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CARVYKTI - Adverse Event - Cytokine Release Syndrome (CRS)

Last Updated: 07/29/2024

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 (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.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

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

CARTITUDE-1 Study Design7,20,21

Abbreviations: CAR, chimeric antigen receptor; CD38, cluster of differentiation 38; cilta-cel, ciltacabtagene autoleucel; CR, complete response; Cy, cyclophosphamide; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; Flu, fludarabine; IMWG, International Myeloma Working Group; MM, multiple myeloma; MRD, minimal residual disease; ORR, overall response rate; OS, overall survival; PD, pharmacodynamics; PFS, progression-free survival; PI, proteasome inhibitor; PK, pharmacokinetics; RP2D, recommended phase 2 dose; sCR, stringent complete response; VGPR, very good partial response.
aTreatment with previously used agent resulting in at least stable disease.
bIncluding a long-term, 15-year follow-up on a separate study.

  • 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

CARTITUDE-1: CRS1,2,26
Total (N=97)
Patients with CRS, n (%)
   Any gradea
92 (95)
   Grade 1
49 (51)
   Grade 2
38 (39)
   Grade 3
3 (3)
   Grade 4
1 (1)
   Grade 5
1 (1)
Median time to onset of CRS, days (IQR)
7 (5-8)
   CRS onset day 4 or later, n (%)
82 (89)
   CRS onset day 6 or later, n (%)
68 (74)
Median duration of CRS, days (IQR)
4 (3-6)b
CRS resolved within 14 days of onset, n (%)
91 (99)
Supportive Measures, n (%)
88 (91)
   Tocilizumab
67 (69)
   Corticosteroids
21 (22)
   Anakinra
18 (19)
   Oxygen
6 (6)
   Vasopressor used
4 (4)
   Intubation/mechanical ventilation
1 (1)
   Cyclophosphamide
1 (1)
   Etanercept
1 (1)
Abbreviations: ASTCT, American Society for Transplantation and Cellular Therapy; CRS, cytokine release syndrome;
HLH, hemophagocytic lymphohistiocytosis; IQR, interquartile range.
aCRS was graded using Lee et al. (Blood 2014) in the phase 1b portion of the study and ASTCT in phase 2; in this combined analysis, Lee et al. criteria were mapped to ASTCT criteria for patients in the phase 1b portion.
bOne patient with 97-day duration died due to CRS/HLH.


CARTITUDE-1: Use of Anakinra Per Study Patient with CRS Event24
Patient
Onset of CRS, day post CARVYKTI infusion
CRS duration, days
Maximum CRS toxicity gradea
Initiation of anakinra, day after onset of CRS
Cumulative anakinra use, days
1b
8
2
1
1
2
2
3
97
5
6
15
3
7
4
1
1
3
4
5
4
2
2
3
5
9
3
2
2
3
6
7
6
1
1
2
7
9
6
3
3
5
8
2
6
1
4
2
9
8
7
1
3
5
10b
7
6
1
2
7
11
5
10
3
2
9
12
4
5
2
4
1
13
6
10
2
3
2
14b
2
7
1
5
2
15b
6
5
2
3
4
16
6
5
2
3
1
17
7
5
2
2
1
18
5
5
2
3
1
Abbreviations: ASTCT, American Society for Transplantation and Cellular Therapy; CRS, cytokine release syndrome.aCRS was graded using Lee et al. (Blood 2014) in the phase 1b portion of the study and ASTCT in phase 2; in this combined analysis, Lee et al. criteria were mapped to 2019 ASTCT criteria for patients in the phase 1b portion.
bPatients received only anakinra and tocilizumab; all other patients received anakinra, tocilizumab, and steroids.

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

CARTITUDE-2 (Cohort A) Initial Subgroup: CRS9,11
Total (N=20)
Patients with CRS, n (%)
   Any Grade
19 (95)
   Grade 3/4
2 (10)
Median time to onset of CRS, days
7
Median duration of CRS, days
3
Supportive Measuresa, n (%)
   Tocilizumab
14 (70)
   Corticosteroids
6 (30)
   IV fluids
8 (40)
   Oxygen
4 (20)
   Anakinra
1 (5)
   Vasopressor
1 (5)
Abbreviations: CRS, cytokine release syndrome.
aIncludes supportive measures to treat CRS events and symptoms

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

CARTITUDE-2 (Cohort B): CRS4,11

Total (N=19)
Patients with a CRS eventa, n (%)
16 (84.2)
Patients with CRS (Grade 3/4)a, n (%)
1 (5.3)
Median time to onset of CRS, days (range)
8 (5-11)
Median duration of CRS, days
4
Supportive Measuresb, n (%)
   Tocilizumab
12 (63)
   Anti-infectives
9 (47)
   Analgesics/anti-inflammatory
9 (47)
   Corticosteroids
4 (21)
   Oxygen
1 (5)
   Vasopressor
1 (5)
   Other
1 (5)
Abbreviation: CRS, cytokine release syndrome.
aCRS was graded according to the American Society for Transplantation and Cellular Therapy criteria.bIncludes supportive measures to treat CRS events and symptoms.

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

CARTITUDE-2 (Cohort C): CRS3,16
Full Cohort
N=20
ADC-Exposeda (n=13)
BsAB-Exposeda (n=7)
All Grades
Grade 3/4
All Grades
Grade 3/4
All Grades
Grade 3/4
CRSb, n (%)
12 (60)
0
6 (46)
0
6 (86)
0
Abbreviations: ADC, antibody drug-conjugate; BCMA, B-cell maturation antigen; BsAb, bispecific antibody; CRS, cytokine release syndrome.aClassification is based on the last anti-BCMA therapy used if patients received more than 1 therapy.bCRS was graded according to American Society for Transplantation and Cellular Therapy criteria.

