BlueCross BlueShield of Tennessee Medical Policy Manual

Bortezomib (Intravenous Only)

NDC CODE(S)

63323-0721-XX BORTEZOMIB 3.5MG Solution Reconstituted (FRESENIUS KABI USA)

DESCRIPTION

Bortezomib is the first antineoplastic agent to target the proteasome, a large intracellular cytoplasmic organelle responsible for the majority of protein degradation in mammalian cells.  Proteins are tagged for destruction when conjugated to ubiquitin.  They then enter the proteasome and are degraded via the ubiquitin-proteasome pathway. This pathway is central to cellular homeostasis, playing an essential role in the cell cycle, cellular proliferation and apoptosis.

Bortezomib, a boron-containing molecule, reversibly inhibits the ubiquitin-proteasome pathway resulting in cell-cycle arrest and apoptosis.  It has been shown in vitro to be cytotoxic to a variety of cancer cells and in vivo causes a delay in tumor growth.

POLICY

MEDICAL APPROPRIATENESS

INITIAL APPROVAL CRITERIA

Universal Criteria

Multiple Myeloma

Mantle Cell Lymphoma – B-Cell Lymphoma

Systemic Light Chain Amyloidosis

Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma

Multicentric Castleman’s Disease – B-Cell Lymphoma

Adult T-Cell Leukemia/Lymphoma

Pediatric Acute Lymphoblastic Leukemia

* Pediatric ALL patients may include certain adolescent and young adult (AYA) patients up to 30 years of age.

Kaposi Sarcoma

Pediatric Hodgkin Lymphoma

* Pediatric Hodgkin Lymphoma patients may include certain adolescent and young adult (AYA) patients up to 39 years of age.

*Bortezomib was approved by the FDA as a 505(b) (2) NDA of the innovator product, Velcade (bortezomib) for Injection, for intravenous use only and thus should NOT be considered therapeutically interchangeable (i.e. not suitable for substitution) for other non-approved indications.

RENEWAL CRITERIA

DOSAGE/ADMINISTRATION

INDICATION

DOSE

Multiple Myeloma –

Initial treatment

1.3 mg/m2 intravenously (IV) in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles. In cycles 1-4, bortezomib is given twice weekly (days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5-9, bortezomib is given once weekly (days 1, 8, 22, and 29).

Multiple Myeloma –

maintenance therapy

Following primary therapy with a bortezomib-containing regimen for transplant-ineligible patients:

1.3 mg/m² IV every two weeks or 1.6 mg/m2 IV weekly (days 1, 8, 15, and 22) every 35 days until disease progression or unacceptable toxicity

Following autologous stem cell transplant:

1.3 mg/m² IV every two weeks until disease progression or unacceptable toxicity

Multiple Myeloma –

re-treatment

1.3 mg/m² IV twice weekly (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21) for up to 8 cycles

Mantle Cell Lymphoma – previously untreated

1.3 mg/m2 IV in combination with rituximab, cyclophosphamide, doxorubicin, and oral prednisone for six 3-week treatment cycles.

Bortezomib is given twice weekly (days 1, 4, 8, and 11) followed by a 10-day rest period on days 12-21. For patients with a response first documented at cycle 6, two additional cycles are recommended.

Multiple Myeloma &

Mantle Cell Lymphoma – relapsed

1.3 mg/m² IV twice weekly (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21)

·         For extended therapy of more than 8 cycles, bortezomib may be administered on the standard schedule or, for relapsed multiple myeloma, 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).

