Description

This document addresses the clinical uses of bortezomib (Velcade, Millennium/Takeda Oncology Co., Cambridge, MA), a reverse proteasome inhibitor drug that interferes with the growth of some cancer cells. Bortezomib is approved by the U.S. Food and Drug Administration (FDA) to treat multiple myeloma, mantle cell lymphoma, and is used as off-label treatment for other conditions.

Clinical Indications

Medically Necessary:

Bortezomib is considered medically necessary for the treatment of any of the following indications:

1. Multiple myeloma (MM).
2. Non-Hodgkin lymphoma (NHL):
   1. Mantle cell lymphoma (MCL); or
   2. Peripheral T-cell lymphomas (that is, peripheral T-cell lymphoma [PTCL], anaplastic large cell lymphoma [ALCL], or angioimmunoblastic T cell lymphoma [AITL]) as therapy for refractory or relapsed disease; or
   3. Waldenström's macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL).
3. Systemic light chain amyloidosis.
4. Other rare plasma cell dyscrasias requiring treatment, including but not limited to, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome.

Not Medically Necessary:

Bortezomib is considered not medically necessary when the medically necessary criteria are not met and for all other indications, including, but not limited to:

• Chronic lymphocytic lymphoma (CLL)
• Chronic myeloid leukemia (CML)
• Diffuse large B-cell lymphoma (DLBCL)
• Follicular lymphoma (FL)
• Gastric and non-gastric mucosa-associated lymphoid tissue (MALT) lymphoma
• Hodgkin lymphoma (HL)
• Mycosis fungoides/Sézary syndrome
• Myelodysplastic syndrome
• Neuroendocrine tumors (for example, carcinoid or islet cell tumors)
• Sarcoma (for example, osteosarcoma)
• Solid tumors (for example, biliary tract, colorectal, head and neck, metastatic melanoma (lung), non-small cell lung cancer [NSCLC], or pancreatic carcinoma)
• Solitary plasmacytoma

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS
J9041	Injection, bortezomib (Velcade), 0.1 mg
J9044	Injection, bortezomib, not otherwise specified, 0.1 mg [Note: code effective 01/01/2019]
ICD-10 Diagnosis
C83.10-C83.19	Mantle cell lymphoma
C84.40-C84.49	Peripheral T-cell lymphoma
C84.60-C84.69	Anaplastic large cell lymphoma, ALK-positive
C84.70-C84.79	Anaplastic large cell lymphoma, ALK-negative
C86.2	Enteropathy-type (intestinal) T-cell lymphoma
C86.5	Angioimmunoblastic T-cell lymphoma
C88.0	Waldenström macroglobulinemia
C90.00-C90.02	Multiple myeloma
D47.Z9	Other specified neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue
E85.81	Light chain (AL) amyloidosis
E88.09	Other disorders of plasma-protein metabolism, not elsewhere classified [when specified as POEMS syndrome]
Z85.72	Personal history of non-Hodgkin lymphomas
Z85.79	Personal history of other malignant neoplasms of lymphoid, hematopoietic and related tissues

Discussion/General Information

Bortezomib is a modified dipeptidyl boronic acid that acts as a reversible inhibitor of the chymotrypsin‐like activity of the 26S proteasome (a cluster of cell proteins) in mammalian cells. The 26S proteasome degrades ubiquitinated (heat stable) proteins responsible in regulating concentrations of specific proteins within cells, thus maintaining homeostasis (equilibrium) within cells. Inhibition of the 26S proteasome prevents this targeted breakdown of proteins, thereby affecting multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Bortezomib is FDA approved for the treatment of multiple myeloma and for individuals with mantle cell lymphoma (Velcade Product Information [PI] label, 2017). Specific National Comprehensive Cancer Network^® (NCCN^®) Clinical Practice Guidelines (CPG) in Oncology include off-FDA label 2A, 2B and 3 recommendations for use of bortezomib for other oncologic indications, including other types of non-Hodgkin lymphomas.