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

CARTITUDE-2 (Cohort D): CRS17
Cohort D
(N=17)

Any Grade
n (%)

Grade 3/4,
n (%)

Time to Onset,
Median, Days

Duration,
Median, Days

CRS
14 (82.4)
0
8.0
2.5
Abbreviations: AE, adverse event; CRS, cytokine release syndrome.

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.6,18

Study Design/Methods

  • The study design is shown in Figure: CARTITUDE-4 Study Design.
  • CRS was graded per American Society for Transplantation and Cellular Therapy consensus grading. Symptoms of CRS were graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.28

CARTITUDE-4 Study Design6,28,29

Abbreviations: BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; cilta-cel, ciltacabtagene autoleucel; CR, complete response; Cy, cyclophosphamide; DPd, daratumumab, pomalidomide, and dexamethasone; ECOG, Eastern Cooperative Oncology Group; Flu, fludarabine; IMWG, International Myeloma Working Group; ISS, International staging system; IV, intravenous; MM, multiple myeloma; MRD, minimal residual disease; ORR, overall response rate; OS, overall survival; PI, proteasome inhibitor; PK, pharmacokinetics; PO, orally; PRO, patient-reported outcome; PVd, pomalidomide, bortezomib, and dexamethasone; SC, subcutaneously.

aRandomization was stratified by choice of PVd vs. DPd, ISS stage at screening (I vs. II vs. III), and number of prior lines of therapy
(1 vs. 2-3).
bTreatment with PVd or DPd continued until disease progression, death, intolerable toxicity, withdrawal of consent, or end of the study, whichever occurred earlier.
c21-day cycles of PVd which included: pomalidomide 4 mg PO on days 1 to 14 in each cycle; bortezomib 1.3 mg/m2 SC on days 1, 4, 8, and 11 (cycles 1 to 8) and on days 1 and 8 (cycle 9 onwards); dexamethasone 20 mg (10 mg/day for participants >75 years of age) PO on days 1, 2, 4, 5, 8, 9, 11, and 12 (cycles 1 to 8) and on days 1, 2, 8, and 9 (cycle 9 onwards).
d28-day cycles of DPd which included: DARZALEX FASPRO 1800 mg SC weekly on days 1, 8, 15, and 22 (cycles 1 and 2), every 2 weeks on days 1 and 15 (cycles 3 to 6) and every 4 weeks on day 1 (Cycle 7 onwards); pomalidomide 4 mg PO on days 1 to 21 (cycle 1 onwards); dexamethasone 40 mg (20mg weekly for participants >75 years of age) PO or IV weekly on days 1, 8, 15, and 22 or split over 2 days (cycle 1 onwards).
eSecondary endpoints were sequentially tested at each prespecified significance level, including (in order) rates of CR or better, OR, MRD negativity, OS, and time to patient-reported symptom worsening as assessed by the MM Symptom and Impact Questionnaire.

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]).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).6,18
      • 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.6
    • A total of 208 patients (98.6%) were dosed with standard care.6
      • Treatment discontinuation occurred in 131 standard care patients (63.0%), mostly due to disease progression (56.3%).6
    • At data cut-off, 143 CARVYKTI patients were ongoing in the post-treatment phase and 77 patients were ongoing on standard care therapy.6
  • High-risk cytogenetics were present in 59.4% of CARVYKTI patients and 62.9% of standard care patients. Patients in both the CARVYKTI and standard care arms had received a median of 2 prior LOT (range, 1-3).6,30

Safety - Adverse Events - CRS

  • CAR-T specific AEs were evaluated in patients treated with CARVYKTI as study treatment (as-treated population; n=176). The incidence and timing/duration of CRS are detailed in Table: CARTITUDE-4: CRS.18
    • 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 as study treatment. The median time to onset of CRS was 8 days, with a median CRS duration of 3 days. Most of the CRS events were grade 1/2. CRS resolved in all patients.18

CARTITUDE-4: CRS18,28
Total (n=176a)
Patients with a CRS event (all grade)b, n (%)
134 (76.1)
   Grade 1
93 (52.8)
   Grade 2
39 (22.2)
   Grade 3/4
2 (1.1)
Median time to onset of CRSc, days (range)
8 (1-23)
Median duration of CRS, days (range)
3 (1-17)
Supportive Treatments, n
131
   Tocilizumab
71
   Oxygen therapy
17
   Corticosteroids
8
   Vasopressor
2
Abbreviations: CRS, cytokine release syndrome.
aAnalyzed in the patients who received CARVYKTI as study treatment.
bCRS was graded according to the American Society for Transplantation and Cellular Therapy criteria.
cTime to onset from CARVYKTI infusion.

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

CARTITUDE-4: CRS in CARVYKTI Patients With 1 Prior LOT and Those With 1 Prior LOT and Functionally High-Risk MM19
1 Prior LOT

1 Prior LOT and Functionally High-Risk MM
CARVYKTI
(n=68)

CARVYKTI
(n=68)

CARVYKTI
(n=40)

CARVYKTI
(n=40)

All
Grade 3 or 4
All
Grade 3 or 4
CRSa,b
44 (64.7)
1 (1.5)
25 (62.5)
0
Abbreviations: AE, adverse event; ASTCT, American Society for Transplantation and Cellular Therapy; CRS, cytokine release syndrome; LOT, line of therapy; MM, multiple myeloma; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.
aAEs of special interest were evaluated in all patients receiving CARVYKTI as second-line treatment (n=68) and in those with functionally high-risk MM status (n=40). AEs were graded per NCI-CTCAE version 5.0.
bCRS was assessed per ASTCT criteria.

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 15 July 2024.

 

References

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