Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2024040
Category:	Pharmacy
Initiated:	August 2024
Last Review:	August 2025

Ciltacabtagene Autoleucel (e.g., Carvykti)

Description:

Ciltacabtagene autoleucel is a BCMA (B cell maturation antigen)-directed, genetically modified autologous T cell immunotherapy, which involves reprogramming an individual’s own T cells with a transgene encoding a chimeric antigen receptor (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.

REGULATORY STATUS

Ciltacabtagene autoleucel has a black box warning because of the risk of cytokine release syndrome and neurologic toxicities that include fatal or life-threatening reactions. It should not be administered to individuals with active infection or inflammatory disorders. It is recommended that severe or life-threatening cytokine release syndrome should be treated with tocilizumab. Individuals should be monitored for neurologic events after treatment.

On February 28, 2022, the Food and Drug Administration approved ciltacabtagene autoleucel (e.g., Carvykti) for the treatment of adult individuals with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

On April 5, 2024, the Food and Drug Administration expanded approved label of ciltacabtagene autoleucel (e.g., Carvykti) for the treatment of adult individuals with relapsed or refractory multiple myeloma after at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide.

On June 26, 2025, the Food and Drug Administration approved streamlined patient monitoring requirements and removed REMS program requirement for ciltacabtagene autoleucel (e.g., Carvykti).

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Please refer to AR policy # 2020001 for separate policy on Adoptive Immunotherapy.

Prior Approval is required for ciltacabtagene autoleucel (e.g., Carvykti).

The use of this drug/therapy requires documentation of direct involvement and ordering by a physician with expertise in specified condition and in a center approved for administration of CAR-T or gene product.

Effective November 1, 2025

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Ciltacabtagene autoleucel (e.g., Carvykti) meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of adults with relapsed or refractory multiple myeloma when ALL the following criteria are met:

MULTIPLE MYELOMA

1. Individual is 18 years of age or older (Carvykti, 2025); AND

2. Individual has a diagnosis of refractory or relapsed multiple myeloma (Carvykti, 2025); AND

3. Individual has received one prior line of therapy including ALL the following (Carvykti, 2025):

a. Immunomodulatory agent (e.g., thalidomide, lenalidomide, pomalidomide); AND

b. Proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib); AND

4. Individual is refractory to lenalidomide (Carvykti, 2025); AND

5. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy and is not the subject of a clinical trial for any of the therapies listed in this policy; AND

6. Individual does not have any of the following circumstances:

a. Combination use with other chemotherapy agents (not including the use of lymphodepleting chemotherapy prior to infusion) and/or biologic agents; OR

b. Prior treatment with chimeric antigen receptor therapy or other genetically modified T-cell therapy; OR

7. Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND

8. Individual does not have evidence of myeloma involving the central nervous system; AND

9. There is only one administration of ciltacabtagene autoleucel per individual per lifetime.

The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication above with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”)]. The use of this drug for off-label indications not listed above is subject to policy 2000030.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Ciltacabtagene autoleucel (e.g., Carvykti), for any indication or circumstance not described above, does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For individuals without primary coverage criteria, ciltacabtagene autoleucel (e.g., Carvykti), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

POLICY GUIDELINES

Provider is responsible for assessing suitability for CAR-T therapy, including verification of adequate renal function (creatinine clearance is not less than or equal to 45 mL/min), adequate cardiovascular function (left cardiac ejection fraction (EF) is not less than 45%, or other clinically significant cardiac disease has not been present within in the past 6 months), adequate immunological status (no active hepatitis B, active hepatitis C, human immunodeficiency virus (HIV) positive, or other active, uncontrolled infection).

DOSAGE AND ADMINISTRATION

For FDA labeled indications, ciltacabtagene autoleucel (e.g., Carvykti) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below:

The recommended dose range is 0.5 - 1.0 x 1 million CAR-positive viable T cells per kg of body weight, with a maximum dose of 100 million Car-positive viable T cells per single infusion.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Effective August 21, 2024 to October 31, 2025

CILTACABTAGENE AUTOLEUCEL (E.G., CARVYKTI) FOR MULTIPLE MYELOMA

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Ciltacabtagene autoleucel meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of adults with relapsed or refractory multiple myeloma when ALL the following criteria are met:

1. Individual is 18 years of age or older; AND

2. Individual has a diagnosis of multiple myeloma; AND

3. Individual has received one prior lines of therapy including ALL the following:

a. Immunomodulatory agent; AND

b. Proteasome inhibitor; AND

4. Individual is refractory to lenalidomide; AND

5. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy and is not the subject of a clinical trial for any of the therapies listed in this policy; AND