Multiple Myeloma

Multiple myeloma is a systemic malignancy of plasma cells that accumulate in the bone marrow, leading to destruction of bone and failure of the bone marrow. The American Cancer Society (ACS, 2018) has estimated 30,770 new cases of multiple myeloma in the United States in 2018, with an estimated 12,770 deaths. The disease is staged by estimating the myeloma tumor cell mass on the basis of the amount of monoclonal (or myeloma) protein (M-protein) in the serum and/or urine along with various clinical parameters, such as the hemoglobin and serum calcium concentrations, the number of lytic bone lesions, and the presence or absence of renal failure. The stage of the disease at presentation is a strong predictor of survival, but has little influence on the choice of therapy since almost all individuals (except for those with solitary bone tumors or extramedullary plasmacytomas) have generalized disease. The age and general health of the individual, prior therapy and the presence of complications of the disease influence treatment selection. Clinical response is transitory in all cases despite achievement of complete remission and apparent eradication of disease, and multiple myeloma is considered incurable with current approaches.

In May 2003, the FDA accelerated approval of bortezomib as third-line treatment of relapsed and refractory multiple myeloma based on an open-label, single-arm multicenter trial (SUMMIT) of 202 individuals who received at least two prior therapies and demonstrated disease progression on the last therapy (Richardson, 2003). A total of 188 participants were evaluated for response; the mean number of cycles administered was 6. The median time to response was 38 days (range 30 to 127 days) with an overall response rate (ORR) of 35% using the European Group for Blood and Marrow Transplantation (EBMT) criteria. The median survival of all participants was 16 months (range, <1 to 18+ months). The response rate was increased to 50% with the addition of dexamethasone on the day of and the day after each injection of bortezomib. Responses were independent of the type or number of previous treatments and chromosome-13 deletion status.

Similar results were demonstrated in the phase II, open-label CREST trial (n=54) where individuals with relapsed myeloma following a single line of therapy were randomized to receive either 1.0 mg/m² or 1.3 mg/m² of bortezomib for up to 24 weeks (up to 8 cycles) (Jagannath, 2004). The complete response (CR) plus partial response (PR) rate for bortezomib alone was 30% (90% confidence interval [CI], 15.7-47.1) and 38% (90% CI, 22.6-56.4) in the 1.0 mg/m² (8 of 27 participants) and 1.3 mg/m² (10 of 26 participants) groups respectively. The CR plus PR rate for participants who received bortezomib alone or in combination with dexamethasone was 37% and 50% for the 1.0 and 1.3 mg/m² cohorts, respectively. The most common grade 3 adverse events were thrombocytopenia (24%), neutropenia (17%), lymphopenia (11%) and peripheral neuropathy (9%). Grade 4 events were observed in 9% (5 of 54 participants).

In March 2005, the FDA approved bortezomib for the treatment of individuals with multiple myeloma who received at least one prior therapy (Richardson, 2005). The APEX study was a randomized phase III trial that compared single-agent bortezomib to high-dose dexamethasone in 699 individuals with multiple myeloma who had relapsed after one or more therapies. Participants who were randomized to receive dexamethasone were permitted to cross over to receive bortezomib in a companion study after disease progression. The results showed a significant survival benefit in the bortezomib group with combined CR and PR rates of 38% in the bortezomib arm versus 18% with dexamethasone alone (p<0.001) and a longer time to progression (the primary endpoint). Median times to progression in the bortezomib and dexamethasone groups were 6.22 months (189 days) and 3.49 months (106 days), respectively (hazard ratio [HR], 0.55; p<0.001). The 1-year survival rate was 80% and 66% among participants taking bortezomib or dexamethasone, respectively (p=0.003). Grade 3 or 4 adverse events were reported in 75% of participants treated with bortezomib and in 60% of those treated with dexamethasone.

