Bortezomib in Multiple Myeloma and Lymphoma

Transcription

1 CED-CCO Special Advice Report 11 ARCHIVED 2012 Bortezomib in Multiple Myeloma and Lymphoma D. Reece, T. Kouroukis, A.E. Haynes, K. Imrie Report Date: November 24, 2008 This CED-CCO Special Advice Report was ARCHIVED IN The report, which consists of consists of a Summary and a Full Report, is available on the CCO web site ( This report updates the evidence and recommendations in Evidence-based Series Report 6-18: Bortezomib in Multiple Myeloma and Lymphoma dated April 3, For information about the PEBC and the most current version of all reports, please visit the CCO web site at or contact the PEBC office at: Phone: ext Fax: ccopgi@mcmaster.ca Report Citation (Vancouver Style): Reece D, Kouroukis T, Haynes AE, Imrie K. Bortezomib in multiple myeloma and lymphoma. Toronto (ON): Cancer Care Ontario; 2008 Nov 24 [Archived 2012]. Program in Evidence-based Care CED-CCO Special Advice Report No.: 11 Archived.

2 CED-CCO Special Advice Report 11 ARCHIVED 2012 Bortezomib in Multiple Myeloma and Lymphoma D. Reece, T. Kouroukis, A.E. Haynes, K. Imrie The 2008 guideline recommendations are ARCHIVED This means that the recommendation will no longer be maintained but may still be useful for academic or other information purposes. This report updates the evidence and recommendations in Evidence-based Series Report 6-18: Bortezomib in Multiple Myeloma and Lymphoma dated April 3, Report Date: November 24, 2008 SUMMARY QUESTION 1. In patients with multiple myeloma, Waldenstrom s macroglobulinemia, or lymphoma, what is the efficacy of bortezomib alone or in combination, as measured by survival, quality of life, disease control (e.g., time-to-progression), response duration, or response rate? 2. What is the toxicity associated with the use of bortezomib? 3. Which patients are more or less likely to benefit from treatment with bortezomib? TARGET POPULATION This evidence-based series applies to adult patients with multiple myeloma, Waldenstrom s macroglobulinemia, or lymphoma of any type, stage, histology, or performance status.

3 RECOMMENDATIONS The following recommendations reflect the opinions of the authors of this special advice report. Multiple Myeloma Relapsed and Refractory The combination of bortezomib and pegylated liposomal doxorubicin (PLD) is the recommended treatment option for patients with relapsed or refractory multiple myeloma refractory to or relapsing within one year of the conclusion of initial or after subsequent treatment(s) (including autologous stem cell transplantation) who are candidates for further chemotherapy who have received less than 240 mg/m 2, or the equivalent cumulative dose of doxorubicin, who have a left ventricular ejection fraction in the normal range and who would be expected to tolerate the myelosuppression of combination therapy. Key Evidence One randomized controlled trial (RCT) compared bortezomib plus PLD (n=324) to bortezomib alone (n=322) in patients with relapsed or refractory multiple myeloma (1) and reported that overall survival at 15 months was superior for the combination compared to bortezomib monotherapy (76% vs. 65%; HR 0.71, 95% confidence interval [CI] 0.43 to 0.998, p=0.0476). Median time-to-progression was also significantly higher in the PLD plus bortezomib arm (9.3 months vs. 6.5 months, respectively; HR 0.55, 95% CI 0.43 to 0.71). For patients with myeloma refractory to or relapsing within one year of the conclusion of initial or after subsequent treatment(s) (including autologous stem cell transplantation) who are candidates for further chemotherapy and are not candidates for the combination of bortezomib and PLD, bortezomib monotherapy is recommended as the preferred treatment option. Key Evidence One RCT compared bortezomib monotherapy (n=333) to dexamethasone (n=336) in patients with relapsed or refractory multiple myeloma (2,3) and reported that median overall survival was significantly higher for patients who received bortezomib (29.8 months versus [vs.] 23.7 months; HR 0.77, p=0.027). Median time-to-progression was also significantly higher in the bortezomib arm (HR 0.55, p<0.001). Of note, grade 3 adverse events were more common in the bortezomib arm (61% vs. 44%, p<0.01). It is the opinion of the authors that bortezomib with or without PLD, as described above, is also a reasonable option for patients relapsing at least one year after initial therapy with or without autologous stem cell transplantation and that thalidomide, alkylating agents, or repeat transplantation may also be options for these patients. However, evaluation of these other options is beyond the scope of this report. Key Evidence Bortezomib + PLD has only been compared to bortezomib alone, and bortezomib monotherapy has only been compared with dexamethasone as a treatment for relapsed or refractory multiple myeloma. Neither regimen has not been directly compared to the other listed options. Multiple Myeloma - Previously Untreated ii

