Last Review Date: 03/03/2020

Date of Origin: 02/06/2018

Dates Reviewed: 02/2018, 05/2018, 09/2018, 10/2018, 12/2018, 03/2019, 06/2019, 09/2019, 12/2019, 03/2020

1. Length of Authorization ^7,30

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

• Maintenance therapy in multiple myeloma post-autologous stem cell transplant, coverage may be renewed up to 2 years of total therapy.
• Waldenström’s macroglobulinemia in combination with rituximab alone: Coverage will be provided for a total of 6 cycles (28-days per cycle) and is not eligible for renewal.

2. Dosing Limits

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

• Bortezomib 3.5 mg powder for injection: 4 vials per 14 day supply

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

• Multiple Myeloma – Maintenance Therapy Only
  • 140 billable units every 14 days
• All Other Indications
  • 140 billable units every 21 days

3. Initial Approval Criteria ^1,2,3

Coverage is provided in the following conditions:

• Patient aged 18 years or older (unless otherwise specified); AND

Universal Criteria

• Will not be administered intrathecally; AND

Multiple myeloma ^{1,2,3,4,5,6,14,16,17,18,19,20,21,25,26,27} †

• Used in combination with a corticosteroid containing regimen as primary therapy for symptomatic disease or for relapse (re-treatment) after 6 months following primary induction therapy with the same regimen; OR
• Used as maintenance therapy as a single agent or in combination with lenalidomide; AND
  • Patient has not received more than 2 years of maintenance therapy with a bortezomib product; OR
• Used as therapy for relapse or progressive disease in combination with a dexamethasone containing regimen

Mantle Cell Lymphoma ^{1,2,3,13,22,23,24,28} †

• Used as initial therapy or after initial treatment with involved site radiation therapy alone as a component of VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) in patients who are not candidates for high-dose therapy/autologous stem cell rescue; OR
• Used as second-line therapy as a single agent, in combination with rituximab, or as a component of VR-CAP; AND
  • Patient had a very good partial response to induction therapy; OR
  • Patient had stable disease or partial response with substantial disease after induction therapy (excludes use as a component of VR-CAP); OR

• • Patient has relapsed or progressive disease following an extended response to prior chemoimmunotherapy (excludes use as a component of VR-CAP)

Systemic Light Chain Amyloidosis ^3,11 ‡

• Patient has newly diagnosed OR relapsed/refractory disease§; AND
  • Used in combination with cyclophosphamide and dexamethasone; OR
  • Used as a single agent; OR
  • Used in combination with dexamethasone with or without melphalan

§Consider repeating initial therapy if relapse-free for several years

Waldenström’s macroglobulinemia/Lymphoplasmacytic Lymphoma ^3,6,12,15,30 ‡

• Used in combination with dexamethasone and rituximab; OR
• Used as a single agent or in combination with rituximab; OR
• Used in combination with dexamethasone

Multicentric Castleman’s Disease ^3,13 ‡

• Must be used as subsequent therapy; AND
• Patient has progressed following treatment for relapsed/refractory or progressive disease; AND
• Used as a single agent or in combination with rituximab

Adult T-Cell Leukemia/Lymphoma ^3,8,10 ‡

• Must be used as a single agent for non-responders to first-line therapy for acute disease or lymphoma subtypes

Pediatric Acute Lymphoblastic Leukemia ^3,9,29 ‡

• Patient is at least 1 year of age or older; AND
• Patient has relapsed or refractory Philadelphia chromosome negative B-cell disease (B-ALL): OR
• Patient has relapsed or refractory Philadelphia chromosome positive B-cell disease (B-ALL); AND
  • Used in combination with dasatinib or imatinib as a component of the COG AALL07P1 regimen; OR
• Patient has relapsed or refractory T-cell disease (T-ALL); AND
  • Used in combination with a corticosteroid, vincristine, doxorubicin, and pegaspargase

*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.

† FDA Approved Indication(s); ‡ Compendia recommended indication(s)

4. Renewal Criteria ^{1,3,10,11,12,13,14,25,29}

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.
• For maintenance therapy of multiple myeloma after autologous stem cell transplant: patient has not received over 2 years of therapy.

5. Dosage/Administration ^{1,2,3,10,11,12,13,14,15,29,30}

6. Billing Code/Availability Information

HCPCS code:

• J9044 – Injection, bortezomib, not otherwise specified, 0.1 mg. 1 billable unit = 0.1 mg

NDC(s):

• Bortezomib 3.5 mg single-use vial powder for injection: 63323-0721-xx (Fresenius Kabi)
• Bortezomib 3.5 mg single-use vial powder for injection: 43598-0865-xx (Dr. Reddy’s Laboratories)

7. References

1. Bortezomib [package insert]. Lake Zurich, IL; Fresenius Kabi, Inc; June 2018. Accessed February 2020.
2. Bortezomib [package insert]. Visakhapatnam, India; Dr. Reddy’s Laboratories, Inc; October 2019. Accessed February 2020.
3. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) for Bortezomib. National Comprehensive Cancer Network, 2020. 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 2020.
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 1.2020. National Comprehensive Cancer Network, 2020. 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 2020.
11. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium^®) Systemic Light Chain Amyloidosis. Version 1.2020. National Comprehensive Cancer Network, 2020. 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 2020.
12. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium^®) Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma. Version 1.2020. National Comprehensive Cancer Network, 2020. 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 2020.
13. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium^®) B-Cell Lymphomas. Version 1.2020. National Comprehensive Cancer Network, 2020. 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 2020.
14. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium^®) Multiple Myeloma. Version 2.2020. National Comprehensive Cancer Network, 2020. 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 2020.
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: 10.1200/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, non-inferiority study. Lancet Oncol. 2011 May;12(5):431-40. doi: 10.1016/S1470-2045(11)70081-X.
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 2.2020. National Comprehensive Cancer Network, 2020. 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 2020.
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. National Government Services, Inc. Local Coverage Article for Bortezomib – Related to LCD L33394 (A52371). Centers for Medicare & Medicaid Services, Inc. Updated on 11/01/2019 with effective date of 11/07/2019. Accessed February 2020.
35. Palmetto GBA, LLC. Local Coverage Article: Billing and Coding: Chemotherapy (A56141). Centers for Medicare & Medicaid Services, Inc. Updated on 10/29/219 with effective date 11/07/2019. Accessed February 2020.
36. CGS Administrators, LLC. Local Coverage Article: Billing and Coding: BORTEZOMIB (Velcade) -J9041 (A56891). Centers for Medicare & Medicaid Services, Inc. Updated on 09/20/2019 with effective date 09/26/2019. Accessed February 2020.

Appendix 1 – Covered Diagnosis Codes

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

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 Determination (NCD), Local Coverage Determinations (LCDs), and Articles may exist and compliance with these policies is required where applicable. They can be found at: http://www.cms.gov/medicare-coverage-database/search/advanced-search.aspx. Additional indications may be covered at the discretion of the health plan.

Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCD/Article):