2.1 Dose

CARVYKTI is provided as a single dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells in one infusion bag.

The recommended dose range is 0.5–1.0×10 6CAR-positive viable T cells per kg of body weight, with a maximum dose of 1×10 8CAR-positive viable T cells per single infusion.

2.2 Administration

CARVYKTI is for autologous use only. The patient's identity must match the patient identifiers on the CARVYKTI cassette and infusion bag. Do not infuse CARVYKTI if the information on the patient-specific labels does not match the intended patient.

2.3 Management of Severe Adverse Reactions

5.1 Increased Early Mortality

In CARTITUDE-4, a randomized (1:1), controlled trial, there was a numerically higher percentage of early deaths in patients randomized to the CARVYKTI treatment arm compared to the control arm. Among patients with deaths occurring within the first 10 months from randomization, a greater proportion (29/208; 14%) occurred in the CARVYKTI arm compared to (25/211; 12%) in the control arm [see Clinical Studies (14)]. Of the 29 deaths that occurred in the CARVYKTI arm within the first 10 months of randomization, 10 deaths occurred prior to CARVYKTI infusion, and 19 deaths occurred after CARVYKTI infusion. Of the 10 deaths that occurred prior to CARVYKTI infusion, all occurred due to disease progression, and none occurred due to adverse events. Of the 19 deaths that occurred after CARVYKTI infusion, 3 occurred due to disease progression, and 16 occurred due to adverse events. The most common adverse events were due to infection (n=12).

5.2 Cytokine Release Syndrome

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with CARVYKTI. Among patients receiving CARVYKTI for relapsed or refractory multiple myeloma in the CARTITUDE-1 and CARTITUDE-4 studies (N=285), CRS occurred in 84% (238/285), including ≥ Grade 3 CRS (ASTCT 2019) in 4% (11/285) of patients. The median time to onset of CRS, any grade, was 7 days (range: 1 to 23 days). Cytokine release syndrome resolved in 82% with a median duration of 4 days (range: 1 to 97 days). The most common manifestations of CRS in all patients combined (≥ 10%) included fever (84%), hypotension (29%) and aspartate aminotransferase increased (11%). Serious events that may be associated with CRS include pyrexia, hemophagocytic lymphohistiocytosis, respiratory failure, disseminated intravascular coagulation, capillary leak syndrome, and supraventricular and ventricular tachycardia [see Adverse Reactions (6.1].

Cytokine release syndrome occurred in 78% of patients in CARTITUDE-4 (3% Grade 3 to 4) and in 95% of patients in CARTITUDE-1 (4% Grade 3 to 4).

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. Please see Section 5.4; Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS).

Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI.

Of the 285 patients who received CARVYKTI in clinical trials, 53% (150/285) patients received tocilizumab; 35% (100/285) received a single dose, while 18% (50/285) received more than 1 dose of tocilizumab. Overall, 14% (39/285) of patients received at least one dose of corticosteroids for treatment of CRS.

Monitor patients at least daily for 10 days following CARVYKTI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids, as indicated in Table 1 [see Dosing and Administration (2.3)] .

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling information (17)].

5.3 Neurologic Toxicities

Neurologic toxicities, which may be severe, life-threatening or fatal, occurred following treatment with CARVYKTI. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, GBS, immune mediated myelitis, peripheral neuropathies and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time [see Patient Counseling Information (17)] .

Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies for relapsed and refractory multiple myeloma, one or more neurologic toxicities occurred in 24% (69/285), including ≥ Grade 3 cases in 7% (19/285) of patients. The median time to onset was 10 days (range: 1 to 101) with 63/69 (91%) of cases developing by 30 days. Neurologic toxicities resolved in 72% (50/69) of patients with a median duration to resolution of 23 days (range: 1 to 544). Of patients developing neurotoxicity, 96% (66/69) also developed CRS. Subtypes of neurologic toxicities included ICANS in 13%, peripheral neuropathy in 7%, cranial nerve palsy in 7%, parkinsonism in 3%, and immune mediated-myelitis in 0.4% of the patients [see Adverse Reactions (6.1)] .