In 2008, the FDA approved bortezomib for individuals with previously untreated multiple myeloma (Jagannath, 2005; Jagannath, 2009). In 2014, the FDA granted supplemental approval of bortezomib for treatment of individuals who had previously responded to bortezomib therapy and who relapsed at least 6 months after completing prior treatment with bortezomib. The updated FDA label includes dosing guidelines as well as safety and effectiveness findings for the use of bortezomib given as a single agent or in combination with dexamethasone in individuals previously treated with bortezomib. Retreatment with bortezomib may be started at the last tolerated dose. The FDA approval was based on supportive data and the phase II single-arm, open-label international RETRIEVE trial that enrolled 130 participants ages 18 years of age and older who had previously responded to bortezomib therapy and relapsed at least 6 months after prior treatment with bortezomib. The study met its primary endpoint of best confirmed response to retreatment as assessed by EBMT criteria. Dexamethasone was administered in combination with bortezomib in 94 participants. Of the 130 participants who received a median of two prior therapies, 1 participant achieved CR and 49 achieved PR (50 of 130; ORR, 38.5%). The median duration of response was 6.5 months (range, 0.6 to 19.3 months). The safety profile seen with bortezomib retreatment was consistent with the known safety profile of intravenous bortezomib in relapsed multiple myeloma. No cumulative toxicities were observed upon retreatment. The most common adverse drug reaction was thrombocytopenia, which occurred in 52% of the participants (grade >3, 24%). Peripheral neuropathy occurred in 28% of participants (grade >3, 6%). Serious adverse reactions included thrombocytopenia (3.8%), diarrhea (2.3%), herpes zoster and pneumonia (each, 1.5%). Adverse reactions leading to discontinuation occurred in 13% of the study participants.

Non-Hodgkin Lymphomas (NHL)

NHL is a diverse group of more than a dozen different lymphoproliferative neoplasms, that is, cancers of the lymphatic system which generates the body's immune defenses. This system includes a network of channels akin to blood vessels through which lymphocytes, important white blood cells of the immune system, patrol the body for invading microbes. Along these lymphatic routes in the neck, armpits, abdomen, and groin are clusters of bean-shaped lymph nodes that house groups of infection-fighting lymphocytes. These cells also cluster in areas that serve as gateways to the body, including the mucous membranes lining the respiratory and digestive tracts, and the skin. Lymphocytes travel in the bloodstream, as well. The lymphatic system also includes such organs as the spleen, thymus and tonsils. Symptoms often include lymph nodes that are larger than normal, fever, and weight loss.  NHL can occur at any age, typically affects an older population, and is the sixth most deadly form of cancer.

According to the National Cancer Institute (NCI, 2018), NHL consists of a heterogeneous group of lymphoproliferative malignancies, divided into aggressive (fast-growing) and indolent (slow-growing) types, and can be formed from either B-cells or T-cells. B-cell non-Hodgkin lymphomas include Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma (MCL). T-cell NHL includes mycosis fungoides (MF), anaplastic large cell lymphoma (ALCL), and precursor T-lymphoblastic lymphoma. Prognosis and treatment depend on the stage and type of disease (NCI, 2018).

Mantle Cell Lymphoma (MCL)

MCL is aggressive form of NHL with a median survival of 4 to 5 years. Standard therapy in the previously untreated consists of aggressive chemotherapy and stem–cell transplantation. For those ineligible for that therapy, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard of care (Robak, 2015).

The 2006 FDA approval of bortezomib was based on data from the pivotal multicenter phase II PINNACLE trial where single-agent bortezomib was used to treat individuals with relapsed or refractory MCL (n=155; 141 evaluable participants) (Fisher, 2006; O’Connor, 2009). Bortezomib induced an ORR of 33% (CR in 8%) with a median duration of response of 9 months. Median time to progression (in all participants) was 6 months. Longer follow-up data also confirmed these initial findings. After a median follow-up time of 26 months, the median OS in all participants was 23.5 months and 35 months in responders (Goy, 2009). Response rates and clinical activity in MCL lymphoma are reported as highest with administration of bortezomib as a single agent (Gerecitano, 2009).

