Bortezomib in multiple myeloma : systematic review and clinical considerations

Bortezomib (Velcade: Millennium Pharmaceuticals, Cambridge, MA, U.S.A.), a first-in-class proteasome inhibitor, has been extensively studied either alone or in combination with other agents for the treatment of multiple myeloma (mm). Bortezomib works in the ubiquitin–proteasome pathway of cellular protein homeostasis by blocking the action of the 26S proteasome, a multicatalytic enzyme that degrades abnormal or misfolded proteins targeted for destruction, particularly those involved in cell cycling and gene transcription. Because those proteins are more abundant during the processes of carcinogenesis, they are key in cancer survival; proteasome inhibition in cancer cells leads to cell apoptosis and is, therefore, a target for therapy1. In 2008, bortezomib was approved by Health Canada for use as a first-line treatment for mm patients who are not candidates for stem-cell transplantation2. Existing consensus-based3,4 and evidence-based5,6 guidelines recommend the use of bortezomib for primary induction therapy in candidates and noncandidates for transplantation, and also for consolidation and salvage therapy after relapse. Given that new data have recently become available, the Hematology Disease Site Group (dsg) at Cancer Care Ontario, in collaboration with the Program in Evidence-Based Care, conducted a systematic review to determine the appropriate use of bortezomib in patients with mm. This review constitutes the evidentiary basis of an updated Cancer Care Ontario guideline on bortezomib for mm and lymphoma (available at https://www.cancercare. on.ca/common/pages/UserFile.aspx?fileId=34323). ABSTRACT


INTRODUCTION
Bortezomib (Velcade: Millennium Pharmaceuticals, Cambridge, MA, U.S.A.), a first-in-class proteasome inhibitor, has been extensively studied either alone or in combination with other agents for the treatment of multiple myeloma (mm).Bortezomib works in the ubiquitin-proteasome pathway of cellular protein homeostasis by blocking the action of the 26S proteasome, a multicatalytic enzyme that degrades abnormal or misfolded proteins targeted for destruction, particularly those involved in cell cycling and gene transcription.Because those proteins are more abundant during the processes of carcinogenesis, they are key in cancer survival; proteasome inhibition in cancer cells leads to cell apoptosis and is, therefore, a target for therapy 1 .
In 2008, bortezomib was approved by Health Canada for use as a first-line treatment for mm patients who are not candidates for stem-cell transplantation 2 .Existing consensus-based 3,4 and evidence-based 5,6 guidelines recommend the use of bortezomib for primary induction therapy in candidates and noncandidates for transplantation, and also for consolidation and salvage therapy after relapse.
Given that new data have recently become available, the Hematology Disease Site Group (dsg) at Cancer Care Ontario, in collaboration with the Program in Evidence-Based Care, conducted a systematic review to determine the appropriate use of bortezomib in patients with mm.This review constitutes the evidentiary basis of an updated Cancer Care Ontario guideline on bortezomib for mm and lymphoma (available at https://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=34323).

ABSTRACT
We conducted a systematic review to determine the appropriate use of bortezomib alone or in combination with other agents in patients with multiple myeloma (mm).We searched medline, embase, the Cochrane Library, conference proceedings, and the reference lists of included studies.We analyzed randomized controlled trials and systematic reviews if they involved adult mm patients treated with bortezomib and if they reported on survival, disease control, response, quality of life, or adverse effects.
Twenty-six unique studies met the inclusion criteria.For patients with previously untreated mm and for candidates for transplantation, we found a statistically significant benefit in time to progression [hazard ratio (hr): 0.48, p < 0.001; and hr: 0.63, p = 0.006, respectively] and a better response with a bortezomib than with a non-bortezomib regimen (p < 0.001).Progression-free survival was longer with bortezomib and thalidomide than with thalidomide alone (p = 0.01).In non-candidates for transplantation, a significant benefit in overall survival was observed with a bortezomib regimen (hr compared with a non-bortezomib regimen: 0.61; p = 0.008), and in transplantation candidates receiving bortezomib, the response rate was improved after induction (p = 0.004) and after a first transplant (p = 0.016).
In previously untreated or in relapsed or refractory mm patients, bortezomib-based therapy has • In patients with mm, what is the efficacy of bortezomib alone or in combination, as measured by survival, quality of life (qol), disease control [for example, time to progression (ttp)], response duration, or response rate?• What is the toxicity associated with the use of bortezomib?• Which patients are more or less likely to benefit from treatment with bortezomib?