5.4 Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS)

Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, HLH/MAS occurred in 1% (3/285) of patients. All events of HLH/MAS had onset within 99 days of receiving CARVYKTI, with a median onset of 10 days (range: 8 to 99 days) and all occurred in the setting of ongoing or worsening CRS. The manifestations of HLH/MAS included hyperferritinemia, hypotension, hypoxia with diffuse alveolar damage, coagulopathy and hemorrhage, cytopenia and multi-organ dysfunction, including renal dysfunction and respiratory failure.

Patients who develop HLH/MAS have an increased risk of severe bleeding. Monitor hematologic parameters in patients with HLH/MAS and transfuse per institutional guidelines. Fatal cases of HLH/MAS occurred following treatment with CARVYKTI [see Adverse Reactions (6.1)].

HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards.

5.5 CARVYKTI REMS

Because of the risk of CRS and neurologic toxicities, CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS [see Boxed Warning, Warnings and Precautions (5.2, 5.3)] . The required components of the CARVYKTI REMS are:

• Healthcare facilities that dispense and administer CARVYKTI must be enrolled and comply with the REMS requirements.
• Certified healthcare facilities must have on-site, immediate access to tocilizumab.
• Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after CARVYKTI infusion, if needed for treatment of CRS.

Further information is available at www.carvyktirems.com or 1-844-672-0067.

5.6 Prolonged and Recurrent Cytopenias

Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI infusion.

Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, Grade 3 or higher cytopenias not resolved by day 30 following CARVYKTI infusion occurred in 62% (176/285) of the patients and included thrombocytopenia 33% (94/285), neutropenia 27% (76/285), lymphopenia 24% (67/285) and anemia 2% (6/285). After Day 60 following CARVYKTI infusion 22%, 20%, 5%, and 6% of patients had a recurrence of Grade 3 or 4 lymphopenia, neutropenia, thrombocytopenia, and anemia respectively, after initial recovery of their Grade 3 or 4 cytopenia. Seventy-seven percent (219/285) of patients had one, two or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Sixteen and 25 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death [see Adverse Reactions (6.1)].

Monitor blood counts prior to and after CARVYKTI infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines.

5.7 Infections

CARVYKTI should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening, or fatal infections, occurred in patients after CARVYKTI infusion.

Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, infections occurred in 57% (163/285), including ≥ Grade 3 in 24% (69/285) of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 12%, viral infections in 6%, bacterial infections in 5%, and fungal infections in 1% of patients. Overall, 5% (13/285) of patients had Grade 5 infections, 2.5% of which were due to COVID-19. Patients treated with CARVYKTI had an increased rate of fatal COVID-19 infections compared to the standard therapy arm [see Adverse Reactions (6.1)].

Monitor patients for signs and symptoms of infection before and after CARVYKTI infusion and treat patients appropriately. Administer prophylactic, pre-emptive and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in 5% of patients after CARVYKTI infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated.

Counsel patients on the importance of prevention measures. Follow institutional guidelines for the vaccination and management of immunocompromised patients with COVID-19.

5.8 Hypogammaglobulinemia

Hypogammaglobulinemia can occur in patients receiving treatment with CARVYKTI.

Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, hypogammaglobulinemia adverse event was reported in 36% (102/285) of patients; laboratory IgG levels fell below 500 mg/dl after infusion in 93% (265/285) of patients. Hypogammaglobulinemia either as an adverse reaction or laboratory IgG level below 500 mg/dl, after infusion occurred in 94% (267/285) of patients treated. Fifty six percent (161/285) of patients received intravenous immunoglobulin (IVIG) post CARVYKTI for either an adverse reaction or prophylaxis [see Adverse Reactions (6.1)] .

Monitor immunoglobulin levels after treatment with CARVYKTI and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

5.9 Hypersensitivity Reactions

Hypersensitivity reactions occurred following treatment with CARVYKTI.

Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, hypersensitivity reactions occurred in 5% (13/285), all of which were ≤ Grade 2. Manifestations of hypersensitivity reactions included flushing, chest discomfort, tachycardia, wheezing, tremor, burning sensation, non-cardiac chest pain, and pyrexia.

Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage patients appropriately according to the severity of the hypersensitivity reaction.

5.10 Secondary Malignancies

Patients treated with CARVYKTI may develop secondary malignancies.

Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, myeloid neoplasms occurred in 5% (13/285) of patients (9 cases of myelodysplastic syndrome, 3 cases of acute myeloid leukemia, and 1 case of myelodysplastic syndrome followed by acute myeloid leukemia). The median time to onset of myeloid neoplasms was 447 days (range: 56 to 870 days) after treatment with CARVYKTI. Ten of these 13 patients died following the development of myeloid neoplasms; 2 of the 13 cases of myeloid neoplasm occurred after initiation of subsequent antimyeloma therapy. Cases of myelodysplastic syndrome and acute myeloid leukemia have also been reported in the post marketing setting.

T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including CARVYKTI. Mature T-cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusions, and may include fatal outcomes [see Boxed Warning, Adverse Reactions (6.1, 6.3), Patient Counseling Information (17)] .

Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc. at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples.

5.11 Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status, seizures, neurocognitive decline or neuropathy, patients receiving CARVYKTI are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurologic toxicities.

6.1 Clinical Trials Experience

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.

The safety data described in the WARNINGS and PRECAUTIONS section reflect exposure to CARVYKTI in 285 patients with relapsed or refractory multiple myeloma: one randomized, open label with 188 patients in CARTITUDE-4 and one single-arm, open label study with 97 patients in CARTITUDE-1.

6.2 Immunogenicity

The immunogenicity of CARVYKTI has been evaluated using a validated assay for the detection of binding antibodies against the extracellular portion of the anti-BCMA CAR pre-dose, and at multiple timepoints post-infusion. In CARTITUDE-1, 19 of 97 (19.6%) patients were positive for anti-product antibodies. In CARTITUDE-4, 39 of 186 patients (21%) were positive for anti-CAR antibodies.

There was no clear evidence that the observed anti-product antibodies impact CARVYKTI kinetics of initial expansion and persistence, efficacy, or safety.

6.3 Postmarketing Experience

Because adverse events to marketed products are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

The following adverse event has been identified during postmarketing use of CARVYKTI.

Neoplasms:T cell malignancies

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Safety and effectiveness of CARVYKTI in pediatric patients have not been established.

8.5 Geriatric Use

Of the 97 patients in CARTITUDE-1 that received CARVYKTI, 28% were 65 to 75 years of age, and 8% were 75 years of age or older. CARTITUDE-1 did not include sufficient numbers of patients aged 65 and older to determine whether the effectiveness differs compared with that of younger patients. In 62 patients less than 65 years of age, all grade and Grade 3 and higher neurologic toxicities occurred in 19% (12/62) and 6% (4/62), respectively. Of the 35 patients ≥65 years of age, all grade and Grade 3 and higher neurologic toxicities occurred in 37% (13/35) and 20% (7/35), respectively.

Of the 188 patients in CARTITUDE-4 that received CARVYKTI, 38% were 65 to 75 years of age, and 2% were 75 years of age or older. In 112 patients less than 65 years of age, all grade and Grade 3 and higher neurologic toxicities occurred in 16% (18/112) and 3% (3/112) respectively. Of the 76 patients ≥65 years of age, all grade and Grade 3 and higher neurologic toxicities occurred in 34% (26/76) and 7% (5/76) respectively.

12.1 Mechanism of Action

CARVYKTI is a BCMA-directed, genetically modified autologous T cell immunotherapy, which involves reprogramming a patient's own T cells with a transgene encoding a CAR that identifies and eliminates cells that express BCMA. The CARVYKTI CAR protein features two BCMA-targeting single-domain antibodies designed to confer high avidity against human BCMA, a 4-1BB co-stimulatory domain and a CD3-zeta (CD3ζ) signaling cytoplasmic domain. Upon binding to BCMA-expressing cells, the CAR promotes T cell activation, expansion, and elimination of target cells.

12.2 Pharmacodynamics

After a single infusion of CARVYKTI, expansion of CAR-positive T cells coincided with decreases of serum soluble BCMA, serum M-protein, and/or free light chains. Across all patients, levels of IL-6, IL-10, IFN-γ and IL-2 receptor alpha increased post-infusion and peaked at Days 7–14. The serum levels of all cytokines generally returned to baseline levels within 2–3 months post-infusion.

12.3 Pharmacokinetics

The pharmacokinetics (PK) of CARVYKTI was assessed in 285 adult patients with relapsed or refractory multiple myeloma in CARTITUDE-1 and CARTITUDE-4 receiving a single infusion at the median dose of 0.71×10 6CAR-positive viable T cells/kg (range: 0.41×10 6to 1.08×10 6cells/kg).