In October 2014, the FDA approved bortezomib for use in adults with previously untreated (treatment-naive) MCL based on the results of an international, randomized, open-label, phase III study of 487 participants who were ineligible or not considered for bone marrow transplantation. Participants randomized to receive bortezomib in combination with rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) experienced a 59% relative improvement in the trial’s primary endpoint of progression-free survival (PFS) (median follow-up, 40 months) compared to those administered the standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) regimen. The majority of participants in both groups received 6 or more cycles of treatment. The CR rate for individuals receiving a VcR-CAP versus R-CHOP regimen was 44% and 34%, respectively. Thrombocytopenia (≥ grade 4) occurred in 32% of the VcR-CAP arm versus 1% of the R-CHOP arm; platelet transfusions were administered to 23% and 3% of the participants in the VcR-CAP arm and the RCHOP arm, respectively. Other side effects included neutropenia (≥ grade 4) in 70% of the VcR-CAP arm and 52% in the R-CHOP arm. Myeloid growth factor support was provided at a rate of 78% in the VcR-CAP arm and 61% in the R-CHOP arm (Velcade PI label, 2017).

Bortezomib combined with rituximab has been evaluated in several small studies in heavily pretreated individuals with relapsed or refractory MCL (Lamm, 2011). In a small multicenter phase II study, Friedberg and colleagues (2011) evaluated the combination of bendamustine and rituximab with bortezomib in individuals with relapsed or refractory indolent lymphomas or MCL. In 29 evaluable participants, the ORR was 83% (52% CR) and the 2-year PFS rate was 47% in 7 participants with MCL histology. The ORR among this small subgroup with MCL was 71%. Multiple randomized clinical trials are currently underway evaluating the use of bortezomib as a single agent or in combination.

Other non-Hodgkin lymphomas

Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphoproliferative disorders arising from mature T-cells of post-thymic origin (Savage, 2007). According to the NCCN CPG for T-cell Lymphomas (2018), PTCL-NOS represents a relatively uncommon group of hematologic malignancies within NHL, accounting for about 6% of NHL cases. The prognosis for PTCL remains poor in comparison to B-cell NHL, due largely to lower response rates and less durable responses to standard combination chemotherapy regimens such as CHOP.

Evidence in the peer-reviewed published medical literature for use of bortezomib in PTCL consists of single case studies and small phase I/II clinical trials (Evens, 2013; Zinzani, 2007). The NCCN CPG for T-cell Lymphomas (V.5.2018) includes a 2B for the off-label use of bortezomib as second-line therapy (non-transplant candidates) for treatment of PTCL-NOS. NCCN notes that while efficacy has been demonstrated in smaller trials, larger clinical trials are needed.

Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma

Lymphoplasmacytic lymphoma (LPL) is an indolent lymphoproliferative disease also known as Waldenström’s macroglobulinemia (WM). According to the NCI (2018), most individuals have bone marrow, lymph node, and splenic involvement, and some individuals may develop hyperviscosity syndrome. The monoclonal serum paraprotein immunoglobulin M (IgM) gammopathy is typically associated with WM. Treatment of acute symptoms usually includes plasmapheresis. Long-term management of individuals with serum viscosity of ≤ 4 is typically managed with chemotherapeutic agents.

Bortezomib has shown to have high levels of activity in the management of WM/LPL as a single agent (Chen, 2007), in combination with rituximab (Ghobrial, 2010), in combination with rituximab and dexamethasone (Chen, 2009; Treon, 2009), or as salvage therapy for disease that does not respond to primary therapy. The NCCN CPG (V.2.2019) for WM/LPL includes a 2A recommendation for use of bortezomib with or without rituximab, bortezomib with dexamethasone, or bortezomib with dexamethasone and rituximab as suggested treatment regimens for non-stem cell toxic (stem cell sparing) in primary therapy or in previous treated disease. In a small phase II uncontrolled clinical trial (Chen, 2007), 27 participants with WM were administered bortezomib (44% were previously untreated; 56% were previously treated) using the standard schedule until they demonstrated progressive disease or were 2 cycles beyond best response. The ORR was 78%, with major responses observed in 44% of participants. Adverse events such as sensory neuropathy occurred in 20 participants after 2 to 4 cycles of therapy with resolution of symptoms in 14 participants, and improvement by one grade in 1 participant at 2 to 13 months. Additional study of bortezomib in combination with other agents is ongoing to determine optimal dosing schedules and when to avoid early discontinuation of therapy because of toxicity.

