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Horizon BCBSNJ
Uniform Medical Policy ManualSection:Drugs
Policy Number:137
Effective Date: 02/14/2020
Original Policy Date:04/26/2016
Last Review Date:01/14/2020
Date Published to Web: 04/26/2016
Subject:
Melphalan (Alkeran and Evomela)

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.

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Alkeran (melphalan) is an injectable alkylating agent approved by the FDA on January 17, 1964. Alkeran is indicated for palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate.

The safety and efficacy of Alkeran were tested in a randomized trial comparing prednisone plus IV melphalan to prednisone plus oral melphalan. One hundred seven patients were randomized to the oral melphalan arm and 203 patients to the IV melphalan arm. More patients had a poor-risk classification (58% versus 44%) and high tumor load (51% versus 34%) on the oral arm compared to the IV arm (P<0.04). Overall Response Rates at Week 22 were comparable (44% in the oral group and 38% in the IV group); however, because of changes in trial design, conclusions as to the relative activity of the 2 formulations after Week 22 are impossible to make.

On March 14, 2016 the FDA approved Evomela (melphalan) for use as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in patients with multiple myeloma and as palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate. Evomela is the first drug to gain FDA approval for the high-dose conditioning indication in multiple myeloma.

Evomela utilizes Captisol technology, a chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. The use of Captisol to reformulate melphalan improved its stability, extending it use time to 5 hours, allowing for slower infusion rates and longer administration durations for pre-transplant chemotherapy. The new formulation eliminates the need to use a propylene glycol containing custom diluent (required with other melphalan formulations) which has been linked to renal and cardiac side effects.

The safety and efficacy of Evomela for myeloablative conditioning were tested in a multicenter, open-label, phase 2b study of 61 patients - five who had relapsed prior to HSCT and 56 with newly diagnosed disease. Patients received 200 mg/m² of Evomela, administered in 100 mg/m² doses on day 3 and day 2 before transplantation. Efficacy was assessed by clinical response at day 100. The study found there was an overall response rate of 95% and a complete response (CR) rate of 31% (16% stringent CRs), as determined by investigator assessment. The overall response rate was 100% and the CR rate was 21% on independent pathology review.

The safety and efficacy of Evomela for palliative treatment of patients with multiple myeloma was based on the study of Alkeran mentioned above.

The most common side effects observed in patients treated with melphalan (over 50% incidence) were decreased levels of neutrophils, white blood cells, lymphocytes, platelets; diarrhea, nausea, fatigue, hypokalemia, anemia, and vomiting. In the studies, there was no treatment-related mortality, and nonhematologic adverse events were mostly grade 1 and grade 2. The incidence of grade 3 mucositis was 10%, of grade 3 stomatitis was 5%, and of treatment-emergent serious adverse events, most of which were grade 3, was 20%.

Alkeran and Evomela have three black box warnings in their package labeling. Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous melphalan to oral melphalan have shown more myelosuppression with the IV formulation. Hematologic laboratory parameters should be monitored. Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation of melphalan. Treatment should be discontinued for serious hypersensitivity reactions. Finally, melphalan produces chromosomal aberrations in vitro and in vivo. Therefore, these products should be considered potentially leukemogenic in humans.

Policy:

Note: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.

Alkeran (melphalan)

    1. Alkeran (melphalan) injection is medically necessary for the palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate.

    2. The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis.

    3. When Alkeran (melphalan) injection is medically necessary, therapy will be approved for 6 months based on FDA-approved recommendations:
        a. 16 mg/m2 administered as a single intravenous infusion at 2-week intervals for 4 doses, then, after adequate recovery from toxicity, at 4-week intervals.
        b. Dosage reduction of up to 50% should be considered in patients with renal insufficiency (BUN ≥30 mg/dL).
    4. Continued therapy with Alkeran (melphalan) injection will be approved every 12 months based on treatment response and absence of intolerable adverse effects
      5. Alkeran (melphalan) injection is considered medically necessary for the following off-label uses:
          a. Classical Hodgkin Lymphoma: Third-line or subsequent therapy for refractory or relapsed disease as a component of mini-BEAM (carmustine, cytarabine, etoposide, and melphalan) regimen.
          b. Melanoma: Isolated limb perfusion or infusion as a single agent for primary and/or second-line treatment of either unresectable stage III disease with clinical satellite or in-transit metastases or unresectable local, satellite and/or in-transit recurrence
          c. Systemic Light Chain Amyloidosis:
            · Treatment for relapsed/refractory disease as either high-dose single-agent therapy with stem cell transplant
                • as either high-dose single-agent therapy with stem cell transplant
                • in combination with dexamethasone
                • in combination with dexamethasone and bortezomib
      6. Alkeran (melphalan) for the treatment of other conditions/diseases is considered investigational.


    Evomela (melphalan)
      1. Evomela (melphalan) is medically necessary for the following FDA-approved indications:
          a. High-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in patients with multiple myeloma.
          b. Palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate.
      2. The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis.
        3. When Evomela (melphalan) is medically necessary, therapy will be approved for 6 months at the FDA-recommended dose for the following indications:
            a. Conditioning Treatment: 100 mg/m2/day by intravenous infusion for 2 consecutive days (Day -3 and Day -2) prior to autologous stem cell transplantation (ASCT, Day 0).
            [INFORMATIONAL NOTE: Based on the FDA approved package, for patients who weigh more than 130% of their ideal body weight, body surface area should be calculated based on adjusted ideal body weight.]
            b. Palliative Treatment: 16 mg/m2 administered as a single intravenous infusion at 2-week intervals for 4 doses, then, after adequate recovery from toxicity, at 4-week intervals.
        4. Continued therapy with Evomela (melphalan) for palliative treatment will be approved every 12 months based on treatment response and absence of intolerable adverse effects.
        5. Evomela (melphalan) for the treatment of other conditions/diseases, including more than 2 consecutive days for conditioning treatment in multiple myeloma, is considered investigational.
      Medicare Coverage

      There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL specific to this drug. Therefore, Medicare Advantage will follow the Horizon Policy. See generally: Local Coverage Article: Approved Drugs and Biologicals; Includes Cancer Chemotherapeutic Agents (A53049). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46

      Medicaid Coverage

      For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

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      Horizon BCBSNJ Medical Policy Development Process:

      This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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      Index:
      Melphalan (Alkeran and Evomela)
      Alkeran (Melphalan)
      Evomela (Melphalan)

      References:
      1. Melphalan hydrochloride [package insert]. Sagent Pharmaceuticals. Schaumburg, IL. May 2016.

      2. Melphalan Label and Approval History. U.S. Food and Drug Administration. Available at: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory

      3. Evomela® [package insert]. Spectrum Pharmaceuticals. Irvine, CA. August 2019.

      4. Ernst D. FDA Approves Evomela for the Treatment of Multiple Myeloma. MPR. March 14, 2016. Available at: www.empr.com/news/fda-approves-evomela-for-the-treatment-of-multiple-myeloma/article/482917

      5. Hari P, et al. A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation. Biology of Blood and Marrow Transplant , Volume 21 , Issue 12 , 2100 – 2105.

      6. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 2.2019. 2019 January, 3. ;National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=64

      7. Melphalan. National Comprehensive Cancer Network: Drugs and Biologics Compendium. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix. aspx?AID=64. Accessed 12/18/2019

      8. ClinicalTrials.gov. Accessed 25 December 2016 at: https://clinicaltrials.gov/ct2/results?term= melphalan=Search

      Codes:
      (The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

      CPT*

      HCPCS
      J9245
      J9246

      * CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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      Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.

      The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy

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