Subject:
Bortezomib (Velcade®)
Description:
_______________________________________________________________________________________
IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
__________________________________________________________________________________________________________________________
Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in the bone marrow, which leads to bone destruction and marrow failure. The mean age for the affected population is 62 years for men (75% older than 70 years) and 61 years for women (79% older than 70 years). In 2003, the SEER database reported a 5-year survival rate of 34%.
Based on clinical and laboratory evaluation, patients are classified as having smoldering (asymptomatic) disease or active (symptomatic) disease. Smoldering (asymptomatic) disease is defined as low concentrations of M-protein (≥30 g/L) and/or bone marrow infiltration greater than or equal to 10% plasma cells with no anemia, renal failure, hypercalcemia, or bone lesions. Active disease is further categorized according to stage based on either the Durie-Salmon staging system or the International Staging System (ISS). Response criteria are categorized to complete response (CR), sCR, very good partial response (VGPR), partial response (PR), stable disease, and progressive disease.
Treatment options for smoldering myeloma generally do not need primary therapy as it may take months to years for disease progression. Treatment options of active (symptomatic) disease include primary therapy followed by high dose chemotherapy with autologous stem cell support. Therapies used include thalidomide-, lenalidomide-, or bortezomib-based regimens. Anticoagulation prophylaxis is recommended for patients receiving thalidomide- or lenalidomide-based therapy. Bortezomib-based therapy may be useful in patients with renal failure and with certain adverse cytogenetic features. The incidence of bortezomib-associated herpes zoster may be reduced with the use of prophylactic acyclovir. The risk of deep vein thrombosis (DVT) is low with bortezomib, but the incidence of peripheral neuropathy and gastrointestinal adverse effects can be greater.
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma. Bortezomib is FDA approved for the treatment of multiple myeloma and for the treatment of mantle cell lymphoma who have received at least 1 prior therapy. Bortezomib is also included in treatment guidelines for Non-Hodgkin’s lymphoma (NHL) and Waldenstrom’s macroglobulinemia.
Five pivotal studies were conducted for the indication of multiple myeloma for Velcade; one trial in untreated patients and four trials in relapsed patients. The phase III VISTA trial compared bortezomib plus melphalan plus prednisone (VMP) with melphalan plus prednisone (MP) in patients previously untreated for multiple myeloma. With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P <0.001); median overall survival (OS) was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. The phase III APEX trial compared bortezomib versus high-dose dexamethasone in patients with progressive MM following 1 to 3 prior therapies. Six hundred sixty-nine patients were randomized to bortezomib or dexamethasone. The primary endpoint, the improvement in time to progression (TTP), was achieved with an improved median TTP of 6.22 vs 3.49 months (HR 0.55, p<0.0001). In another trial, bortezomib subcutaneous was compared to its intravenous (IV) formulation. Patients received a median of eight cycles (range one to ten) in both groups. Overall response rate (ORR) after four cycles was 42% in both groups (61 patients in subcutaneous group and 31 in intravenous group; ORR difference -0·4%, 95% CI -14·3 to 13·5), showing non-inferiority (p=0·002). Two phase 2 studies were conducted, one to determine a dose-response relationship and the other an extension study to examine additional clinical benefit and toxicities.
One pivotal phase 2 study was conducted for the indication of mantle cell lymphoma in patients who have received at least one prior therapy. Prior therapies included an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. The ORR was 31% and the median response duration was 9.3 months. Bortezomib is also being studied in other non-Hodgkin’s lymphomas and some phase 2 data has shown activity in the treatment of relapsed or refractory B-cell lymphomas.
