasopressors (n=2).

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.

Results

Treatment Disposition, Patient Demographics, and Disease/Treatment Characteristics

• A total of 136 patients received 1 prior LOT in the CARTITUDE-4 study.¹⁹
  • 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.¹⁹
  • A total of 68 patients received standard care; 39 of these patients had functionally high-risk MM.¹⁹
  • Functionally high-risk MM defined as progressive disease (PD) ≤18 months after receiving ASCT or the start of initial frontline therapy in patients with no ASCT.¹⁹

Safety - Adverse Events - CRS

• The incidence of CRS at a median follow-up of 15.9 months (range, 0.1-28.3) is detailed in Table: CARTITUDE-4: CRS in CARVYKTI Patients With 1 Prior LOT and Those With 1 Prior LOT and Functionally High-Risk MM.

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 17 June 2025.