Study Selection
Articles were selected for inclusion in this systematic review if they were published full-report articles or meeting abstracts of • randomized studies including adult patients with mm and evaluating bortezomib as a single agent or in combination with other regimens.• systematic reviews (full-report articles only), meta-analyses, or evidence-based clinical practice guidelines of bortezomib in adult patients with mm.
Trials could compare bortezomib with any agent, any combination of agents, or placebo, and could report results on any one or a combination of survival, qol, disease control (for example, ttp), response duration, response rate, and adverse effects.
Articles were excluded if they were clinical practice guidelines without a description of a systematic literature search, abstracts of noncomparative studies, abstract reports of interim analyses, or systematic reviews that were more than 2 years old.Letters, comments, books, news, editorials, or abstract publications of systematic reviews were also excluded, as were articles published in a language other than English.
The methodologist (AEH or FGB) screened the titles and abstracts of the citations identified in the electronic databases and the titles of the abstracts from conference proceedings and excluded reports of studies that did not investigate the use of bortezomib or that did not meet the inclusion criteria for design (that is, they were not randomized trials or systematic reviews for mm).The full text of each remaining article was retrieved, and two authors (AEH or FGB and DER or TCK) reviewed the articles against the selection criteria.
For the evaluation of the quality of included rcts, discrete parameters such as reporting of the sample-size calculation for the study, the randomization method, allocation concealment, blinding, intention-to-treat analysis, final analysis, early termination, losses to follow-up, and ethics approval were considered.

Data Analysis
Data appropriate for meta-analysis were not available because the heterogeneity of the studies did not allow for statistical pooling.A narrative synthesis is therefore presented, and the studies are grouped into untreated mm and into relapsed or refractory disease.

Trial Quality
Two trials reported in abstract form were randomized noncomparative phase ii trials 18,65  arms within each trial on any outcome, neither trial is further discussed here.
Table ii shows the quality assessment of the remaining rcts.
Among the studies reported in abstract form, one study stated that the analysis was final 63 .The other five 69,70,73,75,79 were identified as interim; they are not shown in Table ii and will not be discussed further.

Previously Untreated MM Indirect Comparison:
The network meta-analysis by Kumar et al. 10    Trial was terminated early on recommendation from Data and Safety Monitoring Board after a planned interim analysis demonstrated significantly improved ttp in the bortezomib arm compared with dexamethasone.The a priori sample size requirement was met, but follow-up ended at the early termination date, and all patients in the dexamethasone arm were offered bortezomib.

indirectly compared bortezomib
b Data on overall survival, a secondary outcome, will continue to be collected by the authors, and a final analysis of that outcome will be conducted when 80% of patients have died. c Trial was terminated early on recommendation from Data and Safety Monitoring Board after a planned interim analysis at 230 events demonstrated significantly improved ttp in the pegylated liposomal doxorubicin plus bortezomib arm compared with the bortezomib-alone arm.and thalidomide (both in combination with melphalan and prednisone) in newly diagnosed mm patients.
No differences were detected for most outcomes, but benefits in cr [relative risk (rr): 2.34; 95% confidence interval (ci): 1.12 to 4.90] and in grade 3 or 4 adverse events (rr: 0.53; 95% ci: 0.38 to 0.73) were observed in favour of the bortezomib combination.

3.3.2
Relapsed or Refractory MM Seven rcts examined the use of bortezomib in patients with relapsed or refractory mm.All studies but one were fully published reports.Three included only bortezomib-naïve patients 20,23,25 ; the remaining four 17,22,30,83 included patients who had previously received treatment for mm, including bortezomib.Table iv details the characteristics of the study patients.
The primary outcomes in the studies of patients with relapsed or refractory mm were ttp 21,23,30 , pfs 25,83 , and toxicity 17 .Reece et al. 22 reported on pharmacodynamic and pharmacokinetic parameters, response, and the toxicity of bortezomib.