The use of bortezomib in newly diagnosed multiple myeloma patients for induction therapy prior to stem-cell transplant was studied as a component of various induction regimens. In a phase 2 trial comparing bortezomib plus dexamethasone with vincristine-doxorubicin-dexamethasone (VAD), with or without dexamethasone-cyclophosphamide-etoposide-cisplatin (DCEP) consolidation, progression-free survival and 1-year survival rates were found to be similar in the bortezomib-dexamethasone and VAD arms (progression-free survival: 93 and 90%, respectively; 1-year survival: 97 and 95%, respectively). A phase 3 trial compared bortezomib-thalidomide-dexamethasone (VTD) to thalidomide-dexamethasone (TD), with both regimens followed by a melphalan conditioning regimen. Results from an interim analysis revealed high postinduction and posttransplant response rates with VTD compared with TD. Two studies also looked at bortezomib-dexamethasone compared to either conventional doxorubicin or pegylated liposomal doxorubicin. Another study also investigated bortezomib in combination with cyclophosphamide and dexamethasone.
In October 2014, the FDA approved the use of bortezomib in previously untreated mantle cell lymphoma and also allowed consideration of retreatment in multiple myeloma in those who had previously responded to bortezomib treatment and have relapsed at least 6 months after completing prior bortezomib treatment.
In November 2017, the FDA approved the 505 (b) (2) generic bortezomib (Bortezomib) for all Velcade®-approved indication, except in previously untreated mantle cell lymphoma. It can be used for treating patients with multiple myeloma and patients with mantle cell lymphoma who have received at least 1 prior therapy. The dose of bortezomib varies depending on the indication. Bortezomib has the same mechanism of action as Velcade®. Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome, which disrupts normal cell homeostasis leading to cell death. Bortezomib is available for intra-venous use only, unlike Velcade, which can be administered both IV and SC. The dosage form and strength is the same as Velcade, single use vials with 3.5 mg of bortezomib as a lyophilized powder for reconstitution.
[INFORMATIONAL NOTE: While it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure, there have been post-marketing reports of: atrioventricular block complete, cardiac tamponade, ischemic colitis, encephalopathy, dysautonomia, deafness bilateral, disseminated intravascular coagulation, hepatitis, acute pancreatitis, progressive multifocal leukoencephalopathy (PML), acute diffuse infiltrative pulmonary disease, PRES (formerly RPLS), toxic epidermal necrolysis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), herpes meningoencephalitis, optic neuropathy, blindness and ophthalmic herpes.
Policy:
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance)
The requirements of the Horizon BCBSNJ Bortezomib (Velcade®) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).
I. Bortezomib and Velcade are medically necessary for adults greater than 18 years for the following FDA approved indications
A. Velcade
1. Multiple myeloma
2. Mantle cell lymphoma
B. Bortezomib (generic)
1. Multiple Myeloma
2. Mantle cell lymphoma who have received at least 1 prior therapy
[INFORMATIONAL NOTE: Bortezomib (generic) is NOT FDA APPROVED for subcutaneous use]
II. When Bortezomib or Velcade is considered medically necessary, initial therapy will be eligible at the following FDA approved doses for a period of 6 months:
1. For general dosing, the recommended starting dose is 1.3 mg/m2 administered intravenously at a concentration of 1 mg/mL or subcutaneously at a concentration of 2.5 mg/mL.
2. For previously untreated multiple myeloma: 1.3 mg/m2 /dose administered twice weekly from Cycles 1 through 4 (Days 1, 4, 8, 11, 22, 25, 29, and 32). From Cycles 5 through 9, the recommended dose is 1.3mg/m2/dose administered once weekly (Days 1, 8, 22, and 29). Velcade/bortezomib is to be administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles.
[INFORMATIONAL NOTE: Prior to initiating any cycle of therapy in combination with melphalan and prednisone, platelet count should be at least 70 x 109/L and the absolute neutrophil count (ANC) should be at least 1.0 x 109/L and non-hematological toxicities should have resolved to Grade 1 or baseline.]
3. For untreated mantle cell lymphoma: 1.3 mg/m2/dose twice weekly for 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period in combination with intravenous rituximab, cyclophosphoamide, doxorubicin and oral prednisone for six 3-week treatment cycles. Bortezomib (generic) is NOT FDA APPROVED for this indication.
[INFORMATIONAL NOTE: For patients with a response first documented at cycle 6, two additional cycles are recommended for a total of 8 cycles. At least 72 hours should elapse between consecutive doses of Velcade.]