4 For patients with previously untreated multiple myeloma who are ineligible for autologous stem cell transplantation, the combination of bortezomib, melphalan, and prednisone is an acceptable first-line treatment option and preferred over treatment with melphalan and prednisone alone. Key Evidence One RCT compared bortezomib plus melphalan and prednisone (n=344) to melphalan and prednisone (n=338) in patients with autologous stem cell transplantation ineligible previously untreated multiple myeloma (4). The authors reported significantly higher overall survival for patients who received bortezomib plus melphalan/prednisone compared to melphalan/prednisone (at 24 months: 84% vs. 70%; HR 0.61, p=0.008). Median time-to-progression was also significantly higher for the bortezomib/melphalan/prednisone arm: 24.0 vs (HR 0.48, p<0.001). There is insufficient evidence at this time for any recommendations regarding the use of bortezomib prior to autologous stem cell transplantation in patients with previously untreated multiple myeloma. Key Evidence Two ongoing RCTs of bortezomib as induction prior to autologous stem cell transplantation in previously untreated multiple myeloma patients have been reported: both in abstract form and with interim analyses only. One compared induction therapy with bortezomib plus dexamethasone to vincristine/doxorubicin/ dexamethasone (VAD) prior to autologous stem cell transplantation: both arms were also randomized to receive consolidation or not following induction (5). The second RCT compared induction therapy with bortezomib plus dexamethasone/thalidomide to dexamethasone/thalidomide followed by double ASCT (6). Lymphoma and Waldenstrom s Macroglobulinemia For patients with relapsed or refractory mantle cell lymphoma, bortezomib monotherapy is a reasonable treatment option. Key Evidence One large single-arm phase II trial investigated the use of bortezomib monotherapy in 155 patients with relapsed or refractory mantle cell lymphoma was identified (7,8). The authors reported one year survival of 69% and a median overall survival of 23.5 months (8). No RCTs comparing bortezomib to therapy without bortezomib in patients with relapsed or refractory mantle cell lymphoma were identified. There is insufficient evidence to support the use of bortezomib outside of clinical trials in patients with previously untreated mantle cell lymphoma or other lymphoma histologies. QUALIFYING STATEMENTS Consideration should be given to the use of antiviral prophylaxis against shingles as it is now recognized to occur more frequently during bortezomib therapy in patients with multiple myeloma (2). iii

5 Another systematic review (9) has provided a summary of the evidence for the use of melphalan, prednisone and thalidomide (MPT) as preferred initial therapy for patients with myeloma who are not candidates for an autologous stem cell transplant. There is no direct comparison of thalidomide versus bortezomib in combination with melphalan and prednisone for initial therapy in such patients. As the volume of data is greater with MPT, the authors would suggest a preference for MPT as initial therapy for such patients. However, thalidomide may not be easily available and practitioners may opt to treat certain patient subgroups with bortezomib containing initial therapy (e.g. those with adverse cytogenetic features). For specific details related to the administration of bortezomib therapy, the authors suggest clinicians refer to the protocols used in the major trials. Some of those details are provided below for informational purposes: o Regarding dosage, bortezomib 1.3 mg/m 2 is given as a rapid intravenous bolus over 3-5 seconds on days 1, 4, 8 and 11 of a 21-day cycle; a minimum of 72 hours between doses is required to allow for the recovery of normal proteasome function. Vital signs should be checked before and after each dose. A complete blood count is recommended before each dose, with blood chemistries, including electrolytes and creatinine levels, monitored at minimum on days 1 and 8 of each cycle. The dose of bortezomib should be reduced or held immediately for the development of painful neuropathy, as described in the product monograph; dose modification may also be required for peripheral sensory neuropathy without pain, or other toxicities. Most toxicities are reversible if dose modification guidelines are followed. Multiple myeloma For the combination of bortezomib and PLD in relapsed/refractory myeloma, PLD 30 mg/m 2 is administered as a 1 hour infusion on day 4 of each 21-day cycle of bortezomib at the doses described above. Treatment should be continued for 8 cycles unless disease progression or unacceptable treatment-related toxicity occurs. In keeping with the design of the RCT, patients who are still responding and who are tolerating therapy well may continue until the criteria of progressive myeloma are met, i.e., at least a 25% increase in the serum monoclonal protein level (which must be an absolute minimum increase of 5 g/l). Although not specified in the trial, it is the authors opinion that treatment can be discontinued 2-4 cycles after achievement of complete remission (CR) (determined by negative electrophoresis and immunofixation). For the combination of bortezomib with melphalan and prednisone as initial therapy in patients who are ineligible for autologous stem cell transplantation, melphalan 9 mg/m 2 and prednisone 60 mg/m 2 are given on days 1-4 of a 6-week cycle. Bortezomib 1.3 mg/m 2 is administered intravenously on days 1,4,8,11,22,25,29 and 32 during cycles 1-4, and on days 1,8,22 and 29 of cycles 5-9. A total of 9 cycles is given. o Lymphom: For relapsed or refractory mantle cell lymphoma, treatment should continue until disease progression, intolerance, or until 2-4 cycles after maximal response has been achieved. Responses to treatment are usually apparent by six weeks (two cycles). For patients achieving CR, bortezomib should be given for two additional cycles beyond the date of confirmed CR. In patients with progressive disease after two cycles, or stable disease after four cycles, dexamethasone (20 mg orally the day of, and the day after each iv

