REVLIMID, Lenalidomide Form

Lenalidomide (Revlimid®) is an immunomodulatory agent with antiangiogenic and antineoplastic properties. FDA Approved Indication
Revlimid is indicated for the treatment of patients with: • Multiple myeloma (MM), in combination with dexamethasone • MM as maintenance following autologous hematopoietic stem cell transplantation • Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities • Mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib (Velcade®) • Previously treated follicular lymphoma (FL), in combination with a rituximab product • Previously treated marginal zone lymphoma (MZL), in combination with a rituximab product Limitation of use: Revlimid is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials. 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 Revlimid is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Multiple Myeloma (must meet all):

1. Diagnosis of MM;

   2. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. Will be used for one of the following indications (a, b, c, or d): a. In combination with dexamethasone; b. As a single agent in steroid-intolerant patients with previously treated myeloma with relapse or progressive disease; Page 1 of 16

   CLINICAL POLICY Lenalidomide c. As maintenance therapy following autologous hematopoietic stem cell transplantation and prescribed as one of the following (i or ii): i. Single agent;
   ii. In combination with carfilzomib or bortezomib with dexamethasone;
   d. As maintenance therapy as a single agent or in combination with bortezomib for active (symptomatic) myeloma after response to primary myeloma therapy

2. The requested agent is not prescribed concurrently with Thalomid® or Pomalyst®;
   6. For Revlimid requests, member must use generic lenalidomide, unless contraindicated, clinically significant adverse effects are experienced, or generic is unavailable due to shortage; Generic lenalidomide is currently in short supply and may be unavailable until sometime in 2023
3. Request meets one of the following (a or b): a. Dose does not exceed 25 mg per day; 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:
   Medicaid/HIM - 6 months Commercial – 12 months or duration of request, whichever is less B. Myelodysplastic Syndrome (must meet all):
4. Diagnosis of lower risk (i.e., IPSS-R [Very Low, Low, Intermediate], IPSS [Low/Intermediate-1], WPSS [Very Low, Low, Intermediate]) MDS;
5. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. Member has one of the following (a or b): a. Symptomatic or transfusion-dependent anemia due to MDS, and one of the following (i or ii): i. Presence of deletion 5q abnormality; ii. No deletion 5q abnormality, and either (a or b): a) Serum erythropoietin > 500 mU/mL; b) Serum erythropoietin ≤ 500 mU/mL, and failure of an erythropoiesis- stimulating agent (ESA; Retacrit® is preferred), unless contraindicated or clinically significant adverse effects are experienced; Prior authorization may be required b. MDS and myeloproliferative overlap neoplasms with thrombocytosis and one of the following (i or ii):
      i. SF3B1 mutation;
      ii. Wild-type SF3B1 mutation and ≥ 15% ring sideroblasts;

6. The requested agent is not prescribed concurrently with Thalomid or Pomalyst;

   6. For Revlimid requests, member must use generic lenalidomide, unless contraindicated, clinically significant adverse effects are experienced, or generic is unavailable due to shortage; Generic lenalidomide is currently in short supply and may be unavailable until sometime in 2023
      Page 2 of 16

   CLINICAL POLICY Lenalidomide

7. Request meets one of the following (a or b): a. Dose does not exceed 10 mg per day; 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:
   Medicaid/HIM - 6 months Commercial – 12 months or duration of request, whichever is less C. Mantle Cell Lymphoma (must meet all):
8. Diagnosis of MCL;
   2. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. Will be used for one of the following indications (a or b): a. Relapsed or progressive disease after two prior therapies, one of which included bortezomib (Velcade); b. In combination with rituximab;
      Prior authorization may be required for rituximab.
9. The requested agent is not prescribed concurrently with Thalomid or Pomalyst;
   6. For Revlimid requests, member must use generic lenalidomide, unless contraindicated, clinically significant adverse effects are experienced, or generic is unavailable due to shortage; Generic lenalidomide is currently in short supply and may be unavailable until sometime in 2023
10. Request meets one of the following (a or b): a. Dose does not exceed 25 mg per day; 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:
    Medicaid/HIM - 6 months Commercial – 12 months or duration of request, whichever is less D. Marginal Zone Lymphoma (must meet all):
11. Diagnosis of MZL (including gastric or nongastric mucosa-associated lymphoid tissue (MALT) lymphoma, nodal MZL, and splenic MZL);

