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This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

09-J2000-51

Original Effective Date: 02/15/16

Reviewed: 01/13/16

Revised: 02/16/17

Next Review: 05/10/17

Subject: Ixazomib (Ninlaro®) Capsule

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   Previous Version
           

DESCRIPTION:

Ixazomib (Ninlaro®) is an oral, reversible proteasome inhibitor that preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome resulting in apoptosis of multiple myeloma cells. It was approved by the FDA in November 2015 for the treatment of patients with multiple myeloma (MM), in combination with lenalidomide and dexamethasone, who have received at least one prior therapy. Ixazomib was reviewed by the FDA under priority review and was granted accelerated approval. Ixazomib was granted orphan drug designation by the FDA for the treatment of MM in February 2011. Ixazomib also has an orphan drug designation for the treatment of systemic light chain amyloidosis granted in March 2012.

The safety and efficacy of ixazomib were evaluated in a multicenter, randomized, double-blind, phase III trial (TOURMALINE-MM1, n = 722). The median progression-free survival time was significantly improved with ixazomib plus lenalidomide and dexamethasone vs. placebo plus lenalidomide and dexamethasone (20.6 months vs. 14.7 months; hazard ratio=0.74; 95% CI, 0.59 to 0.94; p=0.012). The overall response rate was 78% with ixazomib and 72% with placebo. Patients who were refractory to lenalidomide or proteasome inhibitors were excluded from the study. Complete, very good partial, and partial response rates were 12%, 36%, and 30% with ixazomib and 7%, 32%, and 33% with placebo. Median time to response was 1.1 months with ixazomib and 1.9 months with placebo.

The National Comprehensive Cancer Network (NCCN) Guidelines for MM (Version 1.2017) lists ixazomib + lenalidomide (Revlimid®) + dexamethasone triplet therapy under “Other Regimens” as a category 2A recommendation for primary therapy for transplant or non-transplant candidates. Ixazomib + lenalidomide + dexamethasone triplet therapy is also listed under the “Preferred Regimens” as a category 1 recommendation for therapy of previously treated MM. A footnote is included for the previously treated MM regimen stating “clinical trials with these regimens primarily included patients who were lenalidomide-naïve or with lenalidomide-sensitive MM.” There are numerous other category 1 preferred regimens listed by NCCN. Ixazomib + dexamethasone doublet therapy is listed under ‘Other Regimens” as a category 2A recommendation for therapy of previously treated MM. Ixazomib monotherapy is no longer recommended.

POSITION STATEMENT:

Comparative Effectiveness

The Food and Drug Administration has deemed the drug(s) or biological product(s) in this coverage policy to be appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility is not considered medically necessary.

Initiation of ixazomib (Ninlaro®) meets the definition of medical necessity when ALL of the following criteria are met:

1. The member is 18 years of age or older

2. The member has ANY of the following diagnoses AND meets all associated criteria:

a. Previously untreated, active (symptomatic) multiple myeloma (MM)

i. Ixazomib will be used in combination with both lenalidomide (Revlimid®) AND dexamethasone for treatment of the member’s MM

b. First-line treatment of active (symptomatic) multiple myeloma (MM) in members who have had intolerable adverse effects (e.g., severe neuropathy) to their current proteasome inhibitor therapy [i.e., bortezomib (Velcade®) or carfilzomib (Kyprolis®)] and may benefit by switching to ixazomib treatment

i. Ixazomib will be used in combination with both lenalidomide (Revlimid®) AND dexamethasone for treatment of the member’s MM

c. Relapsed, progressive, or refractory multiple myeloma (MM)

i. Member has received at least ONE prior therapy for treatment of their MM

ii. Member was NOT previously refractory to proteasome inhibitor-based therapy [e.g., bortezomib (Velcade®) and carfilzomib (Kyprolis®)] at any line (i.e., disease progression on treatment or progression within 60 days after the last dose of a given therapy)

iii. EITHER of the following:

• Ixazomib with be used in combination with dexamethasone

• Ixazomib with be used in combination with both dexamethasone and lenalidomide (Revlimid®) AND the member was not previously refractory to treatment with lenalidomide

3. Ixazomib will NOT be used in combination with another proteasome inhibitor [i.e., bortezomib (Velcade®) and carfilzomib (Kyprolis®)]

4. The dosage of ixazomib does not exceed three 4 mg capsules every 28 days [i.e., 4 mg weekly for 3 weeks of every 4-week cycle (day 1, 8, and 15)]

5. Laboratory documentation of the member’s baseline (i.e., within 30 days prior to initiating treatment with ixazomib) serum monoclonal protein (M-protein) as detected by serum protein electrophoresis (SPEP) is provided*

*If the M-protein is undetectable by SPEP, documentation of a baseline serum free light chain assay (SFLCA) must also be provided.

Approval duration: 6 months

Continuation of ixazomib (Ninlaro®) meets the definition of medical necessity when ALL of the following criteria are met:

1. An authorization/reauthorization for ixazomib has been previously approved by Florida Blue or another health plan in the past 2 years for the treatment of a Florida Blue-covered indication, OR the member previously met ALL indication-specific initiation criteria

2. EITHER of the following:

a. Ixazomib with be used in combination with dexamethasone

b. Ixazomib with be used in combination with both dexamethasone and lenalidomide (Revlimid®)

3. Ixazomib will NOT be used in combination with another proteasome inhibitor [i.e., bortezomib (Velcade®) and carfilzomib (Kyprolis®)]

4. The dosage of ixazomib does not exceed three 4 mg capsules every 28 days [i.e., 4 mg weekly for 3 weeks of every 4-week cycle (day 1, 8, and 15) ],

5. Member meets EITHER of the following (“a” or “b”):

a. ALL of the following for members who have been receiving ixazomib treatment for less than 18 months:

i. Laboratory documentation of the member’s follow-up serum M-protein after at least two cycles of treatment with ixazomib, is provided

ii. Documentation of clinical response must be provided, and must include M-protein labs changes, change in size/number of lytic bone lesions (if any), and change in soft tissue plasmacytoma size (in any)

iii. The member has achieved a minimal response (MR) or better, as defined by the Revised Uniform Response Criteria by the International Myeloma Working Group, while receiving treatment with elotuzumab. This includes ALL of the following‡,,§

• Serum M-protein value decrease of 25% or more compared to baseline, or is undetectable

• If present at baseline, at least a 25% reduction in the size of any soft tissue plasmacytomas

• No increases in the size or number of lytic bone lesions

a. Member has been receiving ixazomib treatment for 18 months or more AND has not experienced disease progression

†If the M-protein was undetectable by SPEP at baseline and a baseline SFCLA is available, a follow-up SFLCA must be provided as necessary documentation of response to treatment.

‡If the M-protein was undetectable by SPEP at baseline and a baseline SFCLA is available, a decrease of 25% or more in the difference between the light chain produced by the myeloma cells (lambda or kappa) and the other light chain must also be achieved.

§An exception is permitted if the baseline M-protein labs are unavailable. In these cases the physician may provide an attestation of a beneficial clinical response. However, the non-lab requirements still must be met (i.e., no increase in the size or number of lytic bone lesion, reduction in plasmacytoma size).

Approval duration: 1 year

Ixazomib (Ninlaro®) meets the definition of medical necessity when used to treat the following orphan indication AND associated criteria are met:

1. Member has a diagnosis of systemic light chain amyloidosis (SCLA)

a. Member has received at least one prior therapy for treatment of their SCLA

b. Member was NOT previously refractory to bortezomib (Velcade®) treatment (i.e., disease progression on treatment or progression within 60 days after the last dose of a given therapy)

c. The dosage of ixazomib does not exceed three 4 mg capsules every 28 days [i.e., 4 mg weekly for 3 weeks of every 4-week cycle (day 1, 8, and 15) ]

d. Ixazomib will NOT be used in combination with another proteasome inhibitor [i.e., bortezomib (Velcade®) and carfilzomib (Kyprolis®)]

Approval duration: 1 year

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

• Indicated in combination with lenalidomide (Revlimid®) and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

• The recommended starting dose of ixazomib is 4 mg administered orally once a week on Days 1, 8, and 15 of a 28-day treatment cycle. The recommended starting dose of lenalidomide is 25 mg administered daily on Days 1 through 21 of a 28-day treatment cycle. The recommended starting dose of dexamethasone is 40 mg administered on Days 1, 8, 15, and 22 of a 28-day treatment cycle. Treatment should be continued until disease progression or unacceptable toxicity.

• Ixazomib should be taken at least one hour before or at least two hours after food. The whole capsule should be swallowed with water. The capsule should not be crushed, chewed or opened.

• Prior to initiating a new cycle of therapy:

o Absolute neutrophil count should be at least 1,000/mm3

o Platelet count should be at least 75,000/mm3

o Non-hematologic toxicities should, at the physician's discretion, generally be recovered to patient's baseline condition or Grade 1 or lower

Dose Adjustments

Hepatic impairment: Reduce the starting dose to 3 mg in patients with moderate (total bilirubin greater than 1.5-3 × ULN) or severe (total bilirubin greater than 3 × ULN) hepatic impairment

Renal impairment: Reduce the starting dose to 3 mg in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease requiring dialysis

• Dose Reductions due to Adverse Reactions – see package insert for more specific information

o First reduction – 3 mg

o Second reduction – 2.3 mg

Drug Availability

• 2.3 mg, 3 mg, and 4 mg capsules in either a 1-count or 3-count blister pack

• May be stored at room temperature

PRECAUTIONS:

Boxed Warning

• None

Contraindications

• None

Precautions/Warnings

• Thrombocytopenia: Platelet nadirs typically occurring between Days 14-21 of each 28-day cycle. Monitor platelet counts at least monthly during treatment and adjust dosing, as needed.

• Gastrointestinal toxicities: Adjust dosing for severe diarrhea, constipation, nausea, and vomiting, as needed.

• Peripheral neuropathy: Monitor patients for symptoms of peripheral neuropathy and adjust dosing, as needed.

• Peripheral edema: Monitor for fluid retention. Investigate for underlying causes, when appropriate. Adjust dosing, as needed.

• Cutaneous reactions: Rash was reported in 19% of patients. Monitor patients for rash and adjust dosing, as needed.

• Hepatotoxicity: Monitor hepatic enzymes during treatment.

• Embryo-fetal toxicity: Ixazomib can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

Lactation: Discontinue nursing.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

J8999

Prescription drug, oral, chemotherapeutic, NOS

ICD-10 Diagnoses Codes That Support Medical Necessity (Effective 10/01/15)

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

E85.9

Amyloidosis, unspecified

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 guideline creation.

DEFINITIONS:

Heavy chain – the larger component of an immunoglobulin. There are five types: IgG, IgA, IgM, IgD, and IgE.

Immunoglobulins (a.k.a., antibodies) proteins made by normal plasma cells that have an important role in fighting infection as part of the humoral immune response. Antibodies are composed of two heavy chains and two light chains that form a larger complex. Each plasma cell produces only one type of heavy chain and one type of light chain.

Light chain – the smaller component of an immunoglobulin. There are two types: kappa and lambda.

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.

Plasma cell - a fully differentiated B lymphocyte (a type of white blood cell) that is specialized for immunoglobulin production and is found primarily in bone marrow.

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

Serum free light chain assay (SFLCA) – a test that detects the amount of unbound or free light chains (i.e., not attached to a heavy chain) in the serum. Normal values - kappa: 3.3 to 19.4 mg/L, lambda: 5.71 to 26.3 mg/L, kappa/lambda ratio: 0.26–1.65 (0.37–3.1 if renal impairment).

Serum Protein Electrophoresis (SPEP) – a test that detects and quantifies the amount of M-protein in the serum. An serum M-protein of greater than 30 g/L is consistent with a diagnosis of MM.

Urine Protein Electrophoresis (UPEP) - a test that detects and quantifies the amount of M-protein (light chain component only) in the urine. This is typically done using a sample of urine collected over a 24-hour period

RELATED GUIDELINES:

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

Carfilzomib (Kyprolis®) IV, 09-J1000-81

Daratumumab (Darzalex) IV, 09-J2000-49

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

Elotuzumab (Empliciti®) IV, 09-J2000

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. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. URL www.clinicalpharmacilogy-ip.com. Accessed 1/7/16.
  2. FDA Orphan Drug Designations and Approvals [Internet]. Washington, D.C. [cited 2016 Jan 27]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/.
  3. Kumar SK, LaPlant B, Roy V, et al. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer J. 2015 Aug 14;5:e338.
  4. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 1/7/16.
  5. National Comprehensive Cancer Network. Cancer Guidelines. Cancer Guidelines and Drugs and Biologics Compendium. Accessed 10/24/16.
  6. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 2.2017. Multiple Myeloma. Available at http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf. Accessed 10/30/16.
  7. Ninlaro (ixazomib) capsule package insert. Cambridge, MA: Takeda Pharmaceutical Company Limited; Nov 2015.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 10/12/16.

GUIDELINE UPDATE INFORMATION:

03/15/16

New Medical Coverage Guideline.

04/15/16

Revision to guideline consisting of clarifying the position statement.

12/15/16

Review and revision to guidelines consisting of updating the lab requirements, clarification on switching proteasome inhibitor therapy in the first-line setting, and removal of monotherapy in the position statement.

02/16/17

Revision: Update to Position Statement.

Date Printed: June 23, 2017: 11:45 AM