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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-J0000-92

Original Effective Date: 04/15/09

Reviewed: 06/08/16

Revised: 02/16/17

Subject: Bortezomib (Velcade®) Injection

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:

Bortezomib (Velcade®) is an antineoplastic agent that inhibits the activity of the 26S proteasome in mammalian cells. The 26S proteasome degrades ubiquitinated proteins and regulates the intracellular concentration of specific cell proteins and maintains cellular homeostasis. This disruption of homeostasis can lead to cell death. Bortezomib has demonstrated cytotoxic actions on cancer cells in vitro and causes delay in tumor growth in vivo in nonclinical tumor models. It was initially approved by the US Food and Drug Administration (FDA) in May 2003 for treatment of persons with multiple myeloma (MM) who received at least two prior therapies and have demonstrated progression of the disease on the last therapy. Velcade was previously granted orphan designation by the FDA for the treatment of MM in early in 2003. Velcade also has orphan designations for the treatment of follicular non-Hodgkin’s lymphoma (2011), mantle cell lymphoma (2012), and acute lymphoblastic leukemia (2015). Since initial approval, the use of bortezomib in other MM settings (e.g., primary therapy, maintenance therapy) is supported by referenced compendia, including National Comprehensive Cancer Network (NCCN). The FDA-approved indication was expanded to treatment of MM patients who have received at least one prior therapy in May 2005, and then to first-line treatment of MM in June 2008. In December 2006, the FDA granted approval for treatment of refractory or recurrent mantle cell lymphoma, a form of non-Hodgkin’s lymphoma (NHL). The indication was expanded to first-line treatment of mantle cell lymphoma in October 2014. In addition to use in MM and NHL, bortezomib therapy is used for treatment of systemic light chain amyloidosis and Waldenström’s macroglobulinemia.

POSITION STATEMENT:

Initiation of bortezomib (Velcade®) injection meets the definition of medical necessity when:

1. Bortezomib is used for ANY indication listed in Table 1, and ALL indication-specific criteria are met.

2. Bortezomib will NOT be used in combination with another proteasome inhibitor [e.g., carfilzomib (Kyprolis®) or ixazomib (Ninlaro®)].

3. The dosage of bortezomib does not exceed EITHER of the following:

a. 1.3 mg/m2 twice weekly for 14 days (4 doses) of a 21-day cycle

b. 1.6 mg/m2 once weekly for 28 days (4 doses) of a 28-day or 35-day cycle

Table 1

Indications and Specific Criteria

Indication

Criteria

Multicentric Castleman's disease (CD)

BOTH of the following:

1. Bortezomib will be used as subsequent therapy for disease that has progressed following treatment of relapsed/refractory or progressive disease (i.e., third-line or later treatment)

2. Bortezomib will be used as either monotherapy or in combination with rituximab (Rituxan®)

Multiple myeloma (MM)

BOTH of the following:

1. Member has active (symptomatic) multiple myeloma

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

Mantle cell lymphoma (MCL)

BOTH of the following:

1. The diagnosis has been confirmed by tissue biopsy with appropriate histology and immunophenotyping

2. Bortezomib will be used in EITHER of the following settings:

a. Less aggressive induction therapy as part of the VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) regimen

b. Second-line or later therapy with or without rituximab for relapsed, refractory, or progressive disease

Systemic light chain amyloidosis

ALL of the following:

1. The diagnosis has been confirmed by the presence of amyloid deposits in tissue AND the deposits are composed of light chains

2. Laboratory documentation of the member’s baseline (i.e., within 30 days prior to initiating treatment with bortezomib) serum free light chains (SFLC) as detected by serum free light chain assay (SFLCA) is provided

3. One of the following regimens will be used:

a. Bortezomib monotherapy

b. Bortezomib + dexamethasone

c. Bortezomib + cyclophosphamide + dexamethasone

d. Bortezomib + melphalan + dexamethasone

Waldenström’s macroglobulinemia
(a.k.a., lymphoplasmacytic lymphoma)

ALL of the following:

1. Member is symptomatic (e.g., hyperviscosity, neuropathy, symptomatic adenopathy or organomegaly, amyloidosis, cryoglobulinemia, cold agglutinin disease, presence of cytopenia)

2. Laboratory documentation of the member’s baseline (i.e., within 30 days prior to initiating treatment with bortezomib) serum IgM level is provided

3. One of the following regimens will be used:

a. Bortezomib monotherapy

b. Bortezomib + dexamethasone

c. Bortezomib + rituximab

d. Bortezomib + rituximab + dexamethasone

Duration of approval: 6 months

Continuation of bortezomib (Velcade®) injection meets the definition of medical necessity when ALL of the following criteria are met:

1. Authorization/reauthorization for bortezomib has been previously approved by Florida Blue or another health plan in the past 2 years for the treatment of any indications listed in Table 1, OR the member previously met ALL indication-specific initiation criteria

2. Documentation of a favorable response to treatment is provided (see indication-specific criteria below):

a. Multicentric Castleman's disease, mantle cell lymphoma, or Waldenström’s macroglobulinemia: provider attestation that the member had not had disease progression during bortezomib treatment

b. Multiple myeloma:

i. If less than18 months of treatment – a serum M-protein value decrease of 25% or more* compared to baseline, or is undetectable, AND no increase in the size or number of lytic bone lesions after at least two cycles of treatment with bortezomib – laboratory documentation of the follow-up serum-M protein must be submitted

ii. 18 or more months of treatment - provider attestation that the member had not had disease progression during bortezomib treatment

c. Systemic light chain amyloidosis:

i. If less than18 months of treatment - there has been a reduction (improvement) in the member’s SFLC level as compared to baseline# after at least two cycles of treatment with bortezomib -- laboratory documentation of the SFLC level must be submitted

ii. If 18 or more months of treatment -- provider attestation that the member had not had disease progression during bortezomib treatment

* An exception is permitted if a baseline serum M-protein value is unavailable. Follow-up laboratory documentation of the serum-M protein still must be submitted, and the non- laboratory requirements still must be met (i.e., no increase in the size or number of lytic bone lesion). If the follow-up serum M-protein is still detectable, the physician must provide an attestation of a beneficial clinical response.

# An exception is permitted if a baseline SFLC value is unavailable. Follow-up laboratory documentation of the SFLC level still must be submitted. The physician must provide an attestation of a beneficial clinical response.

3. Bortezomib will NOT be used in combination with another proteasome inhibitor [e.g., carfilzomib (Kyprolis®) or ixazomib (Ninlaro®)].

4. The dosage of bortezomib does not exceed EITHER of the following:

a. 1.3 mg/m2 twice weekly for 14 days (4 doses) of a 21-day cycle

b. 1.6 mg/m2 once weekly for 28 days (4 doses) of a 28-day or 35-day cycle

Duration of approval: 1 year

Bortezomib (Velcade®) injection meets the definition of medical necessity when: (1) administered for EITHER of the following orphan indications, (2) it will NOT be used in combination with another proteasome inhibitor [e.g., carfilzomib (Kyprolis®) or ixazomib (Ninlaro®)], AND (3) the dosage does not exceed 1.3 mg/m2 twice weekly for 14 days (4 doses) of a 21-day cycle:

1. Acute lymphoblastic leukemia (ALL)

2. Follicular non-Hodgkin lymphoma (NHL)

Duration of approval: 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: bortezomib is indicated for the treatment of persons with multiple myeloma and treatment of persons with mantle cell lymphoma. The recommended dose is 1.3 mg/m2 either as a 3 to 5 second bolus intravenous injection or subcutaneous injection. The frequency of administration is dependent on the indication for therapy. See the package insert for specific dosage recommendations.

Dosage Modifications: See the package insert for specific dosage adjustments based on toxicity. No dosage adjustment is needed in patients with renal impairment. The exposure of bortezomib is increased in patients with moderate (bilirubin ≥1.5 to 3-times the ULN) and severe (bilirubin >3-times the ULN) hepatic impairment, and the starting dose should be reduced.