Question: What is the efficacy of bortezomib alone or in combination?
The subsections that follow summarize the results of the included trials.Detailed efficacy data can be found in Table v.

3.4.1
Previously Untreated MM TTP: Among the studies of patients who were not candidates for asct, the vista study 24 found a significant difference in ttp after induction with bortezomib compared with a non-bortezomibcontaining regimen (hr: 0.48; p < 0.001).The other studies either did not report results for this endpoint 21,26,82 or did not find a significant difference when comparing bortezomib in two different combination regimens 19 .None of the studies involving patients who were candidates for asct reported on this endpoint.
Overall Survival: Among studies of patients who were not candidates for asct, the vista trial 24,56,57 reported a statistically significant difference in overall survival (os) when bortezomib was compared with a non-bortezomib-containing regimen (hr: 0.65; p < 0.001).In the studies of transplant patients, Sonneveld et al. 31 demonstrated a statistically significant difference in os (hr: 0.77; 95% ci: 0.60 to 1.00; p = 0.049); in the other studies, median os was not significantly different for the control groups or was not estimable (see Table v).
PFS: Among studies of patients who were not candidates for asct, Palumbo et al. 21found a statistically significant difference in pfs favouring bortezomib in a 4-drug combination induction regimen plus bortezomib-containing maintenance compared with bortezomib in a 3-drug combination induction alone (hr: 0.67; p = 0.008).In a related abstract publication, Niesvitzky et al. found no significant difference in pfs between the treatment arms 82 .
Among the studies of patients who were candidates for asct, Sonneveld et al. 31 found a significantly longer pfs in patients allocated to bortezomib, doxorubicin, and dexamethasone than in patients allocated to vincristine, doxorubicin, and dexamethasone (hr: 0.74; 95% ci: 0.62 to 0.89; p < 0.001).Cavo et al. 15 suggested a significantly better pfs, projected to be 36 months, for bortezomib, dexamethasone, and thalidomide compared with dexamethasone and thalidomide (hr: 0.63; 95% ci: 0.45 to 0.88; p < 0.006).Harousseau et al. 16 compared a bortezomib-dexamethasone combination with a vincristine-doxorubicin-dexamethasone combination, but pfs did not reach statistical significance in favour of the bortezomib arm (p = 0.057).In an abstract publication, Rosinol et al. 84 found that pfs was statistically significantly longer in the bortezomib-thalidomide arm than in the thalidomide-alone or interferon arms (pfs at 2 years: 78% vs. 63% vs. 49%; p = 0.01).QOL: Health-related qol was measured using various domains of the European Organisation for Research on Treatment of Cancer Quality of Life Questionnaire-Core (qlq-C30) 88 in two studies 47,76 .In a subanalysis of the vista trial 24 , Dhawan et al. 47 showed that newly diagnosed mm patients treated with bortezomib, melphalan, and prednisone had a higher sustained rate of improvement in health-related qol than did patients treated with melphalan and prednisone (14 of 15 domains).They also reported a statistically significant improvement in 3 domains: Nausea/ Vomiting (p = 0.0095), Appetite Loss (p = 0.0170), and Diarrhea (p = 0.0082) 47 .Niesvitsky et al. 76 found no statistically significant differences between arms.