The consensus panels of the International Workshops on WM (IWWM) have updated treatment recommendations for individuals with WM (Dimopoulos, 2014) stating bortezomib-rituximab combinations may be considered a primary option for individuals with specific high-risk features (that is, hyperviscosity) or in younger individuals for whom avoidance of alkylator therapy is sought. The consensus recommendations state:

Single agent bortezomib is associated with responses in approximately (~) 40% of patients with relapsed or refractory WM, including fludarabine and rituximab refractory patients. Bortezomib with rituximab (±dexamethasone) are active, and in the front-line setting, 3 phase 2 studies of bortezomib/rituximab combinations showed response rates (at least PR) between 66% and 83% and rapid times to first response (2-3 months) (Dimopoulos, 2013; Ghobrial, 2010; Treon, 2009)…Bortezomib is not stem cell toxic, and long-term follow-up in myeloma patients does not suggest a risk for secondary malignancies. Prophylaxis against herpes zoster is strongly recommended. Primary therapy with bortezomib is recommended for patients with high levels of IgM, with symptoms of, or at risk of developing, hyperviscosity syndrome, symptomatic cryoglobulinemia or cold agglutinemia, amyloidosis, and renal impairment.

Systemic Light Chain Amyloidosis

Light chain amyloidosis is the most common form of systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. The disease is difficult to recognize because of its broad range of manifestations and what often are vague symptoms. Primary systemic light chain amyloidosis is typically characterized by decreased numbers of monoclonal plasma cells in the bone marrow compared to multiple myeloma; however, the protein produced by these plasma cells has an affinity for visceral organs (such as kidney, heart, liver, and spleen) and this protein causes related end-organ dysfunction. Survival with this disease is often poor due to the end-organ damage by the amyloid protein. Current treatment strategies include systemic therapy to destroy the plasma cells responsible for the synthesis of immunoglobulin light chain.

Bortezomib is rapidly active in systemic light chain amyloidosis with high rates of hematologic and organ responses. The current NCCN CPG (V.1.2018) lists the off-label use of bortezomib with or without dexamethasone as a therapeutic consideration in the management of individuals with untreated and relapsed systemic light chain amyloidosis. This recommendation is based on 2A category of evidence and uniform consensus. According to the NCCN CPG, all individuals should be treated in the context of a clinical trial when possible. The available peer-reviewed literature reports favorable response rates including a data from the National Amyloidosis Center (Britain) (Wechalekar, 2008), a multicenter phase I/II dose-escalation study (Reece, 2009; Reece, 2011), a small study of individuals who had relapsed or progressed on prior therapies (Kastritis, 2007) and data from three international centers from 94 individuals (18 previously untreated) treated with bortezomib that reported a 71% overall response rate (67 out of 93 individuals) with CR in 25% (47% CR in previously untreated individuals) (Kastritis, 2010).

The use of bortezomib for systemic light chain amyloidosis has also been evaluated in combination with melphalan and dexamethasone or cyclophosphamide and dexamethasone in two small independent studies (Mikhael, 2012; Venner, 2012).