12. Prescribed by or in consultation with an oncologist or hematologist;

    3. Age ≥ 18 years;
    4. Will be used for one of the following indications (a, b, or c): a. Second-line or subsequent therapy, and is prescribed in combination with rituximab or Gazyva®; b. Histologic transformation of MZL to non-germinal center diffuse large B-cell lymphoma after multiple lines of chemoimmunotherapy for indolent or transformed disease; c. In combination with Monjuvi®* in non-transplant candidates and have received one of the following (i or ii): i. Minimal or no chemoimmunotherapy prior to histologic transformation to diffuse large B-cell lymphoma and have no response or progressive disease Page 3 of 16

    CLINICAL POLICY Lenalidomide after chemoimmunotherapy (e.g., anthracycline- or anthracenedione-based regimens);
    ii. Multiple prior therapies including ≥ 2 lines of chemoimmunotherapy for indolent or transformed disease; *Prior authorization may be required

13. The requested agent is not prescribed concurrently with Thalomid or Pomalyst;
    6. For Revlimid requests, member must use generic lenalidomide, unless contraindicated, clinically significant adverse effects are experienced, or generic is unavailable due to shortage; Generic lenalidomide is currently in short supply and may be unavailable until sometime in 2023
14. Request meets one of the following (a or b): a. Dose does not exceed 20 mg per day; 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:
    Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less E. Follicular Lymphoma (must meet all):
15. Diagnosis of FL;
    2. Prescribed by or in consultation with an oncologist or hematologist;
    3. Age ≥ 18 years;
    4. Will be used for one of the following indications (a, b, c, or d): a. First-line therapy in combination with rituximab; b. Second-line or subsequent therapy; c. Treatment of histologic transformation to non-germinal center diffuse large B-cell lymphoma after multiple lines of chemoimmunotherapy for indolent or transformed disease; d. In combination with Monjuvi in non-transplant candidates and have received one of the following (i or ii): i. Minimal or no chemoimmunotherapy prior to histologic transformation to diffuse large B-cell lymphoma and have no response or progressive disease after chemoimmunotherapy (e.g., anthracycline- or anthracenedione-based regimens);
       ii. Multiple prior therapies including ≥ 2 lines of chemoimmunotherapy for indolent or transformed disease; *Prior authorization may be required for rituximab.
16. The requested agent is not prescribed concurrently with Thalomid or Pomalyst;
    6. For Revlimid requests, member must use generic lenalidomide, unless contraindicated, clinically significant adverse effects are experienced, or generic is unavailable due to shortage; Generic lenalidomide is currently in short supply and may be unavailable until sometime in 2023

17. Request meets one of the following (a or b):* a. Dose does not exceed 20 mg per day; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Page 4 of 16

    CLINICAL POLICY Lenalidomide *Prescribed regimen must be FDA-approved or recommended by NCCN
    Approval duration:
    Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less F. Other NCCN Compendium Supported Diagnoses/Indications (off-label) (must meet all):