6 bortezomib dose) added to the bortezomib regimen may produce an objective response. Bortezomib (with or without dexamethasone) should be continued in patients showing benefit from therapy (excluding those in CR), unless disease progression or significant toxicity is observed. Therapy should be discontinued in patients who do not respond to bortezomib alone if disease progression is seen within two cycles of the addition dexamethasone. The authors recognize that thalidomide and lenalidomide are active agents in treating patients with multiple myeloma who have relapsed after autologous stem cell transplantation or are refractory to alkylating agent-based chemotherapy. To date, there are no RCTs comparing thalidomide or lenalidomide to bortezomib in this setting. Therefore the authors cannot make any conclusions regarding the use of one agent over another. TREATMENT ALTERNATIVES For myeloma patients who relapse following autologous stem cell transplantation or who are refractory to alkylating agent-based chemotherapy, the principal alternatives to bortezomib treatment are thalidomide-based regimens (such as thalidomide alone or with oral corticosteroids/cyclophosphamide) and the oral combination of lenalidomide + dexamethasone. The principle comparator in recent RCTs, pulsed oral (po) high-dose dexamethasone (40 mg po days 1-4, 9-12, and of each cycle), was consistently inferior to the novel agent (bortezomib or lenalidomide + dexamethasone) with only a median 3-4 month time to progression. Although beyond the scope of this guideline, the opinion of the authors is that high-dose dexamethasone may be used as a short-term bridging treatment. Multi-agent chemotherapy with vincristine, adriamycin, and dexamethasone (VAD) is an active regimen and although it has not been compared to bortezomib, thalidomide, or lenalidomide + dexamethasone, it may be a reasonable alternative in patients who have not received this regimen previously. Neither thalidomide nor VAD have been compared to high-dose dexamethasone or bortezomib, or lenalidomide + dexamethasone in randomized trials (10). The choice of therapy for relapsed myeloma depends on many factors, and will differ based on which first line regimen is administered, biological features of the myeloma (such as cytogenetic subtype and other markers of disease aggressiveness), toxicity profile of the regimen considered, and co-existing medical problems in a given patient (such as peripheral neuropathy, diabetes mellitus or renal failure). Also, most myeloma patients are candidates to receive sequential regimen, which will include bortezomib and immunomodulatory derivatives such as thalidomide and/or lenalidomide, at different time points in the disease course, to prolong survival. FUTURE RESEARCH Studies of bortezomib in combination with other agents are underway. RELATED GUIDELINES Practice Guideline Report #6-4: The Role of Bisphosphonates in the Management of Skeletal Complications for Patients with Multiple Myeloma. Practice Guideline Report #6-6: Optimal Therapy for Patients Diagnosed with Multiple Myeloma and the Role of High-Dose Chemotherapy and Stem Cell Support. Evidence-based Series Report #6-21 (in development): Thalidomide in Multiple Myeloma. v

7 Funding The PEBC is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. Disclaimer Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its application or use in any way. For information about the PEBC and the most current version of all reports, please visit the CCO web site at or contact the PEBC office at: Phone: ext Fax: ccopgi@mcmaster.ca vi

8 REFERENCES SUMMARY 1. Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25(25): Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24): Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110(10): San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9): Harousseau JL, Mathiot C, Attal M, Marit G, Caillot D, Hulin C, et al. Bortezomib/dexamethasone versus VAD as induction prior to autologous stem cell transplantation (ASCT) in previously untreated multiple myeloma (MM): updated data from IFM 2005/01 trial [abstract and slide presentation]. J Clin Oncol (ASCO Annual Meeting Proceedings). 2008;26(15 Suppl):A8505. [Cited 11 Nov 2008]. Slides available at: ail_view&confid=55&abstractid= Cavo M, Patriarca F, Tacchetti P, Galli M, Perrone G, Petrucci MT, et al. Bortezomib (Velcade )-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) in preparation for autologous stem-cell (SC) transplantation (ASCT) in newly diagnosed multiple myeloma (MM) [abstract]. Blood (ASH Annual Meeting Abstracts). 2007;110(11):A Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006;24(30): Goy A, Bernstein S, Kahl B, Djulbegovic B, Robertson M, de Vos S, et al. Durable responses with bortezomib in patients with relapsed or refractory mantle cell lymphoma (MCL): updated time-to-event analyses of the multicenter PINNACLE study [abstract]. Blood (ASH Annual Meeting Abstracts). 2007;110(11):A Hicks LK, Haynes AE, Reece DE, Walker IR, Herst JA, Meyer RM, et al. A meta-analysis and systematic review of thalidomide for patients with previously untreated multiple myeloma. Cancer Treat Rev. 2008;34(5): Reece DE, Leitch HA, Atkins H, Voralia M, Canning LA, LeBlanc R, et al. Treatment of relapsed and refractory myeloma. Leuk Lymph. 2008;49(8): vii

9 FULL REPORT QUESTIONS 1. In patients with multiple myeloma (MM), Waldenstrom s macroglobulinemia, or lymphoma, what is the efficacy of bortezomib alone or in combination as measured by survival, quality of life, disease control (e.g., time-to-progression (TTP)), response duration, or response rate? 2. What is the toxicity associated with the use of bortezomib? 3. Which patients are more or less likely to benefit from treatment with bortezomib? INTRODUCTION Multiple myeloma is a cancer characterized by a malignant proliferation of clonal plasma cells in the bone marrow; these cells typically produce a monoclonal immunoglobulin molecule that can be detected in the serum or urine. Common manifestations include fatigue, anemia, and bone damage related to osteopenia and/or lytic bone lesions; the resulting bone pain, pathologic fractures, or, in some cases, spinal cord compression leads to substantial morbidity. Renal failure, frequent infections, and hypercalcemia also occur in a significant proportion of patients. Treatment of myeloma can result in reductions in levels of monoclonal immunoglobulins and can lead to symptomatic benefit and can delay or improve end-organ complications. The role of chemotherapy and stem cell transplantation in myeloma is summarized in the Program in Evidence-Based Care (PEBC) Practice Guideline Report #6-6 (1). Patients years of age are generally treated with several cycles of high-dose dexamethasone-based induction therapy such as VAD (vincristine, doxorubicin, and dexamethasone), or more recently, dexamethasone as a single agent or in combination with thalidomide, followed by stem cell collection and autologous stem cell transplantation (ASCT). ASCT still represents the current standard of care in this patient group and has demonstrated higher remission rates (including about 20-30% complete remissions) and improved progression-free and overall survival rates than older conventional chemotherapy regimens alone. Over the last few years, a better understanding of the biology of myeloma cells and the relationship between the tumour cells and bone marrow microenvironment has stimulated efforts to develop other novel agents in this disease. Bortezomib (Velcade TM, PS-341), a firstin-class proteasome inhibitor, is the best studied of the next generation of anti-myeloma drugs. Bortezomib blocks the action of the 29S proteasome, a multicatalytic enzyme that has been nicknamed the housekeeper of the cell as it degrades abnormal or misfolded proteins targeted for destruction, particularly those involved in cell cycling and gene transcription. Clinical evidence have demonstrated that this agent is active in myeloma and lymphoma, and bortezomib is often utilized in relapsed and refractory myeloma, as recommended in the original, Version 1, of this Evidence-based Series (2) completed in April Since then new data has emerged that further defines the role of bortezomib in MM as well as its use in lymphoma. In multiple myeloma, most studies have indicated that patients who achieve a complete remission (CR), near complete remission (same as CR but residual monoclonal protein by immunofixation only; ncr), or in some instances at very good partial remission (defined as > 90%; VGPR), particularly after ASCT, have superior progression-free and overall survival rates 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 in higher CR/nCR/VGPR rates before ASCT compared to the rates observed with previous regimens such as VAD or dexamethasone alone. Therefore, one approach to improve the results of ASCT involves utilizing novel agents up front, so that patients will go into 1