Response Rate:
In patients who were not candidates for asct, cr and overall response (or) were found to be statistically significantly different for a bortezomib compared with a non-bortezomibcontaining regimen (cr: 30% vs. 4%, p < 0.001; or:   71% vs. 35%, p < 0.001) 24 and for a 4-drug-plusmaintenance combination compared with a 3-drug combination (cr: 38% vs. 24%, p < 0.001; or: 59% vs. 50%, p = 0.03) 21 .No statistically significant difference was found when comparing two 3-drug combinations containing bortezomib 19 .Among patients who were candidates for transplantation, Harousseau et al. 16 found a statistically significant difference in cr in favour of a bortezomibdexamethasone combination both after induction and after a first transplant (induction: 14.8% vs. 6.4%, p = 0.004; first transplant: 16.1% vs. 8.7%, p = 0.016).Sonneveld et al. 31 found a statistically significant difference in cr in favour of bortezomib at induction and at maintenance (7% vs. 2% and 21% vs. 9% respectively, p < 0.001).For or after first transplant, no statistically significant difference was detected 16 .Cavo et al. 15 reported a significant difference in cr in favour of bortezomib-dexamethasone-thalidomide compared with thalidomide-dexamethasone at induction, after first transplantation, at second transplantation after consolidation, and overall (p values shown in Table iv).Moreau et al. 28 found no statistically significant difference in cr and objective response rate between study arms.
Response Rate: No significant difference in or or cr was detected between bortezomib monotherapy and bortezomib plus pld 20 .Bortezomib monotherapy was significantly better than dexamethasone for cr and or ( p < 0.001) 33 .Bortezomib in a 3-drug    1.69 hr: 1.82        combination with thalidomide and dexamethasone was better than thalidomide and dexamethasone in improving or and cr (45% vs. 25%, p < 0.001, and 45% vs. 11%, p < 0.001) 30 .

QOL:
The qlq-C30 was used in two studies 25,36 to measure qol. Lee et al. 36 reported qol for patients in the vista trial (originally reported by Richardson et al. 23 ).The authors assessed health-related qol using the qlq-C30 89 and adverse events with neurotoxicity symptoms using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity subscale 88,90 .Quality of life was assessed at baseline and every 6 weeks thereafter up to 42 weeks from baseline.A statistically significant difference in Global Health Status favouring bortezomib over dexamethasone during the 42 weeks of the study (p = 0.001) was reported.In addition, the authors reported a statistically significant difference in overall Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity score in favour of bortezomib (p = 0.02).On the other hand, Hjorth et al. 25 found no statistically significant difference between study arms comparing bortezomib with thalidomide (both combined with dexamethasone).

Toxicity
Question: What is the toxicity associated with the use of bortezomib?

3.5.1
Previously Untreated MM Studies in the previously untreated population showed a significant increase in peripheral neuropathy in the bortezomib group when a drug combination including bortezomib was compared with a nonbortezomib-containing regimen 15,16,24,31 .In addition, San Miguel et al. 24 reported higher incidences of diarrhea and nausea in their bortezomib group than in their control group (8% vs. 1% and 4% vs. <1% respectively, p not reported).Table vi presents detailed data on adverse events.
The studies that compared various drug combinations containing bortezomib showed a higher incidence of neutropenia (38% vs. 28%, p = 0.02) 21 and peripheral neuropathy (10% vs. 2%, p < 0.0004) 15 with a 4-drug combination than with a 3-drug combination.A higher incidence of peripheral neuropathy was found when drug combinations with higher bortezomib doses were used (11% vs. 3%, p < 0.003) 28 .The incidence of neutropenia was also higher with a 3-drug combination containing an alkylating agent than with a 3-drug combination containing an immunomodulatory agent (39% vs. 22%, p = 0.008) 19 .Sonneveld et al. 31 reported a higher incidence of peripheral neuropathy in a bortezomib-containing combination (24% vs. 10%, p < 0.01).Palumbo et al. 21lso reported a higher incidence of cardiac events and thromboembolism with a 4-drug combination than with a 3-drug combination (10% vs. 5%, p = 0.04, and 5% vs. 2%, p = 0.05, respectively).Mateos et al. 19 showed that, compared with bortezomib combined with melphalan and an alkylating agent, a 3-drug combination including bortezomib and an immunomodulatory agent was favourable for a significantly lower incidence of thrombocytopenia, neutropenia, and infections (Table vi).However, the same study found a significant difference favouring the 3-drug combination including bortezomib and an alkylating agent for adverse events necessitating discontinuation of the drug and for overall serious adverse events (Table vi).The incidence of cardiac events was also significantly higher in the group that received bortezomib combined with an immunomodulatory agent than in the group that received a combination of bortezomib and an alkylating agent (8% vs. 0%, p = 0.001) 19 .Kumar et al. 26 reported a higher incidence of treatment-related deaths from renal failure in the 4-drug combination that included an immunomodulatory and an alkylating agent (Table vi).

