KYPROLIS, Carfilzomib Form

Carfilzomib (Kyprolis®) is a proteasome inhibitor.
FDA Approved Indication(s) Kyprolis is indicated
• For the treatment of adult patients with relapsed or refractory multiple myeloma (MM) who have received one to three lines of therapy in combination with:
o Lenalidomide and dexamethasone or o Dexamethasone or o Daratumumab and dexamethasone or
o Daratumumab and hyaluronidase-fihj and dexamethasone or o Isatuximab and dexamethasone • As a single agent for the treatment of adult patients with relapsed or refractory MM who have received one or more lines of therapy.
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 Kyprolis is 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;
   3. Age ≥ 18 years;
   4. For primary therapy, Kyprolis is prescribed in one of the following ways (a, b, or c): a. In combination with dexamethasone and lenalidomide; b. In combination with dexamethasone and cyclophosphamide; c. In combination with dexamethasone, lenalidomide, and Darzalex® (daratumumab); Prior authorization may be required.

2. For maintenance therapy, Kyprolis is prescribed in combination with lenalidomide;

   6. For previously treated multiple myeloma for relapsed or refractory disease, Kyprolis is prescribed in one of the following ways (a - h):* Page 1 of 12

   CLINICAL POLICY Carfilzomib a. In combination with dexamethasone or with lenalidomide plus dexamethasone in patients who have received one or three lines of therapy (see Appendix B for examples of prior therapy); b. As a single agent in patients who have received one or more lines of therapy; c. In combination with Darzalex® (daratumumab) or Darzalex Faspro™ (daratumumab/hyaluronidase-fihj) and dexamethasone in patients who have received one or three lines of therapy; d. In combination with Sarclisa (isatuximab-irfc) and dexamethasone in patients who have received one or three lines of therapy; e. In combination with Xpovio (Selinexor) and dexamethasone for relapse or progressive disease; f. In combination with dexamethasone and cyclophosphamide, with or without thalidomide, for relapse or progressive disease; g. In combination with pomalidomide and dexamethasone for patients who have received at least two prior therapies, including an immunomodulatory agent and a proteasome inhibitor and who have demonstrated disease progression on or within 60 days of completion of the last therapy; h. In combination with bendamustine and dexamethasone for patients with late relapse or progressive disease who have failed at least three prior therapies; *Prior authorization may be required.

3. Request meets one of the following (a, b, c, d, or e): a. Monotherapy: dose does not exceed 56 mg/m2 twice weekly each 28-day cycle; b. With dexamethasone and lenalidomide: dose does not exceed 27 mg/m2 twice weekly 3 out of 4 weeks for twelve 28-day cycles, then 27 mg/m2 twice weekly 2 out of 4 weeks for the next six 28-day cycles for up to a total of 18 cycles; c. With dexamethasone ± Darzalex: dose does not exceed (i or ii): i. 70 mg/m2 once weekly each 28-day cycle; ii. 56 mg/m2 twice weekly each 28-day cycle; d. With dexamethasone and Sarclisa: 56 mg/m2 twice weekly each 28-day cycle; e. 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. Waldenstrom’s Macroglobulinemia (Lymphoplasmacytic Lymphoma) (off-label) (must meet all):
   1. Diagnosis of Waldenstrom’s macroglobulinemia (i.e., lymphoplasmacytic lymphoma) (WM/LPL);
4. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Prescribed as a component of CaRD (carfilzomib, rituximab, and dexamethasone) regimen as primary or Kyprolis-relapsed therapy;
      Prior authorization may be required.