10 transplant already in a high-grade remission, hypothesizing that CR/nCR rates, and hence survival, will be improved after ASCT Several phase III randomized trials comparing bortezomib-containing induction regimens have been designed to test this hypothesis, as discussed below (3,4). In the past, older patients generally received less aggressive therapy with oral regimens such as melphalan and prednisone (MP). Partial remissions were observed in approximately 50% of cases, but complete remissions were rare. More recently, several phase III trials have been reported that compare melphalan and prednisone with melphalan and prednisone plus a novel agent such as thalidomide, or most recently, bortezomib. These trials have, in general, demonstrated that the addition of a novel agent results in higher overall and complete remission rates, improved progression-free survival and, in some studies, improved overall survival. Despite effective first line therapy, virtually all myeloma patients eventually relapse and require further therapy. Options for the management of recurrent myeloma include reinstitution of the initial treatment if the duration of response was prolonged (using oral melphalan and prednisone or ASCT), alternative alkylating agent therapy with oral cyclophosphamide plus prednisone, high-dose dexamethasone, or thalidomide alone or in combination with corticosteroids or bortezomib as mentioned above. In addition, the thalidomide derivative lenalidomide has just been approved by Health Canada for use with dexamethasone in the treatment of myeloma that has progressed after at least one prior treatment regimen. As in first line therapy, many phase I-II trials have been performed in which novel agents, particularly bortezomib, have been combined with conventional cytotoxic agents or other novel agents. One randomized phase III trial of bortezomib and pegylated liposomal doxorubicin versus bortezomib alone has now been completed (5). Given the new data that has become available, the Hematology Disease Site Group agreed that an updated systematic review is required to determine the appropriate use of bortezomib in both MM and lymphoma. METHODS This advice report, produced by the Program in Evidence-based Care (PEBC), is a convenient and up-to-date source of the best available evidence on the role of bortezomib in the treatment of adult patients MM an lymphoma, developed through a systematic review of the available evidence. Contributing authors disclosed any potential conflicts of interest. The PEBC is editorially independent of the Ontario Ministry of Health and Long-Term Care. The PEBC has a formal standardized process to ensure the currency of each clinical guidance report. This process consists of the periodic review and evaluation of the scientific literature and, where appropriate, integration of this literature with the original clinical guidance report information. Literature Search Strategy MEDLINE (Ovid) (October 2004 through September Week 2 [September 22] 2008), MEDLINE Daily Update (September 22, 2008), MEDLINE In-Process & Other Non-Indexed Citations (September 22, 2008), EMBASE (Ovid) (2004 Week 42 through Week 38 [September 22]), and the Cochrane Library (2008, Issue 4) databases were searched. The search strategies for MEDLINE and EMBASE are shown in Appendix 1. Search strategies in other databases were similar. In addition, conference proceedings of the American Society of Clinical Oncology ( ) and the American Society of Hematology ( ) were searched for abstracts of relevant trials. The Canadian Medical Association Infobase ( the National Guidelines Clearinghouse ( and the National Institute for Clinical Excellence 2

11 ( were also searched for existing evidence-based practice guidelines. Relevant articles and abstracts were selected and reviewed by two reviewers, and the reference lists from these sources were searched for additional trials. Personal files were also searched. Study Selection Criteria Multiple Myeloma Inclusion Criteria Articles were selected for inclusion in this systematic review of the evidence if they were published full report articles or published meeting abstracts of: 1. Systematic reviews, meta-analyses, or clinical practice guidelines of bortezomib in adult patients with multiple myeloma. 2. Randomized studies including adult patients with multiple myeloma and evaluating bortezomib as a single agent or in combination with other regimens. 3. Trials could compare bortezomib to any agent, any combination of agents, or placebo. 4. Results reporting one or more of the following outcomes: survival, quality of life, disease control (e.g., time-to-progression [TTP]), response duration, response rate, or adverse effects. Exclusion Criteria Studies were excluded if they were: 1. Letters, comments, books, notes, or editorial publication types. 2. Articles published in a language other than English, due to financial considerations. Lymphoma Inclusion Criteria Articles were selected for inclusion in this systematic review of the evidence if they were published full report articles or published meeting abstracts of: 1. Systematic reviews, meta-analyses, or clinical practice guidelines of bortezomib in adult patients with Waldenstrom s macroglobulinemia or lymphoma. 2. Studies including adult patients with Waldenstrom s macroglobulinemia, or lymphoma (any histologic subtype, stage, performance status, or disease type). 3. Randomized trials in which bortezomib could be compared with any agent, any combination of agents, or placebo. 4. Single-arm phase II trials evaluating bortezomib as a single agent or in combination with other regimens. 5. Results reporting one or more of the following outcomes: survival, quality of life, disease control (e.g., time-to-progression [TTP]), response duration, response rate, or adverse effects. Exclusion Criteria Studies were excluded if they were: 1. Letters, comments, books, notes, or editorial publication types. 1. Single-arm phase II trials reporting fewer than 20 patients (all disease types combined). 2. Abstract reports of single-arm phase II trials that have not been previously fully published. 3. Phase I trials. 3

