Ciltacabtagene Autoleucel Form

Ciltacabtagene autoleucel (Carvykti™) is a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (CAR-T) therapy. FDA Approved Indication(s) Caryvkti is indicated for the treatment of adults with relapsed and/or refractory multiple myeloma (MM) after four or more prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody.
Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Carvykti is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Multiple Myeloma (must meet all):
Only for initial treatment dose; subsequent doses will not be covered.

1. Diagnosis of relapsed or refractory MM;
2. Prescribed by or in consultation with an oncologist or hematologist;
3. Age ≥ 18 years;

4. One of the following (a or b): a. Member has measurable disease as evidenced by one of the following assessed within the last 30 days (i, ii, or iii): i. Serum M-protein ≥ 1 g/dL; ii. Urine M-protein ≥ 200 mg/24 h; iii. Serum free light chain (FLC) assay: involved FLC level ≥ 10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal; b. Member has progressive disease, as defined by the IMWG response criteria (see Appendix D), assessed within 60 days following the last dose of the last anti- myeloma drug regimen received;

   5. Member has received ≥ 4 prior lines of therapy (see Appendix B for examples) that include all of the following (a, b, and c): a. A PI (e.g., bortezomib, Kyprolis®, Ninlaro®); b. An IMiD (e.g., Revlimid®, Pomalyst®, Thalomid®); c. An anti-CD38 antibody (e.g., Darzalex®/Darzalex Faspro™, Sarclisa®); Page 1 of 9

   CLINICAL POLICY Ciltacabtagene Autoleucel *Prior authorization may be required. Induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen.

   6. Member does not have active or prior history of central nervous system (CNS) involvement (e.g., seizure, cerebrovascular ischemia) or exhibit clinical signs of meningeal involvement of MM;
   7. Member has not previously received treatment with anti-BCMA targeted therapy (e.g., Blenrep™, Tecvayli™);
   8. Member has not previously received treatment with CAR T-cell immunotherapy (e.g., Abecma®, Breyanzi®, Kymriah™, Tecartus™, Yescarta™);
   9. Carvykti is not prescribed concurrently with other CAR T-cell immunotherapy (e.g., Abecma, Breyanzi, Kymriah, Tecartus, Yescarta);
   10. Dose does not exceed 1 x 108 CAR-positive viable T cells. Approval duration: 3 months (1 dose only, with 4 doses of tocilizumab (Actemra) if requested at up to 800 mg per dose) B. Other diagnoses/indications (must meet 1 or 2):
   11. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
   12. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
       II. Continued Therapy A. Multiple Myeloma:
   13. Continued therapy will not be authorized as Carvykti is indicated to be dosed one time only. Approval duration: Not applicable B. Other diagnoses/indications (must meet 1 or 2):
   14. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or Page 2 of 9

   CLINICAL POLICY Ciltacabtagene Autoleucel b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

   2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
      III. Diagnoses/Indications for which coverage is NOT authorized:
      A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents; B. Active or prior history of CNS involvement (e.g., seizure, cerebrovascular ischemia) or exhibit clinical signs of meningeal involvement of MM. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key BCMA: B-cell maturation antigen CAR: chimeric antigen receptor CNS: central nervous system
      CRS: cytokine release syndrome FDA: Food and Drug Administration FLC: free light chain GBS: Guillain-Barré syndrome
      ICANS: immune effector cell-associated neurotoxicity syndrome
      IMiD: immunomodulatory drug IMWG: International Myeloma Working Group MM: multiple myeloma PI: proteasome inhibitor Appendix B: Therapeutic Alternatives
      This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
      Drug Name Dosing Regimen Varies Varies Varies Dose Limit/ Maximum Dose Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies bortezomib/Revlimid® (lenalidomide)/dexamethasone bortezomib/cyclophosphamide/dexamethasone bortezomib/doxorubicin (or liposomal doxorubicin)/ dexamethasone Kyprolis® (carfilzomib) Revlimid® (lenalidomide)/ dexamethasone Kyprolis® (carfilzomib)/cyclophosphamide/ dexamethasone Kyprolis® (carfilzomib – weekly or twice weekly)/ dexamethasone Ninlaro® (ixazomib)/Revlimid® (lenalidomide)/ dexamethasone Page 3 of 9