[INFORMATIONAL NOTE: Prior to the first day of each cycle (other than Cycle 1), platelet count should be at least 100 x 109/L and absolute neutrophil count (ANC) should be at least 1.5 x 109/L, hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L), and non-hematologic toxicity should have recovered to Grade 1 or baseline.]
4. For relapsed mantle cell lymphoma, relapsed multiple myeloma: 1.3 mg/m2/dose twice weekly for 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period.
[INFORMATIONAL NOTE: 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 23-35).]
[INFORMATIONAL NOTE: At least 72 hours should elapse between consecutive doses of bortezomib. Dose modifications may be required during cycles of combination bortezomib, melphalan, and prednisone if hematologic toxicities, peripheral neuropathy, or hepatic impairment are observed.]
5. For retreatment of relapsed multiple myeloma at least 6 months after prior bortezomib therapy and have previously responded to treatment with bortezomib: start at the last tolerated dose
administered twice weekly (Days 1, 4, 8, and 11) every three weeks
[INFORMATIONAL NOTE: Maximum of 8 cycles allowed. At least 72 hours should elapse between consecutive doses. It may be administered either as a single agent or in combination
with dexamethasone.]
III. Continued therapy will be considered annually if the member has tumor response with stabilization of disease or decrease in size of tumor or tumor spread AND absence of unacceptable toxicity from the drug at the approved doses (e.g.: posterior reversible encephalopathy syndrome, serious peripheral neuropathy, heart failure, acute respiratory distress syndrome, severe pulmonary toxicity, gastrointestinal toxicity, severe hypotension, thrombocytopenia/neutropenia, tumor lysis syndrome, severe hepatotoxicity, or thrombotic microangiopathy)
IV. Bortezomib for subcutaneous or intravenous use is considered medically necessary for the following off label uses in adults greater than 18 years with:
1. Multiple Myeloma
- Primary therapy for active (symptomatic) myeloma or for disease relapse after 6 months following primary induction therapy with the same regimen
- In combination with dexamethasone and lenalidomide (preferred regimen)
- In combination with dexamethasone and cyclophosphamide (preferred initial treatment in patients with acute renal insufficiency or those who have no access to bortezomib/lenalidomide/dexamethasone)
- In combination with dexamethasone for non-transplant candidates (useful under some circumstances)
- In combination with dexamethasone and doxorubicin for transplant candidates (useful in certain circumstances)
- In combination with dexamethasone and thalidomide for transplant candidates (useful under some circumstances)
- In combination with daratumumab, melphalan, and prednisone for non-transplant candidates
- In VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide) regimen for transplant candidates (useful under some circumstances, generally reserved for the treatment of aggressive multiple myeloma)
- Maintenance therapy as a single agent
- For active (symptomatic) myeloma responding to primary myeloma therapy
- For stable or responsive disease following autologous stem cell transplant
- Therapy for previously treated myeloma for disease relapse or for progressive disease in
- Combination with dexamethasone and daratumumab or lenalidomide (preferred regimens)
- With dexamethasone alone or in combination with bendamustine or liposomal doxorubicin or cyclophosphamide or elotuzumab
- VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) regimen (useful under some circumstances, generally reserved for the treatment of aggressive myeloma)
- Combination with pomalidomide and dexamethasone for patients who have received at least two prior therapies, including an immunomodulatory agent and a proteasome inhibitor, and have demonstrated disease progression on or within 60 days of completion of the last therapy
- Combination with panobinostat and dexamethasone for patients who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent
2. B-Cell Lymphomas
- Mantle Cell Lymphoma
- Used for stage I-II disease or aggressive stage II bulky, III, or IV disease or symptomatic indolent stage II bulky, III, or IV disease as
- Less aggressive induction therapy with VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) regimen
- Second-line therapy with or without rituximab to achieve complete response after partial response to induction therapy or for relapsed, refractory, or progressive disease
- Castleman’s Disease
- Subsequent therapy with or without rituximab for multicentric CD that has progressed following treatment of relapsed/refractory or progressive disease
3. Systemic Light Chain Amyloidosis
- Treatment for relapsed/refractory disease as a single agent or in combination with dexamethasone with or without melphalan
