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Date Printed: October 17, 2017: 04:25 PM

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09-J2000-61

Original Effective Date: 06/15/16

Reviewed: 06/14/17

Revised: 07/15/17

Subject: Melphalan HCl, Captisol-Enabled (Evomela®) IV Infusion

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates    
           

DESCRIPTION:

Captisol-enabled melphalan hydrochloride (Evomela) is a propylene glycol -free injectable formulation of melphalan hydrochloride (HCl) that was approved by the US Food and Drug Administration (FDA) in March 2016 for use as a high-dose conditioning treatment prior to an autologous hematopoietic stem-cell transplant (HSCT) in patients with multiple myeloma (MM), and for the palliative treatment of patients with MM for whom oral therapy is not appropriate. Evomela was previously granted orphan drug designation by the FDA in November 2008 for “high dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation.” Evomela is the first drug to be approved by the FDA for high-dose conditioning in MM. While considered an off-label use, standard melphalan HCl (Alkeran) has been a mainstay in high-dose conditioning in MM for decades.

Melphalan HCl is an alkylating agent first approved in 1964 for the palliative treatment of MM and, in addition to its myeloablative role prior to HSCT, it is also used for the treatment of certain other malignancies. Standard melphalan HCl is available as both an oral tablet and powder for injection that must be solubilized in a propylene glycol (PG) diluent. Each 10 mL vial of diluent contains 6 mL of PG. The reconstituted vial must be immediately diluted in normal saline for IV administration, and the IV administration completed within 60 minutes of reconstitution. This is because the solution is unstable. About 1% label strength of melphalan hydrolyzes every 10 minutes after dilution.

Captisol [a.k.a., sulfobutylether-beta-cyclodextrin (SBECD) and Betadex sulfobutyl ether sodium] is a patent-protected, chemically modified cyclodextrin with a structure designed to “optimize the solubility and stability of drugs”. Captisol is currently used in various FDA-approved injectable products such as carfilzomib (Kyprolis), PG-free amiodarone injection (Nexterone), and posaconazole injection (Noxafil). The use of Captisol in Evomela allows for a PG-free formulation of melphalan and enhanced stability. At room temperature, Evomela can be stored up to 1 hour after reconstitution and is stable for an additional 4 hours after preparation of the infusion solution. Stability studies have shown that the rate of degradation for reconstituted solutions of standard melphalan HCl in vials was 17-times faster than reconstituted Evomela, and 5-times faster in infusion bag admixtures. The manufacture claims that the improved stability of Evomela may potentially ensure that cancer patients receive the full, intended therapeutic dose of IV melphalan by increasing the use time and infusion time, and simplifying clinical administration logistics. The clinical benefit of Evomela being PG-free is unclear, especially considering the MM conditioning regimen is only two doses, and the maintenance dose for the palliative treatment of MM is every 4 weeks. Propylene glycol toxicity has been rarely reported in patients who are receiving high-dose continuous infusions of PG-containing medication such as benzodiazepines. There are no reports of PG toxicity resulting from IV melphalan administration.

The FDA-approval of Evomela for high-dose conditioning in MM was based on the results of a phase IIb, open-label, single-arm, non-randomized trial conducted at 5 US centers in 61 patients with symptomatic MM. Fifty-six patients had newly diagnosed disease and five patients had relapsed after stem cell transplant. Evomela was administered at 100 mg/m2/day over 30 minutes by IV infusion for two consecutive days (Day -3 and Day -2) prior to autologous stem cell transplantation (ASCT) (Day 0). The objective of the trial was to determine the overall safety and toxicity profile of Evomela. The efficacy was evaluated by the International Myeloma Working Group response criteria comparing the disease response immediately prior to the ASCT procedure to the disease response assessed 90 to 100 days post-transplant. The overall response rate (partial response or better) improved from 79% (48 of 61) prior to the ASCT procedure to 95% (58 of 61) at 90 to 100 days post-transplant. There was also an increase in the number of patients with a stringent complete response from 0 patients prior to the ASCT procedure to 16% (10 of 61) at 90 to 100 days post-transplant. Myeloablation, neutrophil engraftment and platelet engraftment were achieved by all 61 patients.

FDA-approval for the palliative treatment of patients with MM (the labeled indication for standard melphalan HCl injection) was based on a phase IIa, open-label, randomized, cross-over design bioequivalence study in 24 patients undergoing ASCT for MM. Based on this bioequivalence data, the data from the trial that supported the approval of standard melphalan HCl injection for palliate treatment was able to be used to support the approval of Evomela for this same indication. Of note, the original approval of standard melphalan HCl injection was based on a randomized head-to-head study with oral melphalan that showed comparable overall response rates.

The National Comprehensive Cancer Network (NCCN) does not specifically address the use of Captisol-enabled melphalan (Evomela) in any of its guidelines or compendia. The guidelines only reference “melphalan” in general, while the compendia reference the brand name of Alkeran only. Regarding the use of melphalan in the treatment of MM, the NCCN removed all melphalan-containing regimens as recommendations. The reason for the removal is cited as availability of newer effective and better tolerated agents and that melphalan can cause significant cytopenias that can limit subsequent use of newer drugs. Melphalan is still listed in NCCN as a high-dose conditioning treatment prior to stem cell transplant.

POSITION STATEMENT:

Initiation of Captisol-enabled melphalan (Evomela) meets the definition of medical necessity when ALL of the following criteria are met:

1. The member has a diagnosis of active (symptomatic) multiple myeloma (MM)

2. The member will be receiving Evomela as a high-dose conditioning treatment prior to a hematopoietic progenitor (stem) cell transplantation (HSCT) for treatment of their MM

3. The dosage of Evomela does NOT exceed the following:

a. 100 mg/m2/day for 2 consecutive days (Day -3 and Day -2) prior to HSCT (Day 0)

b. For members who weigh more than 130% of their ideal body weight (IBW), body surface area (BSA) should be calculated based on adjusted ideal body weight (ABW) [ABW=IBW+0.4(actual weight-IBW)]

Approval duration: single one-time approval of up to 200 mg/m2 (i.e., 100 mg/m2 X 2 doses)

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

FDA-approved

• Evomela is indicated for:

o Use as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in patients with multiple myeloma (MM)

o The palliative treatment of patients with MM for whom oral therapy is not appropriate.

• For Conditioning Treatment:

o The recommended dose is 100 mg/m2/day administered over 30 minutes by intravenous infusion for 2 consecutive days (Day -3 and Day -2) prior to autologous stem cell transplantation (ASCT, Day 0).

o For patients who weigh more than 130% of their ideal body weight, body surface area (BSA) should be calculated based on adjusted ideal body weight.

• For Palliative Treatment:

o The recommended dose is 16 mg/m2 administered as a single intravenous infusion over 15 to 20 minutes at 2-week intervals for 4 doses, then, after adequate recovery from toxicity, at 4-week intervals

Dose Adjustments

• Renal Impairment

o For Conditioning Treatment: No dose adjustment is necessary.

o For Palliative Treatment: Dosage reduction of up to 50% should be considered in patients with renal impairment (BUN ≥30 mg/dL)

• Hepatic Impairment

o Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Drug Availability

• 50 mg of lyophilized powder in a single-dose vial for reconstitution. Each vial contains 50 mg melphalan free base equivalent to 56 mg melphalan hydrochloride. Evomela is light sensitive, and must be retained in the original carton until use.

PRECAUTIONS:

Boxed Warning

WARNING: SEVERE BONE MARROW SUPPRESSION, HYPERSENSITIVITY, AND LEUKEMOGENICITY

• Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous (IV) melphalan to oral melphalan have shown more myelosuppression with the IV formulation. Monitor hematologic laboratory parameters

• Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation of melphalan. Discontinue treatment with Evomela for serious hypersensitivity reactions

• Melphalan produces chromosomal aberrations in vitro and in vivo. Evomela should be considered potentially leukemogenic in humans

Contraindications

• History of serious allergic reaction to melphalan

Precautions/Warnings

• Bone Marrow Suppression: See Boxed Warning

• Gastrointestinal Toxicity: Nausea, vomiting, diarrhea or oral mucositis may occur; provide supportive care using antiemetic and antidiarrheal medications as needed. Prophylactic antiemetics should be administered

• Hepatotoxicity: Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported after treatment with melphalan. Hepatic veno-occlusive disease has also been reported. Monitor liver chemistries

• Hypersensitivity: See Boxed Warning

• Secondary Malignancies: See Boxed Warning

• Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to fetus and to avoid pregnancy

• Infertility: Melphalan may cause ovarian function suppression or testicular suppression

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

J9245

Injection, melphalan hydrochloride, 50 mg

ICD-10 Diagnoses Codes That Support Medical Necessity

C90.00

Multiple myeloma not having achieved remission

C90.02

Multiple myeloma in relapse

C90.10

Plasma cell leukemia not having achieved remission

C90.12

Plasma cell leukemia in relapse

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Part D: BCBSF has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

Medicare Advantage: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline review date.