12 Synthesizing the Evidence Data appropriate for pooling or meta-analysis are not expected but will be investigated if the possibility exists. For planned analyses, the primary outcome of interest is progression-free survival, secondary outcomes of interest are response rate and overall survival, and subset analyses will be conducted by histology. MULTIPLE MYELOMA Literature Search Results A total of 327 citations of studies that included patients with multiple myeloma were identified from the Medline, EMBASE, and Cochrane library databases. From those citations, a total of seven full publications (5-11) met eligibility criteria and were included (Figure 1). In addition 117 abstracts presented at ASH or ASCO were identified. Seventeen abstracts met the eligibility criteria and were included. In total five unique trials (3-11) were identified from the seven full publications and 17 abstracts. Only the most recent abstract publication or abstracts reporting additional data were referenced. Figure 1. Study selection for search results from Medline, EMBASE, and the Cochrane Library databases, and the conference proceedings of ASH and ASCO. 327 citations retrieved from Medline, Medline Daily Update, Medline In-Process & Other Non-Indexed Citations, EMBASE, and the Cochrane Library 117 abstracts retrieved from the online databases of conference proceedings of ASH and ASCO. 301 excluded: - Not randomized. - Did not investigate the use of bortezomib. Title and abstract review by single author (AH). Title and abstract reviewed by single author (AH). 100 excluded: - Not randomized. - Did not investigate the use of bortezomib. 26 citations retrieved for full publication review. 17 abstracts reviewed by two authors (AH, DR). 19 excluded: - Not randomized. - Not systematic review. Full publication review by two authors (AH,DR). 17 abstracts of 5 unique trials included. 7 full publications of 3 unique trials indentified and included. A total of 17 abstract reports and 7 full publications detailing 5 unique randomized trials were included. 4

13 Two of the RCTs have had numerous fully published articles associated with the trial results. Table 1 indicates the primary publication for each trial as well as any associated full publication along with the objectives of those publications. The APEX trial alone has had four additional full publications. Two have reported extended follow-up (6,9) and two have reported subgroup analyses (7,8). The primary publication of the APEX trial (12) was identified in our previous systematic review (2) completed in April One other RCT, first reported by Orlowski et al (5) has also had an additional publication that reported the results of a subgroup analysis (10). Table 1. Primary and additional publications of identified randomized trials of bortezomib in multiple myeloma. Study Primary publication Additional full publications Objective of additional publication APEX Richardson, 2005 (12) Richardson, 2007 (6) San Miguel, 2008 (7) Richardson, 2007 (8) Corso, 2006 (9) Extended follow-up Subgroup analysis of patients with renal impairment Subgroup analysis of high risk and elderly patients Update of APEX results Orlowski Orlowski, 2007 (5) Sonneveld, 2008 (10) Subgroup analysis of patients who received prior thalidomide or lenalidomide San Miguel San Miguel, 2008 (11) None NA IFM 2005/01 Harousseau, 2008 (3) [abs] None NA Cavo Cavo, 2007 (4) [abs] None NA Trial Quality As shown in Table 2, three of the randomized trials were available as fully published reports (5,6,11,12). All three fully published RCTs reported the a priori sample size required to find a statistically significant difference in the primary endpoint of time-to-progression (TTP). All three trials reported final analyses that were based on the intent-to-treat (ITT) population. Two trials were stopped early due to significantly better TTP in the bortezomib arm compared to control without bortezomib (6,11,12) and one due to better TTP in the bortezomib plus pegylated liposomal doxorubicin (PLD) compared to PLD alone (5). All three fully published RCTs were open-label studies. One of the two RCTs in abstract form reported that sufficient patients had been enrolled to fulfill the sample size requirement to detect a significant difference in the rate of complete response (CR) plus near complete response (ncr); however, the reported results were of an interim ITT analysis (3). The remaining abstract reported that the primary outcome was CR rate and that the interim analysis was based on the ITT population (4). The authors did not report a sample size requirement. Neither abstract reported on the blinding of participants. None of the five RCTs reported the method of randomization, allocation concealment, or on losses to follow-up. 1