3.5.2
Relapsed and Refractory MM Our review found a higher incidence of hematologic events (Table vi) and peripheral neuropathy, and a significantly higher incidence of diarrhea and nausea (7% vs. 2% and 2% vs. 0% respectively, p < 0.01), in patients with relapsed or refractory mm who received bortezomib than in those who received dexamethasone (control) 23 .Orlowski et al. 20 also showed an increased incidence of neutropenia (Table vi), diarrhea, and nausea in a bortezomib-pld group than in a bortezomib-alone group (7% vs. 4%, p = 0.034, and 2% vs. <1%, p = 0.0241, respectively).A higher incidence of peripheral neuropathy and thrombocytopenia was observed by Sonneveld et al. 31 in patients who received bortezomib in combination with other drugs than in those who received bortezomib alone or a non-bortezomib-containing drug combination (24% vs. 10%, p < 0.001, and 10% vs. 5%, p < 0.01).When various doses of bortezomib were compared, Moreau et al. 28 also showed a higher incidence of peripheral neuropathy with higher doses of bortezomib (11% with full dose vs. 3% with reduced dose, p = 0.03).
Adverse events leading to discontinuation of treatment occurred in 37% of a bortezomib group compared with 29% of a dexamethasone group (reported by Richardson et al. 23 ).A corollary report from the apex study 23 by Chanan-Khan 35 examined the incidence of herpes zoster events in patients treated with bortezomib.The authors found that a significantly higher incidence of herpes zoster was associated with bortezomib than with the control dexamethasone treatment (13% vs. 5%, p = 0.0002).

Subgroups
Question: Which patients are more or less likely to benefit from treatment with bortezomib?e598 Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

3.6.1
Previously Untreated MM The combination of melphalan-prednisone-bortezomib produced better results than did melphalanprednisone 24 in these subgroups: • Patients 75 years of age and older: ttp was identical in the younger and older groups; cr was 26% in the older group and 32% in the younger group, p = 0.29; os, p = 0.17 • Patients with impaired renal function: cr, ttp, and os did not differ for 159 patients with normal renal function and for 185 patients with a creatinine clearance less than 60 mL/min Also, although cytogenetic studies were not available in all participants, the 26 patients with a high-risk cytogenetic profile [t(4;14), t(14;16), and del17p] did not differ from the 142 patients with a standard profile in cr (both groups: 28%), ttp (p = 0.55), and os (p = 0.99) 24 .
In the study by Mateos et al. 19 , patients with cytogenetic abnormalities [t(4;14), t(14;16), and del17p (44 vs. 187)] in both treatment groups did not differ for cr, but experienced shorter pfs and os at induction (hr: 0.6, p = 0.01, and hr: 0.5, p = 0.01, respectively) and maintenance (p = 0.01 and p < 0.0001 respectively).In the study by Neben et al. 71 , a companion study of the hovon-65 study 31 , patients with all chromosomal aberrations treated with bortezomibdoxorubicin-dexamethasone experienced a pfs and os similar or superior to those of patients treated with vincristine-doxorubicin-dexamethasone.The patients that seemed to benefit more from bortezomib treatment had del(17p13): their pfs duration was 26.2 months compared with 12 months in peers not receiving bortezomib (p = 0.024); the associated 3-year os rates were 69% and 17% (p = 0.028).

3.6.2
Relapsed or Refractory MM Extensive subset analyses have been performed using data from the apex trial 23 of bortezomib compared with dexamethasone for relapsed or refractory myeloma [32][33][34][35][36][37][38][39] .Bortezomib was consistently superior to dexamethasone in patients 65 years of age and older (response rate: p = 0.0004; ttp: p = 0.002); in patients with International Staging System stage ii and iii disease (response rate: p < 0.0004; ttp: p = 0.0002); in patients refractory to the most recent therapy and in those who had previously received more than one line of therapy (both subgroups-response rate: p < 0.0001; and ttp: p < 0.0001) 32 ; and in patients with renal impairment 34 .Similarly, bortezomib-pld was more efficacious than bortezomib alone in most subgroups analyzed, including patients of any age; patients with refractory disease; patients with elevated β 2 -microglobulin; and patients previously exposed to asct, anthracyclines, and immunomodulatory drugs (thalidomide or lenalidomide) 20,41 .An advantage for bortezomib-pld compared with bortezomib alone was also observed in patients with cytogenetic abnormalities except for deletion 13q 20 .

DISCUSSION
Introduction of the melphalan-prednisone-bortezomib combination in newly diagnosed mm patients significantly improved outcome in patients who are not candidates for asct 24 .Eligible patients include those more than 65-70 years of age and those with concomitant medical conditions felt to increase the risks of asct.Compared with melphalan and prednisone alone, melphalan-prednisone-bortezomib in a finite course (9 cycles) improved ttp and os and resulted in better or and cr rates.Surprisingly, hematologic toxicity was not increased, and other toxicity rates were similar to those observed in various series using bortezomib.Melphalan-prednisone-bortezomib was superior in all patient subgroups and might have particular benefit in patients with poor prognostic factors in whom melphalan-prednisone has limited efficacy, such as patients with a high β 2 -microglobulin level and adverse cytogenetics.
Making a direct comparison to initial therapy with melphalan-prednisone-thalidomide is difficult.A previously reported systematic review 91 that forms the evidence base of an earlier practice guideline (evidence-based series report #6-21: Thalidomide in Multiple Myeloma) 92 indicated that melphalanprednisone-thalidomide is the preferred treatment option for patients with mm who are not eligible for asct.However, given the lack of actual comparative evidence and the recognition that thalidomide can be difficult to obtain or to tolerate, physicians and patients might choose to initiate therapy with bortezomib-containing therapy-a choice that is currently supported by a network meta-analysis that showed no difference for all outcomes and a significant benefit for cr (rr: 2.34; 95% ci: 1.12 to 4.90) and for grades 3 and 4 adverse events (rr: 0.53; 95% ci: 0.38 to 0.73) in favour of bortezomib 10 .In particular, bortezomib-based therapy might be preferred in patients with disease-related renal dysfunction or cytogenetic abnormalities.Studies testing lenalidomide and dexamethasone as an upfront option are still ongoing, with no results yet available (search for NCT01554852 at http://clinicaltrials.gov/).
In mm, most studies have indicated that patients who achieve a cr, a near-cr (same as cr, but residual monoclonal protein by immunofixation only), or in some instances, a very good partial remission (defined as >90%), particularly after asct, have superior rates of pfs and os compared with lesser degrees of response.Many phase ii studies of combination regimens containing novel agents such as bortezomib as first-line therapy have reported higher rates of cr, near-cr, or very good partial remission before asct compared with the rates observed with older regimens such as vi ncr isti ne -doxorubicin-dexamethasone or Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).dexamethasone alone.One approach to improving the results of asct therefore involves using novel agents upfront so that patients will go into transplantation with a greater depth of remission (on the hypothesis that rates of cr or near-cr, and hence survival, will be improved after asct).Several phase iii randomized trials comparing bortezomib-containing induction regimens were designed to test that hypothesis 15,16 .Those trials found a statistically significant better cr and a favourable pfs in the bortezomib arm.In addition, two studies further supported the use of bortezomib before asct.In the study by Sonneveld et al. 31 , an os benefit was suggested for a bortezomibbased combination before asct given with bortezomibbased consolidation after asct.The dsg is also aware of a study-level meta-analysis, so far published only in abstract form and therefore excluded from this systematic review, which supports a survival benefit with the use of bortezomib before asct 93 .Given the benefits and the recognized toxicities associated with earlier chemotherapy-based regimens, the dsg considers bortezomib-based induction to be a recommended option before asct.
Despite effective first-line therapy, nearly all mm patients eventually relapse and require further therapy.Options for management of recurrent mm include reinstitution of the initial treatment if the duration of response was prolonged, a second asct as salvage therapy, alkylating agents with corticosteroids, high-dose dexamethasone, or thalidomide alone or in combination with corticosteroids.Lenalidomide is now approved by Health Canada for use with dexamethasone in the treatment of mm that has progressed after at least 1 prior treatment regimen.Many phase i-ii trials have combined novel agents, particularly bortezomib, with conventional cytotoxic agents or other novel agents as first-line therapy.Evidence fr om rcts supports the use of bortezomib in combination with pld in patients with relapsed or refractory mm 20 .In patients who cannot tolerate that therapy, the use of bortezomib alone for relapsed or refractory disease is recommended by the dsg.
The Hematology dsg has already recommended bortezomib monotherapy for patients with mm refractory to or relapsing within 1 year of the conclusion of initial or subsequent treatments and who are candidates for further therapy 94 .That recommendation was made based on the benefit in os and ttp observed in the apex trial 23 .The extended follow-up of apex reported by Richardson et al. 33 indicates that the benefit still exists.In relapsed and refractory mm, bortezomib monotherapy and combination therapy with pld are both effective approaches.However, compared with bortezomib alone, the combination with pld improves ttp, pfs, and os significantly 20 .The magnitude of the benefit for the combination of bortezomib and pld is identical to that seen for bortezomib alone compared with dexamethasone in the original pivotal trial of bortezomib, the apex trial 23,33 .However, whether the benefit applies to all patients with mm is unknown, because the authors excluded patients who had previously received more than 240 mg/m 2 or an equivalent dose of doxorubicin 20 .Particular advantages of the pld-bortezomib combination are its avoidance of the use of corticosteroids (which are required in most of the other anti-mm regimens), its efficacy in high-risk groups, and its effectiveness after prior exposure to immunomodulatory derivatives.However, the combination is associated with more toxicity-specifically, myelosuppression, gastrointestinal toxicity, and hand-foot syndrome.Bortezomib monotherapy might therefore be preferable in patients with coexisting medical conditions or in frail patients.

