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Introduction ⬇

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Bortezomib, an inhibitor of the 26S proteasome, is an antineoplastic agent.1,5

Uses ⬆ ⬇

[Section Outline]

Multiple Myeloma !!navigator!!

Previously Untreated Multiple Myeloma

Bortezomib is used in combination with melphalan and prednisone for the treatment of previously untreated multiple myeloma.1,20,24

The current indication for bortezomib in patients with previously untreated multiple myeloma is based principally on the results of a phase 3, open-label, randomized study (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone [VISTA]) involving 682 patients with newly diagnosed multiple myeloma who were considered ineligible (e.g., because of a coexisting medical condition, an age of 65 years or older) for high-dose chemotherapy followed by stem cell transplantation.1,20,24 Patients were assigned to receive either melphalan plus prednisone (MP) or bortezomib plus melphalan and prednisone (VMP).1,20,10001 Patients were stratified according to their baseline β2-microglobulin concentration (less than 2.5, 2.5-5.5, or above 5.5 mg/L), baseline serum albumin concentration (below 3.5 g/dL, equal to or above 3.5 g/dL), and the geographic region where they received treatment.1,20 The planned course of therapy for both regimens was 9 six-week courses for a total treatment duration of 54 weeks.1,20 Patients in the control group received melphalan 9 mg/m2 orally plus prednisone 60 mg/m2 orally (both administered once daily on days 1-4).20,10001 Patients in the study group received the same regimen of melphalan plus prednisone with the addition of bortezomib (1.3 mg/m2 by IV injection) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1-4; during cycles 5-9, bortezomib was administered on days 1, 8, 22, and 29.1,20

At the time of the initial interim analysis (median follow-up of 16.3 months), the complete response rates, defined by immunofixation negativity and using the European Group for Blood and Marrow Transplantation (EBMT) response criteria, were 30 and 4% for VMP and MP, respectively; rates for partial response or better (i.e., partial plus complete) were 69 and 34%, respectively.1,10001 Using the International Uniform Response criteria, rates for partial response or better (i.e., partial response plus very good partial response plus complete response) were 74 and 39%, respectively, for VMP and MP.20 The median time to disease progression (20.7 months versus 15 months) and median progression-free survival (18.3 versus 14 months) were prolonged with VMP compared with MP.1 This study was terminated prematurely at the request of the independent data monitoring committee because of improved time to disease progression, tumor response rate, and progression-free and overall survival observed during the initial prespecified interim analysis in patients receiving VMP.1,10001 Updated analysis of overall survival after a median follow-up of 36.7 months indicated a survival benefit (hazard ratio of 0.65) in patients receiving VMP despite subsequent therapies, including bortezomib-based regimens.1,24 After a median follow-up of 60.1 months, analysis of data also indicated that median overall survival was prolonged in patients receiving VMP compared with those receiving MP (56.4 versus 43.1 months, respectively; hazard ratio of 0.7).1,30 No important differences in the complete response rates, time to progression, or overall survival were reported for patients with impaired renal function (i.e., creatinine clearance less than 60 mL/minute) compared with patients with normal renal function in the VMP group.20,25,30 Similar complete response rates (28%), time to progression, and overall survival rates were reported for patients with high-risk cytogenetic features (e.g., t(4;14), t(14;16) translocation; a 17p or 13q deletion) receiving VMP compared with standard-risk patients.10001,20

Results from this study demonstrated superiority of the VMP regimen compared with the MP regimen for previously untreated patients ineligible for peripheral blood stem cell transplantation and for patients older than 65 years of age.1,20

Relapsed Multiple Myeloma

Bortezomib is used alone for the treatment of relapsed multiple myeloma in patients who have received at least one prior therapy, including those who previously responded to bortezomib-containing therapy and relapsed at least 6 months following completion of therapy.1,3,7,29

The current indication for bortezomib in patients with relapsed multiple myeloma is based principally on the results of a phase 3, randomized, open-label study involving 669 patients8 and several open-label studies in more than 250 patients with multiple myeloma.1,2

In the prospective phase 3 open-label study, random assignment of patients with progressive multiple myeloma was stratified according to number of lines of prior therapy (1 versus greater than 1 line), time of progression relative to prior treatment (during or within 6 months of stopping most recent therapy versus greater than 6 months following completion of most recent therapy), and screening β2-microglobulin concentration (2.5 mg/L or less versus greater than 2.5 mg/L).1 Exclusion criteria included disease refractory to prior therapy with high-dose dexamethasone, grade 2 or higher peripheral neuropathy at baseline, or platelet count less than 50,000/mm3.1,8 Treatment regimens consisted of either bortezomib or high-dose dexamethasone according to the following schedules: bortezomib (1.3 mg/m2 by IV bolus injection) administered in a 3-week standard treatment cycle (twice weekly for 2 weeks on days 1, 4, 8, and 11 followed by a 10-day rest period) for 8 cycles followed by 5-week maintenance treatment cycles (once weekly for 4 weeks on days 1, 8, 15, and 22 followed by a 13-day rest period) for 3 cycles; or dexamethasone (40 mg orally) administered in a 5-week standard treatment cycle (once daily on days 1-4, 9-12, and 17-20, followed by a 15-day rest period) for 4 cycles followed by 4-week maintenance treatment cycles (once daily on days 1-4 followed by a 24-day rest period) for 5 cycles.1,8 Patients experiencing progression of disease during dexamethasone therapy were offered enrollment in a companion study allowing crossover to bortezomib therapy.1,8 Bortezomib was administered for a maximum of 11 cycles (9 months).1 Responses and disease progression were assessed according to EBMT response criteria.1 A complete response was defined as less than 5% plasma cells in the bone marrow, 100% reduction in serum myeloma (M) protein, and a negative immunofixation test; a partial response was defined as reductions in myeloma protein concentrations of at least 50% in serum and at least 90% in urine on at least 2 occasions for a minimum of 6 weeks, and stable bone disease and normal serum calcium concentrations.1

At a planned interim analysis, the study was terminated early and patients receiving dexamethasone were offered therapy with bortezomib.1,8 At the time of early termination of the study, at a median follow-up of 8.3 months, prolonged median time to progression of disease (6.2 versus 3.5 months), prolonged survival (hazard ratio of 0.57), and higher response rates (complete plus partial responses) (38 versus 18%) were observed in patients receiving bortezomib compared with those receiving dexamethasone.1,8 Overall survival was prolonged in patients receiving bortezomib, both for those who had received one prior treatment (hazard ratio of 0.39) and for those who had received more than one prior treatment (hazard ratio of 0.65).1,8 The median duration of response was 8 months in patients receiving bortezomib and 5.6 months in patients receiving dexamethasone.1,8 A higher response rate was observed in patients receiving bortezomib regardless of baseline β2-microglobulin concentration.1 Limitations of the study that may have affected the outcome include previous corticosteroid therapy in most patients, higher dose intensity for bortezomib than dexamethasone, and the short period of follow-up.9 Patients receiving bortezomib experienced a greater frequency of grade 3 toxicity (61 versus 44%) than patients receiving dexamethasone.1,8

The primary phase 2 efficacy study4 enrolled 202 patients with multiple myeloma who had received at least 2 prior chemotherapy regimens and had experienced disease progression following the most recent regimen; patients in this study had received a median of 6 prior chemotherapy regimens, and 64% of patients had received prior stem cell transplantation or other high-dose therapy.4,18 Ninety-eight percent of enrolled patients received the standard 21-day regimen of bortezomib (1.3 mg/m2 by IV injection twice weekly for 2 weeks on days 1, 4, 8, and 11, followed by a 10-day rest period) with subsequent doses adjusted as needed if serious adverse effects occurred;4,18 patients exhibiting progressive disease after 2 cycles or stable disease after 4 cycles were eligible to receive oral dexamethasone (20 mg) on the day of and the day after each dose of bortezomib.4 A mean of 6 treatment cycles was administered.4,18

Using the EBMT response criteria, complete responses or partial responses were observed in 3 or 25%, respectively, of 188 evaluable patients receiving bortezomib.6,18 Clinical remission, as determined by the Southwest Oncology Group (SWOG) criteria (defined as reductions in serum M protein concentrations of at least 75% in serum and/or 90% in urine on at least 2 occasions for a minimum of at least 6 weeks, and stable bone disease and normal serum calcium concentrations), was observed in 18% of these patients.18 Among the 202 enrolled patients, the median time to first response was 38 days, and median survival was 17 months.18 In this study, response to bortezomib was not influenced by gender, type of myeloma, serum concentrations of β2-microglobulin, or number or types of prior chemotherapy treatments.4,18 However, the likelihood of attaining a response was reduced in patients with more than 50% plasma cells or abnormal cytogenetics in the bone marrow.4,18 Responses were observed in patients with or without chromosome 13 abnormalities.4,18

In a small dose-response phase 2 study in 54 patients with relapsed multiple myeloma, the overall response rate (complete plus partial responses) was approximately 30 or 38% in patients receiving bortezomib 1 or 1.3 mg/m2, respectively, by IV injection twice weekly for 2 weeks on days 1, 4, 8, and 11, followed by a 10-day rest period.1,10 A mean of 7 or 6 treatment cycles was administered in patients receiving the 1- or 1.3-mg/m2 dose, respectively.6

Patients from the two phase 2 studies who were expected to benefit from extended therapy were able to continue receiving bortezomib therapy beyond 8 cycles in an extension study.1 A total of 63 patients from the phase 2 multiple myeloma studies were enrolled and received a median of 7 additional cycles of bortezomib therapy for a total median of 14 cycles (range: 7-32 cycles).1 The overall median dosing intensity in this study was similar to that in the phase 2 studies.1 In this study, 67% of patients initiated bortezomib at the same or higher dose intensity compared with that used at the end of the phase 2 studies, and 89% of patients maintained the standard 3-week dosing schedule during the study.1 No new cumulative or long-term toxicities were observed with prolonged bortezomib treatment.1

Efficacy and safety of retreatment with bortezomib (with or without dexamethasone) is based principally on the results of a phase 2 open-label study involving 130 adults with multiple myeloma who had previously achieved at least a partial response to bortezomib-based therapy but had relapsed 6 or more months following completion of therapy.1,29 In this study, patients received the last tolerated dose of bortezomib (up to 1.3 mg/m2 by IV injection) on days 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles;1,29 however, lower doses of bortezomib could be increased to 1.3 mg/m2.29 Patients who had received treatment for multiple myeloma (except for maintenance therapy with an immunomodulatory agent or corticosteroid) following the prior course of bortezomib therapy and those with baseline grade 2 or greater peripheral neuropathy or neuropathic pain were excluded from the study.1,29 The primary measure of efficacy was best confirmed response according to EBMT response criteria.1,29 The overall best confirmed response rate was 38.5%; complete response was achieved in 1 patient.1 At the time of analysis, the median duration of response for all responders was 6.5 months (range: 0.6-19.3 months).1,29 Results of a subgroup analysis suggested that the drug's effect on overall response rate decreased with increasing number of prior therapies.29 The overall response rate with bortezomib retreatment appeared to be higher in patients who had achieved a complete response rather than a partial response to prior bortezomib-based therapy.29

Subcutaneous Versus IV Administration

Efficacy and safety of bortezomib administered by subcutaneous injection are based principally on the results of an open-label, randomized, phase 3 study (MMY-3021) in patients with relapsed multiple myeloma who had not previously received bortezomib.1,27,28 Patients with baseline grade 2 or greater peripheral neuropathy or neuropathic pain or platelet count less than 50,000/mm3 were excluded from the study.1 In this study, 222 patients were randomized in a 2:1 ratio to receive bortezomib 1.3 mg/m2 by either subcutaneous or IV injection on days 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles.1,27 The median number of cycles of bortezomib administered by either route was 8.27 Patients with a suboptimal response (less than a complete response, without disease progression) after 4 cycles could receive oral dexamethasone (20 mg on the day of and the day after bortezomib administration); approximately one-half of patients in both treatment groups received oral dexamethasone.1,27 The primary objective of the study was to show that single-agent bortezomib administered by subcutaneous injection retains at least 60% of the overall response rate attained after 4 cycles with single-agent IV bortezomib.1,27

At a median follow-up of 11.8 months, no significant difference in median time to progression (10.4 versus 9.4 months, respectively), median progression-free survival (10.2 versus 8 months, respectively), and 1-year overall survival (72.6 versus 76.7%, respectively) were observed in patients receiving bortezomib by subcutaneous injection compared with those receiving the drug by IV injection.1,27 The overall response rates with subcutaneous and IV injection were 43 and 42%, respectively, following 4 cycles of bortezomib and 53 and 51%, respectively, following 8 cycles; complete response rates following 8 cycles of bortezomib were 11 and 12%, respectively.1 Overall response rates, median time to progression, median progression-free survival, and overall survival remained similar in both groups at the time of the final analysis after a median follow-up of 17.3 or 17.8 months for patients receiving subcutaneous or IV bortezomib, respectively.28 Adverse effects generally were similar in both treatment groups, although grade 3 or 4 neuralgia (3 versus 9%), peripheral neuropathy (6 versus 15%), neutropenia (13 versus 18%), and thrombocytopenia (8% versus 16%) occurred less frequently in patients receiving bortezomib by subcutaneous injection compared with those receiving the drug by IV injection.1

Induction Therapy Prior to Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma

Bortezomib has been studied as a component of various induction regimens for newly diagnosed multiple myeloma in transplant-eligible patients†.10002,10003,10004,10005,10006,10007,10008,10012,10013,10014,10015,10016,10019,10020,10021,10022,10023,10024,10025,10026,10027,10028,10029

Bortezomib and Dexamethasone

Efficacy and safety of bortezomib in combination with dexamethasone† as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients† have been studied in an open-label, randomized phase 3 study (IFM 2005-01).10002,10012

In the IFM 2005-01 study, 482 patients with previously untreated multiple myeloma were randomized to receive bortezomib in combination with dexamethasone (bortezomib-dexamethasone) or the combination of vincristine, doxorubicin, and dexamethasone (vincristine-doxorubicin-dexamethasone) as an induction regimen; both regimens were administered with or without dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) consolidation therapy.10002,10012 Patients receiving the bortezomib-dexamethasone induction regimen received bortezomib 1.3 mg/m2 as an IV injection on days 1, 4, 8, and 11 of each 3-week cycle for 4 cycles along with dexamethasone 40 mg orally on days 1-4 and 9-12 during cycles 1 and 2 and then on days 1-4 of cycles 3 and 4.10002,10012 Those receiving the vincristine-doxorubicin-dexamethasone induction regimen received vincristine sulfate 0.4 mg and doxorubicin hydrochloride 9 mg/m2 per day by continuous IV infusion on days 1-4 of each 4-week cycle for 4 cycles along with dexamethasone 40 mg orally on days 1-4, 9-12, and 17-20 during cycles 1 and 2 and then on days 1-4 of cycles 3 and 4.10012 The median age of patients enrolled in the study was 57.1 years; 22% had International Staging System (ISS) stage III disease, 57.5% had a baseline β2-microglobulin concentration exceeding 3 mg/L, 42.3% had chromosome 13 deletion (del(13)), and 14.3% had t(4;14) translocation with or without chromosome 17p deletion (del(17p)).10012

The primary measure of efficacy was complete plus near-complete response rate following induction therapy.10012 Tumor responses were assessed using EBMT response criteria.10012 The postinduction complete plus near-complete response rate (14.8 versus 6.4%) and the postinduction overall response rate (78.5 versus 62.8%) were higher in patients receiving bortezomib-dexamethasone compared with those receiving vincristine-doxorubicin-dexamethasone.10012 The complete plus near-complete response rate also was higher following initial transplantation (35 versus 18.4%) and overall (39.5 versus 22.5%), including responses following second transplants when required, in patients receiving bortezomib-dexamethasone compared with those receiving vincristine-doxorubicin-dexamethasone.10012 Postinduction response rates were higher in patients receiving bortezomib-dexamethasone compared with those receiving vincristine-doxorubicin-dexamethasone regardless of disease stage or presence of high-risk cytogenetic features (i.e., del(13), t(4;14) translocation and/or del(17p) chromosomal abnormality).10012 Among patients who received bortezomib-dexamethasone induction therapy, rates of attaining a very good partial response or better were similar regardless of disease stage, use of consolidation therapy, or presence of the t(4;14) translocation with or without del(17p), but were slightly higher in patients with del(13) compared with those without this chromosomal abnormality.10012 Following initial autologous stem cell transplantation, 38.6% of patients who had received bortezomib-dexamethasone induction therapy required a second stem cell transplant compared with 56% of those who had received vincristine-doxorubicin-dexamethasone.10012 Although median overall survival had not been reached at a median follow-up of 32.2 months, median progression-free survival at a median follow-up of 31.2 months was numerically, but not significantly, longer in patients who received induction therapy with bortezomib-dexamethasone compared with those who received vincristine-doxorubicin-dexamethasone (36 versus 29.7 months).10012

Infection (48.1 versus 38.1%), peripheral neuropathy (45.6 versus 28%), thrombocytopenia (10.9 versus 4.6%), and herpes zoster infection (9.2 versus 2.1%) occurred more frequently in patients receiving bortezomib-dexamethasone, while neutropenia (13.8 versus 8%) and thrombosis (12.1 versus 4.6%) occurred more frequently in patients receiving vincristine-doxorubicin-dexamethasone.10012

Based on current evidence,10012 use of bortezomib in combination with dexamethasone may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients; factors that should be considered when selecting a combination chemotherapy regimen for use as induction therapy include performance status and preexisting conditions (e.g., peripheral neuropathy).10032

Bortezomib, Dexamethasone, and Thalidomide

Efficacy and safety of bortezomib in combination with thalidomide and dexamethasone† (bortezomib-thalidomide-dexamethasone) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients† have been studied in several phase 3, open-label, randomized studies.10013,10014,10015,10027

The GIMEMA and PETHEMA/GEM studies compared bortezomib-thalidomide-dexamethasone with the combination of thalidomide and dexamethasone (thalidomide-dexamethasone).10013,10014 In the GIMEMA study, 480 patients were randomized to receive bortezomib-thalidomide-dexamethasone or thalidomide-dexamethasone; both induction regimens were followed by tandem autologous stem cell transplantation and consolidation therapy with the same drug combination used for induction therapy.10013 Patients receiving bortezomib-thalidomide-dexamethasone induction therapy received bortezomib 1.3 mg/m2 as an IV injection on days 1, 4, 8, and 11 along with thalidomide 200 mg orally daily (after initial dose escalation during cycle 1) and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.10013 Those receiving thalidomide-dexamethasone induction therapy received the same dosage of thalidomide; however, dexamethasone 40 mg was administered orally on days 1-4 and 9-12 of each 21-day cycle.10013 Both regimens were continued for a total of 3 cycles.10013 In the PETHEMA/GEM study, 386 patients were randomized to receive bortezomib-thalidomide-dexamethasone, thalidomide-dexamethasone, or alternating cycles of vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) and vincristine, carmustine, doxorubicin, and dexamethasone (VBAD) followed by bortezomib as induction therapy.10014 Patients receiving bortezomib-thalidomide-dexamethasone received bortezomib 1.3 mg/m2 as an IV injection on days 1, 4, 8, and 11 along with thalidomide 200 mg orally daily (after initial dose escalation during cycle 1) and dexamethasone 40 mg orally on days 1-4 and 9-12 of each 4-week cycle for 6 cycles.10014 Patients receiving thalidomide-dexamethasone received the same dosages of thalidomide and dexamethasone.10014 Those receiving VBMCP/VBAD received each regimen in alternating cycles for 4 cycles followed by two 3-week cycles of bortezomib 1.3 mg/m2 administered as an IV injection on days 1, 4, 8, and 11.10014,10017 In the GIMEMA study, the primary measure of efficacy was postinduction complete plus near-complete response rate.10013 In the PETHEMA/GEM study, the primary measures of efficacy were postinduction and posttransplant complete response rates.10014 In both studies, responses were assessed according to EBMT response criteria.10013,10014 In both studies, a higher postinduction response rate and prolonged progression-free survival were observed in patients who received bortezomib-thalidomide-dexamethasone compared with those who received the comparator regimens; however, addition of bortezomib to thalidomide and dexamethasone induction therapy did not provide an overall survival benefit in either study.10013,10014

In the GIMEMA study, postinduction complete plus near-complete response rate was 31% in patients receiving bortezomib-thalidomide-dexamethasone compared with 11% in those receiving thalidomide-dexamethasone; improved responses also were observed with bortezomib-thalidomide-dexamethasone following first (52 versus 31%) and second (55 versus 41%) autologous stem cell transplants and subsequent consolidation therapy (62 versus 45%).10013 The median time to best complete or near-complete response was shorter in patients receiving bortezomib-thalidomide-dexamethasone compared with those receiving thalidomide-dexamethasone (9 versus 14 months).10013 At a median follow-up of 36 months, progression-free survival was prolonged in patients who received bortezomib-thalidomide-dexamethasone compared with those who received thalidomide-dexamethasone (hazard ratio 0.63); however, no difference in estimated 3-year overall survival (86 versus 84%, respectively) was observed between the groups.10013 Subgroup analysis based on poor prognostic factors (i.e., older than 60 years of age, advanced disease stage, elevated serum LDH concentration, high infiltration of bone marrow plasma cells, del(13q), t(4;14) translocation with or without del(17p) chromosomal abnormality) suggested that the progression-free survival benefit of bortezomib-thalidomide-dexamethasone was consistent across these subgroups; however, because the proportion of patients with the del(17p) chromosomal abnormality was substantially smaller than the proportion of patients with other high-risk cytogenetic abnormalities, the effect of bortezomib-thalidomide-dexamethasone on progression-free survival in patients with the del(17p) chromosomal abnormality was not evaluated.10013

In the PETHEMA/GEM study, the complete response rate (35 versus 14%) was higher following induction therapy with bortezomib-thalidomide-dexamethasone compared with thalidomide-dexamethasone; improved complete response rates also were maintained following autologous stem cell transplantation (46 versus 24%).10014 Among patients evaluated for high-risk cytogenetic features, 21% had high-risk features (i.e., t(4;14), t(14;16), and/or del(17p) chromosomal abnormalities); 64 or 31% of these patients had t(4;14) or del(17p) chromosomal abnormalities, respectively.10014 Among the patients with high-risk cytogenetic features, complete response rate was substantially higher in patients who received bortezomib-thalidomide-dexamethasone compared with those who received thalidomide-dexamethasone (35 versus 0%); complete responses were achieved in 38 or 58% of patients receiving bortezomib-thalidomide-dexamethasone who had t(4;14) or del(17p) chromosomal abnormalities, respectively, compared with 0% of patients receiving thalidomide-dexamethasone who had either chromosomal abnormality.10014 At a median follow-up of 35.2 months, median progression-free survival was prolonged in patients who received bortezomib-thalidomide-dexamethasone compared with those who received thalidomide-dexamethasone (56.2 versus 28.2 months); however, no difference in estimated 4-year overall survival (74 versus 65%, respectively) was observed between the treatment groups.10014

In both the GIMEMA and PETHEMA/GEM studies, grade 3 or 4 peripheral neuropathy occurred more frequently in patients receiving bortezomib-thalidomide-dexamethasone (10 and 14%, respectively) compared with those receiving thalidomide-dexamethasone (2 and 5%, respectively).10013,10014

In the third study (IFM2013-04), 340 patients were randomized to receive bortezomib by subcutaneous injection in combination with thalidomide and dexamethasone or in combination with cyclophosphamide and dexamethasone.10027 Patients receiving bortezomib-thalidomide-dexamethasone received bortezomib 1.3 mg/m2 by subcutaneous injection on days 1, 4, 8, and 11 along with thalidomide 100 mg orally daily and dexamethasone 40 mg orally on days 1-4 and 9-12 of each 3-week cycle.10027 Those receiving bortezomib-cyclophosphamide-dexamethasone received the same dosages of bortezomib and dexamethasone along with cyclophosphamide 500 mg/m2 orally on days 1, 8, and 15 of each 3-week cycle.10027 Both induction regimens were continued for a total of 4 cycles.10027 The median age of patients enrolled in the study was approximately 60 years; 22% had ISS stage III disease, and 18% had t(4;14) translocation and/or del(17p) chromosomal abnormalities.10027 The primary measure of efficacy was the rate of very good partial response or better, as assessed according to the International Myeloma Working Group Uniform Response criteria, following induction therapy.10027 Overall response rate (92.3 versus 83.4%) and the rate of very good partial response or better (66.3 versus 56.2%) based on intent-to-treat analysis were higher following induction therapy with bortezomib-thalidomide-dexamethasone compared with bortezomib-cyclophosphamide-dexamethasone; however, no significant difference in complete response rate was observed between the treatment groups.10027 Grade 2 or greater peripheral neuropathy (21.9 versus 12.9%) occurred more frequently in patients receiving bortezomib-thalidomide-dexamethasone, while grade 3 or 4 neutropenia (33.1 versus 18.9%), thrombocytopenia (10.6 versus 4.7%), and anemia (9.5 versus 4.1%) occurred more frequently in patients receiving bortezomib-cyclophosphamide-dexamethasone.10027

Because peripheral neuropathy occurs frequently with bortezomib- and thalidomide-based induction regimens, a modified bortezomib-thalidomide-dexamethasone induction regimen was compared with bortezomib-dexamethasone in another phase 3 study in 199 patients.10015 Patients receiving bortezomib-dexamethasone received bortezomib 1.3 mg/m2 as an IV injection on days 1, 4, 8, and 11 of each 3-week cycle for 4 cycles along with dexamethasone 40 mg orally on days 1-4 and 9-12 during cycles 1 and 2 and then on days 1-4 during cycles 3 and 4.10015 Patients receiving the modified bortezomib-thalidomide-dexamethasone regimen received the same dosage of dexamethasone along with bortezomib 1 mg/m2 as an IV injection on days 1, 4, 8, and 11 and thalidomide 100 mg orally daily during each 3-week cycle for 4 cycles.10015 In patients with an inadequate (less than partial) response after 2 cycles of the modified bortezomib-thalidomide-dexamethasone regimen (7% of patients receiving the regimen), the dose of bortezomib was increased to 1.3 mg/m2 and the dosage of thalidomide was increased to 200 mg daily during subsequent cycles.10015 The median age of patients enrolled in the study was approximately 58 years; 22% had ISS stage III disease and, among those with cytogenetic test results, 20% had t(4;14) translocation or del(17p) chromosomal abnormalities.10015 The primary measure of efficacy was complete response rate, as assessed according to the International Myeloma Working Group Uniform Response criteria, following induction therapy.10015 The rate of very good partial response or better following induction therapy was higher with bortezomib-thalidomide-dexamethasone compared with bortezomib-dexamethasone (49 versus 36%); however, postinduction complete response (13 and 12%, respectively) and overall response (88 and 81%, respectively) rates were similar for both treatment groups.10015 At a median follow-up of 32 months, median progression-free survival was similar in patients who received bortezomib-thalidomide-dexamethasone compared with those who received bortezomib-dexamethasone (26 versus 30 months, respectively).10015 Peripheral neuropathy occurred more frequently in patients receiving bortezomib-dexamethasone compared with those receiving bortezomib-thalidomide-dexamethasone (70 versus 53%).10015

Use of bortezomib in combination with thalidomide and dexamethasone also was investigated in an open-label, noncomparative phase 2 study in 98 patients randomized to receive bortezomib-thalidomide-dexamethasone with or without cyclophosphamide.10016,10020 Patients receiving bortezomib-thalidomide-dexamethasone received bortezomib 1.3 mg/m2 as an IV injection on days 1, 4, 8, and 11 along with thalidomide 100 mg orally daily and dexamethasone 40 mg orally on days 1-4 and 9-12 of each 21-day cycle.10016 Patients receiving bortezomib-thalidomide-dexamethasone-cyclophosphamide received the same dosages of bortezomib, thalidomide, and dexamethasone along with cyclophosphamide 400 mg/m2 IV on days 1 and 8 of each 21-day cycle.10016 Both induction regimens were continued for a total of 4 cycles.10016 Postinduction rates of overall response and complete plus near-complete response were 100 and 51%, respectively, in patients receiving bortezomib-thalidomide-dexamethasone and 94 and 43%, respectively, in those receiving bortezomib-thalidomide-dexamethasone-cyclophosphamide.10016 At a median follow-up of 64.8 months, median progression-free survival was 56.3 months with bortezomib-thalidomide-dexamethasone and 36.3 months with bortezomib-thalidomide-dexamethasone-cyclophosphamide; the difference was not statistically significant and was largely related to an imbalance between treatment groups in the number of patients receiving subsequent therapy for relapsed disease prior to meeting the specified criteria for disease progression.10020 A trend toward improved quality of life (assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 [EORTC QLQ-C30] and EuroQoL EQ-5D health status questionnaire) was observed following the first posttransplantation follow-up visit in patients who received bortezomib-thalidomide-dexamethasone compared with those who received bortezomib-thalidomide-dexamethasone-cyclophosphamide.10016

Use of bortezomib-thalidomide-dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients has improved postinduction response rates and prolonged progression-free survival in several randomized controlled studies;10013,10014,10016,10027 however, the same benefits were not observed in a study evaluating a modified bortezomib-thalidomide-dexamethasone regimen (i.e., reduced bortezomib and thalidomide dosages).10015 Therefore, the role of a modified bortezomib-thalidomide-dexamethasone regimen using reduced dosages of bortezomib and thalidomide10015 is unclear.10033 In addition, in the absence of studies including adequate numbers of patients with the del(17p) chromosomal abnormality, attempts to identify whether these patients might derive clinical benefit (e.g., prolonged progression-free survival) from bortezomib-thalidomide-dexamethasone induction therapy are speculative; additional studies are needed to identify subgroups of patients with high-risk cytogenetic features who might benefit from such therapy.10033 The AHFS Oncology Expert Committee concluded that use of bortezomib in combination with thalidomide and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients may be considered a reasonable choice (accepted; with possible conditions);10033 however, use of a modified bortezomib-thalidomide-dexamethasone regimen using reduced dosages of bortezomib and thalidomide10015 is not fully established because of unclear risk/benefit and/or inadequate experience.10033 Factors that should be considered when selecting a combination chemotherapy regimen for use as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients include performance status and preexisting conditions (e.g., peripheral neuropathy).10033

Bortezomib, Dexamethasone, and Doxorubicin (or Pegylated Liposomal Doxorubicin)

Efficacy and safety of bortezomib in combination with dexamethasone and conventional doxorubicin† (bortezomib-doxorubicin-dexamethasone) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients† have been studied in an open-label, randomized phase 3 study (HOVON-65/GMMG-HD4).10005,10023

In the HOVON-65/GMMG-HD4 study, 827 patients with newly diagnosed multiple myeloma were randomized to receive conventional doxorubicin and dexamethasone in combination with either bortezomib or vincristine as an induction regimen.10023 Patients receiving the bortezomib-doxorubicin-dexamethasone induction regimen received bortezomib 1.3 mg/m2 as an IV injection on days 1, 4, 8, and 11 along with doxorubicin hydrochloride 9 mg/m2 IV per day on days 1-4 and dexamethasone 40 mg orally on days 1-4, 9-12, and 17-20 during each 28-day cycle for 3 cycles.10023 Those receiving the vincristine-doxorubicin-dexamethasone induction regimen received vincristine sulfate 0.4 mg and doxorubicin hydrochloride 9 mg/m2 IV per day on days 1-4 and dexamethasone 40 mg orally on days 1-4, 9-12, and 17-20 during each 28-day cycle for 3 cycles.10023 Patients who received bortezomib-doxorubicin-dexamethasone induction therapy received 2 years of maintenance therapy with bortezomib (1.3 mg/m2 every 2 weeks) following stem cell transplantation, while those who received vincristine-doxorubicin-dexamethasone induction therapy received thalidomide (50 mg daily) as maintenance therapy.10023 The median age of patients enrolled in the study was 57 years; 87% had World Health Organization (WHO) performance status of 0 or 1, and 23% had ISS stage III disease.10023 Among patients for whom cytogenetic tests were performed, 43, 14, or 11% had del(13q), t(4;14) translocation, or del(17p13) chromosomal abnormalities, respectively.10023

The primary measure of efficacy in the HOVON-65/GMMG-HD4 study was progression-free survival.10023 Tumor responses were assessed using EBMT response criteria.10023 At a median follow-up of 41 months, patients who received bortezomib-doxorubicin-dexamethasone had prolonged progression-free survival (35 versus 28 months; hazard ratio: 0.75) and higher postinduction (11 versus 5%) and posttransplant (31 versus 15%) complete plus near-complete response rates compared with those who received vincristine-doxorubicin-dexamethasone.10023 Median overall survival had not been reached at a median follow-up of 66 months; however, no significant difference in 5-year overall survival was observed between the groups.10023 Subgroup analyses based on presence of renal insufficiency or high-risk cytogenetic features (i.e., del(13q14), t(4;14), del(17p13) chromosomal abnormalities) suggested prolonged progression-free and overall survival with bortezomib-doxorubicin-dexamethasone compared with vincristine-doxorubicin-dexamethasone induction therapy in patients with serum creatinine concentrations exceeding 2 mg/dL and in those with del(17p13) chromosomal abnormality, as well as an overall survival benefit for bortezomib-doxorubicin-dexamethasone compared with vincristine-doxorubicin-dexamethasone in patients with del(13q14) chromosomal abnormality.10023 Herpes zoster (2 versus 0%) and grade 3 or 4 thrombocytopenia (10 versus 5%), GI toxicity (11 versus 7%), and peripheral neuropathy (24 versus 10%) occurred more frequently in patients receiving bortezomib-doxorubicin-dexamethasone compared with those receiving vincristine-doxorubicin-dexamethasone.10023

Use of bortezomib and dexamethasone also has been studied in combination with pegylated liposomal doxorubicin† (bortezomib-pegylated liposomal doxorubicin-dexamethasone) as induction therapy for previously untreated multiple myeloma† in 2 open-label, noncomparative phase 2 studies.10004,10024,10025,10026

In the first study, 40 patients with newly diagnosed multiple myeloma received bortezomib 1.3 mg/m2 as an IV injection on days 1, 4, 8, and 11 along with pegylated liposomal doxorubicin hydrochloride 30 mg/m2 IV on day 4 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 during cycle 1.10024 During cycles 2-6, the same dosages of bortezomib and pegylated liposomal doxorubicin were administered, but the dexamethasone dosage was 20 mg orally daily.10024 Treatment cycles were repeated every 3 weeks for a total of 6 cycles.10024 Overall response rate and complete plus near-complete response rate were 85 and 38%, respectively, following 6 cycles of induction therapy with bortezomib-pegylated liposomal doxorubicin-dexamethasone.10024 Among patients who underwent stem cell transplantation, the complete plus near-complete response rate increased to 57% following transplantation, but the overall response rate did not improve substantially.10024 At a median follow-up of 45.1 months, median progression-free survival had not been reached; however, among patients who underwent stem cell transplantation, actuarial 2- and 4-year progression-free survival rates were 93 and 65%, respectively, and actuarial 2- and 4-year overall survival rates were 97 and 67%, respectively.10025 Grade 1 or 2 peripheral neuropathy, fatigue, palmar-plantar erythrodysesthesia (hand-foot syndrome), and constipation occurred in 90, 88, 75, and 70% of patients, respectively.10024

Because bortezomib and pegylated liposomal doxorubicin frequently cause adverse effects, another phase 2 study evaluated a modified bortezomib-pegylated liposomal doxorubicin-dexamethasone regimen in 35 patients with previously untreated multiple myeloma.10026 Patients received bortezomib 1 mg/m2 as an IV injection, pegylated liposomal doxorubicin hydrochloride 5 mg/m2 IV, and dexamethasone phosphate 40 mg IV on days 1, 4, 8, and 11 of each 28-day cycle for a maximum of 8 cycles.10026 Overall response rate was 86%; complete response was achieved in 20% of patients.10026 At a median follow-up of 17.7 months, median time to progression, duration of response, and overall survival had not been reached.10026 Constipation, fatigue, peripheral neuropathy, insomnia, and nausea occurred in 51, 46, 34, 29, and 26%, respectively, of patients.10026

Based on current evidence,10023,10024,10025 use of bortezomib in combination with doxorubicin (or pegylated liposomal doxorubicin) and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients may be considered a reasonable choice (accepted; with possible conditions);10034 however, in the absence of longer follow-up data, use of a modified bortezomib-pegylated liposomal doxorubicin-dexamethasone regimen (i.e., reduced dosages of bortezomib and pegylated liposomal doxorubicin)10026 is not fully established because of unclear risk/benefit and/or inadequate experience.10034 Factors that should be considered when selecting a combination chemotherapy regimen for use as induction therapy include performance status and preexisting conditions (e.g., peripheral neuropathy).10034

Bortezomib, Dexamethasone, and Cyclophosphamide

Efficacy and safety of bortezomib in combination with cyclophosphamide and dexamethasone† (bortezomib-cyclophosphamide-dexamethasone) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients† have been studied in 2 noncomparative phase 2 studies and an open-label, randomized phase 3 study (GMMG-MM5).10006,10007,10008,10019,10021,10022,10028,10029

In the first phase 2 study, patients with newly diagnosed multiple myeloma receiving bortezomib in combination with cyclophosphamide and dexamethasone were compared with a historical control group (34 patients who received lenalidomide 25 mg orally on days 1-21 and dexamethasone 40 mg orally on days 1-4, 9-12, and 17-20 during each 28-day cycle for 4 cycles).10019,10031 In this study, 33 patients received bortezomib 1.3 mg/m2 as an IV injection twice weekly (days 1, 4, 8, and 11) along with cyclophosphamide 300 mg/m2 orally on days 1, 8, 15, and 22 and dexamethasone 40 mg orally on days 1-4, 9-12, and 17-20 during each 28-day cycle for 4 cycles.10019 The mean age of patients enrolled in the study was 60 years; 48% were female and 30% had ISS stage III disease.10019 Among patients for whom cytogenetic tests were performed, 50, 18, or 13% had del(13q), t(4;14) translocation, or del(17) chromosomal abnormalities, respectively.10019 The overall response rate and rate of very good partial response or better after 4 cycles of therapy were 88 and 61%, respectively, in patients who received bortezomib-cyclophosphamide-dexamethasone compared with 91 and 44%, respectively, in the historical control group based on intent-to-treat analysis.10019 Among patients who underwent stem cell transplantation following bortezomib-cyclophosphamide-dexamethasone induction therapy, the posttransplant complete or near-complete response rate was 70%.10019

Patients from this study (twice-weekly bortezomib; cohort 1) also were compared with a subsequent cohort of 30 patients who received bortezomib 1.5 mg/m2 as an IV injection once weekly (days 1, 8, 15, and 22) along with cyclophosphamide (same dosage as in cohort 1) and dexamethasone (same dosage as in cohort 1 during cycles 1 and 2, followed by 40 mg once weekly during cycles 3 and 4).10019,10021 Comparison of the 2 cohorts suggested that overall response rates and rates of very good partial response or better for the regimens containing once-weekly (93 and 60%, respectively) or twice-weekly (88 and 61%, respectively) bortezomib were similar;10021 however, the incidences of grade 3 or 4 thrombocytopenia (0 versus 25%), neutropenia (7 versus 13%), anemia (0 versus 12%), and peripheral neuropathy (0 versus 7%) were lower in patients receiving the regimen containing once-weekly bortezomib compared with those receiving the regimen containing twice-weekly bortezomib.10019,10021 Analysis of pooled data for the 2 cohorts indicated a median progression-free survival of 40 months; in addition, 5-year progression-free and overall survival rates for the 2 cohorts combined were 42 and 70%, respectively.10022 Although the overall response rate was similar in patients with high-risk cytogenetic features and those with standard-risk cytogenetic features, median progression-free survival was shorter and 5-year progression-free and overall survival rates were lower in patients with high-risk cytogenetic features (27.6 months, 33%, and 54%, respectively) compared with those with standard-risk cytogenetic features (55.7 months, 48%, and 81%, respectively).10022

In another phase 2 study, patients with newly diagnosed multiple myeloma received the combination of bortezomib-cyclophosphamide-dexamethasone followed by bortezomib-thalidomide-dexamethasone to determine if sequential combination therapy could improve response rates and tolerability.10008,10029 In this study, 44 patients received bortezomib 1.3 mg/m2 as an IV injection on days 1, 4, 8, and 11 along with cyclophosphamide 300 mg/m2 IV on days 1 and 8 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 during each 21-day cycle for 3 cycles (cycles 1-3) followed by bortezomib 1 mg/m2 as an IV injection on days 1, 4, 8, and 11 along with thalidomide 100 mg orally daily and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 during each 21-day cycle for 3 cycles (cycles 4-6).10029 The median age of patients enrolled in the study was 58 years, and the median Karnofsky performance status was 90%; 60% of patients had ISS stage II or III disease, 49% had a baseline β2-microglobulin concentration of 3.5 mg/L or greater, and 7 patients had cytogenetic abnormalities, including t(4;14) translocation, del(17p), and/or del(13) chromosomal abnormalities.10029 Very good partial response or better was observed in 31 or 57% of 42 evaluable patients following 3 cycles of bortezomib-cyclophosphamide-dexamethasone or 6 cycles of sequential combination therapy, respectively; near-complete response or better was observed following 3 or 6 cycles of therapy in 2 or 36% of patients, respectively.10029 At a median follow-up of 20.9 months, median event-free and overall survival had not been reached; however, estimated 1-year event-free and overall survival rates were 81 and 91%, respectively.10029

In the GMMG-MM5 study, 502 patients with newly diagnosed multiple myeloma were randomized to receive bortezomib in combination with either cyclophosphamide and dexamethasone or doxorubicin and dexamethasone.10028 Patients receiving bortezomib-cyclophosphamide-dexamethasone received bortezomib 1.3 mg/m2 as an IV injection on days 1, 4, 8, and 11 along with cyclophosphamide 900 mg/m2 IV on day 1 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 during each 21-day cycle.10028 Those receiving bortezomib-doxorubicin-dexamethasone received the same dosage of bortezomib along with doxorubicin hydrochloride 9 mg/m2 IV per day on days 1-4 and dexamethasone 20 mg orally on days 1-4, 9-12, and 17-20 of each 28-day cycle.10028 Both regimens were continued for a total of 3 cycles.10028 The route of administration for bortezomib was changed from IV to subcutaneous injection when data from a prior study in patients with relapsed multiple myeloma demonstrated no apparent loss in efficacy or increase in toxicity with subcutaneous administration.10028 The median age of patients enrolled in the GMMG-MM5 study was 59 years, and 29% had ISS stage III disease.10028 Among patients for whom cytogenetic tests were performed, 11, 11, or 40% had del(17p), t(4;14) translocation, or chromosome 1q21 duplication (i.e., 1q21 gain) abnormalities, respectively.10028 The primary measure of efficacy was the rate of very good partial response or better, as assessed according to the International Myeloma Working Group Uniform Response criteria, following induction therapy.10028

Rates of overall response (78.1 versus 72.1%, respectively) and very good partial response or better (37 versus 34.3%, respectively) in the GMMG-MM5 study did not differ significantly between patients receiving bortezomib-cyclophosphamide-dexamethasone and those receiving bortezomib-doxorubicin-dexamethasone.10028 In subgroups of patients with poor prognostic factors (i.e., t(4;14) translocation, del(17p), and/or 1q21 gain; renal impairment [serum creatinine concentration of 2 mg/dL or higher]), response rates attained with bortezomib-cyclophosphamide-dexamethasone appeared to be at least as high as those attained with bortezomib-doxorubicin-dexamethasone; the rate of progressive disease in patients with high-risk cytogenetic features, ISS stage III disease, or renal impairment appeared to be higher in those receiving bortezomib-doxorubicin-dexamethasone compared with those receiving bortezomib-cyclophosphamide-dexamethasone.10028 In an exploratory analysis, overall response rates were similar with IV or subcutaneous injection of bortezomib, including in patients with poor prognostic factors.10030 Grade 3 or greater leukopenia and/or neutropenia (35.2 versus 11.3%) occurred more frequently in patients receiving bortezomib-cyclophosphamide-dexamethasone, while grade 2 or greater neuropathy (14.9 versus 8.4%) occurred more frequently in patients receiving bortezomib-doxorubicin-dexamethasone.10028

Based on current evidence,10019,10021,10022,10028,10029 use of bortezomib in combination with cyclophosphamide and dexamethasone may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients;10035 factors that should be considered when selecting a combination chemotherapy regimen for use as induction therapy include cytogenetic features, performance status, preexisting conditions (e.g., peripheral neuropathy), and tolerability.10035

Non-Hodgkin's Lymphoma !!navigator!!

Previously Untreated Mantle Cell Lymphoma

Bortezomib is used in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone for the treatment of previously untreated mantle cell lymphoma.1,26

The current indication for bortezomib in patients with previously untreated mantle cell lymphoma is based principally on the results of a phase 3, open-label, randomized study (LYM-3002) in patients with newly diagnosed stage II-IV mantle cell lymphoma who were considered ineligible for or were not considered for stem cell transplantation.1,26 In this study, 487 patients were randomized (stratified by International Prognostic Index [IPI] score and disease stage) in a 1:1 ratio to receive either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP).1,26 The planned course of therapy for both regimens was six 21-day cycles; patients were permitted to receive up to 2 additional cycles if a response was first observed at cycle 6.1,26 Patients in the control group received rituximab 375 mg/m2 IV, cyclophosphamide 750 mg/m2 IV, doxorubicin hydrochloride 50 mg/m2 IV, and vincristine sulfate 1.4 mg/m2 (maximum dose of 2 mg) IV on day 1 plus prednisone 100 mg/m2 orally on days 1-5 of each 21-day cycle.26 Patients in the study group received the same dosages of rituximab, cyclophosphamide, doxorubicin hydrochloride, and prednisone with the addition of bortezomib 1.3 mg/m2 by IV injection on days 1, 4, 8, and 11 of each 21-day cycle.1,26 The median number of cycles for patients receiving R-CHOP or VR-CAP was 6;1,26 17 or 14% of patients receiving R-CHOP or VR-CAP, respectively, received up to 2 additional cycles of their respective chemotherapy regimen.1 The primary end point of this study was progression-free survival as assessed by an independent review committee.26 The median age of patients enrolled in the study was 66 years; 74% of patients were male, 66% were white, 54% had an IPI score of 3 or greater, 76% had stage IV disease, and 69% had a positive bone marrow aspirate and/or bone marrow biopsy for mantle cell lymphoma.1,26

At a median follow-up of 40 months, median progression-free survival was prolonged in patients who received VR-CAP compared with those who received R-CHOP (25 versus 14 months; hazard ratio of 0.63).1,26 The overall response rates with VR-CAP and R-CHOP were 88 and 85%, respectively, with 44% of patients receiving VR-CAP and 34% of those receiving R-CHOP achieving complete responses.1 Median overall survival had not been reached at the time of the analysis.26

Relapsed Mantle Cell Lymphoma

Bortezomib is used for treatment of mantle cell lymphoma in patients who have received at least one prior therapy.1,13,14,21 The current indication for bortezomib in patients with relapsed mantle cell lymphoma is based principally on the results of a phase 2, open-label, single-arm, clinical study involving 155 patients (median age: 65 years; range: 42-89 years).1,21 Patients received bortezomib 1.3 mg/m2 by IV injection administered in 21-day treatment cycles (on days 1, 4, 8, and 11 followed by a 10-day rest period on days 12-21) for a maximum of 17 cycles; patients achieving a complete response or an unconfirmed complete response were treated for 4 cycles beyond the first evidence of complete response or unconfirmed complete response.1,21 Therapy was discontinued if progressive disease or unacceptable toxicity occurred or based on a decision by the patient and clinician.21 The median number of cycles administered in all patients was 4; in responding patients, the median number of cycles was 8.1,21

Responses were assessed according to International Workshop Response Criteria (IWRC) based on independent review of CT scans.1,21 The median time to response was 40 days (range: 31-204 days).1 The overall response rate (complete responses, unconfirmed complete responses, and partial responses) was 31%, and the median duration of response was 9.3 months.1 A complete response or an unconfirmed complete response was reported in 8%.1

Other Non-Hodgkin's Lymphomas

Bortezomib is being investigated for use in the treatment of other non-Hodgkin's lymphomas†.12 In small phase 2 uncontrolled studies, bortezomib has shown activity in the treatment of relapsed or refractory B-cell lymphomas.13,14

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Clinicians should consult the respective manufacturers' labelings for information on the dosage and method of administration of other antineoplastic agents used in combination regimens.1

Because reactivation of latent varicella zoster virus infection has been reported in bortezomib-treated patients, the manufacturer recommends that antiviral prophylaxis be considered in patients receiving the drug.1

Reconstitution and Administration !!navigator!!

Bortezomib is administered by IV injection (over 3-5 seconds) or by subcutaneous injection;1,4,6 the drug should not be administered by any other route.1 (See Cautions: Contraindications.) A sticker indicating the route of administration is provided by the manufacturer and should be affixed directly to the syringe following reconstitution.1 Subcutaneous administration of bortezomib may be considered in patients with preexisting peripheral neuropathy and those at high risk for developing peripheral neuropathy.1 (See Relapsed Multiple Myeloma under Uses: Multiple Myeloma.) Recommended sites for subcutaneous injection of bortezomib include the thigh and abdominal region.1 Injection sites should be rotated, with new injections administered at least one inch from the previous injection site; any area that is tender, erythematous, bruised, or indurated should be avoided.1

The manufacturer recommends that procedures for proper handling (e.g., use of gloves or protective clothing) and disposal of bortezomib be used.1

Prior to administration, bortezomib powder for injection must be reconstituted using proper aseptic technique.1 The manufacturer states that only 0.9% sodium chloride injection should be used to reconstitute the lyophilized powder.1 The reconstituted bortezomib solution should be inspected visually for particulate matter and/or discoloration prior to administration and should be discarded if either is present.1

For IV injection, bortezomib sterile powder for injection is reconstituted by adding 3.5 mL of 0.9% sodium chloride injection to a vial labeled as containing 3.5 mg of the drug to yield a final concentration of 1 mg/mL.1

For subcutaneous injection, bortezomib sterile powder for injection is reconstituted by adding 1.4 mL of 0.9% sodium chloride injection to a vial labeled as containing 3.5 mg of the drug to yield a final concentration of 2.5 mg/mL.1 If local injection site reactions occur following subcutaneous administration of the drug at a reconstituted concentration of 2.5 mg/mL, the manufacturer states that the solution may be reconstituted to a lower concentration of 1 mg/mL; however, administration of subsequent doses of the drug by IV injection also should be considered.1

Unreconstituted bortezomib powder for injection should be stored in unopened vials at a controlled room temperature of 25°C but may be exposed to temperatures ranging from 15-30°C.1 Unopened vials should be retained in the original package to protect from light.1 The reconstituted drug may be stored at 25°C in the original vial and/or syringe but should be administered within 8 hours after reconstitution.1

Dosage !!navigator!!

The amount of bortezomib contained in one 3.5-mg vial may exceed the usual single dose required.1 Because the final concentration of reconstituted bortezomib solutions varies depending on the route of administration, caution should be exercised in calculating the dose and respective volume of bortezomib to be administered to prevent overdosage.1

Previously Untreated Multiple Myeloma

For the treatment of previously untreated multiple myeloma, bortezomib is administered in combination with melphalan and prednisone as part of the VMP regimen.1 The recommended adult dosage of bortezomib during cycles 1-4 (of the recommended nine 6-week cycles) is 1.3 mg/m2 by IV injection over 3-5 seconds or by subcutaneous injection twice weekly during weeks 1, 2, 4, and 5 (days 1, 4, 8, 11, 22, 25, 29, and 32 of the 6-week cycle) followed by a 10-day rest period (days 33-42).1,20 For cycles 5-9, the same dosage of bortezomib is administered once weekly during weeks 1, 2, 4, and 5 (days 1, 8, 22, and 29) followed by a 13-day rest period.1,20 In all 9 cycles, melphalan 9 mg/m2 and prednisone 60 mg/m2 are administered orally once daily on days 1-4.1 The manufacturer states that at least 72 hours should elapse between consecutive doses of bortezomib.1

Previously Untreated Mantle Cell Lymphoma

For the treatment of previously untreated mantle cell lymphoma, bortezomib is administered in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as part of the VR-CAP regimen in 3-week cycles for 6 cycles.1 The recommended adult dosage of bortezomib is 1.3 mg/m2 by IV injection over 3-5 seconds twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12-21).1,26 Rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin hydrochloride 50 mg/m2 are administered IV on day 1 and prednisone 100 mg/m2 is administered orally on days 1-5 of each 3-week cycle.1,26 For patients in whom a response is first observed at cycle 6, the manufacturer recommends 2 additional cycles of the VR-CAP regimen.1 The manufacturer states that at least 72 hours should elapse between consecutive doses of bortezomib.1

Relapsed Multiple Myeloma and Mantle Cell Lymphoma

For the treatment of relapsed multiple myeloma and mantle cell lymphoma, the recommended adult dosage of bortezomib for the standard schedule is 1.3 mg/m2 by IV injection over 3-5 seconds or by subcutaneous injection twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12-21).1,4,5 For extended therapy of more than 8 treatment cycles, bortezomib may be administered on the standard schedule or, for patients with relapsed multiple myeloma, on a maintenance schedule consisting of bortezomib 1.3 mg/m2 by IV injection or by subcutaneous injection once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest period (days 23-35).1 The manufacturer states that at least 72 hours should elapse between consecutive doses of bortezomib.1

For the retreatment of multiple myeloma in patients who previously responded to bortezomib-based therapy and relapsed at least 6 months following therapy, the last tolerated dose of bortezomib is administered twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12-21) for up to 8 cycles.1 Bortezomib may be reinitiated with or without dexamethasone.1 The manufacturer states that at least 72 hours should elapse between consecutive doses of bortezomib.1

Induction Therapy Prior to Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma

Bortezomib and Dexamethasone

When bortezomib has been used in combination with dexamethasone† as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients†, bortezomib 1.3 mg/m2 has been administered by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21) of each 21-day cycle for 4 cycles.10002,10012 In cycles 1 and 2, dexamethasone 40 mg was administered orally on days 1-4 and 9-12; in cycles 3 and 4, dexamethasone 40 mg was administered orally on days 1-4.10002,10012

Bortezomib, Dexamethasone, and Thalidomide

Bortezomib has been used in several regimens in combination with thalidomide and dexamethasone† as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients†.10013,10014,10016,10027

When bortezomib has been used in combination with thalidomide and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients, bortezomib 1.3 mg/m2 has been administered by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 and thalidomide 200 mg orally daily (after initial dosage escalation during cycle 1 with 100 mg orally on days 1-14 followed by 200 mg orally daily thereafter).10013 Treatment cycles were repeated every 21 days for 3 cycles.10013

Bortezomib 1.3 mg/m2 also has been administered by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1-4 and 9-12 and thalidomide 200 mg orally daily (after initial dosage escalation during cycle 1 with 50 mg orally on days 1-14 followed by 100 mg orally on days 15-28).10014 Treatment cycles were repeated every 4 weeks for 6 cycles.10014

Bortezomib 1.3 mg/m2 also has been administered by subcutaneous or IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1-4 and 9-12 and thalidomide 100 mg orally daily.10016,10027 Treatment cycles were repeated every 3 weeks for 4 cycles.10016,10027

A modified regimen using reduced dosages of bortezomib and thalidomide10015 is not fully established.10033

Bortezomib, Dexamethasone, and Doxorubicin (or Pegylated Liposomal Doxorubicin)

Bortezomib has been used in several regimens in combination with doxorubicin (or pegylated liposomal doxorubicin) and dexamethasone† as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients†.10023,10024,10026

When bortezomib has been used in combination with doxorubicin and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients, bortezomib 1.3 mg/m2 has been administered by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) along with doxorubicin hydrochloride 9 mg/m2 IV per day on days 1-4 and dexamethasone 40 mg orally on days 1-4, 9-12, and 17-20 of each 28-day cycle for 3 cycles.10023

Bortezomib 1.3 mg/m2 also has been administered by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) along with pegylated liposomal doxorubicin hydrochloride 30 mg/m2 IV on day 4 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 during cycle 1.10024 During cycles 2-6, the same dosages of bortezomib and pegylated liposomal doxorubicin were administered along with dexamethasone 20 mg orally daily.10024 Treatment cycles were repeated every 3 weeks for a total of 6 cycles.10024

A modified regimen using reduced dosages of bortezomib and pegylated liposomal doxorubicin10026 is not fully established.10034

Bortezomib, Dexamethasone, and Cyclophosphamide

Bortezomib has been used in several regimens in combination with cyclophosphamide and dexamethasone† as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients†.10019,10021,10028,10029

When bortezomib has been used in combination with cyclophosphamide and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients, bortezomib 1.3 mg/m2 has been administered by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) along with cyclophosphamide 300 mg/m2 orally on days 1, 8, 15, and 22 and dexamethasone 40 mg orally on days 1-4, 9-12, and 17-20 of each 28-day cycle for 4 cycles.10019

Bortezomib 1.5 mg/m2 also has been administered by IV injection once weekly (days 1, 8, 15, and 22) along with cyclophosphamide 300 mg/m2 orally on days 1, 8, 15, and 22 of each 28-day cycle for 4 cycles, with dexamethasone 40 mg administered orally on days 1-4, 9-12, and 17-20 during cycles 1 and 2 and then once weekly during cycles 3 and 4.10021

Bortezomib 1.3 mg/m2 also has been administered by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) along with cyclophosphamide 300 mg/m2 IV on days 1 and 8 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles (cycles 1-3) followed by bortezomib 1 mg/m2 by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) along with thalidomide 100 mg orally daily and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles (cycles 4-6).10029

Bortezomib 1.3 mg/m2 also has been administered by subcutaneous or IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) along with cyclophosphamide 900 mg/m2 IV on day 1 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles.10028

Dosage Modification for Toxicity !!navigator!!

Dosage Modification in Patients with Newly Diagnosed Multiple Myeloma Receiving Bortezomib with Melphalan and Prednisone (VMP)

The manufacturer of bortezomib states that before administration of any cycle of VMP, platelet counts should be 70,000/mm3 or higher and the absolute neutrophil count (ANC) should be 1000/mm3 or above.1 In addition, any nonhematologic toxicities should have resolved to grade 1 or baseline before any VMP cycle is administered.1

Hematologic Toxicity

If prolonged grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding, was observed in the previous VMP cycle, reduction of the melphalan dose by 25% in the next cycle should be considered.1

If the platelet count is 30,000/mm3 or less or if the ANC is 750/mm3 or less on a day when bortezomib is to be administered (other than on day 1), the dose of bortezomib should be withheld.1 If several doses of bortezomib were withheld because of toxicity in consecutive cycles, it is recommended that the dose of bortezomib be reduced by one dose level (i.e., a dose of 1.3 mg/m2 reduced to 1 mg/m2; a dose of 1 mg/m2 reduced to 0.7 mg/m2).1

Nonhematologic Effects

If nonhematologic toxicities (other than neuropathy) of grade 3 or more in severity occur during VMP therapy, bortezomib therapy should be withheld until symptoms of the toxicity have resolved to grade 1 or baseline.1 Bortezomib may then be reinitiated with a reduction of one dose level (i.e., a dose of 1.3 mg/m2 reduced to 1 mg/m2; a dose of 1 mg/m2 reduced to 0.7 mg/m2).1

If neuropathic pain and/or peripheral neuropathy occurs during VMP therapy, bortezomib should be withheld or the dose reduced as recommended in patients with relapsed multiple myeloma or mantle cell lymphoma who develop such manifestations.1 (See Peripheral Neuropathy under Dosage Modification for Toxicity: Dosage Modification in Patients with Relapsed Multiple Myeloma or Mantle Cell Lymphoma, in Dosage and Administration.)

Dosage Modification in Patients with Newly Diagnosed Mantle Cell Lymphoma Receiving Bortezomib with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (VR-CAP)

The manufacturer of bortezomib states that before administration of cycles 2-6 of VR-CAP therapy, platelet counts should be at least 100,000/mm3, ANC should be at least 1500/mm3, hemoglobin concentration should be at least 8 g/dL, and any nonhematologic toxicities should have resolved to grade 1 or baseline.1

Hematologic Toxicity

If neutropenia of grade 3 or more in severity or platelet count less than 25,000/mm3 occurs on a day when bortezomib is to be administered (other than on day 1 of the cycle), the dose of bortezomib should be withheld for up to 2 weeks until ANC reaches or exceeds 750/mm3 and platelet count reaches or exceeds 25,000/mm3; bortezomib may then be resumed at one dose level lower than the previous dosage (i.e., a dose of 1.3 mg/m2 reduced to 1 mg/m2; a dose of 1 mg/m2 reduced to 0.7 mg/m2).1 If hematologic toxicity has not resolved after withholding bortezomib for 2 weeks, bortezomib therapy should be discontinued.1

Nonhematologic Effects

If nonhematologic toxicities (other than neuropathy) of grade 3 or more in severity occur during VR-CAP therapy on a day when bortezomib is to be administered (other than on day 1 of the cycle), bortezomib therapy should be withheld until symptoms of the toxicity have resolved to grade 2 or less.1 Bortezomib may then be reinitiated with a reduction of one dose level (i.e., a dose of 1.3 mg/m2 reduced to 1 mg/m2; a dose of 1 mg/m2 reduced to 0.7 mg/m2).1

If neuropathic pain and/or peripheral neuropathy occurs during VR-CAP therapy, bortezomib should be withheld or the dose reduced as recommended in patients with relapsed multiple myeloma or mantle cell lymphoma who develop such manifestations.1 (See Peripheral Neuropathy under Dosage Modification for Toxicity: Dosage Modification in Patients with Relapsed Multiple Myeloma or Mantle Cell Lymphoma, in Dosage and Administration.)

Dosage Modification in Patients with Relapsed Multiple Myeloma or Mantle Cell Lymphoma

Peripheral Neuropathy

Adjustment of the dose and/or frequency of administration of bortezomib may be required in patients who develop new or worsening peripheral neuropathy.1 In patients who develop grade 1 peripheral neuropathy (asymptomatic, loss of deep tendon reflexes or paresthesia) without pain or loss of function, no dosage modification is necessary.1 However, in patients who develop grade 1 peripheral neuropathy with pain or grade 2 peripheral neuropathy (moderate symptoms resulting in interference with instrumental activities of daily living), the dose of bortezomib should be reduced to 1 mg/m2.1,5 In patients who develop grade 2 peripheral neuropathy with pain or grade 3 peripheral neuropathy (severe symptoms resulting in interference with self-care activities of daily living), bortezomib therapy should be temporarily discontinued; once manifestations of toxicity have resolved, the drug may be reinitiated at a dosage of 0.7 mg/m2 once weekly.1 Bortezomib therapy should be discontinued in patients who develop grade 4 peripheral neuropathy (sensory neuropathy that is disabling or motor neuropathy that is life threatening or leads to paralysis).1 The manufacturer states that bortezomib should be used in patients with preexisting severe neuropathy only after careful assessment of the risks and benefits for the individual patient.1

Other Nonhematologic or Hematologic Effects

Bortezomib therapy should be temporarily discontinued in patients who develop any grade 3 nonhematologic or grade 4 hematologic toxicities (e.g., grade 4 thrombocytopenia [platelet count less than 25,000/mm3]).1,6 Once manifestations of toxicity have resolved, bortezomib may be reinitiated but dosage of the drug should be reduced by 25% (i.e., a dose of 1.3 mg/m2 reduced to 1 mg/m2; a dose of 1 mg/m2 reduced to 0.7 mg/m2).1

Special Populations !!navigator!!

Bortezomib is metabolized by hepatic enzymes, and exposure to the drug is increased in patients with moderate hepatic impairment (defined as bilirubin concentrations ranging from more than 1.5 to 3 times the upper limit of normal with any AST concentrations) or severe hepatic impairment (defined as bilirubin concentrations exceeding 3 times the upper limit of normal with any AST concentrations).1,23 The manufacturer recommends that doses of bortezomib during the first cycle of treatment be reduced to 0.7 mg/m2 in patients with moderate or severe hepatic impairment.1 Based on patient tolerance, dosage in subsequent cycles may be increased to 1 mg/m2 or further reduced to 0.5 mg/m2.1 The manufacturer states that no adjustment in the initial dose is needed in patients with mild hepatic impairment (defined as bilirubin concentrations at or below the upper limit of normal with AST concentrations exceeding the upper limit of normal or bilirubin concentrations ranging from more than 1 to 1.5 times the upper limit of normal with any AST concentrations); such patients should be treated with the usual recommended initial dosage.1

The pharmacokinetics of bortezomib are not influenced by the degree of renal impairment; therefore, dosage adjustment is not necessary in such patients.1 Because dialysis may decrease bortezomib concentrations, the drug should be administered after a dialysis procedure.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Bortezomib is contraindicated in patients with known hypersensitivity (except for local reactions) to bortezomib, boron, or mannitol.1 Anaphylactic reactions have been reported in patients receiving bortezomib.1

Intrathecal administration of bortezomib is contraindicated.1 Intrathecal administration of bortezomib has resulted in death.1

Warnings/Precautions !!navigator!!

Peripheral Neuropathy

Bortezomib mainly causes sensory peripheral neuropathy, but severe motor peripheral neuropathy also has been reported.1 Patients with preexisting manifestations of peripheral neuropathy (e.g., numbness, pain, or burning sensation in feet or hands) may experience worsening peripheral neuropathy (including grade 3 or higher) during therapy with bortezomib.1

In clinical studies in patients with relapsed multiple myeloma or mantle cell lymphoma, peripheral neuropathy occurred in 38% of patients receiving IV bortezomib and was grade 3 or higher in approximately 11% of patients receiving the drug.1 In the phase 3 randomized study in patients with relapsed multiple myeloma, dosage adjustments resulted in amelioration or resolution of peripheral neuropathy in 48% of patients with grade 2 or higher peripheral neuropathy within a median of 3.8 months from onset.1 In the phase 2 trials in patients with relapsed multiple myeloma, amelioration or resolution of peripheral neuropathy occurred in 73% of patients who discontinued bortezomib therapy because of grade 2 peripheral neuropathy or who had grade 3 or 4 peripheral neuropathy; the median time to improvement of one grade or more from the last dose of bortezomib was 47 days.1 The long-term outcome of peripheral neuropathy has not been elucidated in patients with mantle cell lymphoma.1 About 8% of patients with multiple myeloma or mantle cell lymphoma discontinued IV bortezomib therapy because of peripheral neuropathy.1

In the phase 3 study evaluating subcutaneous administration of bortezomib in patients with relapsed multiple myeloma, grade 2 or higher peripheral neuropathy occurred in 39% of patients receiving bortezomib by IV injection compared with 24% of those receiving subcutaneous bortezomib.1 Grade 3 or higher peripheral neuropathy occurred more frequently in patients receiving bortezomib by IV injection compared with those receiving subcutaneous bortezomib (15 versus 6%).1 (See Dosage and Administration: Reconstitution and Administration.)

Patients receiving bortezomib should be monitored for manifestations of neuropathy (e.g., burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness).1 Adjustment of the dose and/or frequency of administration of bortezomib may be required in patients who experience new onset or exacerbation of peripheral neuropathy.1 (See Dosage and Administration: Dosage Modification for Toxicity.)

Hypotension

In clinical studies in patients with relapsed multiple myeloma or mantle cell lymphoma, hypotension, including orthostatic hypotension, was reported in 8% of patients receiving IV bortezomib; grade 3 or higher hypotension occurred in approximately 2% of patients receiving the drug.1 Hypotension was reported as a serious adverse event in 2% of patients receiving bortezomib, and 1% of patients discontinued bortezomib therapy because of hypotension.1 In addition, less than 1% of patients who developed hypotension also experienced a concurrent syncopal event.1

The manufacturer states that bortezomib should be used with caution in patients with a history of syncope, in patients receiving drugs known to be associated with hypotension, and in patients who are dehydrated.1 Orthostatic hypotension may be managed with adjustment of antihypertensive therapy, hydration, and administration of mineralocorticoids and/or sympathomimetic agents.1

Cardiovascular Effects

Death from cardiogenic shock, congestive heart failure, or cardiac arrest has occurred in patients receiving bortezomib.1 Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported in association with bortezomib therapy, including in patients who had no risk factors for decreased left ventricular ejection fraction.1 Patients with existing heart disease and patients with increased risk for heart disease should be monitored closely during bortezomib therapy.1 In the phase 3 study in patients with relapsed multiple myeloma, the incidence of any treatment-emergent cardiac disorder was 8 or 5% in patients receiving bortezomib or dexamethasone, respectively.1 The incidence of cardiac failure and congestive cardiac failure was similar in patients receiving bortezomib versus dexamethasone (less than 1%); however, acute pulmonary edema, cardiogenic shock, and pulmonary edema each occurred in less than 1% of patients receiving bortezomib compared with none of those receiving dexamethasone.1 Isolated cases of prolonged QT interval have been reported; a causal relationship to bortezomib has not been established.1

Pulmonary Effects

Death from respiratory insufficiency has occurred in patients receiving bortezomib.1 Acute diffuse infiltrative pulmonary disease of unknown etiology (e.g., pneumonitis, interstitial pneumonia, lung infiltration) and acute respiratory distress syndrome, sometimes fatal, have been reported in patients receiving bortezomib.1 Pulmonary hypertension in the absence of left heart failure or substantial pulmonary disease also has been reported.1 If new or worsening cardiopulmonary symptoms occur, a prompt comprehensive diagnostic evaluation should be conducted; temporary interruption of therapy should be considered pending evaluation of symptoms.1

Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred in patients receiving bortezomib.1 RPLS may manifest with seizures, hypertension, headache, lethargy, confusion, blindness, and other visual and neurologic disturbances.1 Brain imaging, preferably magnetic resonance imaging, is used to confirm the diagnosis.1 Bortezomib should be discontinued in patients who develop RPLS.1 The safety of reinitiating bortezomib in patients previously experiencing RPLS has not been established.1

GI Effects

Nausea, diarrhea, constipation, vomiting, loss of appetite, dyspepsia, and dysgeusia can occur in patients receiving bortezomib therapy; ileus also may occur.1 In clinical studies in patients with relapsed multiple myeloma or mantle cell lymphoma, 75% of patients receiving IV bortezomib experienced at least one GI disorder; grade 3 or higher adverse GI effects occurred in approximately 14% of patients receiving the drug, and serious adverse GI effects occurred in 7% of patients.1 About 4% of patients receiving bortezomib discontinued therapy because of adverse GI effects.1

Because adverse GI effects may be severe and sometimes may require use of antiemetics and antidiarrheals, the manufacturer states that fluid and electrolyte replacement should be used in patients receiving bortezomib therapy to prevent dehydration.1 If severe adverse GI effects occur, temporary interruption of therapy is recommended.1

Hematologic Effects

In clinical studies in patients with relapsed multiple myeloma or mantle cell lymphoma, thrombocytopenia was reported in 32% of patients receiving IV bortezomib and was grade 3 or higher in 26% of patients receiving the drug.1 Neutropenia was reported in 15% of patients receiving bortezomib and was grade 3 or higher in approximately 10% of patients receiving the drug.1 Thrombocytopenia or neutropenia was reported as a serious adverse event in 2 or less than 1%, respectively, of patients receiving bortezomib.1 In these studies, thrombocytopenia or neutropenia occurred during days 1-11 of each cycle and platelet and neutrophil counts returned toward baseline during the 10-day rest period.1

Dose-related decreases in absolute neutrophil count (ANC) and platelet count followed a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle.1 The pattern of ANC and platelet count decreases and recovery remained consistent with no evidence of cumulative neutropenia or thrombocytopenia in the regimens evaluated for the treatment of multiple myeloma or mantle cell lymphoma.1

In the phase 3 randomized study in patients with relapsed multiple myeloma, the platelet count nadir in patients receiving bortezomib averaged approximately 40% of the baseline platelet count.1 The severity of thrombocytopenia associated with bortezomib was related to pretreatment platelet count.1 In this study, platelet count less than 10,000/mm3 occurred in 1 (14%) of 7 patients with a baseline platelet count of 10,000-49,999/mm3, in 2 (14%) of 14 patients with a baseline platelet count of 50,000-74,999/mm3, and in 8 (3%) of 309 patients with a baseline platelet count of at least 75,000/mm3; platelet count of 10,000-25,000/mm3 occurred in 5 (71%) of 7 patients with a baseline platelet count of 10,000-49,999/mm3, in 11 (79%) of 14 patients with a baseline platelet count of 50,000-74,999/mm3, and in 36 (12%) of 309 patients with a baseline platelet count of at least 75,000/mm3.1 Grade 3 or higher bleeding events occurred in 2% of patients receiving bortezomib compared with less than 1% of patients receiving dexamethasone.1 GI and intracerebral hemorrhage associated with thrombocytopenia have been reported in patients receiving bortezomib.1

In the phase 3 clinical study evaluating bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) in patients with previously untreated mantle cell lymphoma, grade 4 or higher thrombocytopenia or neutropenia was reported in 32 or 70%, respectively, of patients receiving VR-CAP compared with 1 or 52%, respectively, of those receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).1 Grade 3 or higher bleeding events or grade 4 or higher febrile neutropenia occurred in 1 or 5%, respectively, of patients receiving VR-CAP compared with less than 1 or 6%, respectively, of those receiving R-CHOP.1 Platelet transfusions were administered in 23 or 3% of patients receiving VR-CAP or R-CHOP, respectively.1 Granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor support was administered in 78 or 61% of patients receiving VR-CAP or R-CHOP, respectively.1

The manufacturer states that complete blood cell counts should be performed frequently in patients receiving bortezomib therapy.1 Platelet counts should be monitored prior to the administration of each dose of bortezomib.1 Depending on the severity of thrombocytopenia or neutropenia, temporary interruption of bortezomib followed by dosage reduction may be required.1 (See Dosage and Administration: Dosage Modification for Toxicity.) Supportive care (e.g., transfusions) should be administered according to published guidelines.1

Tumor Lysis Syndrome

Tumor lysis syndrome has been reported in patients receiving bortezomib.1 The risk of tumor lysis syndrome is increased in patients with a large tumor burden; such patients should be monitored closely and appropriate precautions should be taken.1

Hepatic Effects

Acute liver failure has been reported in patients with serious underlying medical conditions who were receiving bortezomib with multiple concomitant drugs.1 Increases in hepatic enzyme concentrations, hyperbilirubinemia, and hepatitis also have been reported.1,16 If such effects occur, the manufacturer recommends interrupting therapy with the drug to assess reversibility of adverse hepatic effects.1 Information on the results of rechallenge with the drug in these patients is limited.1

Fetal/Neonatal Morbidity and Mortality

There are no adequate and well-controlled studies of bortezomib in pregnant women; however, based on animal findings, bortezomib may cause fetal harm.1 Embryofetal toxicity (i.e., decreased fetal weight) and lethality were observed in pregnant animals receiving bortezomib at a dosage approximately 0.5 times the recommended human dosa no evidence of teratogenicity was observed.1

Pregnancy should be avoided during therapy.1 (See Advice to Patients.) If bortezomib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.1

Herpes Virus Infections

In randomized studies in patients with previously untreated or relapsed multiple myeloma, reactivation of varicella zoster virus infection was more common in patients receiving bortezomib (6-11%) compared with those receiving other therapies (3-4%).1 The frequency of herpes simplex virus infection was similar in patients receiving bortezomib and those receiving other therapies (1-3%).1 In the phase 3 study in patients with previously untreated multiple myeloma, reactivation of latent varicella zoster virus infection occurred less frequently in patients receiving bortezomib plus melphalan and prednisone (VMP) with prophylactic antiviral therapy (3%) compared with patients receiving VMP without antiviral prophylaxis (17%).1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

Lactation

It is not known whether bortezomib is distributed into milk.1 Because of the potential for serious adverse reactions to bortezomib in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Pediatric Use

Efficacy of bortezomib has not been established in pediatric patients with relapsed pre-B acute lymphoblastic leukemia (ALL).1 In a study evaluating the activity and safety of bortezomib (1.3 mg/m2 IV) in combination with intensive reinduction chemotherapy in pediatric patients and young adults with lymphoid malignancies, bortezomib did not alter complete remission rates at day 36 in the subset of patients with pre-B ALL compared with a historical control.1 No new safety concerns were identified in this study.1

In pediatric patients, clearance of bortezomib normalized to body surface area (BSA) was comparable to that observed in adults.1

Geriatric Use

Although no overall differences in efficacy or safety were observed between geriatric and younger patients receiving bortezomib, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.1 Exposure to bortezomib may be increased in geriatric patients compared with younger adults.1

Of the 669 patients with relapsed multiple myeloma enrolled in the phase 3 randomized trial, 245 (37%) were 65 years of age or older.1 Among geriatric patients, longer median time to progression (5.5 versus 4.3 months), longer median duration of response (8 versus 4.9 months), and higher rates of overall response (40 versus 18%) were observed for those receiving bortezomib versus dexamethasone.1 Among patients receiving bortezomib, grade 3 or 4 adverse effects were reported in 64% of patients 50 years of age or younger, 78% of patients 51-64 years of age, and 75% of patients 65 years of age or older.1

In patients with multiple myeloma, exposure to bortezomib (based on dose-normalized area under the concentration-time curve [AUC] and peak plasma concentrations) following the first 1- or 1.3-mg/m2 IV dose of the drug was 25% lower in patients younger than 65 years of age compared with older adults.1

Renal Impairment

In a pharmacokinetic study in patients with normal renal function or with varying degrees of renal impairment, exposure to bortezomib (based on dose-normalized AUC and peak plasma concentrations) was comparable among all the groups.1 However, because dialysis may decrease bortezomib concentrations, the drug should be administered after a dialysis procedure.1 (See Dosage and Administration: Special Populations.)

Hepatic Impairment

Bortezomib is metabolized by hepatic enzymes (e.g., cytochrome P-450 [CYP] microsomal enzymes),1,5,6 and exposure to the drug is increased in patients with moderate or severe hepatic impairment.1,23 In a pharmacokinetic study in cancer patients, exposure to bortezomib (based on dose-normalized AUC) was increased by approximately 60% in patients with moderate or severe hepatic impairment compared with patients with normal hepatic function; mild hepatic impairment did not alter the dose-normalized AUC of bortezomib.1 Patients with moderate or severe hepatic impairment should receive reduced initial dosages of bortezomib and be closely monitored for adverse effects.1,23 (See Dosage and Administration: Special Populations.)

Common Adverse Effects !!navigator!!

Adverse effects reported in 10% or more of patients with previously untreated multiple myeloma receiving IV bortezomib plus melphalan and prednisone (VMP) include thrombocytopenia,1,24 neutropenia,1,24 peripheral neuropathy,1,24 nausea,1 diarrhea,1 neuralgia,1 anemia,1,24 leukopenia,1,24 vomiting1 , fatigue,1 constipation,1 lymphopenia,1,24 anorexia,1 asthenia,1 pyrexia,1 paresthesia,1 herpes zoster,1 rash,1 abdominal pain (upper quadrant),1 and insomnia.1 Serious (grade 3 or higher) adverse effects reported in 5% or more of patients receiving VMP include neutropenia,1 leukopenia,1 thrombocytopenia,1 lymphopenia,1 anemia,1 peripheral neuropathy,1 neuralgia,1 diarrhea,1 fatigue,1 asthenia,1 hypokalemia,24 and pneumonia.24

Adverse effects reported in 10% or more of patients with relapsed multiple myeloma receiving IV bortezomib include nausea,1 diarrhea,1 fatigue,1 peripheral neuropathy,1 thrombocytopenia,1 constipation,1 vomiting,1 anorexia,1 pyrexia,1 paresthesia,1 anemia,1 headache,1 neutropenia,1 rash,1 decreased appetite,1 dyspnea,1 abdominal pain,1 dizziness (excluding vertigo),1 and weakness.1 Serious (grade 3 or higher) adverse effects reported in 5% or more of patients receiving bortezomib include thrombocytopenia,1 neutropenia,1 diarrhea,1 peripheral neuropathy,1 anemia,1 and fatigue.1

Adverse effects reported in 10% or more of patients with relapsed multiple myeloma receiving bortezomib by subcutaneous injection include peripheral neuropathy,1,27 thrombocytopenia,1,27 neuralgia,1,27 neutropenia,1,27 anemia,1,27 diarrhea,1,27 leukopenia,1,27 nausea,1,27 pyrexia,1,27 vomiting,27 asthenia,27 weight loss,27 constipation,27 and fatigue.27 Serious (grade 3 or higher) adverse effects reported in 5% or more of patients receiving bortezomib by subcutaneous injection include neutropenia,1,27 anemia,1,27 leukopenia,1,27 peripheral neuropathy,1,27 thrombocytopenia,1,27 and pneumonia.27

Adverse effects reported in 10% or more of patients with previously untreated mantle cell lymphoma receiving IV bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) include neutropenia,1,26 thrombocytopenia,1,26 leukopenia,1,26 anemia,1,26 peripheral neuropathy,1,26 lymphopenia,1,26 diarrhea,1,26 nausea,1,26 pyrexia,1,26 cough,26 constipation,1,26 fatigue,1,26 febrile neutropenia,1,26 loss of appetite,1,26 peripheral edema,26 alopecia,1 asthenia,1,26 pneumonia,26 neuralgia,1 and vomiting.1 Serious (grade 3 or higher) adverse effects reported in 5% or more of patients receiving VR-CAP include thrombocytopenia,1,26 leukopenia,1,26 neutropenia,1,26 anemia,1,26 febrile neutropenia,1,26 lymphopenia,1,26 peripheral neuropathy,1,26 pneumonia,1,26 diarrhea,1,26 and fatigue.1,26

Adverse effects reported in 10% or more of patients with relapsed mantle cell lymphoma receiving IV bortezomib include peripheral neuropathy,1 fatigue,1 diarrhea,1 nausea,1 constipation,1 rash,1 vomiting,1 dizziness (excluding vertigo),1 thrombocytopenia,1 anorexia,1 anemia,1 weakness,1 headache,1 and pyrexia.1 Serious (grade 3 or higher) adverse effects reported in 5% or more of patients receiving bortezomib include peripheral neuropathy,1 fatigue,1 thrombocytopenia,1 and diarrhea.1

Drug Interactions ⬆ ⬇

[Section Outline]

Bortezomib is metabolized principally by cytochrome P-450 (CYP) isoenzymes 1A2, 2C19, and 3A4 and, to a lesser extent, by CYP2C9 and 2D6.1 In vitro, bortezomib may inhibit CYP2C19.1 However, bortezomib is a poor inhibitor of CYP1A2, 2C9, 2D6, and 3A4 and does not induce CYP1A2 or CYP3A4 in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes !!navigator!!

Inhibitors of CYP3A4

Concomitant use of bortezomib with potent inhibitors of CYP3A4 may result in increased systemic exposure of bortezomib.1 Concomitant administration of the potent CYP3A4 inhibitor ketoconazole with bortezomib increased systemic exposure of bortezomib by 35%.1

If bortezomib is used concomitantly with a potent CYP3A4 inhibitor, patients should be monitored for bortezomib-associated toxicity and a reduced dosage of bortezomib should be considered.1

Inducers of CYP3A4

Concomitant use of bortezomib with potent inducers of CYP3A4 may result in decreased systemic exposure and reduced efficacy of bortezomib.1 Concomitant administration of the potent CYP3A4 inducer rifampin with bortezomib is expected to decrease bortezomib exposure by at least 45%, although larger reductions in exposure may occur.1 Concomitant use with St. John's wort ( Hypericum perforatum ) may result in unpredictable decreases in bortezomib exposure.1 Concomitant use of bortezomib with potent inducers of CYP3A4 (e.g., rifampin, St. John's wort) should be avoided.1

Concomitant administration of the weak CYP3A4 inducer dexamethasone with bortezomib did not alter systemic exposure of bortezomib.1

Inhibitors of CYP2C19

Concomitant administration of the potent CYP2C19 inhibitor omeprazole with bortezomib did not alter systemic exposure of bortezomib.1

Melphalan and Prednisone !!navigator!!

Concomitant administration of melphalan and prednisone with bortezomib resulted in a 17% increase in systemic exposure of bortezomib.1 However, the manufacturer states that this increase is unlikely to be clinically relevant.1

Oral Antidiabetic Agents !!navigator!!

In clinical studies, hypoglycemia and hyperglycemia have been reported in patients with diabetes mellitus who received bortezomib concomitantly with oral antidiabetic agents.1,5 If bortezomib is used concomitantly with oral antidiabetic agents, blood glucose concentrations should be monitored carefully and dosage of the antidiabetic agent adjusted as necessary.1

Hypotensive Agents !!navigator!!

Concomitant use of bortezomib with drugs that can cause hypotension may result in an increased risk of hypotension.1 Dosage adjustment of hypotensive agents may be necessary.1

Other Information ⬆ ⬇

Description

Bortezomib, a modified dipeptidyl boronic acid, is an antineoplastic agent.1,4,5 The drug reversibly inhibits the 26S proteasome, a large protein complex that degrades ubiquitinated proteins.1,5 The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells.1 Inhibition of the 26S proteasome by bortezomib prevents targeted proteolysis and causes disruption of normal homeostatic mechanisms, which can lead to cell death.1,5 In vitro studies indicate that bortezomib is cytotoxic to a variety of cancer cell types.1,5 Bortezomib has been shown to cause a delay in tumor growth in vivo in tumor models, including multiple myeloma.1

Systemic exposure to bortezomib was similar following IV or subcutaneous administration in patients with multiple myeloma receiving repeated 1.3-mg/m2 doses of the drug.1,27,31 Bortezomib is approximately 83% bound to plasma proteins.1 In vitro studies indicate that bortezomib is metabolized by the cytochrome P-450 (CYP) enzyme system, principally by isoenzymes 1A2, 2C19, and 3A4, to inactive metabolites; metabolism by isoenzymes 2C9 and 2D6 is minor.1,5 Following repeated IV administration of bortezomib 1 or 1.3 mg/m2 in patients with multiple myeloma, the mean terminal half-life of the drug was 40-193 or 76-108 hours, respectively.1 Exposure to bortezomib is increased in patients with moderate or severe hepatic impairment and in patients 65 years of age or older;1 pharmacokinetics of bortezomib are not influenced by renal impairment or gender.1,23 (See Dosage and Administration: Special Populations and see Specific Populations under Cautions: Warnings/Precautions.)

Advice to Patients

Risk of fatigue, dizziness, syncope, or orthostatic hypotension; do not drive a motor vehicle or operate machinery if any of these symptoms are experienced.1

Risk of dehydration secondary to vomiting and/or diarrhea.1 Importance of advising patients regarding appropriate measures (e.g., adequate fluid intake) to avoid dehydration.1 Importance of advising patients to inform a clinician if dizziness, lightheadedness, fainting spells, or muscle cramps develop.1

Necessity of advising women to use an effective method of contraception and to avoid breast-feeding while receiving bortezomib therapy.1 Importance of women informing a clinician immediately if they are or plan to become pregnant or plan to breast-feed.1 Advise pregnant women of risk to the fetus.1

If used concomitantly with oral antidiabetic agents, importance of frequent monitoring of blood glucose concentrations and informing a clinician of any unusual change.1

Risk of peripheral neuropathy.1 Importance of informing a clinician of new-onset or worsening symptoms of peripheral neuropathy (e.g., tingling, numbness, pain, burning sensation in hands or feet, weakness in arms or legs).1

Risk of reversible posterior leukoencephalopathy syndrome (RPLS).1 Importance of reporting any possible manifestations of RPLS (e.g., seizure, persistent headache, reduced eyesight, blurred vision, confusion, lethargy, inability to think, difficulty walking).1

Risk of cardiac effects.1 Importance of informing clinician if swelling (of the feet, ankles, or legs) or other cardiac-related problems occur.1

Risk of pulmonary effects.1 Importance of informing clinician if shortness of breath, cough, or other pulmonary problems occur.1

Risk of hepatotoxicity.1 Importance of reporting any possible manifestations of hepatotoxicity (e.g., jaundice, abdominal pain [particularly in the right upper quadrant]).1

Importance of informing clinician if rash, severe injection site reactions, or dermatologic pain occurs.1

Risk of reactivation of latent varicella zoster virus infection.1 Importance of discussing with clinician whether antiviral prophylaxis should be initiated.1

Importance of informing clinician if increase in blood pressure, bleeding, fever, constipation, or loss of appetite occurs.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Bortezomib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV or subcutaneous use

3.5 mg

Velcade®

Millennium

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions August 6, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

1. Millennium Pharmaceuticals. Velcade® (bortezomib) for injection prescribing information. Cambridge, MA; 2015 Sept.

2. Food and Drug Administration, Center for Drug Evaluation and Research. Drug information: questions and answers on Velcade. From FDA website. [Web]

3. Anon. Press release: FDA approves VELCADE® (bortezomib) for injection for the treatment of relapsed and refractory multiple myeloma. May 13, 2003. From Millennium website. [Web]

4. Richardson PG, Barlogie B, Berenson J et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med . 2003; 348:2609-17. [PubMed 12826635]

5. Anon. Bortezomomib (Velcade) for multiple myeloma. Med Lett Drugs Ther . 2003; 45:57-58. [PubMed 12865865]

6. Millennium, Cambridge, MA: Personal communication.

7. Multiple myeloma and other plasma cell neoplasms. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2005 Apr 12.

8. Richardson PG, Sonneveld P, Schuster MW et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med . 2005; 352:2487-98. [PubMed 15958804]

9. Dispenzieri A. Bortezomib for myeloma—much ado about something. N Engl J Med . 2005; 352:2546-8. [PubMed 15958811]

10. 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; 127:165-72. [PubMed 15461622]

11. Jagannath S, Barlogie B, Berenson JR et al. Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impaired renal function. Cancer . 2005; 103:1195-200. [PubMed 15690325]

12. Adult non-Hodgkin's lymphoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2005 Jun 23.

13. Goy A, Younes A, McLaughlin P et al. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol . 2005; 23:667-75. [PubMed 15613697]

14. O'Connor OA, Wright J, Moskowitz C et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol . 2005; 23:676-84. [PubMed 15613699]

15. Engelhardt M, Muller AM, Maier W et al. Severe irreversible bilateral hearing loss after bortezomib (VELCADE) therapy in a multiple myeloma (MM) patient. Leukemia . 2005; 19:869-70. [PubMed 15772697]

16. Rosinol L, Montoto S, Cibeira MT et al. Bortezomib-induced severe hepatitis in multiple myeloma: a case report. Arch Intern Med . 2005; 165:464-5. [PubMed 15738379]

17. Jagannath S, Durie BG, Wolf J et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol . 2005; 129:776-83. [PubMed 15953004]

18. Millennium Pharmaceuticals. Velcade® (bortezomib) for injection prescribing information. Cambridge, MA; 2006 Mar.

20. San Miguel JF, Schlag R, Khuageva N et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008; 359:906-17. [PubMed 18753647]

21. 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; 24:4867-74. [PubMed 17001068]

23. Food and Drug Administration, Center for Drug Evaluation and Research. FDA alert: Velcade (bortezomib) Starting dose adjustment for patients with hepatic impairment. Rockville MD: Food and Drug Administration; 2010 Jan 26. Available from FDA website. Accessed 2010 Sep 24. From FDA website. [Web]

24. Mateos MV, Richardson PG, Schlag R 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; 28:2259-66. [PubMed 20368561]

25. Dimopoulos MA, Richardson PG, Schlag R et al. VMP (Bortezomib, Melphalan, and Prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: cohort analysis of the phase III VISTA study. J Clin Oncol . 2009; 27:6086-93. [PubMed 19858394]

26. Robak T, Huang H, Jin J et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med . 2015; 372:944-53. [PubMed 25738670]

27. 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; 12:431-40. [PubMed 21507715]

28. Arnulf B, Pylypenko H, Grosicki S et al. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica . 2012; 97:1925-8. [PubMed 22689676]

29. 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; 160:649-59. [PubMed 23293914]

30. 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; 31:448-55. [PubMed 23233713]

31. Moreau P, Karamanesht II, Domnikova N et al. Pharmacokinetic, pharmacodynamic and covariate analysis of subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma. Clin Pharmacokinet . 2012; 51:823-9. [PubMed 23018466]

10001. San Miguel JF, Schlag R, Khuageva N et al. MMY-3002: A phase 3 study comparing bortezomib-melphalan-prednisone (VMP) with melphalan-prednisone (MP) in newly diagnosed multiple myeloma. Blood. 2007; 110: Abstract 76 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 9). :

10002. Harousseau JL, Mathiot C, Attal M et al. Velcade/Dexamethasone (Vel/D) versus VAD as induction treatment prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM): updated results of the IFM 2005/01 trial. Blood. 2007; 110: Abstract 450 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 10).

10003. Cavo M, Patriarca F, Tacchetti P et al. Bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) in preparation for autologous stem-cell (SC) transplantation (ASCT) in newly diagnosed multiple myeloma (MM). Blood. 2007. 110; Abstract 73 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 9).

10004. Palumbo A, Avonto I, Patriarca F et al. Bortezomib, pegylated-lyposomal-doxorubicin and dexamethasone followed by melphalan 100 mg/m2 in elderly new diagnosed patients: an interim analysis. Blood. 2007; 110: Abstract 448 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 10).

10005. Popat R, Oakervee H, Hallam S et al. Bortezomib, doxorubicin, and dexamethasone (PAD) front line treatment of multiple myeloma: updated results after long term follow up. Br J Haematol. 2008; 141: 512-16. [PubMed 18371113]

10006. Reeder CB, Stewart AK, Hentz JG et al. Efficacy of induction with CyBorD in newly diagnosed multiple myeloma. J Clin Oncol. 2008; 26: Abstract 8517 (presented at the 44th Annual ASCO meeting. Chicago, IL: 2008 May 31).

10007. Reeder C, Reece D, Fonseca Ret al. A phase II trial of myeloma induction therapy with cyclophosphamide, bortezomib and dexamethasone (Cybor-D): improved response over historical lenalidomide-dexamethasone controls. Blood. 2007; 110: Abstract No. 3601.

10008. Jagannath S, Bensinger B, Vescio Ret al. A phase II study of bortezomib (Velcade®), cyclophosphamide (Cytoxan®), thalidomide and dexamethasone as first-line therapy for multiple myeloma. Blood. 2007; 110: Abstract 188 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 10).

10009. Facon T, Mary JY, Hulin C et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomized trial. Lancet. 2007; 370: 1209-18. [PubMed 17920916]

10010. Palumbo A, Bringhen S, Caravita T et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: a randomized trial. Lancet. 2006: 367; 825-831.

10011. Hulin C, Facon T, Rodon P et al. Melphalan-prednisone-thalidomide (MP-T) demonstrates a significant survival advantage in elderly patients ≥ 75 years with multiple myeloma compared with melphalan-prednisone (MP) in a randomized, double-blind, placebo-controlled trial, IFM-01/01. Blood. 2007; 110; Abstract 75 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 9).

10012. Harousseau JL, Attal M, Avet-Loiseau H et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol . 2010; 28:4621-9. [PubMed 20823406]

10013. Cavo M, Tacchetti P, Patriarca F et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet . 2010; 376:2075-85. [PubMed 21146205]

10014. Rosiñol L, Oriol A, Teruel AI et al. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood . 2012; 120:1589-96. [PubMed 22791289]

10015. Moreau P, Avet-Loiseau H, Facon T et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood . 2011; 118:5752-8; quiz 5982. [PubMed 21849487]

10016. Ludwig H, Viterbo L, Greil R et al. Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. J Clin Oncol . 2013; 31:247-55. [PubMed 23091109]

10017. GEM05 for patients with multiple myeloma under 65 years (GEM05MENOS65). From ClinicalTrials.gov registry. Accessed 2016 Nov 18.

10019. Reeder CB, Reece DE, Kukreti V et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia . 2009; 23:1337-41. [PubMed 19225538]

10020. Ludwig H, Greil R, Masszi T et al. Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up. Br J Haematol . 2015; 171:344-54. [PubMed 26153365]

10021. Reeder CB, Reece DE, Kukreti V et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood . 2010; 115:3416-7. [PubMed 20413666]

10022. Reeder CB, Reece DE, Kukreti V et al. Long-term survival with cyclophosphamide, bortezomib and dexamethasone induction therapy in patients with newly diagnosed multiple myeloma. Br J Haematol . 2014; 167:563-5. [PubMed 24974945]

10023. 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; 30:2946-55. [PubMed 22802322]

10024. Jakubowiak AJ, Kendall T, Al-Zoubi A et al. Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol . 2009; 27:5015-22. [PubMed 19738129]

10025. Dytfeld D, Griffith KA, Friedman J et al. Superior overall survival of patients with myeloma achieving very good partial response or better to initial treatment with bortezomib, pegylated liposomal doxorubicin, and dexamethasone, predicted after two cycles by a free light chain- and M-protein-based model: extended follow-up of a phase II trial. Leuk Lymphoma . 2011; 52:1271-80. [PubMed 21699382]

10026. Berenson JR, Yellin O, Chen CS et al. A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients. Br J Haematol . 2011; 155:580-7. [PubMed 21950583]

10027. Moreau P, Hulin C, Macro M et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood . 2016; 127:2569-74. [PubMed 27002117]

10028. Mai EK, Bertsch U, Dürig J et al. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia . 2015; 29:1721-9. [PubMed 25787915]

10029. Bensinger WI, Jagannath S, Vescio R et al. Phase 2 study of two sequential three-drug combinations containing bortezomib, cyclophosphamide and dexamethasone, followed by bortezomib, thalidomide and dexamethasone as frontline therapy for multiple myeloma. Br J Haematol . 2010; 148:562-8. [PubMed 19919652]

10030. Merz M, Salwender H, Haenel M et al. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica . 2015; 100:964-9. [PubMed 25840597]

10031. Lacy MQ, Gertz MA, Dispenzieri A et al. Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc . 2007; 82:1179-84. [PubMed 17908524]

10032. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.

10033. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with thalidomide and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.

10034. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with doxorubicin and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.

10035. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with cyclophosphamide and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.