Other Rare Plasma Cell Dyscrasias including POEMS Syndrome

POEMS syndrome, also known as Takatsuki syndrome or osteosclerotic myeloma, is a rare paraneoplastic syndrome that occurs in the setting of a plasma cell dyscrasia with features that include polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Other important characteristics of POEMS syndrome include ascites, papilledema, extravascular volume overload, pleural effusions, sclerotic bone lesions, and thrombocytosis/erythrocytosis. The pathophysiology of POEMS syndrome is not well understood, but it may be related to changes in the levels of a cytokine or an overproduction of vascular endothelial growth factor (VEGF), probably secreted by clonal plasma cells. Therapeutic options for the treatment of POEMS have included use of alkylators and steroids, high-dose chemotherapy with autologous peripheral blood stem cell transplantation, lenalidomide, and bortezomib. The use of bortezomib in the treatment of POEMS syndrome has been evaluated in single and small case series; however, the benefit of bortezomib needs to be weighed against the risk of exacerbating any existing peripheral neuropathy (Dispenzieri, 2014; Ishii, 2013; Li, 2013).

Kidney Transplantation

Approximately 15% of all individuals awaiting a deceased donor kidney transplant are sensitized to human leukocyte antigen (HLA) because of pregnancy, blood transfusion or previous graft (Lemy, 2010). These preformed anti-HLA antibodies are associated with a higher risk of antibody-mediated rejection (AMR) and decreased graft survival, especially when these antibodies are donor-specific, strongly positive or related to a remote positive complement-dependent cytotoxicity (CDC) XM (Lemy, 2010). Bortezomib works by inducing the apoptosis of antibody-producing plasma cells thereby reducing the number of antibodies (Lee, 2015). Prior to 2010, studies evaluating bortezomib as a potential treatment in the reversal of acute rejection or to decrease anti-HLA antibodies were limited to cases series. Recently additional studies have reported some promising results in amongst several groups either awaiting transplantation or experiencing antibody-mediated rejection (Ejaz, 2013; Jeong, 2016; Lee, 2015, Woodle, 2015). However, these have been small early non-randomized trials and further large-scale randomized trials are needed to confirm these early results and to define which populations might benefit from the bortezomib therapy. The Renal Society clinical practice guidelines on the post-operative care of kidney transplant recipient (2017) includes a 2C recommendation on the use of bortezomib to treat antibody mediated rejection (AMR). This recommendation was based on conflicting low quality trials and small non-randomized studies and case reports.

Other Proposed Uses of Bortezomib

Adult T cell leukemia/lymphoma (ATLL) is a rare form of PTCL which comprises approximately 2% or less of all confirmed cases in the US. ATLL can result following a distant exposure to the human T-cell lymphotropic virus type 1 (HTLV-1). In a phase 1/2 study (Ratner, 2016), 36 individuals were treated with dose-adjusted infusional chemotherapy (DA-EPOCH) with bortezomib and raltegravir added on the second cycle. The response rate was similar to the rates reported in a previous DA-EPOCH trial which did not include bortezomib and raltegravir. The authors noted that while the response rates were short-lived, bortezomib could serve as a bridge to allogeneic stem cell transplantation which could lead to longer lived responses. Ishitsuka and colleagues (2015) reported on a phase 2, single arm study which evaluated the efficacy and safety of bortezomib monotherapy in individuals with relapsed or refractory ATLL. A total of 15 individuals received bortezomib in the initial stage of the study. At the completion of the initial stage, all individuals had discontinued treatment due to progression, adverse effects or anxiety. The study was terminated because single activity did not appear to be promising in this patient population. The NCCN has given a 2A recommendation for bortezomib to treat ATLL as a second line therapy when there is intention to proceed to high-dose therapy or allogeneic stem cell rescue or as a subsequent therapy in individuals with acute or lymphoma subtypes who are non-responders to first line therapy.

Multicentric Castleman disease (MCD) is a rare, lymphoproliferative disorder. Unlike unicentric CD, which is limited to a single group of lymph nodes, MCD affects more than one group of lymph nodes and can involve other areas of the body containing lymphoid tissue. While MCD is not considered cancer, disease symptoms and progression mimic cancer and leads to an increased risk of the development of lymphoma. MCD is prevalent in those with a human immunodeficiency virus (HIV) infection. The NCCN CPG for B-cell lymphomas (V.5.2018) lists the off-label use of bortezomib as a single agent or in combination therapy with rituximab as a therapeutic consideration in the management of MCD that has progressed following treatment of refractory or progressive disease as a 2A recommendation. Additional evidence regarding the use of bortezomib to treat MCD is limited to single case studies (Hess, 2006; Khan, 2012; Sorbas, 2010; Yuan, 2009).