    1. Prescribed for one of the following NCCN category 1 or 2a recommended indications:
       a. Myelofibrosis-associated anemia, in combination with prednisone taper, and one of the following (i or ii): i. Serum erythropoietin ≥ 500 mU/mL; ii. Serum erythropoietin < 500 mU/mL, and failure of an ESA (Retacrit is preferred), unless contraindicated or clinically significant adverse effects are experienced; b. Systemic light chain amyloidosis and one of the following (i or ii):
       i. Newly diagnosed disease or relapsed/refractory disease as a repeat of initial therapy if relapse-free for several years in combination with dexamethasone and bortezomib; ii. Relapsed/refractory disease in combination with one of the following (1, 2, or 3): 1) Dexamethasone; 2) Dexamethasone and cyclophosphamide; 3) Dexamethasone and ixazomib;
       c. Primary central nervous system (CNS) lymphoma as a single agent or in combination with rituximab for relapsed or refractory disease, or if member is unsuitable or intolerant to high-dose methotrexate; d. Classic Hodgkin lymphoma as fourth-line or subsequent therapy for relapsed or refractory disease;
       e. Langerhans cell histiocytosis as a single agent therapy; f. Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin change (POEMS) syndrome, in combination with dexamethasone and one of the following (i and ii):
       i. As induction therapy for transplant eligible patients;
       ii. for transplant ineligible patients;
       g. Any of the following non-Hodgkin lymphoma subtypes: i. Adult T-cell leukemia/lymphoma as second-line or subsequent therapy; ii. HIV-related B-cell lymphoma as second-line or subsequent therapy (including in combination with Monjuvi in non-transplant candidate); iii. Kaposi sarcoma (KS), and both of the following (1 and 2): 1) If AIDS-related, Revlimid is prescribed in combination with antiretroviral therapy; 2) Failure of liposomal doxorubicin and paclitaxel, unless clinically significant adverse effects are experienced or both are contraindicated; iv. Castleman's disease (CD) as subsequent therapy following treatment of relapsed, refractory, or progressive disease; Page 5 of 16

    CLINICAL POLICY Lenalidomide v. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) as second-line and subsequent therapy; vi. Diffuse large B-cell lymphoma as second-line or subsequent therapy (including in combination with Monjuvi in non-transplant candidates); vii. Hepatosplenic gamma-delta T-cell lymphoma for refractory disease after two primary treatment regimens; viii. High-grade B-cell lymphoma as second-line or subsequent therapy (including in combination with Monjuvi in non-transplant candidate); ix. Peripheral T-cell lymphoma as initial palliative intent therapy, second-line or subsequent therapy; x. Post-transplant lymphoproliferative disorders of B-cell lymphomas as second- line or subsequent therapy (including in combination with Monjuvi in non- transplant candidates); *Prior authorization may be required for rituximab and ESAs

18. Prescribed by or in consultation with one of the following specialists (a or b): a. AIDS-related KS: an oncologist or immunologist; b. All other diagnoses: an oncologist or hematologist;
19. Age ≥ 18 years;
    4. The requested agent is not prescribed concurrently with Thalomid or Pomalyst;
    5. For Revlimid requests, member must use generic lenalidomide, unless contraindicated, clinically significant adverse effects are experienced, or generic is unavailable due to shortage; Generic lenalidomide is currently in short supply and may be unavailable until sometime in 2023
20. Request meets one of the following (a or b): a. Dose does not exceed 25 mg per day; 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:
    Medicaid/HIM - 6 months Commercial – 12 months or duration of request, whichever is less G. Other diagnoses/indications (must meet 1 or 2):
21. 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

22. 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 Page 6 of 16

    CLINICAL POLICY Lenalidomide of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    II. Continued Therapy A. All Indications in Section I (must meet all):

23. Currently receiving medication via Centene benefit or documentation supports that member is currently receiving Revlimid for a covered indication and has received this medication for at least 30 days;
24. Member is responding positively to therapy;
    3. The requested agent is not prescribed concurrently with Thalomid or Pomalyst;
    4. For Revlimid requests, member must use generic lenalidomide, unless contraindicated, clinically significant adverse effects are experienced, or generic is unavailable due to shortage; Generic lenalidomide is currently in short supply and may be unavailable until sometime in 2023
25. If request is for a dose increase, request meets one of the following (a or b): a. New dose does not exceed one of the following (i, ii, or iii):
    i. 10 mg per day for MDS; ii. 20 mg per day for MZL and FL,
    iii. 25 mg per day for all other indications; 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:
    Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less B. Other diagnoses/indications (must meet 1 or 2):
26. 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