Systemic Light Chain Amyloidosis

Single agent:

1.6 mg/m2 IV weekly (days 1, 8, 15, and 22) every 35 days or 1.3 mg/m² IV twice weekly (days 1, 4, 8, and 11) every 21 days for up to 8 cycles

In combination with cyclophosphamide and/or dexamethasone:

1.3 mg/m² IV twice weekly (days 1, 4, 8, and 11) every 21 or 28 days for up to 8 cycles

In combination with melphalan and dexamethasone:

1.3mg/m2 IV twice weekly (days 1, 4, 8, and 11) every 28 days for up to 9 cycles

In combination with lenalidomide and dexamethasone:

1.3mg/m2 IV twice weekly (days 1, 8, and 15) every 28 days for up to 8 cycles

In combination with daratumumab and hyaluronidase-fihj, cyclophosphamide, and dexamethasone:

1.3mg/m2 IV weekly (days 1, 8, 15, and 22) every 28 days for up to 2 years

Waldenström’s

Macroglobulinemia

Single agent:

·         1.3 mg/m² IV twice weekly (days 1, 4, 8, and 11) every 21 days, until disease progression or unacceptable toxicity

In combination with rituximab and/or dexamethasone:

·         1.3 mg/m² IV twice weekly (days 1, 4, 8, and 11) every 21 days for 4 continuous cycles, followed by a 12-week rest period, then up to 4 additional cycles given every 12 weeks

·         1.6 mg/m2 IV weekly (days 1, 8, and 15, and 22) every 28 days for up to 6 cycles

Adult T-Cell Leukemia/

Lymphoma

1.3 mg/m² IV twice weekly (days 1, 4, 8, and 11) every 21 days for up to 8 cycles

Kaposi Sarcoma

1.6 mg/m2 IV weekly (days 1, 8, and 15) every 28 days

Pediatric Hodgkin

Lymphoma

1.2 mg/m2 IV on days 1, 4, and 8 every 21 days for up to 4 cycles

All Other Indications

1.3 mg/m² IV twice weekly (days 1, 4, 8, and 11) every 21 days

LENGTH OF AUTHORIZATION

Coverage will be provided for 6 months and may be renewed unless otherwise specified.

DOSING LIMITS

Max Units (per dose and over time) [HCPCS Unit]:

APPLICABLE TENNESSEE STATE MANDATE REQUIREMENTS

BlueCross BlueShield of Tennessee’s Medical Policy complies with Tennessee Code Annotated Section 56-7-2352 regarding coverage of off-label indications of Food and Drug Administration (FDA) approved drugs when the off-label use is recognized in one of the statutorily recognized standard reference compendia or in the published peer-reviewed medical literature.

IMPORTANT REMINDER

We develop Medical Policies to provide guidance to Members and Providers.  This Medical Policy relates only to the services or supplies described in it.  The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy.  For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed.  If there is a conflict between the Medical Policy and a health plan, the express terms of the health plan will govern.

ADDITIONAL INFORMATION 

For appropriate chemotherapy regimens, dosage information, contraindications, precautions, warnings, and monitoring information, please refer to one of the standard reference compendia (e.g., the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) published by the National Comprehensive Cancer Network®, Drugdex Evaluations of Micromedex Solutions at Truven Health, or The American Hospital Formulary Service Drug Information).

SOURCES

1.     Bortezomib [package insert]. Lake Zurich, IL; Fresenius Kabi, Inc; July 2018. Accessed January 2021.

2.     Bortezomib [package insert]. Visakhapatnam, India; Dr. Reddy’s Laboratories, Inc; October 2019. Accessed January 2021.

3.     Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) for Bortezomib. National Comprehensive Cancer Network, 20201. The NCCN Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed January 2021.

4.     Boccadoro M, Bringhen S, Gaidano G, et al, “Bortezomib, Melphalan, Prednisone, and Thalidomide (VMPT) Followed by Maintenance With Bortezomib and Thalidomide (VT) for Initial Treatment of Elderly Multiple Myeloma Patients,” J Clin Oncol, 2010, 28(7s):8013 [abstract 8013 from 2010 ASCO Annual Meeting].

5.     Palumbo A, Bringhen S, Rossi D, et al, “Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Followed by Maintenance With Bortezomib and Thalidomide for Initial Treatment of Elderly Multiple Myeloma Patients,” Blood, 2009, 114(22):128 [abstract 128 from ASH 2009 Annual Meeting].

