Last Review Date: 03/05/2024

Date of Origin: 11/28/2011

Dates Reviewed: 12/2011, 03/2012, 06/2012, 09/2012, 12/2012, 03/2013, 06/2013, 09/2013, 12/2013, 03/2014, 06/2014, 09/2014, 12/2014, 03/2015, 05/2015, 08/2015, 11/2015, 02/2016, 05/2016, 08/2016, 11/2016, 02/2017, 05/2017, 08/2017, 11/2017, 02/2018, 05/2018, 09/2018, 12/2018, 03/2019, 06/2019, 09/2019, 12/2019, 03/2020, 06/2020, 09/2020, 03/2021, 03/2022, 12/2022, 12/2023, 03/2024

1. Length of Authorization ^1-7,49

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

• Pediatric Hodgkin Lymphoma: Coverage will be provided for a total of 4 cycles (21-days per cycle).

2. Dosing Limits

1. Quantity Limit (max daily dose) [NDC Unit]:

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

• Multiple Myeloma & Systemic Light Chain Amyloidosis:
  • 280 billable units every 35 days
• Kaposi Sarcoma & Waldenström’s Macroglobulinemia:
  • 210 billable units every 28 days
• Pediatric Hodgkin Lymphoma:
  • 105 billable units every 21 days
• All Other Indications:
  • 140 billable units every 21 days

3. Initial Approval Criteria ^1-6

Coverage is provided in the following conditions:

• Patient is at least 18 years of age, unless otherwise specified; AND

Universal Criteria ^1-6

• Will not be administered intrathecally; AND

Multiple Myeloma †‡Ф ^{1-9,11,18,20-25,29-31,35-37,47,48}

Mantle Cell Lymphoma – B-Cell Lymphoma †‡Ф ^{1-7,17,26-28,32}

• Used as induction or additional therapy in combination with a rituximab-based regimen; OR
• Used as subsequent therapy as a single agent or in combination with rituximab

Systemic Light Chain Amyloidosis ‡ ^{7,15,39-41,44,45,50,51}

• Used in one of the following treatment settings:

• Newly diagnosed disease
• Repeat initial therapy if relapse-free for several years
• Relapsed or refractory disease; AND
  • Used in combination with a dexamethasone-containing regimen; OR
  • Used as a single agent

Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma (WM/LPL) ‡ ^{7,10,16,19,34,43}

• Used in combination with dexamethasone and rituximab

Castleman Disease ‡ ^7,38,52,53

• Patient has multicentric disease; AND
• Used as subsequent therapy; AND
• Used as a single agent or in combination with rituximab

Adult T-Cell Leukemia/Lymphoma ‡ ^7,12,14,42

• Used as a single agent; AND
• Used as subsequent therapy

Adult* Acute Lymphoblastic Leukemia (ALL) ‡ ^7,13

• Used in combination with chemotherapy; AND
• Patient has relapsed/refractory T-cell disease (T-ALL)

*NCCN recommendations for ALL may be applicable to adolescent and young adult (AYA) patients within the age range of 15-39 years.

Pediatric Acute Lymphoblastic Leukemia (ALL) ‡ ^7,13,33

• Patient is at least 1 year of age**; AND
  • Patient has relapsed or refractory B-cell disease (B-ALL); AND
    • Used as a component of the COG AALL07P1 regimen (bortezomib, vincristine, doxorubicin, PEG-asparaginase, prednisone); AND
      • Patient has Philadelphia (Ph) chromosome negative disease; OR
      • Patient has Philadelphia (Ph) chromosome positive disease and also used in combination with dasatinib or imatinib; OR
  • Patient has relapsed or refractory T-cell disease (T-ALL); AND
    • Used in combination with vincristine, doxorubicin, pegaspargase or calaspargase, and prednisone or dexamethasone; OR
  • Patient has T-lymphoblastic lymphoma (T-LL); AND
    • Used in combination with BFM backbone chemotherapy

**NCCN recommendations for Pediatric ALL may be applicable to certain adolescent and young adult (AYA) patients up to 30 years of age.