27. 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 – Page 7 of 16

    CLINICAL POLICY Lenalidomide 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 AIDS: acquired immune deficiency syndrome CD: Castleman’s disease CLL: chronic lymphocytic leukemia ESA: erythropoiesis-stimulating agent FDA: Food and Drug Administration
    FL: follicular lymphoma KS: Kaposi sarcoma MALT: mucosa-associated lymphoid tissue MCL: mantle cell lymphoma MDS: myelodysplastic syndrome MM: multiple myeloma MZL: marginal zone lymphomas NCCN: National Comprehensive Cancer Network POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin change
    REMS: Risk Evaluation and Mitigation Strategy SLL: small lymphocytic lymphoma 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.
    Dosing Regimen Drug Name Dose Limit/ Maximum Dose melphalan/ prednisone (MP) Multiple Myeloma (Conventional primary therapy) As recommended in dosing regimen vincristine/ doxorubicin/ dexamethasone (VAD) dexamethasone (pulse dose as single agent) melphalan 8 mg/m2/day PO days 1-4; prednisone 60 mg/m2/day PO days 1-4.
    Repeat cycle every 28 days Multiple Myeloma (Conventional primary therapy) vincristine 0.4 mg/day IV continuous infusion days 1- 4; doxorubicin 9 mg/m2/day IV continuous infusion days 1-4; dexamethasone 40 mg PO days 1-4, 9-12, 17-20.
    Repeat cycle every 28-35 days Multiple Myeloma (Conventional primary therapy) dexamethasone 40 mg PO
    days 1-4, 9-12, 17-20 As recommended in dosing regimen As recommended in dosing regimen Page 8 of 16

    CLINICAL POLICY Lenalidomide Drug Name Dosing Regimen Dose Limit/ Maximum Dose Thalomid® (thalidomide)/ dexamethasone Pomalyst® (pomalidomide) Kyprolis® (carfilzomib) Bortezomib (Velcade) liposomal doxorubicin (Doxil®, Lipodox® 50) paclitaxel ESAs Aranesp® (darbepoetin alfa)
    Multiple Myeloma (Conventional primary therapy) As recommended in dosing regimen thalidomide 200 mg/day PO daily; dexamethasone 40 mg/day days 1-4, 9- 12,17-20 for odd cycles and
    days 1-4 for even cycles.
    Repeat cycle every 28 days Multiple Myeloma 4 mg PO QD on days 1-21 of repeated 28- day cycles until disease progression. Pomalyst may be given in combination with dexamethasone. Pomalyst may be given in combination with Kyprolis/dexamethasone Avoid Pomalyst in patients with a serum creatinine greater than 3.0 mg/dL Multiple Myeloma Varies Mantle Cell Lymphoma 1.3 mg/m2/dose SC or IV BIW for 2 weeks (Days 1, 4, 8, and 11) followed by a 10- day rest period (Days 12-21) for six 3- week cycles. For extended therapy of more than 8 cycles, Velcade may be administered on the standard schedule or on a maintenance schedule of once weekly for 4 weeks (Days 1, 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35).
    At least 72 hours should elapse between consecutive doses of Velcade KS 20 mg/m2 IV every 2-3 weeks with a cumulative lifetime dose of 400-450 mg/m2 due to cardiotoxicity KS 135 mg/m2 IV every 3 weeks or 100 mg/m2 every 2 weeks 4 mg/day Varies depending on combination regimen 1.3 mg/m2/dose See regimen See regimen Anemia associated with MDS† 150-300 mcg SC every other week 500 mcg every other week Page 9 of 16