CONCLUSIONS
In patients with previously untreated mm who are not candidates for asct, bortezomib combined with melphalan and prednisone is the preferred firstline therapy.In patients who are eligible for asct, bortezomib-based induction before transplantation is a recommended option.
In patients with relapsed or refractory mm, the combination of pld plus bortezomib is a more effective treatment option than is bortezomib alone.The combination can be considered for use in patients with a cumulative doxorubicin dose less than 240 mg/m 2 (or the equivalent).In patients with poor steroid tolerance, with brittle bones, or with diabetes mellitus, this combination is particularly useful.For individuals who cannot access or tolerate this therapy, treatment with bortezomib alone is recommended.Consideration should be given to the use of antiviral prophylaxis against herpes zoster (shingles), because that condition is now recognized to occur more frequently during bortezomib therapy 23,35 .
For specific details related to the administration of bortezomib therapy, the authors suggest that clinicians refer to the protocols used in the major trials and to the product monograph.Most toxicities are reversible if dose modification guidelines are followed.

ACKNOWLEDGMENTS
The Program in Evidence-Based Care is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario.All work produced by the Program in Evidence-Based Care is editorially independent from its funding source.

CONFLICT OF INTEREST DISCLOSURES
The authors of this report disclosed potential conflicts.One author (DER) was the principal investigator or the local investigator and received research funding for four trials.DER was also a consultant for

figure 1
figure 1 Systematic review on bortezomib for multiple myeloma (mm): study flow chart.ASH = American Society of Hematology; ASCO = American Society of Clinical Oncology; RCT = randomized controlled trial; abs = abstract.
Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
population (B-M-P: n = 337; M-P: n = 331).b Median follow-up was 36.7 months for overall survival and 16.3 months for time to progression in the original publication.An update 55 confirmed a statistically significant survival benefit for B-M-P compared with M-P at a median follow-up of 25.9 months (hr: 0.64; p = 0.003).In a further publication 59 , 3-year rates of overall survival were estimated at 68.5% for B-M-P compared with 54% with M-P.c Results for primary outcome.d Bortezomib on a weekly schedule.e The original data cut-off was April 28, 2006, at which time the median follow-up was 7.2 months; survival and time to event data were reanalyzed with a data cut-off of November 28, 2006, upon request by the U.S. Food and Drug Administration.Median follow-up for overall survival and time to progression were not reported.f Results in the evaluable population (B-D: n = 223 after induction, n = 197 after first transplant; V-Dox-D: n = 218 after induction, n = 184 after first transplant).g Median overall has not been reached in either group.Overall survival rates were 81.4% with B-D and 81.4% with V-Dox-D.h The estimated 3-year overall survival was 86% compared with 84% (p = 0.30).i Data from an additional publication 41 .j Terminated early because of low accrual.pfs = progression-free survival; ttp = time to progression; or = odds ratio; cr = complete response; os = overall survival; asct = autologous stem-cell transplantation; Int = intervention group; B = bortezomib; M = melphalan; P = prednisone; nr = not reported; hr = hazard ratio; ne = not reached or not estimable; T = thalidomide; ns = statistically nonsignificant; D = dexamethasone; C = cyclophosphamide; L = lenalidomide; abs.= abstract; E = etoposide; Cis = cisplatinum; V = vincristine; Dox = doxorubicin; ato = arsenic trioxide; peg-Dox = pegylated liposomal doxorubicin; ci = confidence interval.
Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