5. 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
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   CLINICAL POLICY Carfilzomib C. Systemic Light Chain Amyloidosis (off-label) (must meet all):

6. Diagnosis of Systemic Light Chain Amyloidosis;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Request is for relapsed/refractory non-cardiac disease;
   5. Prescribed in one of the following ways (a or b): a. As a single agent; b. In combination with dexamethasone;
7. 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
   D. Other diagnoses/indications (must meet 1 or 2):
8. 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
9. 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 (must meet all):
10. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Kyprolis for a covered indication and has received this medication for at least 30 days;

11. Member is responding positively to therapy;

    3. If request is for a dose increase, request meets one of the following (a, b, c, d, or e):* a. Monotherapy: new dose does not exceed 56 mg/m2 twice weekly each 28-day cycle; b. With dexamethasone and lenalidomide: new dose does not exceed 27 mg/m2 twice weekly 3 out of 4 weeks for twelve 28-day cycles, then 27 mg/m2 twice weekly 2 out of 4 weeks for the next six 28-day cycles for up to a total of 18 cycles; c. With dexamethasone ± Darzalex: new does not exceed (i or ii): i. 70 mg/m2 once weekly each 28-day cycle; Page 3 of 12

    CLINICAL POLICY Carfilzomib ii. 56 mg/m2 twice weekly each 28-day cycle; d. With dexamethasone and Sarclisa: 56 mg/m2 twice weekly each 28-day cycle; e. 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 B. Waldenstrom’s Macroglobulinemia (Lymphoplasmacytic Lymphoma) (off-label) (must meet all):

    1. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Kyprolis for a covered indication and has received this medication for at least 30 days;
12. Member is responding positively to therapy;
    3. 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 C. Systemic Light Chain Amyloidosis (off-label) (must meet all):
13. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Kyprolis for a covered indication and has received this medication for at least 30 days;
14. Member is responding positively to therapy;
    3. 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 D. Other diagnoses/indications (must meet 1 or 2):
15. 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

16. 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.
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    CLINICAL POLICY Carfilzomib 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 CaRD: carfilzomib, rituximab, dexamethasone
    FDA: Food and Drug Administration MM: multiple myeloma NCCN: National Comprehensive Cancer Network WM/LPL: Waldenstrom’s macroglobulinemia/lymphoplasmacytic lymphoma 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 Varies Kyprolis (carfilzomib), bortezomib (Velcade® ),
    lenalidomide (Revlimid), cyclophosphamide, dexamethasone MM: Examples of primary therapy • Bortezomib/dexamethasone • Bortezomib/lenalidomide/dexamethasone • Bortezomib/cyclophosphamide/dexamethasone • Bortezomib/doxorubicin/dexamethasone • Bortezomib/thalidomide/dexamethasone • Carfilzomib/cyclophosphamide/dexamethasone • Carfilzomib/lenalidomide/dexamethasone • Cyclophosphamide/lenalidomide/dexamethasone • Daratumumab/lenalidomide/dexamethasone • Daratumumab/lenalidomide/bortezomib/ dexamethasone • Daratumumab/carfilzomib/lenalidomide/ dexamethasone • Daratumumab/cyclophosphamide/bortezomib/ dexamethasone • Daratumumab/bortezomib/thalidomide/ dexamethasone • Daratumumab/bortezomib/melphalan/prednisone • Dexamethasone/thalidomide/cisplatin/doxorubicin/ cyclophosphamide/etoposide/bortezomib (VTD- PACE) • Ixazomib/cyclophosphamide/dexamethasone Page 5 of 12