14 A priori sample size requirement met Primary outcome Double blinding Appropriate randomization method Allocation concealment ITT analysis Final analysis Early termination Losses to follow-up Ethical approval CED-CCO SPECIAL ADVICE REPORT 11 ARCHIVED 2012 Table 2. Quality characteristics of included RCTs of bortezomib in multiple myeloma. Author, year (ref) Fully published trials Richardson, 2007, 2005 (6,12) Yes TTP No - - Yes Yes Yes - Yes Orlowski, 2007 (5) Yes TTP No - - Yes Yes Yes - Yes San Miguel, 2008 (11) Yes TTP No - - Yes Yes Yes - Yes Abstracts Harousseau, 2008 (3) [abstract] Yes CR/nCR - - Yes No Cavo, 2007 (4) [abstract] - CR/nCR Yes No Notes: - indicates that the published report did not describe this characteristic of the trial; CR=complete response; ITT=intention-to-treat; ncr=near complete response; TTP=time-to-progression; VGPR=very good partial response; yrs=years. Trial and Patient Characteristics Relapsed or Refractory Multiple Myeloma Two RCTs examined the use of bortezomib in patients with relapsed or refractory MM. Table 3 provides trial inclusion criteria and intervention details. Richardson et al (6) reported results of the APEX trial with extended median follow-up of 22 months. Compared to the original report by Richardson et al, 2005 (12), the updated analysis includes an additional 14 months of follow-up data. The earlier publication was included in our original systematic review. The authors randomized patients with relapsed or refractory MM to induction with bortezomib (n=333) or dexamethasone (n=336). The treatment arms were well balanced with respect to a number of demographic variables and other characteristics (12). The remaining RCT (5) randomized relapsed or refractory MM patients to induction with bortezomib (n=322) or bortezomib plus PLD (n=324). The treatment arms were well balanced for a variety of demographic variables and other characteristics. Of note, patients who had received more than 240 mg/m 2 or the equivalent dose of doxorubicin were excluded from the study. Previously Untreated Multiple Myeloma Three RCTs examined the use of bortezomib in patients with previously untreated MM. Table 3 details the trials inclusion criteria and intervention details. One trial enrolled patients who were not candidates for autologous stem cell transplantation (ASCT) due to age greater than or equal to 65 years, or due to other coexisting conditions (11). Those patients were randomized to induction with bortezomib plus melphalan and prednisone (MP) or to MP alone. The median age of patients in both arms was 71 years. The two remaining RCTs, reported in abstract form only, enrolled previously untreated MM patients who were candidates for ASCT (3,4). Harousseau et al (3) randomized patients to induction with bortezomib plus dexamethasone followed by ASCT (n=240) or to induction with vincristine plus doxorubicin (VAD) followed by ASCT (n=242). The authors also randomized patients in each arm (1:1) to receive or not receive consolidation therapy with prior to ASCT. The median age was 57.2 years in the bortezomib arm and 57.1 years in the VAD arm. Cavo et al (4) randomized patients to induction with bortezomib plus dexamethasone/thalidomide (TD) (n=92) or to TD alone (n=95). 2

15 Table 3. Patient characteristics and intervention details for trials of patients with multiple myeloma. Author, Patient characteristics Intervention N year (ref) Relapsed or Refractory Multiple Myeloma Richardson, 2007, 2005 (6,12) Orlowski, 2007 (5) Relapsed/refractory MM (1-3 prior therapies); pts who received prior B excluded as were dex-refractory pts Relapsed/refractory MM with measurable disease; ECOG PS 0-1. Excluded: pts who have received 240 mg/m 2 or equivalent cumulative dose of dox Previously Untreated Multiple Myeloma San Miguel, 2008 (11) Harousseau, 2008 (3) [abstract] Cavo, 2007 (4) [abstract] Newly diagnosed, previously untreated, symptomatic, measurable MM. Excluded pts who were not candidates for high-dose therapy + ASCT due to age 65y. Newly diagnosed MM, age 65y Previously untreated MM B 1.3 mg/m 2 iv bolus d1,4,8,11 every 21d cycles 1-8 then on d1,8,15,22 of cycles 9-11 until a max treatment period of 273d. Dex 40mg/d orally d1-4,9-12,17-20 of cycles 1-4 (35d cycles) and on d1-4 of cycles 5-9 (28d cycles) until a max treatment period of 280d. B 1.3 mg/m 2 iv bolus d1,4,8,11 every 21d until disease progression, unacceptable treatment-related toxicity, or for 8 cycles. B 1.3 mg/m 2 iv bolus d1,4,8,11 + PLD 30 mg/m 2 1-hr iv d4 every 21d until disease progression, unacceptable treatment-related toxicity, or for 8 cycles. B 1.3 mg/m 2 d1,4,8,11,22,25,29,32 (cycles 1-4) and d1,8,22,29 (cycles 5-9) + mel 9 mg/m 2 + pred 60 mg/m 2 d1-4 for 9 cycles. Age, mdn (y) Mel 9 mg/m 2 + pred 60 mg/m 2 d1-4 for 9 cycles Induction: B 1.3 mg/m 2 d1,4,8,11 + dex 40 mg d1-4 (cycles 1-4) and d9-12 (cycles 1-2) every 21d for 4 cycles with or without consolidation A : dex 40 mg d1-4 + cyclo 15 mg/m 2 + etop 400 mg/m 2 + cisplatinum 10 mg/m 2 d1-4 c.i.v every 28d for 2 cycles ASCT. Induction: vinc 0.4 mg/m 2 civ d1-4 + dox 9 mg/m 2 civ d1-4 + dex 40 mg d1-4 (cycles 1-4) and d9-12,17-20 (cycles 1-2) every 28d for 4 cycles with or without consolidation B : dex 40 mg d1-4 + cyclo 15 mg/m 2 + etop 400 mg/m 2 + cisplatinum 10 mg/m 2 d1-4 civ every 28d for 2 cycles ASCT. Induction: B 1.3 mg/m 2 d1,4,8,11 + dex 40 mg/d d1,2,4,5,8,9,11,12 + thal 200 mg/d d1-63 consolidation: NR double ASCT. Induction : thal 200 mg/d d dex 40 mg/d d1-4,9-12 every 21d consolidation: NR double ASCT NR 95 NR Notes: ASCT=autologous stem cell transplantation; B=bortezomib; civ=continuous intravenous infusion;cyclo=cyclophosphamide; d=day(s); dex=dexamethasone; dox=doxorubicin; ECOG=Eastern Cooperative Oncology Group; etop=etoposide; mdn=median; mel=melphalan; MM=multiple myeloma; N=number of patients; NR=not reported; PLD=pegylated liposomal doxorubicin; pred=prednisone; PS=performance status; pts=patients; q=every; ref=reference; thal=thalidomide; vinc=vincristine; WHO=World Health Organization; wk=week(s); y=years. A Patients were randomized to receive or not receive consolidation therapy: consolidation, n=121; no consolidation, n=121. B Patients were randomized to receive or not receive consolidation therapy: consolidation, n=119; no consolidation, n=121. 3