Following a single infusion, CARVYKTI exhibited an initial expansion phase followed by a rapid decline, and then a slower decline. However, high inter-individual variability was observed.

After the cell expansion, the persistence phase of CARVYKTI was observed for all patients. At the time of analysis in CARTITUDE-1 (n=65) and CARTITUDE-4 (n=87) studies, the median time for CAR transgene levels in peripheral blood to return to the pre-dose baseline level was approximately 100 days (range: 28 to 365 days) and 109 days (range: 29 to 366 days) post-infusion respectively.

Detectable CARVYKTI exposures in bone marrow indicate a distribution of CARVYKTI from systemic circulation to bone marrow. Similar to blood transgene levels, bone marrow transgene levels declined over time and exhibited high inter-individual variability.

Patients with higher CAR-T cell expansion tended to have higher rates of CRS. Some patients required tocilizumab, corticosteroids, and anakinra for the management of CRS. CARVYKTI continues to expand and persist following administration of tocilizumab, corticosteroids, and anakinra. In CARTITUDE-1, CARVYKTI median C maxand AUC 0–28din patients treated with tocilizumab (n=68) for CRS were 168% and 209% of those in patients (n=29) who did not receive tocilizumab for CRS, respectively. The median C maxand AUC 0–28dof CARVYKTI in patients who received corticosteroids (n=21) for CRS were 186% and 307% of those in patients who did not receive corticosteroids (n=76) for CRS, respectively. In addition, the median C maxand AUC 0–28dof CARVYKTI in patients who received anakinra (n=18) for CRS were 139% and 232% of those in patients who did not receive anakinra (n=79) for CRS, respectively. In CARTITUDE-4, the results related to tocilizumab and corticosteroid were consistent with CARTITUDE-1.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No genotoxicity or carcinogenicity studies have been performed with CARVYKTI as they were not indicated. In vitrostudies with CARVYKTI manufactured from healthy donors and patients with multiple myeloma showed no evidence of cytokine independent growth and no preferential integration near genes associated with oncogenic transformation.

No studies have been conducted to evaluate the effects of CARVYKTI on fertility.

CARTITUDE-4

Efficacy of CARVYKTI was evaluated in CARTITUDE-4 (NCT04181827) a randomized, open label, multicenter controlled study in adult patients with relapsed and lenalidomide-refractory multiple myeloma, who previously received at least 1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent. A total of 419 patients were randomized 1:1 to receive either a sequence of apheresis, bridging therapy, lymphodepletion and CARVYKTI (n=208) or standard therapy which included daratumumab, pomalidomide and dexamethasone (DPd) or bortezomib, pomalidomide and dexamethasone (PVd) selected by physician prior to randomization based on patient's prior antimyeloma therapy (n=211). Randomization was stratified by physician's choice of treatment (DPd vs. PVd), ISS (I vs. II vs. III) and number of prior lines of therapy (1 vs. 2 or 3).

Patients with known active or prior history of central nervous system involvement, patients who exhibit clinical signs of meningeal involvement of multiple myeloma and patients with a history of Parkinson's disease or other neurodegenerative disorder, were excluded from the trial.

In the overall study population (N=419), the median age was 61 years (range: 27 to 80 years), 57% were male, 75% were White, 3% were Black or African American, 9% were Asian, and 7% were Hispanic or Latino. Most patients (94%) were International Staging System (ISS) Stage I or II. High-risk cytogenetics [presence of t(4:14), (14:16), and 17p13 del] were present in 34% of patients. Nineteen percent of patients had presence of soft tissue plasmacytoma.

Patients had received a median of 2 (range: 1 to 3) prior lines of therapy and 85% of patients had received prior autologous stem cell transplantation (ASCT). Ninety-nine percent of patients were refractory to their last line of prior therapy. Forty-seven percent were refractory to a proteasome inhibitor (PI) and 100% were refractory to an immunomodulatory agent.

All 208 patients randomized to the CARVYKTI arm underwent apheresis, twelve (6%) were not treated with CARVYKTI due to progressive disease (n=10) or death (n=2), and twenty (10%) progressed prior to infusion with CARVYKTI but were able to receive CARVYKTI as subsequent therapy. Eight (4%) patients received CAR-T positive T cells that did not meet product release specification for CARVYKTI (non-conforming product).