6. Individual does not have any of the following circumstances:

a. Combination use with other chemotherapy agents (not including the use of lymphodepleting chemotherapy prior to infusion) and/or biologic agents; OR

b. Prior allogeneic stem cell transplant; OR

c. Prior treatment with chimeric antigen receptor therapy or other genetically modified T-cell therapy; OR

d. Creatinine clearance less than or equal to 45 mL/min; OR

e. Left cardiac ejection fraction (EF) less than 45%, or other clinically significant cardiac disease within in the past 6 months; OR

f. Active hepatitis B, active hepatitis C, human immunodeficiency virus (HIV) positive, or other active, uncontrolled infection; OR

g. Repeated administration of idecabtagene vicleucel or ciltacabtagene autoleucel; AND

7. Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND

8. Individual does not have evidence of myeloma involving the central nervous system; AND

9. There is only one administration of idecabtagene vicleucel or ciltacabtagene autoleucel per individual per lifetime; AND

10. Must be dosed in accordance with the FDA label.

The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).

Dosage and Administration

Dosing per FDA Guidelines

The recommended dose range is 0.5 - 1.0 x 1 million CAR-positive viable T cells per kg of body weight, with a maximum dose of 1 x 100 million Car-positive viable T cells per single infusion.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Ciltacabtagene autoleucel, for any indication or circumstance not described above, does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For individuals without primary coverage criteria, ciltacabtagene autoleucel, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

For coverage criteria prior to August 21, 2024 for Ciltacabtagene Autoleucel (e.g., Carvykti), please email codespecificinquiry@arkbluecross.com for a hardcopy print of the coverage policy.

Rationale:

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. Adoptive immunotherapy has been investigated for the treatment of relatively common cancers in which novel treatments have been adopted when randomized clinical trials show efficacy. The selected studies included only new randomized clinical trials.

PRACTICE GUIDELINES AND POSITION STATEMENTS

Current guidelines from the National Comprehensive Cancer Network do not include recommendations for adoptive immunotherapy to treat cancers of the bladder, central nervous system, head and neck, hepatobiliary system, kidney, pancreatic, stomach, or thyroid, melanoma, Hodgkin lymphoma, or non-small-cell lung cancer (NCCN, 2017).

Current NCCN guidelines for acute lymphoblastic leukemia (v.2.2019) recommend (category 2A) tisagenlecleucel as a treatment option for:

Philadelphia chromosome-positive patients 26 years or less in age with refractory disease or 2 or more relapses and failure of 2 tyrosine kinase inhibitors.
Philadelphia chromosome-negative patients 26 years or less in age with refractory disease or 2 or more relapses.

CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis.

This single-arm, open-label, phase 1b/2 study done at 16 centers in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR-positive viable T cells per kg) was administered 5-7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207.

Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 106 CAR-positive viable T cells per kg. As of the Sept 1, 2020, clinical cutoff, median follow-up was 12·4 months (IQR 10·6-15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2-99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9-1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9-not estimable), neither was progression-free survival (16·8-not estimable). The 12-month progression-free rate was 77% (95% CI 66·0-84·3) and overall survival rate was 89% (80·2-93·5). Hematological adverse events were common; grade 3-4 hematological adverse events were neutropenia (92 [95%] of 97 patients), anemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5-8) and median duration of 4·0 days (IQR 3-6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and hemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study: six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events.

A single cilta-cel infusion at the target dose of 0·75 × 106 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions. (Berdeja JG, Madduri D, Usmani SZ, et.al., 2021)

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2024.

2025 Update

FDA approval for earlier use of ciltacabtagene is based on positive results from the Phase 3 CARTITUDE-4 study, which demonstrated that the earlier use of ciltacabtagene reduced the risk of disease progression or death by 59 percent compared to standard therapies—pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd)—in adults with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy (Carvykti, 2025). The study, which was presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting and published in The New England Journal of Medicine, also included and reported key secondary results such as overall response (OR) and overall survival (OS).

The safety profile for ciltacabtagene includes a boxed warning for Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), Parkinsonism and Guillain-Barre syndrome and their associated complications, Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), Prolonged and Recurrent Cytopenias and Secondary Malignancies including myelodysplastic syndrome, acute myeloid leukemia, and T-cell malignancies. Warnings and Precautions include Increased Early Mortality, Hypogammaglobulinemia, Infections, Hypersensitivity Reactions and Effects on Ability to Drive and Use Machines.

CPT/HCPCS:

References:

Berdeja JG, Madduri D, Usmani SZ, et.al.,(2021) Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021 Jul 24;398(10297):314-324. doi: 10.1016/S0140-6736(21)00933-8. Epub 2021 Jun 24. Erratum in: Lancet. 2021 Oct 2;398(10307):1216. doi: 10.1016/S0140-6736(21)02132-2. PMID: 34175021.

Carvykti(2024) package insert Janssen biotech, Inc., Horsham, PA. 2024

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants.