1. Aetna considers Velcade (bortezomib) medically necessary for treatment of persons with progressive solitary plasmacytoma or multiple myeloma.

2. Aetna considers bortezomib medically necessary for treatment of systemic light-chain amyloidosis.

3. Aetna considers bortezomib medically necessary for treatment of Waldenström's macroglobulinemia.

4. Aetna considers bortezomib medically necessary as the second-line treatment of persons with mantle cell lymphoma.

5. Aetna considers bortezomib medically necessary as the second-line treatment of persons with relapsed or refractory peripheral T-cell lymphoma who are not candidates for high-dose chemotherapy and autologous stem cell transplantation.

6. Aetna considers bortezomib experimental and investigational for all other indications, including the following:
   1. As monotherapy or in combination with other chemotherapeutics for the treatment of other hematological malignancies (e.g., Hodgkin's disease,  diffuse large B-cell lymphoma, myelodysplasia, chronic lymphocytic leukemia, and chronic myeloid leukemia), solid tumors (e.g., breast cancer, colon cancer, ovarian cancer, pancreatic cancer, renal carcinoma, head and neck cancer, metastatic melanoma (lung), non-small cell lung cancer, and androgen-dependent prostate cancer), neuroendocrine tumors (e.g., carcinoid or islet cell tumors), or sarcoma; or

   2. For the treatment of HIV infection and immunological/inflammatory conditions (e.g., reperfusion injury, multiple sclerosis, arthritis, and asthma).

   3. For the treatment of kidney transplant rejection.

See also CPB 404 - Interferons, CPB 497 - High Dose Chemotherapy Bone Marrow or Peripheral Stem Cell Transplant for Multiple Myeloma, CPB 524 - Zoledronic Acid, CPB 634 - Non-myeloablative Bone Marrow/Peripheral Stem Cell Transplantation (Mini-Allograft / Reduced Intensity Conditioning Transplant), and CPB 672 - Pamidronate (Aredia).

The proteasome, a multi-catalytic protease present in all eukaryotic cells, plays an important role in the regulation of cell cycle, neoplastic growth, and metastasis.  Proteasome inhibitors specifically induce apoptosis in cancer cells, but most proteasome inhibitors are not suitable for clinical development.  Velcade (bortezomib), a specific, selective inhibitor of the 26S proteasome, is a novel dipeptide boronic acid that is the first proteasome inhibitor to have progressed to clinical trials.  A unique feature of bortezomib involves the inhibition of nuclear factor (NF)-kappaB activation through stabilization of the inhibitor protein IkappaB.  Pre-clinical studies have demonstrated that through the prevention of IkappaB degradation, bortezomib may block chemotherapy-induced NF-kappaB activation and augment the apoptotic response to chemotherapeutic agents.  NF-kappaB is a transcription factor that increases the production of growth factors (e.g., interleukin-6), cell-adhesion molecules, and anti-apoptotic factors, all of which contribute to the growth of the tumor cell and/or protection from apoptosis.  In addition, bortezomib appears to enhance the stabilization of p21 and p27, as well as transcription factor p53. 

In pre-clinical models of breast, lung, pancreatic, and ovarian tumor types, bortezomib inhibited tumor growth and showed anti-angiogenic properties.  Bortezomib exhibited the greatest activity when combined with standard chemotherapeutic agents, such as irinotecan, gemcitabine, and docetaxel, suggesting its potential additive/synergistic role in overcoming resistance to conventional chemotherapy.  Evidence from early clinical trials suggested that bortezomib can be given at pharmacologically active doses in combination with standard doses of chemotherapy with manageable toxicities.  Responses have been seen and no evidence of additive toxicity has been exhibited in combination agent trials.

Bortezomib was initially approved as a third-line treatment of relapsed and refractory multiple myeloma (MM) by the FDA under the accelerated approval program. The FDA evaluated the safety and effectiveness of bortezomib based on a study of 202 patients with relapsed and refractory MM who had received at least two prior therapies and showed disease progression on their most recent therapy (the SUMMIT trial).  Bortezomib was administered intravenously at 1.3 mg/m2/dose twice-weekly for 2 weeks, followed by a 10-day rest period (21-day treatment cycle) for a maximum of 8 treatment cycles.  In the study population, the median number of previous therapies was six, and 64% of patients had received stem cell transplant or other high dose therapy.  Results (Blade criteria -- a rigorous assessment standard used to describe changes in disease status, including a confirmation 6 weeks later) in the 188 eligible and evaluable subjects included complete response (CR) in 5 patients, for a CR rate of 2.7% (95 CI: 1%, 6%); partial responses (PR) occurred in 47 patients for a PR rate of 25% (95 CI: 19%, 32%).  Clinical remissions by SWOG criteria were observed in 17.6% of patients (95CI: 12%, 24%).  The response lasted a median time of 1 year. 

Another trial in 54 subjects with relapsed MM (the CREST trial) showed similar responses.  Patients were randomized to receive either 1.0 mg/m2 or 1.3 mg/m2 of bortezomib for Injection therapy for up to 24 weeks (days 1, 4, 8 and 11 of a 21-day cycle, for up to eight cycles).  For patients in the 1.3 mg/m2 treatment group, the overall response (defined as the combined total of complete and partial remissions and minimal responses) was 69%.  For patients in the 1.0 mg/m2 treatment group, the overall response was 59%.  The overall median time to progression was 11 months.

The U.S. Food and Drug Administration (FDA) approved a supplemental New Drug Application (sNDA) for Velcade, which expands the label to include the treatment of patients with MM who have received at least one prior therapy. The approval was based on data from the randomized phase III APEX study that compared single-agent bortezomib to high-dose dexamethasone in 669 patients with relapsed MM who had received one to three prior therapies (Richardson, et al., 2005). The study demonstrated a significant survival advantage with bortezomib in patients with MM who had received one to three prior therapies. The combined complete and partial response rates were 38% for bortezomib and 18% for dexamethasone (p < 0.001), and the complete response rates were 6% and less than 1%, respectively (p < 0.001). 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, 0.55; p < 0.001). The one-year survival rate was 80% among patients taking bortezomib and 66% among patients taking dexamethasone (p = 0.003), and the hazard ratio for overall survival with bortezomib was 0.57 (p = 0.001). Grade 3 or 4 adverse events were reported in 75% of patients treated with bortezomib and in 60% of those treated with dexamethasone.

Mantle cell lymphoma (MCL) is a lymphoma that is refractory to most current chemotherapy regimens.  Several clinical studies have demonstrated that bortezomib has clinical effects on MCL.  Lenz, et al. (2004) stated that new therapeutic strategies such as radioactively labeled antibodies or molecular targeting agents (e.g. bortezomib or flavopiridol) are urgently warranted to further improve the clinical outcome of MCL.  The NCCN guidelines (2004) also recommend bortezomib as a second-line treatment of MCL.  According to the NCCN, first line treatment of mantle cell lymphoma includes rituximab plus combination chemotherapy (e.g., hyperCVAD, CHOP, EPOCH).

Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of generally aggressive neoplasms, which constitute less than 15% of all non-Hodgkin's lymphomas (NHLs) in adults.  For the myriad forms of aggressive peripheral T-cell lymphomas, treatment approaches similar to those used for B-cell lymphomas have been used for patients with either localized or advanced stage disease, with autologous hematopoietic cell transplantation utilized in selected patients.  Phase II studies of bortezomib showed encouraging results in B-cell lymphomas (Goy, 2005; O'Connor, 2005).  In addition, NCCN guidelines (2008) recommend bortezomib as second-line therapy for relapsed or refractory peripheral T-cell lymphoma in persons who are not candidates for high-dose chemotherapy and autologous stem cell rescue.   A multi-center phase II trial of bortezomib combined with a standard chemotherapy regimen in the treatment of previously untreated individuals with peripheral T-cell lymphoma is currently ongoing.

Bortezomib is administered intravenously (bolus) at a dose of 1.3 mg/m2 twice a week for two weeks, followed by a 10-day rest period.  At least 3 days should elapse between consecutive doses of bortezomib.  The most common side effects associated with bortezomib include nausea, fatigue, diarrhea, constipation, headache, decreased appetite, decreased platelets and red blood cells, fever, vomiting, and peripheral neuropathy (numbness and tingling, and occasionally pain in the extremities).  Bortezomib should be interrupted for any grade-3 non-hematological (excluding neuropathy) or grade-4 hematological toxicity.

In a phase II clinical trial (n = 27), Markovic, et al. (2005) reported that single-agent bortezomib, administered twice weekly for 2 of every 3 weeks at a dose of 1.5 mg/m2, was not found to be effective in the treatment of patients with metastatic melanoma.

In a multi-center phase II study (n = 21), Maki, et al. (2005) stated that bortezomib has minimal activity in soft tissue sarcoma as a single agent.  These researchers concluded that if studied further in sarcomas, bortezomib should be investigated in combination with agents with demonstrated pre-clinical synergy.  In another phase II clinical (n = 16), Shah, et al. (2005) found that despite achieving the surrogate biologic end point, single-agent bortezomib did not induce any objective responses in patients with metastatic carcinoid or islet cell tumors.

