Clinical Policy: Lenalidomide (Revlimid) Reference Number: ERX.SPMN.43 Effective Date: 03/14 Revision Log Last Review Date: 09/16

See Important Reminder at the end of this policy for important regulatory and legal information.

Policy/Criteria It is the policy of health plans affiliated with Envolve Pharmacy Solutions® that lenalidomide (Revlimid®) capsules for oral use are medically necessary when one of the following criteria are met:

I. Initial Approval Criteria A. Multiple Myeloma (must meet all): 1. Diagnosis of multiple myeloma (MM); 2. Will be used for one of the following indications: a. FDA approved use: i. In combination with dexamethasone; b. NCCN recommended use (i or ii): i. As maintenance therapy as a single agent for one of the following: a) Active (symptomatic) myeloma responding to primary myeloma therapy; b) Stable or responsive disease following stem cell transplant; c) With second tandem transplant for stable or responsive disease following autologous stem cell transplant; ii. For previously treated myeloma on or off clinical trials for disease relapse or for progressive or refractory disease as a single agent for steroid- intolerant patients.

Approval duration: 3 months B. Myelodysplastic Syndrome (must meet all): 1. Diagnosis of myelodysplastic syndrome (MDS); 2. Will be used for one of the following indications: a. FDA approved use (all of the following): i. Transfusion-dependent anemia due to MDS; ii. MDS is low- or intermediate-1-risk; iii. MDS is associated with a deletion 5q cytogenetic abnormality; b. NCCN recommended use (i or ii): i. Use as initial treatment of lower risk disease associated with symptomatic anemia and del(5q); ii. Use as treatment of lower risk disease associated with symptomatic anemia, no del(5q) and one of the following: a) Serum erythropoietin levels > 500 mU/mL with a low probability of response to immunosuppressive therapy as initial treatment;

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b) Serum erythropoietin levels ≤ 500 mU/mL, no response to erythropoietins, and no response or intolerance to immunosuppressive therapy.

Approval duration: 3 months C. Mantle Cell Lymphoma (must meet all): 1. Diagnosis of mantle cell lymphoma (MCL); 2. Will be used for one of the following indications: a. FDA approved use: i. Disease has relapsed/progressed after two prior therapies, one of which includes bortezomib; b. NCCN recommended use: i. Use as second-line therapy for stage I-II disease or aggressive stage II bulky, III, or IV disease for relapsed, refractory, or progressive disease.

Approval duration: 3 months

D. Other diagnoses/indications (must meet all): 1. Additional Revlimid uses outlined in the NCCN compendium, and which meet NCCN category 1, 2a, or 2b, are covered for the following indications per the ERX.SPMN.16 Global Biopharm Policy: a. Classical Hodgkin lymphoma; b. Non-Hodgkin lymphoma (NHL) - adult T-cell leukemia/lymphoma; c. NHL - AIDS-related B-cell lymphoma; d. NHL - Castleman's disease (CD); e. NHL - chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); f. NHL - diffuse large B-cell lymphoma; g. NHL - follicular lymphoma; h. NHL - gastric MALT lymphoma; i. NHL - mycosis fungoides (MF)/Sezary syndrome (SS); j. NHL - nongastric MALT lymphoma; k. NHL - peripheral T-cell lymphoma; l. NHL - primary cutaneous B-cell lymphoma; m. NHL - primary cutaneous CD30+ T-cell lymphoproliferative disorders; n. NHL - splenic marginal zone lymphoma; o. Systemic light chain amyloidosis.

II. Continued Approval A. All Indications (must meet all): 1. Currently receiving medication via health plan benefit or member has previously met all initial approval criteria.

Approval duration: 6 months

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B. Other diagnoses/indications (must meet 1 or 2): 1. Currently receiving medication via health plan benefit and documentation supports positive response to therapy; or 2. Refer to ERX.SPMN.16 - Global Biopharm Policy.

Background Description/Mechanism of Action: Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including multiple myeloma, mantle cell lymphoma, and del(5q) myelodysplastic syndromes in vitro. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including multiple myeloma. Immunomodulatory properties of lenalidomide include activation of T cells and natural killer (NK) cells, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-a and IL-6) by monocytes. In multiple myeloma cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis.

Formulations: Revlimid is available in 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg and 25 mg capsules for oral administration. Revlimid capsules contain lactose.

FDA Approved Indications: Revlimid is a thalidomide analogue/oral capsule formulation indicated for the treatment of patients with:  Multiple myeloma (MM), in combination with dexamethasone.  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.

Limitations 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. Appendices Appendix A: Abbreviation Key ALCL: anaplastic large cell lymphoma CD: Castleman's disease CLL: chronic lymphocytic leukemia MALT: mucosa associated lymphoid tissue MCL: mantle cell lymphoma MDS: myelodysplastic syndromes MF: mycosis fungoides

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MM: multiple myeloma NHL: non-Hodgkin lymphoma SLL: small lymphocytic lymphoma SS: Sezary syndrome

Reviews, Revisions, and Approvals Date Approval Date Policy created. 02/1 03/14 4 Modified statement under Policy/Approval Criteria to indicate that off- 02/1 03/15 label use will be covered for cancer diagnosis; modified Revlimid initial 5 algorithm to redirect PA review for off-label use where FDA approved indication does not apply, added Figure 2 - off-label use algorithm, added appendix D and E for off-label use to provide details of off-label approval, validated and updated references. Policy converted to new template. 08/1 09/16 Added NCCN recommended and compendial uses. Directed to global 6 biopharm policy for review of approvable compendial uses. Removed all safety criteria and requests for documentation. Removed requirement to try other therapies before Revlimid for MM as Revlimid is for both newly diagnosed and relapsed/refractory MM. Modified approval periods to 3 months for initial and 6 months for re-auth. References 1. Revlimid Prescribing Information. Summit, NJ: Celgene Corporation; February 2015. 2. Lenalidomide. In: National Comprehensive Cancer Network Drugs and Biologics Compendium. Available at www.NCCN.org. Accessed May 16, 2016.

Important Reminder This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information.

This Clinical Policy is not intended to dictate to providers how to practice medicine, nor does it constitute a contract or guarantee regarding payment or results. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members.

This policy is the property of Envolve Pharmacy Solutions. Unauthorized copying, use, and distribution of this Policy or any information contained herein is strictly prohibited. By accessing this policy, you agree to be bound by the foregoing terms and conditions, in addition to the Site Use Agreement for Health Plans associated with Envolve Pharmacy Solutions.

©2016 Envolve Pharmacy Solutions. All rights reserved. All materials are exclusively owned by Envolve Pharmacy Solutions and are protected by United States copyright law and international

Page 4 of 5 CLINICAL POLICY Lenalidomide copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of US Script. You may not alter or remove any trademark, copyright or other notice contained herein.

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