- Treatment for newly diagnosed disease or consider for relapsed/refractory disease as a repeat of initial therapy if relapse-free for several years
- In combination with cyclophosphamide and dexamethasone (preferred)
- As a single agent or in combination with dexamethasone with or without melphalan
4. Waldenstrom’s macroglobulinemia/Lymphoplasmacytic Lymphoma
- Used as a single agent, in combination with dexamethasone, or in combination with rituximab with or without dexamethasone as primary therapy OR therapy for previously treated disease that does not respond to primary therapy or for progressive or relapsed disease,
5. T-Cell Lymphomas
- Adult T-Cell Leukemia/Lymphoma
- Second-line therapy (with intention to proceed to high-dose therapy/allogeneic stem cell rescue [HDT/ASCR]) or subsequent therapy to HDT/ASCR as a single agent for non-responders to first-line therapy for acute or lymphoma subtypes
6. Pediatric Acute Lymphoblastic Leukemia
- Therapy for relapsed/refractory T-ALL as a component of a bortezomib-containing regimen (e.g. bortezomib, vincristine, doxorubicin, pegaspargase, and prednisone or dexamethasone)
- Therapy for relapsed/refractory Philadelphia-negative B-ALL, or in combination with dasatinib or imatinib for relapsed/refractory Philadelphia-positive B-ALL as a component of COG AALL07P1 regimen
V. Other uses of bortezomib are considered investigational including, but not limited to: neuroblastoma, acute myeloid leukemia (AML), graft versus host disease, non-small cell lung cancer, relapsed or refractory indolent B-cell non-Hodgkin’s lymphoma, cholangiocarcinoma, myasthenia gravis.
Medicare Coverage
There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ medical policy.
Medicaid Coverage
For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf
________________________________________________________________________________________
Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
___________________________________________________________________________________________________________________________
Index:
Bortezomib (Velcade®)
Velcade® (Bortezomib)
Bortezomib
References:
1. Velcade® Product Information, Cambridge, MA: Millennium Pharmaceuticals, Inc.; April 2019.
2. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Multiple Myeloma. Version 2019. Available at: http://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf.
3. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: T-Cell Lymphomas. Version . Available at: https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf
4. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Waldenström's Macroglobulinemia / Lymphoplasmacytic Lymphoma. Version. Available at: http://www.nccn.org/professionals/physician_gls/pdf/waldenstroms.pdf
5. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Systemic Light Chain Amyloidosis. Version 1.2018.Available at: https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf
7. AHFS Drug Information. Bortezomib. Bethesda, MD: American Society of Health Systems Pharmacists; 2013. p.898-905.
8. Mateos MV, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010 May 1;28(13):2259-66.
9. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487-2498.
10. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110(10):3557-3560.
11. Landau H, et al. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. doi: 10.1038/leu.2012.274. Epub 2012 Sep 27.
12. Oakervee HE, et al. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005 Jun;129(6):755-62.
13. NCCN Drugs and Biologics Compendium. Bortezomib. [Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=70(Accessed on October 24, 2019.)]
14. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: B-cell Lymphomas. Version 5.2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
15. Bortezomib ® Product Information, Lake Zurich, IL: Fresenius Kabi; November 2017.
16. Lee J, Kim BS, Park Y, et al. The Effect of Bortezomib on Antibody-Mediated Rejection after Kidney Transplantation. Yonsei Med J. 2015;56(6):1638-42.
17. Bia M, Adey DB, Bloom RD, Chan L, Kulkarni S, Tomlanovich S. KDOQI US commentary on the 2009 KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Kidney Dis. 2010;56(2):189-218.
18. ClinicalTrials.gov. Velcade. Available at https://clinicaltrials.gov/ct2/results?cond=&term=velcade&cntry=&state=&city=&dist=. Accessed April 28, 2019
Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
CPT*
HCPCS
J9041
J9044
* CPT only copyright 2019 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
_________________________________________________________________________________________
Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.
The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
____________________________________________________________________________________________________________________________ |