Kaposi Sarcoma ‡ ^7,46

• Used as subsequent therapy for relapsed or refractory disease; AND
• Patient has advanced cutaneous, oral, visceral, or nodal disease; AND
  • Used as a single-agent in patients without human immunodeficiency virus (HIV); OR
  • Used in combination with antiretroviral therapy (ART) for patients with HIV

Pediatric Hodgkin Lymphoma ‡ ^7,49

• Patient age is ≤ 18 years of age***; AND
• Used as subsequent therapy for relapsed or refractory disease; AND
• Used in combination with ifosfamide and vinorelbine

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

† FDA Approved Indication(s); ‡ Compendia Recommended Indication(s); Ф Orphan Drug

4. Renewal Criteria ^1-6

Coverage can be renewed based upon the following criteria:

• Patient continues to meet universal and other indication-specific relevant criteria such as concomitant therapy requirements (not including prerequisite therapy), performance status, etc. identified in section III; AND
• Disease response with treatment as defined by stabilization of disease or decrease in size of tumor or tumor spread; AND
• Absence of unacceptable toxicity from the drug. Example of unacceptable toxicity include: peripheral neuropathy, hypotension, cardiac toxicity, pulmonary toxicity, posterior reversible encephalopathy syndrome (PRES), gastrointestinal toxicity, thrombocytopenia, neutropenia, tumor lysis syndrome, hepatic toxicity, thrombotic microangiopathy, etc.

5.   Dosage/Administration ^{1-6,10,13,19,38,40-44-46,49-52}

6. Billing Code/Availability Information
7. References

1. Velcade [package insert]. Lexington, MA; Millennium Pharmaceuticals, Inc; August 2022. Accessed January 2024.
2. Bortezomib [package insert]. Lake Zurich, IL; Fresenius Kabi, Inc; March 2022. Accessed January 2024.
3. Bortezomib [package insert]. Visakhapatnam, India; Dr. Reddy’s Laboratories, Inc; February 2022. Accessed January 2024.
4. Bortezomib [package insert]. Lake Forest, IL; Hospira, Inc; December 2022. Accessed January 2024.

5. Bortezomib [package insert]. Princeton, NJ; MAIA Pharmaceuticals, Inc; August 2022. Accessed January 2024.
6. Bortezomib [package insert]. Durham, NC; Accord Healthcare, Inc; July 2022. Accessed November 2023.
7. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) for Bortezomib. National Comprehensive Cancer Network, 2024. 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 2024.
8. 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].
9. 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].
10. 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.
11. 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.
12. 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.

13. 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.
14. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) T-Cell Lymphomas. Version 1.2024. National Comprehensive Cancer Network, 2024. 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 2024.

15. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) Systemic Light Chain Amyloidosis. Version 2.2024. National Comprehensive Cancer Network, 2024. 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 2024.
16. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma. Version 2.2024. National Comprehensive Cancer Network, 2024. 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 2024.
17. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) B-Cell Lymphomas. Version 1.2024. National Comprehensive Cancer Network, 2024. 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 2024.
18. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) Multiple Myeloma. Version 2.2024. National Comprehensive Cancer Network, 2024. 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 2024.
19. 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.
20. 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.
21. 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: 10.1200/JCO.2012.41.6180. Epub 2012 Dec 10.
22. 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.

23. 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.

24. 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.

25. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011 May;12(5):431-40. doi: 10.1016/S1470-2045(11)70081-X. Epub 2011 Apr 18.
26. 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.
27. 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.
28. 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. doi: 10.1056/NEJMoa1412096.
29. 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.

30. 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.

31. Petrucci MT, Giraldo P, Corradini P, et al. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. J Haematol. 2013 Mar;160(5):649-59. doi: 10.1111/bjh.12198. Epub 2013 Jan 7.
32. 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 Oct 20;24(30):4867-74. Epub 2006 Sep 25.
33. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) Pediatric Acute Lymphoblastic Leukemia. Version 4.2024. National Comprehensive Cancer Network, 2024. 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 February 2024.

34. 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.
35. 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.
36. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352:2487.
37. 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.
38. 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.
39. 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.
40. 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.
41. 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.
42. 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.
43. Chen CI, Kouroukis CT, White D, et al. Bortezomib is active in patients with untreated or relapsed Waldenstrom'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.
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45. 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.
46. 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.
47. 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.
48. Palumbo A, Bringhen S, Larocca A, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-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.
49. 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.
50. 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.
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53. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) Castleman Disease 1.2024. National Comprehensive Cancer Network, 2024. 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 2024.
54. National Government Services, Inc. Local Coverage Article (LCA): Billing and Coding: Bortezomib (A52371). Centers for Medicare & Medicaid Services, Inc. Updated on 09/29/2023 with effective date of 10/01/2023. Accessed February 2024.

Appendix 1 – Covered Diagnosis Codes

Appendix 2 – Centers for Medicare and Medicaid Services (CMS)

The preceding information is intended for non-Medicare coverage determinations. Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determinations (NCDs) and/or Local Coverage Determinations (LCDs) may exist and compliance with these policies is required where applicable. Local Coverage Articles (LCAs) may also exist for claims payment purposes or to clarify benefit eligibility under Part B for drugs which may be self-administered. The following link may be used to search for NCD, LCD, or LCA documents: https://www.cms.gov/medicare-coverage-database/search.aspx. Additional indications, including any preceding information, may be applied at the discretion of the health plan.