Patients randomized to CARVYKTI were to receive lymphodepleting chemotherapy consisting of fludarabine 30 mg/m 2/day and cyclophosphamide 300 mg/m 2/day concurrently for 3 days followed by CARVYKTI infusion 5 to 7 days after start of lymphodepleting chemotherapy. At least one cycle of DPd or PVd bridging therapy was received for disease control between leukapheresis and the start of the lymphodepleting chemotherapy.

CARVYKTI was administered as a single IV infusion 5 to 7 days after the start of a lymphodepleting chemotherapy at a median dose of 0.71×10 6CAR-positive viable T-cells/kg (range: 0.39 to 1.07×10 6cells/kg).

In the 176 patients that received CARVYKTI as study treatment, the median time from the day after receipt of apheresis material at manufacturing facility to release of product for infusion was 44 days (range: 25 to 127 days) and the median time from first apheresis to CARVYKTI infusion was 79 days (range: 45 days to 246 days).

The primary efficacy measure was progression-free survival (PFS) analyzed based on the Intent-To-Treat Analysis Set (see Table 8and Figure 1). After a median follow-up of 15.9 months, median PFS was 12 months (95% CI: 9.8, 14) for standard therapy arm and NE (95% CI: 22.8, NE) for CARVYKTI arm (Hazard ratio: 0.41 [95% CI: 0.30, 0.56]). The estimated PFS rate at 12 months was 75.9% (95% CI: 69.4%, 81.1%) in the CARVYKTI arm and 49.5% (95% CI: 42.3%, 56.3%) in the standard therapy arm.

Figure 1. Kaplan-Meier Curve of PFS in CARTITUDE-4 (Intent-To-Treat Analysis Set)
Note: Intent-to-treat analysis set consists of subjects who were randomized in the study. Data cutoff date: November 1, 2022

In the CARVYKTI arm, the estimated median duration of response (DOR) has not been reached in patients who achieved PR or better or in patients who achieved CR or better. In the standard therapy arm, the estimated median DOR was 16.6 months (95% CI: 12.9, NE).

A higher proportion of patients in the CARVYKTI arm compared to the standard therapy arm died within the first 10 months of randomization as shown in Figure 2.

Figure 2. Kaplan-Meier Curve of Overall Survival in CARTITUDE-4 (Intent-to-Treat Analysis Set)
Note: Intent-to-treat analysis set consists of subjects who were randomized to the study. Data cutoff date: November 1, 2022. 34% of the planned OS events have occurred.

CARTITUDE-1

The efficacy of CARVYKTI was evaluated in CARTITUDE-1 (NCT03548207), an open-label, single-arm, multicenter trial in adult patients with relapsed or refractory multiple myeloma, who previously received at least 3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody [see Adverse Reactions (6.1)] .

Patients with known active or prior history of significant central nervous system (CNS) disease, including CNS multiple myeloma, plasma cell leukemia, allogeneic stem cell transplant within 6 months before apheresis or ongoing treatment with immunosuppressants, creatinine clearance <40 mL/min, absolute lymphocyte concentration <300/µL, absolute neutrophil count <750 cells/mm 3, platelet count <50,000/mm 3, hepatic transaminases >3 times the upper limit of normal, cardiac ejection fraction <45%, or with active serious infection were excluded from the trial.

Of the 113 patients who underwent leukapheresis, 16 patients did not receive CARVYKTI due to progressive disease (n=2), death (n=9), or withdrawal from study (n=5). There were 97 patients in the efficacy evaluable population who received CARVYKTI, including 17 patients (18%) with manufacturing failures either because they received CARVYKTI that did not meet product release specifications for CARVYKTI or received CARVYKTI for which there were insufficient data to confirm product release specifications for CARVYKTI.

Of the 97 efficacy-evaluable patients, the median age was 61 years (range: 43 to 78 years), 59% were male, 71% were white, and 18% were black. Most patients (86%) were ISS Stage I or II. Of the 91 patients for whom baseline cytogenetic data were available, high-risk cytogenetics (presence of t(4:14), t(14:16), or 17p13 del) were present in 24% of patients. Thirteen percent of the patients had extramedullary disease.

The median number of prior lines of therapy was 6 (range: 3 to 18), with 82% of patients receiving 4 or more prior lines of therapy, 90% of patients had received prior autologous stem cell transplantation (ASCT) and 8% of patients received an allogeneic transplant. Ninety-nine percent of patients were refractory to their last line of prior therapy, and 88% were refractory to a proteasome inhibitor (PI), immunomodulatory agent, and anti-CD38 antibody.