The peer-reviewed published medical literature includes studies of off-label use of bortezomib as a single agent or in combination with other chemotherapy regimens for the following conditions (not an all-inclusive list): advanced solid tumors (Lieu, 2009; Papandreou, 2004; Ramaswamy, 2010), treatment-naïve (Kim, 2012) or relapsed or refractory DLBCL (Dunleavy, 2009; Elstrom, 2012; Goy, 2005; O’Connor, 2005; Ribrag, 2009; Zinzani, 2013), biliary tract carcinomas (Denlinger, 2014), metastatic neuroendocrine (carcinoid or islet cell) tumors (Shah, 2005), metastatic malignant melanoma (Markovic, 2005), NSCLC (Besse, 2012; Edelman, 2010; Li, 2010; Lilenbaum, 2009; Scagliotti, 2010), recurrent or metastatic adenoid cystic or squamous cell head and neck carcinoma (Argiris, 2010; Chung, 2010), recurrent ovarian or primary peritoneal cancer (Aghajanian, 2005), relapsed or refractory MALT lymphoma (Conconi, 2011; Troch, 2009), solitary plasmacytoma (Katodritou, 2014), soft tissue sarcomas (recurrent or metastatic) (Maki, 2005), and relapsed, refractory, or secondary pediatric acute myeloid leukemia (AML) (Horton 2014). The published literature consists of case reports, small case series, observational studies, and randomized and nonrandomized uncontrolled Phase I/II trials. In numerous studies, use of bortezomib was withdrawn due to high rates of adverse events or grade 3 or 4 toxicities, including cardiac or hematologic events (for example, thrombocytopenia, lymphopenia, neutropenia), pneumonia, peripheral neuropathy, and other neurotoxicities. At this time, the evidence to support the use of bortezomib is limited and precludes drawing reliable conclusions on its safety and clinical utility to improve health outcomes for individuals with any of these conditions. To date, the FDA has not approved bortezomib for use in any of these indications.

Huang and colleagues (2014) completed a meta-analysis on 32 studies on the use of bortezomib to treat solid tumors. Bortezomib was used as a monotherapy in 15 of the studies and in the remainder added bortezomib to other anti-tumor drugs. A total of 18 types of cancer were represented within the studies including, renal cell, lung, melanoma, colorectal, gastric, esophageal, gastroesophageal junction adenocarcinoma, prostate, breast, thyroid, sarcomas, urothelial carcinoma, neuroendocrine tumor, malignant pleural mesothelioma, hepatocellular carcinoma, head and neck squamous cell carcinoma, glioblastoma, pancreatic, and ovarian. The majority of subjects had recurrent or metastatic cancer and had failed previous treatments. Overall, in those studies with bortezomib as a monotherapy, the results did not support that bortezomib showed adequate anti-tumor activity in solid tumors to justify use. As an additive therapy, bortezomib did not appear to improve the therapeutic response and may increase the toxicity.

The use of bortezomib as second-line systemic therapy regimen in the treatment of MF and Sézary syndrome was added as a category 3 recommendation in the NCCN CPG T-Cell in 2016. In addition, bortezomib has been studied for previously untreated FL and low-grade B-cell lymphomas (Sehn, 2011; Sinha, 2012) and indolent B-cell lymphoma that has relapsed or was refractory to rituximab (Di Bella, 2010). In the latter study, the authors concluded that bortezomib had modest activity against marginal zone and FL. In a phase II multicenter trial where bortezomib was evaluated in pretreated individuals with subtypes of NHL (no more than 3 prior chemotherapies), for those with FL, the ORR after 2 cycles of bortezomib was 50% (9 of 18 subjects), with 4 subjects experiencing CR. The median time to treatment response for FL was 12 weeks, whereas the median time to treatment response for other subtypes of NHL was only 4 weeks (O’Connor, 2010). Other studies have evaluated the safety and effectiveness of bortezomib in combination therapy with rituximab or with bendamustine and rituximab for the treatment of relapsed or refractory FL (Coiffier, 2011; De Vos, 2009; Fowler, 2011). However, the current published evidence is insufficient to support the use of bortezomib for these non-FDA approved indications.