   CLINICAL POLICY Ciltacabtagene Autoleucel Drug Name Dosing Regimen Varies Varies Varies Varies Varies Dose Limit/ Maximum Dose Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Ninlaro® (ixazomib)/dexamethasone Ninlaro® (ixazomib)/pomalidomide/dexamethasone bortezomib/dexamethasone bortezomib/Thalomid® (thalidomide)/dexamethasone cyclophosphamide/Revlimid® (lenalidomide)/ dexamethasone Revlimid® (lenalidomide)/dexamethasone VTD-PACE (dexamethasone/Thalomid® (thalidomide)/ cisplatin/doxorubicin/cyclophosphamide/etoposide/ bortezomib) Revlimid® (lenalidomide)/low-dose dexamethasone Darzalex® (daratumumab) or Darzalex Faspro™ (daratumumab/hyaluronidase-fihj)/bortezomib/ melphan/prednisone Darzalex® (daratumumab) or Darzalex Faspro™ (daratumumab/hyaluronidase-fihj)/ bortezomib/dexamethasone Darzalex® (daratumumab) or Darzalex Faspro™ (daratumumab/hyaluronidase-fihj)/Revlimid® (lenalidomide)/dexamethasone Darzalex® (daratumumab) or Darzalex Faspro™ (daratumumab/hyaluronidase-fihj) Darzalex® (daratumumab) or Darzalex Faspro™ (daratumumab/hyaluronidase-fihj)/pomalidomide/ dexamethasone Empliciti® (elotuzumab)/Revlimid® (lenalidomide)/ dexamethasone Empliciti® (elotuzumab)/bortezomib/dexamethasone Varies Empliciti® (elotuzumab)/pomalidomide/dexamethasone Varies Varies bendamustine/bortezomib/dexamethasone bendamustine/Revlimid® (lenalidomide)/ Varies dexamethasone Varies panobinostat/bortezomib/dexamethasone panobinostat/Kyprolis® (carfilzomib) Varies panobinostat/Revlimid® (lenalidomide)/dexamethasone Varies Varies pomalidomide/cyclophosphamide/dexamethasone pomalidomide/dexamethasone Varies Varies pomalidomide/bortezomib/dexamethasone pomalidomide/Kyprolis® (carfilzomib)/dexamethasone Varies Sarclisa® (isatuximab-irfc)/pomalidomide/ Varies dexamethasone Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Page 4 of 9

   CLINICAL POLICY Ciltacabtagene Autoleucel Appendix C: Contraindications/Boxed Warnings • Contraindication(s): none reported • Boxed warning(s): cytokine release syndrome (CRS), neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged and recurrent cytopenia Appendix D: General Information
   • • In the CARTITUDE-1 trial, induction with or without hematopoietic stem cell transplant and with or without maintenance therapy was considered a single line of therapy. Patients were required to have undergone at least one complete cycle of treatment for each line of therapy, unless progressive disease was the best response to the regimen. In the CARTITUDE-1 trial, a line of therapy is defined as one or more cycles of a planned treatment program. This may consist of one or more planned cycles of single- agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous stem cell transplantation, followed by maintenance is considered one line of therapy. A new line of therapy starts when a planned course of therapy is modified to include other treatment agents (alone or in combination) as a result of disease progression, relapse, or toxicity. A new line of therapy also starts when a planned period of observation off therapy is interrupted by a need for additional treatment for the disease. • The clinical trial protocol for CARTITUDE-1 did not define or provide details on the investigator assessment for determining active CNS disease for possible trial exclusion, this was left to the discretion of the principle investigator to determine patient fitness for trial enrollment. According to the NCCN Guidelines for Central Nervous System Cancers for leptomeningeal metastases, MRI or the brain and spine should be performed for accurate staging. A definitive diagnosis is most commonly made by CSF analysis via lumbar puncture with CSF protein that is typically increased, there may be a pleocytosis or decreased glucose levels, and ultimately positive CSF cytology for tumor cells. Most CNS myeloma patients present with cerebral symptoms, such as headaches and cognitive dysfunction, but a significant proportion also can have either spinal root/cord symptoms (e.g., limb sensory changes, motor loss, and urinary retention) or positive spinal leptomeningeal imaging. Given the frequent multi-focality of disease identified on imaging, it is reasonable to routinely perform whole spine imaging in any patient with suspected CNS myeloma • Patients receiving Carvykti may experience fatal or life-threatening ICANS following treatment with Carvykti, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. ICANS occurred in 23% (22/97) of patients receiving Carvykti including Grade 3 or 4 events in 3% (3/97) and Grade 5 (fatal) events in 2% (2/97). • Of the 25 patients in the CARTITUDE-1 study experiencing any neurotoxicity, five male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from ICANS. One patient died of neurologic toxicity with parkinsonism 247 days after administration of Carvykti; two patients with ongoing parkinsonism died of infectious causes 162 and 119 days after administration of Carvykti; in the remaining 2 Page 5 of 9

   CLINICAL POLICY Ciltacabtagene Autoleucel patients, symptoms of parkinsonism were ongoing up to 530 days after administration of Carvykti. • A fatal outcome following Guillain-Barré syndrome (GBS) has occurred in another ongoing study of Carvykti despite treatment with intravenous immunoglobulins. Carvykti prescribing information recommends to monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS. • The IMWG response criteria for multiple myeloma definition of progressive disease requires only one of the following: o Increase of 25% from lowest response value in any of the following:  Serum M-component (absolute increase must be ≥ 0.5 g/dL), and/or  Urine M-component (absolute increase must be ≥ 200 mg/24 h), and/or o Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be > 10 mg/dL) o Only in patients without measurable serum and urine M protein levels and without measurable disease by FLC levels, bone marrow plasma cell percentage irrespective of baseline status (absolute increase must be ≥ 10%) o Appearance of a new lesion(s), ≥ 50% increase from nadir in SPD (sum of the products of the maximal perpendicular diameters of measured lesions) of > 1 lesion, or ≥ 50% increase in the longest diameter of a previous lesion >1 cm in short axis; o ≥ 50% increase in circulating plasma cells (minimum of 200 cells per μL) if this is the only measure of disease V. Dosage and Administration Indication MM Dosing Regimen 0.5 to 1 x106 chimeric CAR- positive viable T cells/kg Maximum Dose 1 x108 chimeric CAR- positive viable T cells VI. Product Availability
   Single-dose unit infusion bag: frozen suspension of genetically modified autologous T-cells labeled for the specific recipient VII.