Most patients (75%) treated with CARVYKTI received bridging therapy for control of their multiple myeloma during the manufacturing process. The median time from leukapheresis to product availability was 32 days (range: 27 to 66 days).

The most commonly used agents as bridging therapies (≥20% of patients) included dexamethasone: 62 patients (64%), bortezomib: 26 patients (27%), cyclophosphamide: 22 patients (23%), and pomalidomide: 21 patients (22%).

Efficacy was established on the basis of overall response rate, complete response rate and duration of response as assessed by the Independent Review Committee (IRC) using International Myeloma Working Group (IMWG) criteria (see Table 9and 10). The median time to first response was 1 month (range: 0.9 to 10.7 months).

The IRC assessed overall response in the 113 patients that underwent leukapheresis was 84% (95% CI: 76, 90) with stringent CR rate of 69% (95% CI: 60, 77), VGPR rate of 12% (95% CI: 7, 20) and PR rate of 3% (95% CI: 1, 8).

Store and transport below -120°C, e.g., in a container for cryogenic storage in the vapor phase of liquid nitrogen.

Store CARVYKTI in the original packaging containing the cassette protecting the infusion bag.

Thaw CARVYKTI prior to infusion [see Dosage and Administration (2)] .

Increased Early Mortality

Inform patients of the risk of early mortality. In a clinical study, treatment in the CARVYKTI arm was associated with a higher rate of death (14%) compared to the control arm (12%) in the first 10 months from randomization. This higher rate of death was observed before receiving CARVYKTI and after treatment with CARVYKTI. The reasons for death were progression of multiple myeloma and adverse events [see Warnings and Precautions (5.1), Clinical Studies (14)] .

Cytokine Release Syndrome (CRS)

Signs or symptoms of CRS, including fever, chills, fatigue, headache, tachycardia, hypotension, hypoxia, dizziness/lightheadedness or organ toxicities [see Warnings and Precautions (5.2), Adverse Reactions (6.1)].

Neurologic Toxicities

Signs or symptoms associated with neurologic events, some of which occur days, weeks or months following the infusion including [see Warnings and Precautions (5.3), Adverse Reactions (6.1)] :

ICANS:e.g., aphasia, encephalopathy, depressed level of consciousness, seizures, delirium, dysgraphia

Parkinsonism:e.g., tremor, micrographia, bradykinesia, rigidity, shuffling gait, stooped posture, masked facies, apathy, flat affect, lethargy, somnolence

Guillain Barré Syndrome:e.g., motor weakness and polyradiculoneuritis

Peripheral neuropathy:e.g., peripheral motor and/or sensory nerve dysfunction

Cranial Nerve Palsies:e.g., facial paralysis, facial numbness

Prolonged and Recurrent Cytopenias

Signs or symptoms associated with bone marrow suppression including neutropenia, thrombocytopenia, anemia, or febrile neutropenia for several weeks or months. Signs or symptoms associated with bone marrow suppression may recur [see Warnings and Precautions (5.6), Adverse Reactions (6.1)] .

Infections

Signs or symptoms associated with infection [see Warnings and Precautions (5.7), Adverse Reactions (6.1)] .

Hypersensitivity Reactions

Signs or symptoms associated with hypersensitivity reactions including flushing, chest tightness, tachycardia, and difficulty breathing [see Warnings and Precautions (5.9)].

Secondary Malignancies

Secondary hematological malignancies, including myelodysplastic syndrome, acute myeloid leukemia, and T-cell malignancies have occurred [see Boxed Warning, Warnings and Precautions (5.10), Adverse Reactions (6.1, 6.3)].

Advise patients of the need to:

• Have periodic monitoring of blood counts before and after CARVYKTI infusion [see Warnings and Precautions (5.6)] .
• Contact Janssen Biotech, Inc. at 1-800-526-7736 if they are diagnosed with a secondary malignancy [see Warnings and Precautions (5.10)] .
• Refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks after treatment and in the event of any new onset of neurologic toxicities [see Warnings and Precautions (5.11)] .
• Tell their physician about their treatment with CARVYKTI before receiving a live virus vaccine [see Warnings and Precautions (5.8)] .