16 Question 1: What is the efficacy of bortezomib alone or in combination? Relapsed or Refractory Multiple Myeloma The original systematic review (2) identified one RCT investigating the use of bortezomib in relapsed or refractory MM (12). The results of that trial were updated in 2007 in a full publication reported by Richardson et al (6). The results of the extended follow-up for that trial (6) as well as the remaining RCTs identified in the updated literature search are presented below. Survival Richardson et al (6) reported significantly higher overall survival for patients that received bortezomib (median, 29.8 months) compared to dexamethasone (median, 23.7 months); hazard ratio (HR) 0.77, p=0.027 (Table 4). This analysis includes a median of 22 months of follow-up, during which more than 62% of patients crossed over to the bortezomib arm after the study completion date. Orlowski et al (5) reported significantly higher overall survival for patients that received bortezomib plus PLD (15-months: 76%) compared to bortezomib alone (65%); HR 0.71, 95% confidence interval (CI) 0.42 to 0.998, p= Patients in this trial who received bortezomib alone were not allowed to cross over to the PLD arm. Of note, patients in this trial had previously received less than 240 mg/m 2 or the equivalent dose of doxorubicin. Disease control Richardson et al (6) reported significantly longer TTP for patients that received bortezomib compared to dexamethasone (median, 6.2 vs. 3.5 months; HR 0.55, p<0.001). Orlowski et al (5) reported significantly longer TTP for patients that received bortezomib plus PLD compared to bortezomib alone (median, 9.3 vs. 6.5 months; HR 0.55, 95% CI 0.43 to 0.71). Response Richardson et al (6) did not report whether the differences in response rates observed between the bortezomib and dexamethasone arms were statistically significant or not. Orlowski et al (5) reported that the objective response rate was not significantly higher for patients that received bortezomib plus PLD compared to bortezomib alone (Table 4). Quality of life None of the trials reported data on quality of life. Previously Untreated Multiple Myeloma The original systematic review (2) did not identify any randomized trials investigating the use of bortezomib in patients with previously untreated MM. The results of the RCTs identified in the updated literature search are presented below. Survival Only San Miguel et al (11) reported a significant difference in overall survival (Table 4). In ASCT-ineligible patients, the authors reported that survival at 24 months was 84% for patients who received bortezomib plus MP compared to 70% for MP alone (HR 0.61, p=0.008). In ASCT-eligible patients who were scheduled to receive consolidation and ASCT following induction, Harousseau et al (3) reported that 18-month overall survival was 89.5% of 223 patients who received bortezomib plus dexamethasone induction compared to 85.1% of 219 patients who received VAD (p=0.38). The median follow-up was 18 months. 4

17 Table 4. Randomized trials of patients with multiple myeloma: efficacy. Author, year OR CR PR OS, mdn Intervention N (ref) (%) (%) (%) (mos) Relapsed or Refractory Multiple Myeloma Richardson, B 1.3 mg/m , 2005 Dex 40 mg A HR 0.77, (6,12) Orlowski, 2007 (5) B 1.3 mg/m B 1.3 mg/m 2 + PLD 30 mg/m Previously Untreated Multiple Myeloma San Miguel, 2008 (11) Harousseau, 2008 (3) [abstract] Cavo, 2007 (4) [abstract] 44 p= p= mos 65% 76% HR ( ; p=0.0476) TTP, mdn (mos) 3.5 HR 0.55, p< HR 1.82 (95% CI ; p= ) B + MP C 30 C 40 C 24 mos 84% D 24.0 MP 338 B 1.3 mg/m 2 + dex 40 mg ± consolidation ASCT VAD consolidation ASCT B + dex + thal double ASCT Dex + thal double ASCT 35 C p= C p< C p=ns % D HR=0.61 p= mos 89.5% 85.1% p= HR 0.48 p< mos 92.4% 89.3% p=0.45 Follow-up, mdn (mos) 92 NR 38 E 60 F NR NR NR 95 NR 7 E 25 F NR NR NR Notes: ASCT=autologous stem cell transplantation; B=bortezomib; CR=complete response; dex=dexamethasone; Mdn=median; MP=melphalan + prednisone; mos=months; N=number of patients; NR=not reported; OR=objective response; OS=overall survival; PLD=pegylated liposomal doxorubicin; PR=partial response; pred=prednisone; ref=reference; thal=thalidomide; TTP=time-to-progression; VAD=vincristine, doxorubicin, dexamethasone; y=year; =followed by. A Sixty-two percent of patients crossed over to the bortezomib arm at study completion. B The original data cut-off was April 28, 2006 at which time the median follow-up was 7.2 months; the survival and time to event data were reanalyzed with a data cut-off of November 28, 2006 after a United States Food and Drug Administration request. Median follow-up for OS and TTP were not reported. C The authors analyzed the response data using the evaluable patient population (B-MP: 337; MP: 331). D Estimated from survival curve. E The authors reported CR and near-cr together. F The authors reported PR together with very good PR B