c
In addition, bortezomib alone was discontinued in another 19% of patients.d Deaths within 30 days after the last study medication.e Adverse events reported during induction.f A significant difference was reported for between-groups grades 1-4 herpes zoster (p < 0.05).g Grade 3 adverse event.h Adverse events reported during induction.Pts = patients; asct = autologous stem-cell transplantation; B = bortezomib; M = melphalan; P = prednisone; ns = statistically nonsignificant; nr = not reported; abs.= abstract; T = thalidomide; D = dexamethasone; C = cyclophosphamide; L = lenalidomide; ato = arsenic trioxide; V = vincristine; Dox = doxorubicin; E = etoposide; Cis = cisplatinum; peg-Dox = pegylated liposomal doxorubicin.SYSTEMATIC REVIEW OF BORTEZOMIB IN MULTIPLE MYELOMA e597 Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

e575 Current OnCOlOgy-VOlume 21, number 4, August 2014
. Because the authors of those trials did not compare the treatment Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

table i
Primary and additional publications of identified randomized trials of bortezomib in multiple myeloma Compare the number needed to treat as a measure of drug benefit from data in the apex apexRichardson et al., 2005 23Efficacy: bortezomib compared with high-dose dexamethasone in relapsed disease Richardson et al., 2007 32 Update of apex results Richardson et al., 2007 33 Extended follow-up San-Miguel et al., 2008 34 Subgroup analysis of patients with renal impairment Chanan-Khan et al., 2008 35 Herpes zoster events in bortezomib-treated patients Lee et al., 2008 36 Health-related qol analysis Niesvizky et al., 2008 37 Response and clinical benefit in bortezomib-treated patients Richardson et al., 2009 38 Reversibility of peripheral neuropathy in bortezomib-treated patients Vogl et al., 2009 39Prior exposure to specific therapies

Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright
vista San Miguel et al., 2008 24 Efficacy: melphalan-prednisone compared with melphalan-prednisone-bortezomib in previously untreated disease San Miguel et al., 2008 45 (abs.)Updated follow-up and results of subsequent therapy Harousseau et al., 2008 46 Assess the prognostic impact of response on time-to-event parameters Dhawan et al., 2009 47 (abs.)Health-related qol Dimopoulos et al., 2009 48 Subgroup of patients with renal impairment Mateos et al., 2010 49 e577 Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).(abs.)Efficacy and toxicity: bortezomib-thalidomide-dexamethasone compared with bortezomib-thalidomide-dexamethasone plus cyclophosphamide in previously untreated patients gimema Cavo et al., 2010 15 Effectiveness: bortezomib-thalidomide-dexamethasone compared with thalidomide-dexamethasone as front-line therapy Cavo et al., 2009 58 (abs.)© 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

asct Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright
© 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

e581 Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright
© 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).itt Final Palumbo et al., 2010 21 B-M-P-T plus pfs 250 Per arm to detect Int: 254 os Moreau et al., e583 Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).itt Final Hjorth et al., 2012 25 T-D vs. B-D nr Sonneveld et al., nr e584 Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
Table iii details inclusion criteria and intervention details for those trials.

e586 Current OnCOlOgy-VOlume 21, number 4, August 2014
Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).e587 Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
Years of age or older, with relapsed disease Significant cardiac disease, active systemic infection, 61.5 anc 1000 μL or greater, creatinine clearance 30 mL/min or greater e589 Current OnCOlOgy-VOlume 21, number 4, August 2014 Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).