• Reece D, Imrie K, Smith CA, Stevens A, Hematology Disease Site Group. Bortezomib in multiple myeloma and lymphoma: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Apr. 36 p. (Evidence-based series; no. 6-18). [33 references]

• Multiple myeloma
• Waldenstrom's macroglobulinemia
• Lymphoma

Assessment of Therapeutic Effectiveness
Treatment

Oncology

Physicians

• To evaluate the efficacy of bortezomib alone or in combination in patients with multiple myeloma, Waldenstrom's macroglobulinemia, or lymphoma, as measured by survival, quality of life, disease control (e.g., time-to-progression), response duration, or response rate
• To evaluate the toxicity associated with the use of bortezomib
• To determine which patients are more or less likely to benefit from treatment with bortezomib

Adult patients with myeloma, Waldenstrom's macroglobulinemia, or lymphoma of any type, stage, histology, or performance status

1. Bortezomib
2. Oral alkylating agent-based chemotherapy

• Survival
• Quality of life
• Disease control (e.g., time-to-progression)
• Response duration
• Response rate
• Toxicity

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

In total, 20 publications of 16 trials in myeloma and lymphoma were identified. For myeloma, one randomized controlled trial (RCT), one randomized phase II trial, four non-randomized phase II trials, and five dose-escalation trials were included. For lymphoma, four non-randomized phase II and one phase I/II trials were included.

Expert Consensus (Committee)

Not applicable

Systematic Review with Evidence Tables

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.

Expert Consensus

This systematic review was developed by Cancer Care Ontario's Program in Evidence-based Care (PEBC). Evidence was selected and reviewed by two member of the PEBC Hematology Disease Site Group (DSG).

This systematic review is a convenient and up-to-date source of the best available evidence on bortezomib in multiple myeloma and lymphoma. The body of evidence in this review is primarily comprised of randomized controlled trial (RCT) data. That evidence forms the basis of a clinical practice guideline developed by the Hematology DSG. The systematic review and companion practice guideline are intended to promote evidence-based practice in Ontario, Canada. The PEBC is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

External Review

Section 2 in the original guideline document reports the results of the systematic review of bortezomib for patients with multiple myeloma and lymphoma. On the basis of that evidence and the interpretation by members of the Disease Site Group (DSG), draft recommendations were developed and circulated to Ontario practitioners for feedback. Section 3 in the original guideline document details the results from the practitioner feedback, changes made to the draft report, and the final recommendations that were submitted to the Program in Evidence-based Care (PEBC) Report Approval Panel (RAP) for review and final approval.

The recommendations were submitted with the systematic review (Section 2 in the original guideline document) to a sample of 161 hematologists, medical oncologists, and radiation oncologists in Ontario. The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. The practitioner feedback survey was mailed out on November 15, 2005, and reminder cards and complete repeat mailings sent thereafter.

Report Approval Panel

The final evidence-based series report was reviewed and approved by the Program in Evidence-based Care Report Approval Panel in March 2006. The Panel consists of two members, including an oncologist, with expertise in clinical and methodology issues. No significant issues were raised by the panel, and the report was approved for distribution.

Based on the results of a large well conducted randomized controlled trial (RCT), which represents the only published randomized study in relapsed myeloma, the Hematology Disease Site Group (DSG) offers the following recommendations:

• For patients with myeloma refractory to or relapsing within one year of the conclusion of initial or subsequent treatment(s) (including autologous stem cell transplantation) who are candidates for further chemotherapy, bortezomib is recommended as the preferred treatment option.
• Bortezomib is also a reasonable option for patients relapsing at least one year after autologous stem cell transplantation. The Disease Site Group is aware 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 Practice Guideline.
• For patients with myeloma relapsing at least one year after the conclusion of alkylating agent-based chemotherapy who are candidates for further chemotherapy, further treatment with alkylating agent-based chemotherapy is recommended.
• There is insufficient evidence to support the use of bortezomib outside of clinical trials in patients with non-Hodgkin's lymphoma or Waldenstrom's macroglobulinemia.

None provided

The recommendations are supported by randomized and non-randomized trials.

• One randomized controlled trial (RCT) compared bortezomib with high-dose dexamethasone in patients with relapsed myeloma and reported superior median time to progression (6.2 versus 3.5 months; p<0.001) and greater one-year survival (80% versus 66%; p=0.003) in the bortezomib arm.
• Two phase II trials, the Stanford University Medical Media and Information Technology (SUMMIT) and Carotid Revascularization Endarterectomy versus Stent Trial (CREST) trials, reported response rates of 33-44% with median response durations of 9.5-13.7 months. In both studies, the addition of dexamethasone in non-responders increased the response rate by 18-33%.

• One randomized controlled trial (RCT) that compared bortezomib with high-dose dexamethasone in patients with relapsed myeloma, reported that Grade 3 adverse events were more common in the bortezomib arm (61% versus 44%; p=0.01).
• See the original guideline document for a detailed review of the toxicities observed in the trials reviewed.

• There is limited evidence to support the appropriateness of a specific time-to-relapse period as being indicative of treatment-insensitive disease. The one-year threshold provided in the above recommendations is based on the opinion of the Hematology Disease Site Group (DSG).
• For specific details related to the administration of bortezomib therapy, the DSG suggests clinicians refer to the protocols used in the major trials. Some of those details are provided below for informational purposes:
  • Regarding dosage, bortezomib 1.3 mg/m² 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.
  • Responses to treatment are usually apparent by six weeks (two cycles). For patients achieving complete remission (CR) (determined by negative electrophoresis and immunofixation), bortezomib should be given for two additional cycles beyond the date of confirmed complete remission. In patients with progressive disease after two cycles, or stable disease after four cycles, dexamethasone (20 mg by mouth [po] the day of, and the day after each 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 complete remission), 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 Hematology DSG recognizes that thalidomide is an active agent 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 randomized controlled trials reporting evaluations of thalidomide in this role, and, specifically, no trials comparing thalidomide with bortezomib. With these limitations, members of the Hematology DSG regard thalidomide or bortezomib to be alternative therapies to dexamethasone.
• Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the evidence-based series 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 (CCO) makes no representation or guarantees of any kind whatsoever regarding their content or use or application and disclaims any for their application or use in any way.

An implementation strategy was not provided.

Living with Illness

Effectiveness

• Reece D, Imrie K, Smith CA, Stevens A, Hematology Disease Site Group. Bortezomib in multiple myeloma and lymphoma: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Apr. 36 p. (Evidence-based series; no. 6-18). [33 references]

Not applicable: The guideline was not adapted from another source.

2006 Apr 3

Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]

The Program in Evidence-based Care (PEBC) is a Province of Ontario initiative sponsored by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Cancer Care Ontario
Ontario Ministry of Health and Long-Term Care

Provincial Hematology Disease Site Group

The working group members for this topic and the Chair of the Hematology Disease Site Group (DSG) disclosed potential conflicts of interest relating to the topic of this evidence-based series. The lead author of this evidence-based series was the principal investigator or the local investigator and received research funding for four trials, including the randomized controlled trial (RCT) reported here. That author was also a consultant for the manufacturer of bortezomib, received honoraria, and was an advisory board participant for a future trial.

None available

This NGC summary was completed by ECRI on June 29, 2006. The updated information was verified by the guideline developer on July 7, 2006.