CurrentmhnPolicy CP.PHAR.302

Clinical Policy: Ixazomib (Ninlaro)

Defines medical necessity criteria, prescribing conditions, and authorization requirements for ixazomib (Ninlaro) for multiple myeloma and select off‑label hematologic indications for members of Centene‑affiliated health plans.

Policy Summary

Payermhn

PolicyClinical Policy: Ixazomib (Ninlaro)

Policy CodePolicy CP.PHAR.302

Change TypeNo material changes

Effective Date02.01.17

Next Review Date

Key ActionPrior authorization required and prescriber must be or consult with an oncologist/hematologist; provider must submit documentation supporting that the member meets all approval criteria.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

≥1Prior therapies required for FDA-approved multiple myeloma indication

≥18Minimum patient age for covered indications

4 mg/weekDose limit for typical regimen

12 moCommercial approval duration

6 moMedicaid/HIM initial approval duration

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Coverage and Medical Necessity Criteria

Initial Therapy - Multiple Myeloma

Covered when ALL of the following are met for Multiple Myeloma (Initial Approval):

Multiple Myeloma Initial: 1. Diagnosis of multiple myeloma; 2. Prescribed by or in consultation with an oncologist or hematologist; 3. Age ≥ 18 years; 4. Member has received at least one prior therapy; 5. Prescribed in one of the following ways: a) In combination with dexamethasone and either lenalidomide or cyclophosphamide; OR b) Member is lenalidomide- or anti‑CD‑38‑refractory and all of the following: i. Prescribed in combination with dexamethasone and pomalidomide; ii. Member has received at least two prior therapies including an immunomodulatory agent and a proteasome inhibitor; iii. Member has demonstrated disease progression on or within 60 days of completion of the last therapy; OR c) In combination with venetoclax and dexamethasone for patients with t(11;14); OR d) As primary treatment or for disease relapse >6 months after primary induction when used as a substitute for bortezomib or carfilzomib in non‑transplant candidates due to intolerance or logistical reasons.; 6. Request meets one of the following: a) Dose does not exceed 4 mg (1 tablet) per week for 3 weeks of a 28‑day cycle; OR 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.

Initial Therapy - Systemic Light Chain Amyloidosis (off-label)

Covered when ALL of the following are met for Systemic Light Chain Amyloidosis (off-label):

AL amyloidosis: 1. Diagnosis of relapsed or refractory systemic light chain (AL) amyloidosis; 2. Prescribed by or in consultation with an oncologist or hematologist; 3. Age ≥ 18 years; 4. Prescribed in one of the following ways: a) In combination with dexamethasone; OR b) In combination with dexamethasone and lenalidomide; OR c) In combination with dexamethasone and cyclophosphamide; 5. Dose is within the FDA maximum limit for any FDA‑approved indication or 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.

Initial Therapy - Waldenstrom Macroglobulinemia (off-label)

Covered when ALL of the following are met for Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma (off-label):

Waldenstrom: 1. Diagnosis of Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma; 2. Prescribed by or in consultation with an oncologist or hematologist; 3. Age ≥ 18 years; 4. Prescribed in combination with rituximab and dexamethasone; 5. Dose is within the FDA maximum limit for any FDA‑approved indication or 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.

Continuation Therapy

Continuation/Renewal Criteria (All Indications in Section I):

Continuation: 1. Currently receiving Ninlaro via the Centene benefit, or documentation supports that the member has been receiving Ninlaro for at least 30 days; 2. Member is responding positively to therapy; 3. If request is for a dose increase, request meets one of the following: a) New dose does not exceed 4 mg (1 tablet) per week for 3 weeks of a 28‑day cycle; OR 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.

Requests for ixazomib (Ninlaro) to treat diagnoses that are not FDA‑approved and are not specifically addressed by this policy are not authorized unless the provider submits sufficient documentation demonstrating efficacy and safety per the applicable off‑label use policy (see CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid) or other evidence of coverage documents.

Use of Ninlaro as maintenance therapy for multiple myeloma is not recommended outside of controlled clinical trials. NCCN assigns a category 2B recommendation for maintenance and the Ninlaro prescribing information notes that two randomized trials in the maintenance setting demonstrated increased deaths; therefore treatment in this setting may be denied.

Use of ixazomib in the maintenance setting or for newly diagnosed multiple myeloma when given in combination with lenalidomide and dexamethasone is not recommended outside of controlled clinical trials per the Ninlaro prescribing information and guideline recommendations.

Permitted Drug Regimens and Combinations

Indication	Regimen / Combination	Coverage Status	Notes / Requirements
Multiple myeloma after ≥1 prior therapy
Ixazomib in combination with lenalidomide and dexamethasone; alternatives include ixazomib with dexamethasone plus cyclophosphamide; for lenalidomide- or anti-CD38-refractory disease: ixazomib with dexamethasone and pomalidomide (requires ≥2 prior therapies including an IMiD and a proteasome inhibitor and progression on or within 60 days of last therapy); for t(11;14): ixazomib with venetoclax and dexamethasone; or as substitute for bortezomib or carfilzomib in non-transplant candidates for primary treatment or relapse >6 months after primary induction when intolerant or for logistical reasons.
Covered
Member must be ≥18 years, prescribed by or in consultation with an oncologist/hematologist, and have received ≥1 prior therapy. Dose must not exceed 4 mg (1 tablet) per week for 3 weeks of a 28-day cycle unless supported by guidelines or literature (prescriber must submit evidence). Prior authorization may be required for lenalidomide, pomalidomide, cyclophosphamide, or venetoclax.

Indication	Regimen / Combination	Coverage Status	Notes / Requirements
Relapsed/refractory systemic light chain (AL) amyloidosis (off-label)
Ixazomib in combination with dexamethasone OR ixazomib with dexamethasone plus lenalidomide OR ixazomib with dexamethasone plus cyclophosphamide.
Covered (off-label)
Member must be ≥18 years and prescribed by or in consultation with an oncologist/hematologist. Dose must be within FDA maximum limits for any approved indication or supported by practice guidelines/peer-reviewed literature (prescriber must submit supporting evidence). Prior authorization may be required for lenalidomide.

Indication	Regimen / Combination	Coverage Status	Notes / Requirements
Waldenstrom macroglobulinemia / lymphoplasmacytic lymphoma (off-label)
Ixazomib in combination with rituximab and dexamethasone.
Covered (off-label)
Member must be ≥18 years and prescribed by or in consultation with an oncologist/hematologist. Dose must be within FDA maximum limits for any approved indication or supported by practice guidelines/peer-reviewed literature (prescriber must submit supporting evidence). Prior authorization may be required for rituximab.

Indication / Context	Regimen / Combination (appendix examples)	Coverage Status	Notes / Requirements
Multiple myeloma (regimens and combinations)
Ixazomib (Ninlaro) in combination with lenalidomide and dexamethasone; other combinations listed in appendices include daratumumab- (Darzalex) or isatuximab-containing regimens (e.g., daratumumab/lenalidomide/dexamethasone), and multi-agent regimens such as VTD-PACE and Darzalex-containing combinations.
Mixed (coverage depends on indication and whether regimen meets policy criteria)
Dosing for MM: 4 mg PO on Days 1, 8, and 15 of a 28-day cycle (maximum 4 mg/week for 3 weeks per cycle). Appendix regimens have varied dosing; prescribed regimen must be FDA-approved or recommended by NCCN and supported by guidelines or literature if dose exceeds standard limits. Prior authorization/prior therapy requirements apply per policy appendices.

Line and Sequencing Requirements

second-line

Second‑line (line of therapy): Ixazomib is indicated in combination with lenalidomide and dexamethasone for multiple myeloma in patients who have received at least one prior therapy (post‑first‑line).

Per policy requirement that member has received ≥1 prior therapy.

salvage

Salvage (refractory setting): If lenalidomide‑ or anti‑CD38‑refractory, ixazomib use requires combination with dexamethasone and pomalidomide, prior receipt of at least two prior therapies including an IMiD and a proteasome inhibitor, and documented disease progression on or within 60 days of completion of the last therapy.

Reflects salvage requirements for refractory disease per NCCN‑aligned policy.

second-line

Second‑line (documented updates): Policy revisions clarify requirements such as member having received at least one prior therapy for MM and combination‑specific conditions (e.g., use with venetoclax for t(11;14); substitution for bortezomib/carfilzomib in select non‑transplant candidates).

See references and appendix updates in policy history.

Prescriber Requirements, Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization required. Prescriptions must be written by or in consultation with an oncologist or hematologist. PA may be required per line of business for Ninlaro and for co‑medications (e.g., lenalidomide, pomalidomide, cyclophosphamide, Venclexta, rituximab) — verify specific LOB PA rules.

Prior authorization required for Ninlaro and may be required for listed combination agents per LOB.
Prescriber must be or consult with an oncologist/hematologist.

Denial Risk

Off‑Label Use / Non‑Covered Indication Risk

Requests for indications not FDA‑approved and not listed in this policy may be denied unless the prescriber provides sufficient supporting evidence of efficacy and safety consistent with the plan’s off‑label use procedures (see CP.CPA.09 for commercial, HIM.PA.154 for HIM, CP.PMN.53 for Medicaid). When approval is requested for an off‑label use, the prescriber must submit supporting practice guideline or peer‑reviewed literature.

Non‑FDA approved indications require sufficient documentation per the applicable off‑label use policy.
Prescriber must submit supporting evidence (guidelines or peer‑reviewed literature) for off‑label dosing or indications.

Documentation Required

Follow Prescribing Information and Guidelines

Prescribers must follow Ninlaro (ixazomib) prescribing information for dosing, administration, contraindications, and co‑dosing guidance. Refer to Ninlaro PI and current NCCN guidelines for regimen selection and sequencing. Relevant references include the Ninlaro Prescribing Information and NCCN Drug & Biologics Compendium and disease guidelines.

See Ninlaro Prescribing Information for recommended MM dosing: 4 mg PO on Days 1, 8, and 15 of a 28‑day cycle; max 4 mg/week for 3 weeks of a 28‑day cycle.
Key references: Ninlaro PI (July 2024; updated July 2024), NCCN Multiple Myeloma and Compendia (accessed 2025).

Note

Therapeutic Alternatives / Substitution

Therapeutic alternatives and substitution options are provided in Appendix B. Preferred alternatives include bortezomib‑, carfilzomib‑, and lenalidomide‑based regimens (e.g., bortezomib/lenalidomide/dexamethasone; bortezomib/cyclophosphamide/dexamethasone; carfilzomib/lenalidomide/dexamethasone). These alternatives may require prior authorization and may not be formulary for all LOBs.

Appendix B lists preferred alternative regimens and dosing considerations.
Substitution of Ninlaro for bortezomib or carfilzomib as primary treatment or for relapse in non‑transplant candidates is allowed per NCCN (see Appendix B) when intolerance/logistical reasons apply.

Step Therapy

Step / Sequencing and Limitations

Sequencing and step requirements in the approval criteria must be followed. For multiple myeloma, member must have received at least one prior therapy (and for certain combinations, at least two prior therapies including an IMiD and a proteasome inhibitor). Combination regimens authorized by this policy are tied to prior therapies and NCCN recommendations; prescribers must document prior treatments and disease progression timelines where required.

MM: member must have received ≥1 prior therapy; for ixazomib + pomalidomide + dexamethasone the member must be lenalidomide‑ or anti‑CD38‑refractory and have had ≥2 prior therapies including an IMiD and a proteasome inhibitor, with progression on or within 60 days of last therapy.
Requests for dose increases or off‑label dose regimens must be supported by guidelines or literature and documented.
Maintenance use: Ninlaro is not recommended for maintenance outside controlled trials due to increased deaths observed in some studies (see Appendix D and PI).

Policy Revision History

2021-04-02annual_review

3Q 2021 annual review: updated HIM off-label reference to HIM.PA.154 and reviewed/updated references; revised approval duration for Commercial line of business to 12 months (effective 01.20.22).

2022-05-12annual_review

3Q 2022 annual review: clarified multiple myeloma requirements including removal of single-agent use in transplant candidates (NCCN 2B), added requirement that member has received at least one prior therapy, clarified pomalidomide combination requires two prior therapies, and added limitations for maintenance and newly diagnosed MM; references reviewed and updated.

2023-04-14annual_review

3Q 2023 annual review: per NCCN removed option for use in MM with dexamethasone alone and removed single-agent option for systemic light chain amyloidosis; references revised and updated.

2024-05-06annual_review

3Q 2024 annual review: per NCCN Compendium added ixazomib use in combination with venetoclax and dexamethasone for patients with t(11;14) and added cyclophosphamide + dexamethasone option for systemic light chain amyloidosis; references reviewed and updated.

2025-04-14annual_reviewLatest

3Q 2025 annual review: added NCCN Compendium–supported use as primary treatment as a substitute for bortezomib or carfilzomib and clarified pomalidomide combination applies when member is lenalidomide‑ or anti‑CD38‑refractory; references reviewed and updated.

OpenPayer

Clinical Policy: Ixazomib (Ninlaro)

Coverage and Medical Necessity Criteria

Permitted Drug Regimens and Combinations

Line and Sequencing Requirements

Prescriber Requirements, Authorization, and Documentation

Dosing Limits and Product Information

Biomarker and Genetic Requirements

Drug and Term Definitions

Background and Rationale

Policy Revision History