    Dose Limit/ Maximum Dose Varies CLINICAL POLICY Carfilzomib Drug Name Dosing Regimen Kyprolis (carfilzomib), bortezomib (Velcade), lenalidomide (Revlimid), Darzalex® (daratumumab), Ninlaro® (ixazomib), Pomalyst (pomalidomide), Empliciti® (elotuzumab),
    Thalomid® (thalidomide), bendamustine, cyclophosphamide, dexamethasone, Sarclisa® (istatuximab-irfc), Xpovio® (selinexor) • Ixazomib/lenalidomide/dexamethasone • Lenalidomide/low-dose dexamethasone MM: Examples of therapy for previously treated for relapsed or refractory disease: • Bendamustine • Bendamustine/bortezomib/dexamethasone • Bendamustine/lenalidomide/dexamethasone • Bendamustine/carfilzomib/dexamethasone • Bortezomib/dexamethasone • Bortezomib/lenalidomide/dexamethasone • Bortezomib/liposomal doxorubicin/dexamethasone • Bortezomib/cyclophosphamide/dexamethasone • Carfilzomib/cyclophosphamide/dexamethasone • Carfilzomib/dexamethasone • Carfilzomib/lenalidomide/dexamethasone • Carfilzomib/cyclophosphamide/dexamethasone • Carfilzomib/cyclophosphamide/thalidomide/ dexamethasone • Cyclophosphamide/lenalidomide/dexamethasone • Cyclophosphamide • Daratumumab • Daratumumab/bortezomib/dexamethasone • Daratumumab/carfilzomib/dexamethasone • Daratumumab/cyclophosphamide/bortezomib/ dexamethasone • Daratumumab/lenalidomide/dexamethasone • Daratumumab/pomalidomide/dexamethasone • Dexamethasone/cyclophosphamide/etoposide/cisplatin • Dexamethasone/thalidomide/cisplatin/doxorubicin/ cyclophosphamide/etoposide/ +/- bortezomib
    • Elotuzumab/lenalidomide/dexamethasone • Elotuzumab/bortezomib/dexamethasone • Elotuzumab/pomalidomide/dexamethasone • Istatuximab-irfc/carfilzomib/dexamethasone • Ixazomib/cyclophosphamide/dexamethasone • Ixazomib/lenalidomide/dexamethasone • Ixazomib/pomalidomide/desamethasone • Isatuximab-irfc/pomalidomide/dexamethasone • Lenalidomide/dexamethasone Pomalidomide/bortezomib/dexamethasone Page 6 of 12

    CLINICAL POLICY Carfilzomib Drug Name Dosing Regimen • Pomalidomide/carfilzomib/dexamethasone • Pomalidomide/cyclophosphamide/dexamethasone • Pomalidomide/dexamethasone • Selinexor/bortezomib/dexamethasone • Selinexor/carfilzomib/dexamethasone • Selinexor/daratumumab/dexamethasone • Selinexor/opomalidomide/dexamthasone • Venetoclax/dexamethasone • Ideocabtagene vicleucel • Ciltacabtagene autoleucel • Teclistamab-cqyv • Benlantamab mafodotin-blmf
    WM/LPL: CaRD (carfilzomib, rituximab, and dexamethasone) rituximab (Rituxan®), Kyprolis (carfilzomib) dexamethasone Dose Limit/ Maximum Dose Varies 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/Black Box Warnings None reported V. Dosage and Administration
    Indication Dosing Regimen MM Kyprolis + Dexamethasone: • Cycles: Kyprolis IV as a 30-minute infusion (28-day Maximum Dose 70 mg/m2 cycles). o Cycle 1: administer Kyprolis 20 mg/m2 on Day 1 and 70 mg/m2 on Days 8 and 15 o Cycle 2 and later: 70 mg/m2 on Day 1, 8, and 15 • Dose (once weekly 20/70 mg/m2 regimen): o Starting dose of Kyprolis 20 mg/m2 on Cycle 1, Day 1 o If tolerated, escalate Kyprolis to 70 mg/m2 on Day 8 of Cycle 1.
    o Dexamethasone: 40 mg PO or IV on Days 1, 8, 15 of all 28-day cycles and on Day 22 of Cycles 1-9.
    Kyprolis + Dexamethasone, OR Monotherapy: Page 7 of 12