Drug Availability: bortezomib is supplied as a single-use vial containing 3.5 mg of bortezomib as lyophilized powder. Each route of administration (i.e., IV or SQ) has a different reconstitution concentration and caution should be used when calculating the volume to be administered.

PRECAUTIONS:

Contraindications:

• Persons with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions.

• Intrathecal administration is contraindicated. Only administer intravenously or subcutaneously.

Warnings/Precautions:

• Cardiac toxicity: worsening of and development of cardiac failure has occurred. Closely monitor persons with existing disease or risk factors for heart disease.

• Hepatic toxicity: Acute liver failure has been reported in persons receiving multiple concurrent medications and with serious underlying medical conditions. Monitor hepatic enzymes during treatment.

• Hypotension: use caution when treating members prescribed antihypertensive medications, with a history of syncope, or with dehydration as this can result in increased risk of orthostatic and postural hypotension.

• Pulmonary Toxicity: acute respiratory syndromes have occurred; monitor closely for new or worsening symptoms.

• Gastrointestinal toxicity: nausea, diarrhea, constipation and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement.

• Peripheral neuropathy: new onset or exacerbation of pre-existing peripheral neuropathy may occur; managed with dose modification or discontinuation.

• Posterior Reversible Encephalopathy Syndrome (PRES): consider MRI imaging for onset of visual or neurological symptoms; discontinue bortezomib therapy in persons developing PRES.

• Thrombocytopenia and neutropenia: monitor complete blood counts regularly throughout treatment.

• Tumor lysis syndrome may occur. Closely monitor members with a high tumor burden.

• Pregnancy category D: may cause embryo-fetal harm. Women should avoid becoming pregnant while being treated with bortezomib.

• Diabetes: patients with diabetes may require close monitoring of blood glucose and adjustment of anti-diabetic medication.

• Drug interactions: co-administration with strong CYP3A4 inhibitors can increase bortezomib exposure; closely monitor. Co-administration with strong CYP3A4 inducers can decrease bortezomib exposure; avoid concomitant use.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding:

J9041

Injection, bortezomib, 0.1 mg

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

C82.00 – C82.99

Follicular lymphoma

C83.00 – C83.09

Small cell B-cell lymphoma

C83.10 – C83.19

Mantle cell lymphoma

C88.0

Waldenstrom macroglobulinemia

C90.00 – C90.02

Multiple myeloma

C90.10 – C90.12

Plasma cell leukemia

C90.20

Extramedullary plasmacytoma not having achieved remission

C90.22

Extramedullary plasmacytoma in relapse

C90.30

Solitary plasmacytoma not having achieved remission

C90.32

Solitary plasmacytoma in relapse

C91.00 – C91.02

Acute lymphoblastic leukemia [ALL]

D47.Z2

Castleman disease

E85.9

Amyloidosis, unspecified

REIMBURSEMENT INFORMATION:

Refer to section entitled POSTION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage Products: No National Coverage Determination (NCD) was found at the time of the last guideline revised date. The following Local Coverage Determination (LCD) was reviewed on the last guideline review date: Bortezomib (Velcade), (L33273) located at fcso.com.

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.

Plasmacytoma – a discrete tumor consisting of neoplastic, monoclonal (originating from a single cell) plasma cells in either bone or soft tissue (extramedullary).

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 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.

Smoldering (Asymptomatic) myeloma: defined as M-protein in serum of 30 g/dL or more and/or bone marrow clonal plasma cells of 10% or more, but no related organ or tissue impairment (no end organ damage, including bone lesions) or symptoms.

RELATED GUIDELINES:

Allogeneic Bone Marrow and Stem Cell Transplantation, 02-38240-01
Carboplatin (Paraplatin®) IV, 09-J0000-93

Carfilzomib (Kyprolis) IV, 09-J1000-81

Daratumumab (Darzalex) IV, 09-J2000-49

Docetaxel (Taxotere®) IV, 09-J0000-95

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

Elotuzumab (Empliciti) IV, 09-J2000

Interferons for Oncology Use, 09-J1000-37

Ixazomib (Ninlaro), 09-J2000-51

Lenalidomide (Revlimid®), 09-J0000-80

Melphalan, Captisol-Enabled (Evomela®) IV, 09-J2000-61

Oprelvekin; Interleukin 11 (Neumega®), 09-J0000-63

Panobinostat (Farydak®), 09-J2000-37

Pomalidomide (Pomalyst®) Capsule, 09-J1000-95

Thalidomide (Thalomid®) Capsules, 09-J1000-56

OTHER:

None applicable.

