Meta-Analysis of the Efficacy and Safety of Bortezomib Retreatment in Patients with Multiple Myeloma (MM)

Bortezomib is approved for the treatment of MM, and bortezomib-based therapies are a cornerstone of care for both first-line and relapsed and/or refractory MM. As bortezomib is administered for a finite course, as opposed to treatment being continued to disease progression, patients may remain sensitive to bortezomib-based therapy at relapse. A number of prospective and retrospective studies in patients with relapsed and/or refractory MM have demonstrated the efficacy of subsequent retreatment with bortezomib-containing regimens. We report a systematic literature review and meta-analysis to assess the efficacy and safety of bortezomib-based retreatment in relapsed and/or refractory MM.

Using PubMed and major hematology/oncology conference proceedings, a systematic literature review was performed to identify studies from January 2005 to May 2012 of bortezomib-based therapy in patients with relapsed and/or refractory MM. All studies of bortezomib-based retreatment in MM patients with prior exposure to bortezomib were systematically selected. Treatments were classified as bortezomib ± dexamethasone (dex) or bortezomib-based combinations. The proportion of bortezomib-refractory patients was identified for each study where available. Additional prognostic factors, including number of prior therapies, proportion of patients with prior autologous stem cell transplant (ASCT), and time since last bortezomib, were extracted and used in weighted stratified analyses of time to progression (TTP), progression-free survival (PFS), and overall survival (OS). Random-effect pooled estimates (taking into account heterogeneity across studies) were calculated for overall response rate (ORR; partial response or better) and rates of common adverse events (AEs). A meta-regression was conducted to explore the interactive effects of prognostic factors on ORR.

Twenty-three studies (N=1051 patients) were identified. Bortezomib was administered IV in all studies. Retreatment comprised bortezomib ± dex in 5 studies and combination therapy in 18. Bortezomib-refractory patients were included in 11 studies (10–100% of patients), 6 studies included only relapsed patients, and data were not available for 6 studies. Across studies in which data were available, the pooled, weighted average ORR was 39% (95% CI: 31–47) and the pooled, weighted average median TTP, PFS, and OS were 7.5, 5.8, and 16.6 months, respectively. Data from stratified univariate analyses are shown in the table. Outcomes appeared generally consistent across groups while patients with fewer prior therapies (≤4) and relapsed (but not refractory) patients achieved higher ORRs of 43% (95% CI: 31–55) and 57% (95% CI: 45–69), respectively. Random-effects meta-regression analysis controlling for number of prior therapies and % prior ASCT confirmed that, compared to refractory patients, relapsed patients were associated with a higher ORR by 28–41 percentage points. In studies of bortezomib ± dex in patients with a median age >65 years and with a lower % of patients receiving prior ASCT (≤30%), retreatment remained active (pooled average ORR of 51%, median TTP and OS of 8.4 and 19.2 months). The most common grade 3/4 AEs included thrombocytopenia (35%), neutropenia (15%), anemia (14%), pneumonia (10%), and peripheral neuropathy (3%).

Based on these findings, retreatment with bortezomib alone or in combination is efficacious and well tolerated in relapsed patients, with an ORR of 57% and median TTP and OS of 8.5 and 19.7 months. In an era of new and emerging treatment options for relapsed and/or refractory MM, these data indicate bortezomib retreatment remains a highly effective therapeutic option in previously treated patients.

Knopf:Millennium Pharmaceuticals, Inc.: Consultancy. Duh:Millennium Pharmaceuticals, Inc.: Research Funding. Lafeuille:Millennium Pharmaceuticals, Inc.: Research Funding. Gravel:Millennium Pharmaceuticals, Inc.: Research Funding. Lefebvre:Millennium Pharmaceuticals, Inc.: Research Funding. Niculescu:Millennium Pharmaceuticals, Inc.: Employment. Ba-Mancini:Millennium Pharmaceuticals, Inc.: Employment. Ma:Millennium Pharmaceuticals, Inc.: Employment. Shi:Millennium Pharmaceuticals, Inc.: Employment. Comenzo:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.