6.     Ghobrial IM, Hong F, Padmanabhan S, et al, “Phase II Trial of Weekly Bortezomib in Combination With Rituximab in Relapsed or Relapsed and Refractory Waldenstrom Macroglobulinemia,” J Clin Oncol, 2010, 28(8):1422-8.

7.     Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. doi: 10.1200/JCO.2011.39.6820. Epub 2012 Jul 16.

8.     Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:4293-4297.

9.     Horton, T. M., Whitlock, J. A., Lu, X. , et al. Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group. Br J Haematol 2019;186:274-285. doi:10.1111/bjh.15919

10.  Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) T-Cell Lymphomas. Version 1.20201. National Comprehensive Cancer Network, 20201. The NCCN Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed January 2021.

11.  Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) Systemic Light Chain Amyloidosis. Version 1.20201. National Comprehensive Cancer Network, 20201. The NCCN Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed January 2021.

12.  Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma. Version 21.20201. National Comprehensive Cancer Network, 20201. The NCCN Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed January 2021.

13.  Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) B-Cell Lymphomas. Version 21.20201. National Comprehensive Cancer Network, 20201. The NCCN Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed January 2021.

14.  Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) Multiple  Myeloma. Version 4.20201. National Comprehensive Cancer Network, 20201. The NCCN Compendium® is a derivative work of the NCCN Guidelines®.NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed January 2021.

15.  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 Aug 10;27(23):3830-5. doi: 10.1200/JCO.2008.20.4677. Epub 2009 Jun 8.

16.  Mateos MV, Oriol A, Martínez-López J, et al. Outcomes with two different schedules of bortezomib, melphalan, and prednisone (VMP) for previously untreated multiple myeloma: matched pair analysis using long-term follow-up data from the phase 3 VISTA and PETHEMA/GEM05 trials. Ann Hematol. 2016 Dec;95(12):2033-2041. Epub 2016 Oct 14.

17.  San Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013 Feb 1;31(4):448-55. doi:  0.1200/JCO.2012.41.6180. Epub 2012 Dec 10.

18.  Harousseau JL, Palumbo A, Richardson PG, et al. Superior outcomes associated with complete response in newly diagnosed multiple myeloma patients treated with nonintensive therapy: analysis of the phase 3 VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone. Blood. 2010 Nov 11;116(19):3743-50. doi: 10.1182/blood-2010-03-275800. Epub 2010 Jul 13.

19.  San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 28;359(9):906-17. doi:10.1056/NEJMoa0801479.

20.  Dimopoulos MA, Orlowski RZ, Facon T, et al. Retrospective matched-pairs analysis of bortezomib plus dexamethasone versus bortezomib monotherapy in relapsed multiple myeloma. Haematologica. 2015 Jan;100(1):100-6. doi: 10.3324/haematol.2014.112037. Epub 2014 Sep 26.

21.  Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, noninferiority study. Lancet Oncol. 2011 May;12(5):431-40. doi: 10.1016/S1470-2045(11)70081-X.trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:4293-4297.

22.  Robak T, Jin J, Pylypenko H, et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Nov;19(11):1449-1458. doi: 10.1016/S1470-2045(18)30685-5. Epub 2018 Oct 19.

23.  Verhoef G, Robak T, Huang H, et al. Association between quality of response and outcomes in patients with newly diagnosed mantle cell lymphoma receiving VR-CAP versus R-CHOP in the phase 3 LYM-3002 study. Haematologica. 2017 May;102(5):895-902. doi:10.3324/haematol.2016.152496. Epub 2017 Feb 9.

24.  Robak T, Huang H, Jin J, et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med 2015; 372:944.

25.  Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004 Oct;127(2):165-72.

26.  Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17.

27.  Petrucci MT, Giraldo P, Corradini P, et al. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol 2013; 160:649.

28.  Fisher RI, Bernstein SH, Kahl BS, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 2006; 24:4867.

29.  Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) Pediatric Acute Lymphoblastic Leukemia. Version 2.20201. National Comprehensive Cancer Network, 20201. The NCCN Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed January 2021.

