Melphalan flufenamide (Pepaxto) Form

Melphalan flufenamide (Pepaxto®) is an alkylating drug. FDA Approved Indication(s)
Pepaxto is indicated in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody. 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 confirmatory trial(s). Limitation(s) of use: Pepaxto is not indicated and is not recommended for use as a conditioning regimen for transplant outside of controlled clinical trials. _ Oncopeptides, the manufacturer of Pepaxto, voluntarily withdrew Pepaxto after data from the confirmatory Phase 3 OCEAN study revealed Pepaxto did not meet the requirements of the FDA Accelerated Approval regulation. The FDA withdrew its approval for the product (see Appendix D). 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 Pepaxto is medically necessary when the following criteria are met:
I. Initial Approval Criteria A. Multiple Myeloma (must meet all):

1. Provider attestation of acknowledgement of FDA’s request for withdrawal of product due to reduced overall survival and failure to demonstrate superior progression-free survival (PFS) compared to Pomalyst® in combination with dexamethasone;

2. Diagnosis of multiple myeloma;

   3. Prescribed by or in consultation with an oncologist or hematologist;
   4. Age ≥ 18 years;
   5. Pepaxto is prescribed in combination with dexamethasone; Page 1 of 8

   CLINICAL POLICY Melphalan Flufenamide

3. Member has received ≥ 4 prior lines of therapy (see Appendix B for examples) that include all of the following (a, b, and c): a. One proteasome inhibitor (e.g., bortezomib, Kyprolis®, Ninlaro®); b. One immunomodulatory agent (e.g., Revlimid®, Pomalyst®, Thalomid®); c. One anti-CD38 antibody (e.g., Darzalex®/Darzalex Faspro™, Sarclisa®); *Prior authorization may be required
4. Request meets one of the following (a or b): a. Dose does not exceed 40 mg every 4 weeks; 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. 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. Multiple Myeloma (must meet all):
7. Provider attestation of acknowledgement of FDA’s request for withdrawal of product due to reduced overall survival and failure to demonstrate superior PFS compared to Pomalyst in combination with dexamethasone;
8. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Pepaxto for a covered indication and has received this medication for at least 30 days;

9. Member is responding positively to therapy;

   4. Pepaxto is prescribed in combination with dexamethasone;
   5. If request is for a dose increase, request meets one of the following (a or b): a. New dose does not exceed 40 mg every 4 weeks; 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 2 of 8

   CLINICAL POLICY Melphalan Flufenamide B. Other diagnoses/indications (must meet 1 or 2):

10. 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

11. 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 CI: confidence interval FDA: Food and Drug Administration HR: hazard ratio PFS: progression free survival 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 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 Page 3 of 8

    CLINICAL POLICY Melphalan Flufenamide Drug Name Dosing Regimen Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Ninlaro® (ixazomib)/Revlimid® (lenalidomide)/ dexamethasone 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 Varies pomalidomide/dexamethasone pomalidomide/bortezomib/dexamethasone Varies pomalidomide/Kyprolis® (carfilzomib)/dexamethasone Varies Sarclisa® (isatuximab-irfc)/pomalidomide/ Varies dexamethasone Varies Varies Varies Varies Dose Limit/ Maximum Dose Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Page 4 of 8

    CLINICAL POLICY Melphalan Flufenamide 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): history of serious hypersensitivity reaction to melphalan flufenamide or melphalan
    • Boxed warning(s): none reported Appendix D: Withdrawal from Market • Oncopeptides, the manufacturer of Pepaxto, voluntarily withdrew Pepaxto after data from the confirmatory Phase 3 OCEAN study revealed Pepaxto did not meet the requirements of the FDA Accelerated Approval regulation. The FDA Oncologic Drugs Advisory Committee review of the OCEAN study concluded the following: o The median overall survival was 19.7 months in the Pepaxto arm, compared to 25 months in the Pomalyst arm, HR 1.104 (95% CI 0.846, 1.441), indicating a safety concern. o The PFS results showed no statistical difference, with a HR 0.82 (95% CI 0.654, 1.027), indicating a lack of confirmed clinical benefit. • Previously at the FDA’s request, Oncopeptides stopped marketing Pepaxto in the US on October 22, 2021, and Pepaxto is currently not commercially available in the US but was available via the Individual Patient Expanded Access Investigational Drug Application (IND) process if deemed appropriate by the treating physician. At this same time Oncopeptides indicated that they planned to voluntarily withdraw Pepaxto, but later rescinded the withdrawal request and submitted additional analyses of the OCEAN study. This led to the September 2022 Oncologic Drugs Advisory Committee review that voted 14 to 2 that Pepaxto’s benefit/risk profile was unfavorable. • The Multiple Myeloma Research Foundation suggests those currently on Pepaxto therapy should contact their treating physician to see if remaining on therapy is appropriate. V. Dosage and Administration Indication Multiple myeloma Dosing Regimen 40 mg IV infusion on Day 1 of each 28-day treatment cycle, in combination with dexamethasone. Maximum Dose 40 mg/dose VI. Product Availability
    Lyophilized powder in a single-dose vial for reconstitution and dilution for injection: 20 mg VII.