Dimopoulos, et al. (2005) noted that bortezomib is a selective proteasome inhibitor which has shown significant activity in a variety of hematologic malignancies including multiple myeloma, mantle cell lymphoma and marginal zone lymphoma.  Thus, this agent is worth studying in patients with Waldenstrom's macroglobulinemia (WM).  Patients with refractory or relapsed WM were treated with bortezomib administered intravenously at a dose of 1.3 mg/m2 on days 1, 4, 8 and 11 in a 21-day cycle for a total of four cycles.  A total of 10 previously treated patients with WM were treated with bortezomib.  Most patients had been exposed to all active agents for WM and 8 patients had received three or more regimens.  Six of these patients achieved a partial response which occurred at a median of 1 month.  The median time to progression in the responding patients is expected to exceed 11 months.  Bortezomib was relatively well-tolerated.  The more common toxicities were mild or moderate thrombocytopenia, fever and fatigue while peripheral neuropathy occurred in 3 patients and 1 patient developed severe paralytic ileus.  The authors concluded that these preliminary data indicated that bortezomib is an active agent in patients with heavily pretreated relapsed/refractory WM.  Four cycles of this agent may be adequate to assess sensitivity in this disease.  They noted that further studies are needed to confirm their results and to evaluate combinations of bortezomib with other active agents.

In a phase II clinical study, Chen, et al. (2007) evaluated the effectiveness and toxicity of single-agent bortezomib in WM.  Symptomatic patients, untreated or previously treated, received bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, and 11 on a 21-day cycle until two cycles past complete response (CR), stable disease (SD) attained, progression (PD), or unacceptable toxicity.  Responses were based on both para-protein levels and bi-dimensional disease measurements.  A total of 27 patients were enrolled.  A median of six cycles (range of 2 to 39) of bortezomib were administered.  Twenty-one patients had a decrease in immunoglobulin M (IgM) of at least 25 %, with 12 patients (44 %) reaching at least 50 % IgM reduction.  Using both IgM and bi-dimensional criteria, responses included 7 partial responses (PRs; 26 %), 19 SDs (70 %), and 1 PD (4 %).  Total response rate was 26 %.  IgM reductions were prompt, with nodal responses lagging.  Hemoglobin levels increased by at least 10 g/L in 18 patients (66 %).  Most non-hematological toxicities were grade 1 to 2, but 20 patients (74 %) developed new or worsening peripheral neuropathy (5 patients with grade 3, no grade 4), a common cause for dose reduction.  Onset of neuropathy was within two to four cycles and reversible in the majority.  Hematological toxicities included grade 3 to 4 thrombocytopenia in 8 patients (29.6 %) and neutropenia in 5 (19 %).  Toxicity led to treatment discontinuation in 12 patients (44 %), most commonly because of neuropathy.  The authors concluded that bortezomib is effective in WM, but neurotoxicity can be dose limiting.  The slower response in nodal disease may require prolonged therapy, perhaps with a less intensive dosing schedule to avoid early discontinuation because of toxicity.  They stated that future studies of bortezomib in combination with other agents are warranted.  Furthermore, Vijay and Gertz (2007) noted that novel agents such as bortezomib, perifosine, atacicept, oblimersen sodium, and tositumomab show promise as rational targeted therapy for WM.

The published evidence for bortezomib in large B-cell lymphoma is limited to small uncontrolled studies.  Current guidelines from the NCCN (2008) and the National Cancer Institute (NCI, 2008) do not state that bortezomib is effective for diffuse large B-cell lymphoma (DLBCL).  Evidence-based guidelines from Cancer Care Ontario (Reece et al, 2006) reviewed the evidence for bortezomib in DLBCL and other NHLs; the guidelines stated that there is insufficient evidence to support the use of bortezomib outside of clinical trials in patients with NHL.

There is limited published evidence for the use of bortezomib for systemic light chain amyloidosis, consisting of 1 phase II clinical study (Kastritis et al, 2007), small case series (Wechalekar et al, 2008), and case reports (Borde et al, 2008).  NCCN's Drug and Biologics Compendium (2008) lists systemic light chain amyloidosis as an indication for bortzomib. However, NCCN guidelines (2009) indicate that this and other treatments for systemic light chain amyloidosis should be provided in the context of a clinical trial.