DEFINITIONS:

Minimal response (MR) (according to the Revised Uniform Response Criteria by the International Myeloma Working Group)ALL of the following:

• ≥25% but ≤49% reduction of serum M-protein

• Reduction in 24-hour urine M-protein by 50% to 89%

• In addition, if present at baseline, 25% to 49% reduction in size of soft tissue plasmacytomas is also required

• No increase in size or number of lytic bone lesions (development of compression fractures dose not exclude response).

Myeloma Protein (M-Protein) - a nonfunctional immunoglobulin protein or protein fragment produced by malignant plasma cells (or myeloma cells). Since myeloma cells are monoclonal, the M-proteins for a given patient are structurally identical. Both portions of an immunoglobulin (the heavy chain and light chain) can be found in the serum, while only light chains can be found in the urine.

Primary refractory MM - patients who never achieve at least a MR to initial induction therapy and progress while on therapy

Progressive MM - at least a 25% increase from nadir in the serum M-protein (absolute increase must be ≥0.5 g/dL) or urine M-protein (absolute increase must be ≥200mg/24 hours), or in the difference between involved and uninvolved serum-free light-chain (FLC) levels (with an abnormal FLC ratio and FLC difference >100 mg/L).

Relapsed and refractory MM - patients who never achieve at least a MR or who progress within 60 days of their last therapy

RELATED GUIDELINES:

Allogeneic Bone Marrow and Stem Cell Transplantation, 02-38240-01
Bortezomib (Velcade) IV, 09-J0000-92

Carfilzomib (Kyprolis) IV, 09-J1000-81

Doxorubicin HCl Liposome (Doxil) IV, 09-J0000-91

Elotuzumab (Empliciti) IV, 09-J2000

Ixazomib (Ninlaro), 09-J2000-51

Lenalidomide (Revlimid), 09-J0000-80

Panobinostat (Farydak), 09-J2000-37

Pomalidomide (Pomalyst) Capsule, 09-J1000-95

Thalidomide (Thalomid) Capsules, 09-J1000-56

OTHER:

None

REFERENCES:

  1. Aljitawi OS, Ganguly S, Abhyankar SB, et al. Phase IIa cross-over study of propylene glycol-free melphalan (LGD-353) and Alkeran in multiple myeloma autologous transplantation. Bone Marrow Transplant 2014; 49(8):1042-1045.
  2. Alkeran (melphalan hydrochloride kit) [prescribing information]. GlaxoSmithKline; Research Triangle Park, NC. February 2012.
  3. Alkeran (melphalan tablet) [prescribing information]. GlaxoSmithKline; Research Triangle Park, NC. August 2016.
  4. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2017 [cited 2017 May 25]. Available from: http://www.clinicalpharmacology.com/
  5. DRUGDEX System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2017 May 25]. Available from: http://www.thomsonhc.com/.
  6. Evomela (melphalan hydrochloride injection) [prescribing information]. Spectrum Pharmaceuticals, Inc.; Irvine, CA. March 2016.
  7. Fowles JR, Banton MI, Pottenger LH. A toxicological review of the propylene glycols. Crit Rev Toxicol. 2013 Apr;43(4):363-90.
  8. Hari P, Aljitawi OS, Arce-Lara C, 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. Biol Blood Marrow Transplant. 2015 Dec;21(12):2100-5. Epub 2015 Aug 29.
  9. Lim TY, Poole RL, Pageler NM. Propylene glycol toxicity in children. J Pediatr Pharmacol Ther. 2014 Oct-Dec;19(4):277-82.
  10. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 3.2017. Multiple Myeloma. Available at http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf. Accessed
  11. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2017 [cited 2017 May 25]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/
  12. Palumbo A, Bringhen S, Caravita T, et al.; Italian Multiple Myeloma Network, GIMEMA. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006 Mar 11;367(9513):825-31.
  13. Palumbo A, Rajkumar SV, Man Miguel JF, et al. International Myeloma Working Group Consensus Statement for the Management, Treatment, and Supportive Care of Patients With Myeloma Not Eligible for Standard Autologous Stem-Cell Transplantation. J Clin Oncol. 2014;32:527-600.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 6/14/17.

GUIDELINE UPDATE INFORMATION:

06/15/16

New Medical Coverage Guideline.

07/15/17

Review and revision to guidelines consisting of updating the position statement to only include use as a high-dose conditioning treatment prior to stem cell transplantation for treatment of MM. The NCCN no longer recommends melphalan as part of any MM treatment regimen.

Date Printed: October 17, 2017: 04:25 PM