An evidenced-based guideline published by Cancer Care Ontario reviewed the evidence for bortezomib in the treatment of DLBCL and other NHLs. The guidelines state there is insufficient evidence to support the use of bortezomib outside of clinical trials in individuals with NHL (Reece, 2006).

As of 2014, the NCCN Drugs & Biologics Compendium no longer includes a recommendation for bortezomib for the treatment of gastric MALT lymphoma, non-gastric MALT lymphoma, and splenic marginal zone lymphoma.

Contraindications, Warnings and Precautions, Drug Interactions, and Use in Specific Populations

The FDA PI label (2017) for Velcade includes the following contraindications, warnings and precautions, drug interactions, and use in specific populations:

Contraindications

• Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions.
• Contraindicated for intrathecal administration.

  Warnings and Precautions

• Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with Velcade only after careful risk-benefit assessment.
• Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.
• Cardiac toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease.
• Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms.
• Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue Velcade if suspected.
• Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement.
• Thrombocytopenia or neutropenia: Monitor complete blood counts regularly throughout treatment.
• Tumor lysis syndrome: Closely monitor patients with high tumor burden.
• Hepatic toxicity: Monitor hepatic enzymes during treatment.
• Embryo-fetal risk: VELCADE can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to avoid pregnancy.

  Drug Interactions

• Co-administration with strong CYP3A4 inhibitors can increase Velcade exposure. Closely monitor patients receiving Velcade in combination with strong CYP3A4 inhibitors.
• Co-administration with strong CYP3A4 inducers can decrease Velcade exposure. Avoid concomitant use of strong CYP3A4 inducers.

  Use in Specific Populations

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

Definitions

Adjuvant therapy: Treatment given after the primary treatment to increase the chances of a cure; may include chemotherapy, radiation, hormone or biological therapy.

Complete response (CR): The disappearance of all signs of cancer as a result of treatment; also called complete remission; does not indicate the cancer has been cured.

Line of therapy:

• First-line therapy: The first or primary treatment for the diagnosis. This may include surgery, chemotherapy, radiation therapy or a combination of these therapies.
• Second-line therapy: Treatment given when initial treatment (first-line therapy) is not effective or there is disease progression.
• Third-line therapy: Treatment given when both initial (first-line therapy) and subsequent treatment (second-line therapy) are not effective or there is disease progression.

Maintenance therapy: Treatment given to help keep cancer from coming back after it has disappeared following the initial therapy.

Metastasis: A cancer that has spread from one part of the body to another; a metastatic tumor contain cells that are like those in the original (primary) tumor that has spread beyond the local lymph nodes.

Off-label: Utilization of an FDA approved drug for uses other than those listed in the FDA approved label.

Partial response (PR): A decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment; also called partial remission.

Progressive disease (PD): Cancer that is growing, spreading, or getting worse.

Relapse or recurrence: After a period of improvement, during which time a disease (for example, cancer) could not be detected, the return of signs and symptoms of illness or disease. For cancer, it may come back to the same place as the original (primary) tumor or to another place in the body.

Stable disease (SD): Cancer that is neither decreasing nor increasing in extent or severity.

References

Peer Reviewed Publications:

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Government Agency, Medical Society, and Other Authoritative Publications:

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3. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms. Available at: http://www.cancer.gov/publications/dictionaries/cancer-terms?CdrID=44756. Accessed on October 9, 2018.

Index

Reverse Proteasome Inhibitor

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.

History