Kastritis and colleagues (2007) assessed the activity and feasibility of the combination of bortezomib and dexamethasone (BD) in patients with AL amyloidosis.  A total of 18 patients, including 7 who had relapsed or progressed after previous therapies were treated with BD; 11 (61 %) patients had 2 or more organs involved; kidneys and heart were affected in 14 and 15 patients, respectively.  The majority of patients had impaired performance status and high brain natriuretic peptide values; serum creatinine was elevated in 6 patients.  Among evaluable patients, 94 % had a hematological response and 44 % a hematological complete response, including all 5 patients who had not responded to prior high dose dexamethasone-based treatment and 1 patient under dialysis.  Five patients (28 %) had a response in at least 1 affected organ.  Hematological responses were rapid (median of 0.9 months) and median time to organ response was 4 months.  Neurotoxicity, fatigue, peripheral edema, constipation and exacerbation of postural hypotension were manageable although necessitated dose adjustment or treatment discontinuation in 11 patients.  The authors concluded that the combination of BD is feasible in patients with AL amyloidosis.  Patients achieve a rapid hematological response and toxicity can be managed with close follow-up and appropriate dose adjustment.  This treatment may be a valid option for patients with severe heart or kidney impairment.

Wechalekar et al (2008) reported preliminary observations on the effectiveness of bortezomib in 20 patients with primary (AL) amyloidosis whose clonal disease was active despite treatment with a median of 3 lines of prior chemotherapy, including a thalidomide combination in all cases.  Patients received a median of 3 (range of 1 to 6) cycles of bortezomib and 9 (45 %) patients received concurrent dexamethasone.  Three (15 %) patients achieved complete hematological responses, and a further 13 (65 %) achieved partial responses.  Fifteen (75 %) patients experienced some degree of toxicity, which in 8 (40 %) cases resulted in discontinuation of bortezomib.  The authors stated that bortezomib shows promise in the treatment of systemic AL amyloidosis.

Guidelines from the National Comprehensive Cancer Network indicates bortezomib as a single agent for primary treatment of symptomatic hyperviscosity in Waldenstrom's macroglobulinemia. Treon, et al. (2007) reported on an uncontrolled clinical study which found bortezomib as an active agent in relapsed and refractory Waldenstrom's macroglobulinemia. In this study, 27 patients with Waldenstrom's macroglobulinemia received up to eight cycles of bortezomib. All but one patient had relapsed/or refractory disease.  Following therapy, median serum IgM levels declined from 4,660 to 2,092 mg/dL (p < 0.0001). The overall response rate was 85%, with 10 and 13 patients achieving minor and major responses, respectively. The investigators reported that responses were prompt and occurred at median of 1.4 months. The median time to progression for all responding patients was 7.9 months. The most common grade III/IV toxicities were sensory neuropathies (22.2%), leukopenia (18.5%), neutropenia (14.8%), dizziness (11.1%), and thrombocytopenia (7.4%). The investigators observed that sensory neuropathies resolved or improved in nearly all patients following cessation of therapy.

Chen, et al. (2007) also found bortezomib an active agent in Waldenstrom's macroglobulinemia. In an uncontrolled clinical trial, symptomatic patients with Waldenstrom's macroglobulnemia (n = 27), untreated or previously treated, received bortezomib on a 21-day cycle until two cycles past complete response (CR), stable disease (SD) attained, progression (PD), or unacceptable toxicity. A median of six cycles (range, two to 39) of bortezomib were administered. The investigators reported that 21 patients had a decrease in immunoglobulin M (IgM) of at least 25%, with 12 patients (44%) reaching at least 50% IgM reduction. Using both IgM and bidimensional criteria, responses included seven partial responses (PRs; 26%), 19 SDs (70%), and one PD (4%). Total response rate was 26%. The investigators reported that IgM reductions were prompt, with nodal responses lagging. Hemoglobin levels increased by at least 10 g/L in 18 patients (66%). The investigators observed that most nonhematologic toxicities were grade 1 to 2, but 20 patients (74%) developed new or worsening peripheral neuropathy (five patients with grade 3, no grade 4), a common cause for dose reduction. Onset of neuropathy was within two to four cycles and reversible in the majority. Hematologic toxicities included grade 3 to 4 thrombocytopenia in eight patients (29.6%) and neutropenia in five (19%). Toxicity led to treatment discontinuation in 12 patients (44%), most commonly because of neuropathy.