18 Disease control San Miguel et al (11) reported significantly longer median TTP for patients that received bortezomib plus MP compared to MP alone (24.0 months vs months; HR 0.48, p<0.001). Harousseau et al (3) reported no significant difference in TTP for patients that received bortezomib plus dexamethasone compared to VAD (18 months: 92.4% vs. 89.3%; p=0.45). Response San Miguel reported a significantly higher rate of both objective response (71% vs. 35%, p=0.003) and CR (30% vs. 4%, p<0.001) among patients who received bortezomib compared to those who did not (11). The authors reported no statistically significant difference in partial response rate (40% vs. 31%, p=not reported). Both RCTs of ASCT-eligible patients reported higher rates of objective response, partial response, and CR for patients who received bortezomib compared to those who did not; however, the authors did not report whether those differences were statistically significant (3,4). Quality of life None of the trials reported data on quality of life. Question 2: What is the toxicity associated with the use of bortezomib? Relapsed or Refractory Multiple Myeloma Richardson et al (6,12) reported that the rates of serious or life-threatening neutropenia, thrombocytopenia, nausea, diarrhea, and peripheral neuropathy were significantly higher in patients who received bortezomib compared to dexamethasone (Table 5). Orlowski et al (5) reported that the rate of any grade of neutropenia was significantly higher for patients who received bortezomib plus PLD compared to bortezomib alone (35% vs. 20%, p<0.001). The authors also reported that the rates of any grade as well as grade 3/4 nausea/vomiting were significantly higher for patients that received the combination of bortezomib and PLD (Table 5). In addition, a significantly higher rate of patients also experienced a grade 3/4 diarrhea. Finally, only patients receiving PLD experienced hand foot syndrome (HFS), with an overall incidence of 16%; the incidence of grade 3 HFS was 5% and 5% discontinued PLD due to this toxicity. However, the incidence and severity of neurotoxicity did not differ (overall incidence 39% versus 35% with bortezomib alone versus with bortezomib + PLD; see Table 5), nor did the risk of cardiac toxicity (overall incidence 7% versus 10%, respectively). Recently, an association between bortezomib administration and the development of varicella zoster reactivation (shingles), with its attendant pain and other potential complications, has been recognized. The APEX trial demonstrated that the incidence of varicella zoster was 13% in patients given bortezomib, compared with only 5% in those assigned to dexamethasone (p<0.001) (12). Previously Untreated Multiple Myeloma None of the RCTs of bortezomib in patients with previously untreated MM reported whether statistically significant differences existed between the treatment arms for any adverse events. The rate of patients who experienced a serious or life threatening event for a select group of toxicities can be found in Table 5. 6

19 Table 5. Randomized trials of patients with multiple myeloma: grade 3 or 4 adverse events. Author, year (ref) Intervention N Neut (%) Thromb (%) Anemia (%) N/V (%) Diarrhea (%) Peripheral neuropathy (%) Relapsed or Refractory Multiple Myeloma Richardson, B 1.3 mg/m A,B 24 B 24 B NR 2007, 2005 Dex 40 mg A,B 6 B 11 B NR (6,12) p<0.01 p<0.05 p<0.01 p<0.01 p<0.01 Harousseau, 2008 (3) [abstract] Infection (%) Orlowski, B 1.3 mg/m */19* 34 9 NR 2007 (5) B 1.3 mg/m */31* 43 PLD 30 mg/m p<0.001 *p<0.03 p= NR Previously Untreated Multiple Myeloma San Miguel, B + MP A D 2008 (11) MP <1 A D B 1.3 mg/m 2 + dex 40 mg ± consolidation C ASCT Cavo, 2007 (4) [abstract] VAD consolidation ASCT B + dex + thal double ASCT Dex + thal double ASCT C NR NR NR NR NR 8 NR 95 NR NR NR NR NR 2 NR Notes: AE=adverse events; ASCT=autologous stem cell transplantation; B=bortezomib; dex=dexamethasone; G3(/4)=grade 3 (or 4); MP=melphalan + prednisone; N=number of patients; neut=neutropenia; NR=not reported; N/V=nausea/vomiting; PLD=pegylated liposomal doxorubicin; ref=reference; thal=thalidomide; thromb=thrombocytopenia; VAD=vincristine, doxorubicin, dexamethasone; y=year; =followed by. A Patients with nausea. B Grade 3 adverse event. C Patients with any grade gastrointestinal adverse events. D Patients with pneumonia. 7

20 Question 3: Which patients are more or less likely to benefit from treatment with bortezomib? Relapsed or Refractory Multiple Myeloma Extensive subset analyses have been performed using data from the APEX trial of bortezomib versus dexamethasone for relapsed or refractory myeloma. Consistently, bortezomib was superior to dexamethasone in patients 65 years of age, patients with International Staging System (ISS) stage II and III disease, patients refractory to the most recent therapy and patients who have previously received more than 1 prior line of therapy (8), as well as in patients with renal impairment (7). Similarly, bortezomib plus PLD was more efficacious than bortezomib alone in most subgroups analyzed, including patients of any age, patients with refractory disease, patients with an elevated β 2-microglobulin level and patients previously exposed to ASCT, prior anthracyclines and immunomodulatory drugs (thalidomide or lenalidomide) (5,10). An advantage of bortezomib and PLD compared to bortezomib alone was observed in patients with cytogenetic abnormalities except for deletion 13q, likely because bortezomib is primarily responsible for the anti-myeloma effect in this setting (5). Previously Untreated Multiple Myeloma The combination of melphalan, prednisone and bortezomib produced better results than melphalan and prednisone alone in the following subgroups: patients 75 years of age, patients with an elevated β 2-microglobulin level and patients with a creatinine clearance < 60 ml/min. Although cytogenetic studies were not available in all individuals, the complete response rate, time to progression and overall survival were similar in patients with and without high-risk cytogenetics, including deletion 13q (11). 8