DARZALEX, Daratumumab Form

Daratumumab (Darzalex®) is a CD38-directed cytolytic antibody. Daratumumab/hyaluronidase- fihj (Darzalex Faspro™) is a combination of daratumumab and hyaluronidase, an endoglycosidase. FDA Approved Indication(s) Darzalex and Darzalex Faspro are indicated for the treatment of adult patients with multiple myeloma (MM): • In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant (ASCT) and in patients with relapsed or refractory MM myeloma who have received at least one prior therapy In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for ASCT In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for ASCT In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy • • • • As monotherapy, in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent In combination with carfilzomib and dexamethasone in patients with relapsed or refractory MM who have received one to three prior lines of therapy • Darzalex is additionally indicated for the treatment of adult patients with MM: • In combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a PI Darzalex Faspro is additionally indicated for the treatment of adult patients with: • MM in combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a PI.
• Light chain (AL) amyloidosis in combination with bortezomib, cyclophosphamide, and dexamethasone in newly diagnosed adult patients. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). Page 1 of 11

CLINICAL POLICY
Daratumumab and Daratumumab/Hyaluronidase-fihj Limitations of Use: Darzalex Faspro is not indicated and is not recommended for the treatment of patients with (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials.
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 Darzalex and Darzalex Faspro are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Multiple Myeloma (must meet all):

1. Diagnosis of MM;
   2. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. Darzalex or Darzalex Faspro is prescribed in one of the following ways (a or b): a. Primary therapy (i or ii): i. Ineligible for ASCT and in combination with one of the following (a or b): a) lenalidomide and dexamethasone; b) bortezomib, melphalan, and prednisone; ii. Eligible for ASCT in combination with one of the following (a, b, c, or d): a) bortezomib, thalidomide, and dexamethasone; b) bortezomib, lenalidomide, and dexamethasone; c) bortezomib, cyclophosphamide, dexamethasone; d) carfilzomib, lenalidomide, and dexamethasone; b. Subsequent therapy (i, ii, or iii): i. In combination with dexamethasone and either lenalidomide, bortezomib (with or without cyclophosphamide), carfilzomib, or Xpovio after ≥ 1 prior therapy; ii. In combination with pomalidomide and dexamethasone after ≥ 1 prior therapies including both of the following (a and b): a) An immunomodulatory agent (e.g., thalidomide, lenalidomide); b) A PI (e.g., ixazomib, bortezomib, carfilzomib); iii. As monotherapy after ≥ 3 prior lines of therapy including a PI and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent; Prior authorization may be required.

2. Request meets one of the following (a or b):
   a. Dose does not exceed the maximum indicated regimen in section V;
   b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).
   Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration: 6 months B. Systemic Light Chain Amyloidosis (must meet all):

   1. Diagnosis of systemic light chain amyloidosis; Page 2 of 11

   CLINICAL POLICY
   Daratumumab and Daratumumab/Hyaluronidase-fihj

3. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. Member meets one of the following (a or b): a. Darzalex Faspro is prescribed in combination with bortezomib, cyclophosphamide, and dexamethasone; b. Darzalex or Darzalex Faspro is prescribed for relapsed or refractory disease after ≥ 1 prior therapy (e.g., bortezomib, lenalidomide) (off-label*); Prior authorization may be required. *If request is for off-label use, refer to NCCN for dosing regimen.
4. Dose is within FDA maximum limit for any FDA-approved indication in Section V or is supported by practice guidelines or peer-reviewed literature for the relevant off- label use (prescriber must submit supporting evidence).Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration: 6 months C. Other diagnoses/indications (must meet 1 or 2):
5. 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
6. 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. All Indications in Section I (must meet all):
7. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Darzalex of Darzalex Faspro for a covered indication and has received this medication for at least 30 days;

8. Member is responding positively to therapy;

   3. If request is for a dose increase, request meets one of the following (a or b):
      a. New dose does not exceed the maximum indicated regimen in section V;
      b. New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).
      Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration: 12 months Page 3 of 11

   CLINICAL POLICY
   Daratumumab and Daratumumab/Hyaluronidase-fihj B. Other diagnoses/indications (must meet 1 or 2):

9. 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

10. 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. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ASCT: autologous stem cell transplant FDA: Food and Drug Administration MM: multiple myeloma
    NCCN: National Comprehensive Cancer Network 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 Dose Limit/ Maximum Dose Agents with FDA-approved dosing for MM. Ninlaro® (ixazomib) bortezomib (Velcade®) Kyprolis® (carfilzomib) Revlimid® (lenalidomide) 4 mg PO on days 1, 8, and 15 of every 28-day treatment cycle 1.3 mg/m2 SC or IV; frequency of administration varies based on specific use 20 mg/m2, 27 mg/m2, and/or 56 mg/m2 IV; frequency of administration varies based on specific use 10 mg or 25 mg PO QD; dose and frequency of administration vary based on specific use See dosing regimen Page 4 of 11