    CLINICAL POLICY Lenalidomide Drug Name Dosing Regimen Dose Limit/ Maximum Dose epoetin alfa (Epogen®, Procrit®, Retacrit®) Anemia associated with MDS† 40,000-60,000 units SC one to two times weekly Varies depending on indication and frequency of administration Anemia associated with myelofibrosis† n a clinical trial, patients initially received erythropoietin 10,000 units SC 3 days per week. Erythropoietin was increased to 20,000 units 3 days per week if a response was not obtained after 2 months and erythropoietin was discontinued in patients who did not experience a response at 3 months 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. †Off-label
    Appendix C: Contraindications/Boxed Warnings • Contraindication(s): pregnancy; hypersensitivity
    • Boxed warning(s): embryo-fetal toxicity, hematologic toxicity, venous and arterial thromboembolism Appendix D: General Information
    • Anemia is defined as hemoglobin level less than 10 g/dL. • Transfusion dependence was defined in two different studies as either greater than 2 units or greater than 4 units of RBCs within 8 weeks prior to enrollment into the studies. • According to NCCN guideline, current drug therapies for MCL include: a) induction therapy (including CHOP [Cytoxan, Adriamycin, vincristine, and prednisone], hyperCVAD [Cytoxan, vincristine, Adriamycin, and dexamethasone], RDHA [Rituxan, dexamethasone, cytarabine], NORDIC regimen, bendamustine + Rituxan, VR-CAP [bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone]), and b) second- line therapy (including Calquence®, Venclexta®, Imbruvica® ± Rituxan, bortezomib ± Rituxan, bendamustine ± Rituxan and Revlimid ± Rituxan). • The FDA notified the public of an increased risk of second primary malignancies in patients with newly-diagnosed MM who received Revlimid. Clinical trials conducted after Revlimid was approved showed that newly-diagnosed patients treated with Revlimid had an increased risk of developing acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma. • Revlimid is only available under a restricted distribution program called the Revlimid REMS program due to the black box warning for fetal risk, hematologic toxicity, and deep vein thrombosis/pulmonary embolism. Patient and physician enrollment in the manufacturer’s REMS program is required. Page 10 of 16

    CLINICAL POLICY Lenalidomide V. Dosage and Administration
    Indication MDS MM (maintenance therapy) MM
    (primary therapy for newly diagnosed patients) MM
    (previously treated patients) Relapsed MM (previously treated patients) Maximum Dose 10 mg/day 15 mg/day 25 mg/day 25 mg/day 25 mg/day Dosing Regimen 10 mg PO QD 10 mg PO QD continuously (Days 1- 28 of repeated 28-day cycles) until disease progression or unacceptable toxicity. After 3 cycles of maintenance therapy, the dose can be increased to 15 mg once daily if tolerated.
    25 mg PO QD days 1-21 of repeated 28 day cycles with dexamethasone 40 mg PO QD on days 1, 8, 15, 22 of each 28 day cycle. 25 mg PO QD days 1-21 of repeated 28 days cycles with dexamethasone 40 mg QD days 1-4, 9-12 and 17- 20 of each 28 day cycle for the first 4 cycles then 40 mg QD for days 1-4 every 28 days. 25 mg PO QD days 1-21 of repeated 28 day cycles with dexamethasone 40 mg PO QD on days 1, 8, 15, 22 and Kyprolis. Maximum 18 cycles for Kyprolis. Cycle 1: 20 mg/m2 IV over 10 minutes on days 1-2. If tolerated, increase to target dose of 27 mg/m2 IV over 10 minutes on days 8, 9, 15, 16 Cycles 2-12: 27 mg/m2 IV over 10 minutes on days 1, 2, 8, 9, 15, 16 Cycles 3-18 27 mg/m2 IV over 10 minutes on days 1, 2, 15, 16 MCL MZL and FL Kyprolis dosed at a maximum body surface area of 2.2 m2 25 mg PO QD on Days 1- 21 of repeated 28-day cycles 20 mg PO QD on Days 1- 21 of repeated 28-day cycles 25 mg/day 20 mg/day Page 11 of 16

    CLINICAL POLICY Lenalidomide VI. Product Availability
    Capsules: 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg VII.