Eom and associates (2009) performed a retrospective analysis of 69 patients with MM who received bortezomib-containing regimens (n = 30) or vincristine, doxorubicin and dexamethasone (VAD; n = 39) before collection of peripheral blood stem cells and autologous stem cell transplantation (ASCT). Objective response rate (at least a partial response) prior to ASCT was documented in 27 (90 %) of 30 and 31 (81.6 %) of evaluable 38 patients with bortezomib-containing regimens and VAD, respectively. The difference between the two groups was not significant (p = 0.494). However, the high-quality response rate with very good partial response (VGPR) or more in the bortezomib group was significantly higher compared with the VAD group (66.7 % versus 34.2 %, respectively, p = 0.006). The superiority of bortezomib-containing regimens in the high-quality response rate remained significant for only the newly diagnosed patients (n = 16, p = 0.008). The engraftment data as well as stem cell harvesting were comparable between the two groups. The major bortezomib-related toxicities were thrombocytopenias and peripheral neuropathies; toxicities of VAD were hematologic and infectious. After ASCT, the difference between the two groups did not reach the level of statistical significance with respect to progression-free survival and overall survival  (OS) (p = 0.498 and 0.835, respectively). The authors concluded that the results of this retrospective comparison of bortezomib-containing regimens with the VAD as induction treatment prior to ASCT for MM provided a demonstration of the superiority of bortezomib therapy in terms of achieving a high-quality response. However, survivals following ASCT did not differ according to the induction regimens.

In a single institution, phase II study, Uy and colleagues (2009) examined the role of bortezomib as induction therapy before ASCT and its role as maintenance therapy after ASCT for patients with MM. A total of 40 patients were given bortezomib sequentially pre-ASCT and as maintenance therapy post ASCT. Pre-transplant bortezomib was administered for 2 cycles followed by high-dose melphalan 200 mg/m(2) with ASCT of granulocyte colony stimulating factor-mobilized peripheral blood mononuclear cells. Post-transplant bortezomib was administered weekly for 5 out of 6 weeks for 6 cycles. No adverse effects were observed on stem cell mobilization or engraftment. An overall response rate of 83 % with a complete response + VGPR of 50 % was observed with this approach. Three-year Kaplan-Meier estimates of disease-free survival and OS were 38.2 % and 63.1%, respectively. Bortezomib reduced CD8(+) cytotoxic T cell and CD56(+) natural killer cell peripheral blood lymphocytes subsets and was clinically associated with high rates of viral reactivation to varicella zoster. The authors stated that interpretation of the role of bortezomib maintenance in myeloma based on this single study is limited because of the relatively small sample size and relatively short duration of maintenance therapy. They noted that larger prospective randomized studies of post transplant bortezomib are needed and are currently ongoing.

Perry et al (2009) noted that antibody production by normal plasma cells (PCs) against human leukocyte antigens (HLA) can be a major barrier to successful transplantation. These investigators tested 4 reagents with possible activity against PCs (rituximab, polyclonal rabbit anti-thymocyte globulin (rATG), intravenous immunoglobulin (IVIG) and the proteasome inhibitor, bortezomib) to determine their ability to cause apoptosis of human bone marrow-derived PCs and subsequently block IgG secretion in vitro. Rituximab, IVIG, and rATG all failed to cause apoptosis of PCs and neither rituximab nor rATG blocked antibody production. In contrast, bortezomib treatment led to PC apoptosis and thereby blocked anti-HLA and anti-tetanus IgG secretion in vitro. Two patients treated with bortezomib for humoral rejection after allogeneic kidney transplantation demonstrated a transient decrease in bone marrow PCs in vivo and persistent alterations in allo-antibody specificities. Total IgG levels were unchanged. The authors concluded that proteasome activity is important for PC longevity and its inhibition may lead to new techniques of controlling antibody production in vivo.

Everly et al (2009) described the biochemistry and physiology of proteasome inhibition and discussed recent studies with proteasome inhibitor therapy in organ transplantation. Traditional anti-humoral therapies do not deplete PCs. Proteasome inhibition depletes both transformed and non-transformed PCs in animal models and human transplant recipients. Bortezomib is a first in a class proteasome inhibitor that has been shown to effectively treat antibody-mediated rejection in kidney transplant recipients. In this experience, bortezomib provided reversal of histological changes and also induced a reduction in donor-specific anti-HLA antibody levels. Recent experiences have also shown that bortezomib reduces donor-specific anti-HLA antibody in the absence of rejection. Finally, evidence has been presented that bortezomib therapy depletes HLA-specific antibody producing PCs. The authors concluded that proteasome inhibition induces a complex series of biochemical events that results in pleiotropic effects on multiple cell populations, and PCs in particular. Initial clinical results have provided evidence that bortezomib effectively treats antibody-mediated rejection and acute cellular rejection and reduces or eliminates donor-specific anti-HLA antibody. They stated that carefully designed clinical trials are needed to accurately define the role of proteasome inhibition in transplant recipients.