    CLINICAL POLICY
    Daratumumab and Daratumumab/Hyaluronidase-fihj Drug Name Dosing Regimen Dose Limit/ Maximum Dose Thalomid® (thalidomide)
    100 mg, 200 mg, or 400 mg PO QD; dose and frequency of administration vary based on specific use 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. Appendix C: Contraindications/Boxed Warnings • Contraindication(s): hypersensitivity • Boxed warning(s): none reported Appendix D: General Information • The National Comprehensive Cancer Network compendium makes the following recommendation for Darzalex Faspro (category 2A): For multiple myeloma, may be used as a single agent or in combination with other systemic therapies where intravenous daratumumab is recommended. Drug Name Darzalex V. Dosage and Administration
    Indication MM in combination with lenalidomide or pomalidomide (4- week cycle dosing regimens) and low- dose dexamethasone and for monotherapy MM in combination with bortezomib, melphalan and prednisone ([VMP], 6- week cycle dosing regimen MM in combination with bortezomib, thalidomide and dexamethasone ([VTd]; 4-week cycle dosing regimen) Maximum Dose See dosing regimen - Package Insert, Table 1 See dosing regimen - Package Insert, Table 2 See dosing regimen - Package Insert, Table 3 Dosing Regimen Weeks 1 to 8: 16 mg/kg IV weekly Weeks 9 to 24: 16 mg/kg IV every 2 weeks Weeks 25 onwards until disease progression: 16 mg/kg IV every 4 weeks Weeks 1 to 6:
    16 mg/kg IV weekly
    Weeks 7 to 54: 16 mg/kg IV every 3 weeks
    Weeks 55 onwards until disease progression:
    16 mg/kg IV every 4 weeks Induction Weeks 1 to 8:
    16 mg/kg IV weekly
    Weeks 9 to 16: 16 mg/kg IV every 2 weeks
    Consolidation Weeks 1 to 8: Page 5 of 11

    CLINICAL POLICY
    Daratumumab and Daratumumab/Hyaluronidase-fihj Drug Name Indication MM in combination with bortezomib and dexamethasone (3- week cycle dosing regimen) MM in combination with carfilzomib and dexamethasone (4- week cycle dosing regimen) Darzalex Faspro MM in combination with lenalidomide or pomalidomide and dexamethasone (4- week cycle) or as monotherapy MM in combination with bortezomib, melphalan and prednisone ([VMP]; 6- week cycle)
    Maximum Dose See dosing regimen - Package Insert, Table 4 See dosing regimen - Package Insert, Table 5 See dosing regimen - Package Insert, Table 1 See dosing regimen - Package Insert, Table 2 Dosing Regimen 16 mg/kg IV every 2 weeks Weeks 1 to 9: 16 mg/kg IV weekly Weeks 10 to 24: 16 mg/kg IV every 3 weeks Weeks 25 onwards until disease progression: 16 mg/kg IV every 4 weeks Week 1: 8 mg/kg IV days 1 and 2 Weeks 2 to 8: 16 mg/kg IV weekly Weeks 9 to 24: 16 mg/kg IV every 2 weeks Weeks 25 onwards until disease progression: 16 mg/kg IV every 4 weeks 1,800 mg daratumumab -30,000 units hyaluronidase SC into the abdomen over approximately 3 to 5 minutes
    Weeks 1 to 8: weekly Weeks 9 to 24: every 2 weeks Weeks 25 onwards until disease progression: every 4 weeks 1,800 mg daratumumab -30,000 units hyaluronidase SC into the abdomen over approximately 3 to 5 minutes
    Weeks 1 to 6: weekly Weeks 7 to 54: every 3 weeks
    Page 6 of 11

    CLINICAL POLICY
    Daratumumab and Daratumumab/Hyaluronidase-fihj Drug Name Indication MM in combination with bortezomib, thalidomide, and dexamethasone ([D- VTd]; 4-week cycle) MM in combination with bortezomib and dexamethasone ([D- Vd]; 3-week cycle) Darzalex Faspro Light Chain Amyloidosis – in combination with bortezomib, cyclophosphamide, and dexamethasone (D-VCd) Maximum Dose See dosing regimen - Package Insert, Table 3 See dosing regimen - Package Insert, Table 4 See dosing regimen - Package Insert, Table 5 Dosing Regimen Weeks 55 onwards until disease progression: every 4 weeks 1,800 mg daratumumab -30,000 units hyaluronidase SC into the abdomen over approximately 3 to 5 minutes
    Induction: Weeks 1 to 8: weekly (total of 8 doses) Weeks 9 to 16: every 2 weeks (total of 4 doses) Consolidation: Weeks 1 to 8 (following ASCT): every 2 weeks (total of 4 doses) 1,800 mg daratumumab -30,000 units hyaluronidase SC into the abdomen over approximately 3 to 5 minutes
    Weeks 1 to 9: weekly Weeks 10 to 24: every 3 weeks Weeks 25 onwards until disease progression: every 4 weeks 1,800 mg daratumumab -30,000 units hyaluronidase SC into the abdomen over approximately 3 to 5 minutes
    Weeks 1 to 8: weekly (total of 8 doses) Weeks 9 to 24: every 2 weeks (total of 8 doses) Weeks 25 onwards until disease progression or a maximum of 2 years: every 4 weeks Page 7 of 11

    CLINICAL POLICY
    Daratumumab and Daratumumab/Hyaluronidase-fihj VI. Product Availability
    Drug Name Daratumumab (Darzalex) Daratumumab/hyaluronidase-fihj (Darzalex Faspro) Availability Single-dose vial: 100 mg/5 mL, 400 mg/20 mL Single-dose vial: providing 1,800 mg of daratumumab and 30,000 units of hyaluronidase/15 mL VII.