    CLINICAL POLICY Carfilzomib Indication Dosing Regimen • Cycles: Kyprolis IV as a 30-minute infusion (28-day Maximum Dose cycles). o Cycle 1: administer Kyprolis 20 mg/m2 on Days 1 and 2, and 56 mg/m2 on Day 8, 9, 15, and 16 o Cycle 2 and later: administer Kyprolis 56 mg/m2 on Days 1, 2, 8, 9, 15 and 16 o For monotherapy: Cycle 13 and later: administer Kyprolis 56 mg/m2 on Days 1, 2, 15 and 16
    • Dose (twice weekly 20/56 mg/m2 regimen): o Starting dose of Kyprolis 20 mg/m2 on Cycle 1, Days 1 o If tolerated, escalate Kyprolis to 56 mg/m2 on Day 8 of and 2 Cycle 1.
    Do not include if Monotherapy: o Dexamethasone: 20 mg PO or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day cycle.
    Kyprolis + lenalidomide + Dexamethasone, OR Monotherapy: • Cycles: Kyprolis IV as a 10-minute infusion for 28-day cycles. o Cycle 1: administer Kyprolis 20 mg/m2 on Days 1 and 2, and 27 mg/m2 on Days 8, 9, 15 and 16 o Cycle 2 to 12: administer Kyprolis 27 mg/m2 on Days 1, 2, 8, 9, 15 and 16 o Cycle 13 and later, administer Kyprolis 27mg/m2 on Day 1, 2, 15 and 16
    o Discontinue Kyprolis after Cycle 18 and continue lenalidomide and dexamethasone thereafter.
    • Dose (twice weekly 20/27 mg/m2 regimen):
    o Starting dose of Kyprolis: 20 mg/m2 on Cycle 1, Days o If tolerated, escalate Kyprolis to 27 mg/m2 on Day 8 of 1 and 2 Cycle 1. Do not include if Monotherapy: o Lenalidomide: 25 mg PO QD on Days 1–21 of each cycle. o Dexamethasone: 40 mg PO or IV on Days 1, 8, 15, and 22 of each 28-day cycle. Kyprolis + Darzalex + Dexamethasone: Twice weekly 20/56 mg/m2 regimen: • Cycles: Kyprolis IV as a 30-minute infusion (28-day cycles). Page 8 of 12

    CLINICAL POLICY Carfilzomib Indication Dosing Regimen Maximum Dose o Cycle 1: administer Kyprolis 20 mg/m2 on Days 1 and 2 and 56 mg/m2 on Days 8, 9, 15 and 16 o Cycle 2 and later: administer Kyprolis 56 mg/m2 on Days 1, 2, 8, 9, 15 and 16
    • Dose:
    o Starting dose of Kyprolis: 20 mg/m2 on Cycle 1, Days o If tolerated, escalate Kyprolis to 56 mg/m2 on Day 8 of 1 and 2 Cycle 1
    o See prescribing information for Darzalex, Darzalex Faspro, and dexamethasone dosing.
    Once weekly 20/70 mg/m2 regimen: • Cycles: Kyprolis IV as a 30-minute infusion (28-day cycles). o Cycle 1: administer Kyprolis 20 mg/m2 on Day 1 and 70 mg/m2 on Days 8 and 15 o Cycle 2 and later: administer Kyprolis 70 mg/m2 on Days 1, 8 and 15
    • Dose:
    o Starting dose of Kyprolis: 20 mg/m2 on Cycle 1, Days o If tolerated, escalate Kyprolis to 70 mg/m2 on Day 8 of 1 and 2
    Cycle 1
    o See prescribing information for Darzalex, Darzalex Faspro, and dexamethasone dosing.
    Kyprolis + Sarclisa + Dexamethasone: Twice weekly 20/56 mg/m2 regimen: • Cycles: Kyprolis IV as a 30-minute infusion (28-day cycles). o Cycle 1: administer Kyprolis 20 mg/m2 on Days 1 and 2 and 56 mg/m2 on Days 8, 9, 15 and 16 o Cycle 2 and later: administer Kyprolis 56 mg/m2 on Days 1, 2, 8, 9, 15 and 16
    • Dose:
    o Starting dose of Kyprolis: 20 mg/m2 on Cycle 1, Days o If tolerated, escalate Kyprolis to 56 mg/m2 on Day 8 of 1 and 2 Cycle 1
    o See prescribing information for Sarclisa dosing.
    __ Calculate the Kyprolis dose using the patient’s actual body surface area at baseline. In patients with a body surface area greater than 2.2 m2, calculate the dose based upon a body surface area of 2.2 m2. Page 9 of 12

    CLINICAL POLICY Carfilzomib VI. Product Availability
    Single-dose vial: 10 mg, 30 mg, 60 mg VII.