REFERENCES:

  1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. URL www.clinicalpharmacilogy-ip.com. Accessed 5/10/16. .
  2. Du XL, Chen Q. Recent advancements of bortezomib in acute lymphocytic leukemia treatment. Acta Haematol. 2013;129(4):207-14. doi: 10.1159/000345260. Epub 2013 Jan 3. Review.
  3. Fowler N, Kahl BS, Lee P, et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol. 2011 Sep 1;29(25):3389-95. doi: 10.1200/JCO.2010.32.1844. Epub 2011 Aug 1.
  4. Goy A, Bernstein SH, Kahl BS, et al. Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Ann Oncol. 2009 Mar;20(3):520-5.
  5. Kastritis E, Wechalekar AD, Dimopoulos MA, et al. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7.
  6. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 5/10/16.
  7. National Comprehensive Cancer Network. Cancer Guidelines. Cancer Guidelines and Drugs and Biologics Compendium. 5/10/16.
  8. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 3.2016. Multiple Myeloma. Available at http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf. Accessed 5/24/16.
  9. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 3.2016. Non-Hodgkin’s Lymphomas. Available at http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. Accessed 5/24/16.
  10. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 1.2015. Systemic Light Chain Amyloidosis. Available at http://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf. Accessed 5/24/16.
  11. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 2.2016. Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma. Available at http://www.nccn.org/professionals/physician_gls/PDF/waldenstroms.pdf. Accessed 5/24/16.
  12. Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010 Apr 22;115(16):3416-7.
  13. Robak T, Huang H, Jin J, et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015 Mar 5;372(10):944-53.
  14. Treon SP, Ioakimidis L, Soumerai JD, et al. Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone and rituximab: WMCTG clinical trial 05-180. J Clin Oncol 2009;27(23):3830-3835.
  15. Velcade (bortezomib) [package insert]. Millennium Pharmaceuticals, Inc. Cambridge (MA): March 2015.
  16. Zinzani PL, Khuageva NK, Wang H, et al. Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial. Hematol Oncol. 2012 Oct 22;5:67. doi: 10.1186/1756-8722-5-67.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 06/08/16.

GUIDELINE UPDATE INFORMATION:

04/15/09

New Medical Coverage Guideline.

10/15/09

Revision; consisting of clarifying dosage and updating coding.

07/15/10

Review and revision; consisting of updating references.

08/01/10

Revision; consisting of updating coding.

02/01/11

Revision; consisting of updating coding.

02/15/11

Revision; consisting of adding ICD-10 codes.

07/15/11

Review and revision to guideline; consisting of updating coding and references.

07/15/12

Review and revision to guideline; consisting of updating coding, references and exceptions.

12/15/12

Revision to guideline; consisting of updating coding.

07/15/13

Review and revision to guideline; consisting of revising position statement to include updated NCCN category 1 and 2A recommendations; reformatting/revising dosage/administration, precautions, program exceptions, and description section; updating references and coding.

12/15/13

Revision to guideline; consisting of revising medical necessity criteria for coverage of mantle cell lymphoma.

07/15/14

Review and revision to guideline; consisting of revising position statement, updating references and coding.

12/15/14

Revision to guideline; consisting of position statement, dosing/administration.

07/15/15

Review and revision to guideline; consisting of updating description, position statement, dosage/administration, precautions, coding/billing, and references.

10/01/15

Revision consisting of update to Program Exceptions section.

11/01/15

Revision: ICD-9 Codes deleted.

07/15/16

Review and revision to guideline consisting of updating position statement, billing/coding information, definitions, related guidelines, and references.

10/01/16

Revision: ICD-10 code updates.

02/16/17

Revision: Update to Position Statement.

Date Printed: June 23, 2017: 06:25 PM