30.  Ghobrial IM, Xie W, Padmanabhan S, et al. Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenström Macroglobulinemia. Am J Hematol. 2010 Sep;85(9):670-4. doi: 10.1002/ajh.21788.

31.  Niesvizky R, Flinn IW, Rifkin R, et al. Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. doi: 10.1200/JCO.2014.58.7618.

32.  Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352:2487.

33.  Richardson PG, Barlogie B, Berenson J, et al. Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma: final time-to-event results from the SUMMIT trial. Cancer. 2006 Mar 15;106(6):1316-9.

34.  Khan AA, Siraj F, Bhargava M, Aggarwal S. Successful treatment of multicentric Castleman's disease accompanying myeloma with bortezomib. BMJ Case Rep. 2012;2012:bcr2012007646. Published 2012 Dec 20. doi:10.1136/bcr-2012-007646.

35.  Gasparetto C, Sanchorawala V, Snyder RM, et al. Use of melphalan (M)/dexamethasone (D)/bortezomib in AL amyloidosis. J Clin Oncol 2010; 28:Abstract 8024.

36.  Venner CP, Lane T, Foard D, et al. Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival. Blood. 2012 May 10;119(19):4387-90. doi: 10.1182/blood-2011-10-388462.

37.  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. doi: 10.1200/JCO.2009.23.8220.

38.  Ishitsuka K, Utsunomiya A, Katsuya H, et al. A phase II study of bortezomib in patients with relapsed or refractory aggressive adult T-cell leukemia/lymphoma. Cancer Sci. 2015;106(9):1219-1223. doi:10.1111/cas.12735.

39.  Chen CI, Kouroukis CT, White D, et al. Bortezomib is active in patients with untreated or relapsed Waldenström’s macroglobulinemia: a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 Apr 20;25(12):1570-5.

40.  Palladini G, Perfetti V, Obici L, et al. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8.

41.  Reece DE, Sanchorawala V, Hegenbart U, et al. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. doi: 10.1182/blood-2009-02-203398.

42.  Reid EG, Suazo A, Lensing SY, et al. Pilot Trial AMC-063: Safety and Efficacy of Bortezomib in AIDS-associated Kaposi Sarcoma. Clin Cancer Res. 2020;26(3):558-565. doi:10.1158/1078-0432.CCR-19-1044.

43.  Zhang S, Kulkarni AA, Xu B, et al. Bortezomib-based consolidation or maintenance therapy for multiple myeloma: a meta-analysis. Blood Cancer J. 2020;10(3):33. Published 2020 Mar 6. doi:10.1038/s41408-020-0298-1.

44.  Palumbo A, Bringhen S, Larocca A, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomibmelphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. doi: 10.1200/JCO.2013.52.0023.

45.  Horton TM, Drachtman RA, Chen L, et al. A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children's Oncology Group study. Br J Haematol. 2015;170(1):118-122. doi:10.1111/bjh.13388.

46.  Palladini G, Kastritis E, Maurer M, et al Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. Blood 2020 Jul 2;136(1):71-80. doi: 10.1182/blood.2019004460.

47.  Kastritis E, Dialoupi I, Gavriatopoulou M, et al. Primary treatment of light-chain amyloidosis with bortezomib, lenalidomide, and dexamethasone. Blood Adv. 2019;3(20):3002-3009. doi:10.1182/bloodadvances.2019000147.

48.  Lexi-Comp Online. (2021, February). AHFS-DI. Bortezomib. Retrieved March 5, 2021 from Lexi-Comp Online with AHFS.

49.  MICROMEDEX Healthcare Series. Drugdex Drug Evaluations. (2021, January). Bortezomib. Retrieved March 5, 2021 from MICROMEDEX Healthcare Series.

ORIGINAL EFFECTIVE DATE:  7/9/2005

MOST RECENT REVIEW DATE:    6/30/2021

ID_MRx

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