Maintenance Therapy with Immunomodulatory Drugs after Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials

Abstract Background: Bortezomib is a proteasome inhibitor that can lead to cell-cycle arrest and apoptosis. Bortezomib-based regimens are widely used as induction therapy of multiple myeloma (MM). Unlike lenalidomide (an immunomodulatory drug), the role of bortezomib in the consolidation and maintenance therapy of multiple myeloma is less clear. This study aims to examine the efficacy and safety of bortezomib-based regimens as consolidation/maintenance therapy in MM patients following induction therapy with or without autologous stem cell transplantation (ASCT). Methods: PubMed, ASH, and ASCO databases were searched for randomized controlled trials (RTC) of bortezomib-based regimens (either single-agent or combination) as consolidation/maintenance therapy for MM patients through July 2018. Study endpoints included overall survival (OS), progression-free survival (PFS), and adverse events (AE). Pooled hazard ratios (HR) for survival outcomes and relative risks (RR) for dichotomous data with 95% confidence interval (CI) were calculated with a random effect model using MedCalc (MedCalc Software, Ostend, Belgium). For studies that did not report HRs for survival outcomes but provided graphical survival curves, the log HRs and variances were estimated based on the method by Parmar et al (Stat Med 1998; 17: 2815-2834). Heterogeneity was assessed using the I2 statistic of inconsistency, with statistically significant heterogeneity defined as I2 > 50% or p-value < 0.1. Results: Eight randomized controlled trials (7 phase III, 1 phase II; 2 were published in a single article) were identified. Bortezomib-based regimens were administered as consolidation treatment in 5 RTCs and maintenance therapy in 3 RTCs, following induction therapy +/- ASCT. A total of 2439 patients were included: 1154 patients received bortezomib-based regimens, and 1285 patients received non-bortezomib-based regimens or observation. Two RCTs (1 for consolidation, 1 for maintenance) did not provide HRs, which were estimated as described as above. Pooled data from the 8 RCTs showed that bortezomib-based consolidation/maintenance therapy improved progression-free survival (HR 0.71, 95% CI 0.64-0.79, P < 0.001; I2 = 6.61%) and overall survival (HR 0.80, 95% CI 0.68-0.94, P = 0.005; I2 = 0%) compared to observation or regimens without bortezomib. When the 2 RCTs that did not report HRs were excluded from the meta-analysis, it did not alter the favorable outcome of bortezomib-based consolidation/maintenance therapy: PFS (HR 0.70, 95% CI 0.60-0.82, P < 0.001; I2 = 40.54%) and OS (HR 0.76, 95% CI 0.64-0.91, P = 0.002; I2 = 0%). The PFS benefit was maintained in a subgroup analysis by the setting of treatment (consolidation, HR 0.73, 95% CI 0.63-0.85, P < 0.001; I2 = 0%, maintenance, HR 0.70, 95% CI 0.56-0.0.86, P = 0.001; I2 = 55.63%). Bortezomib-based therapy prolonged OS in the maintenance setting (HR 0.71, 95% CI 0.58-0.86, P < 0.001; I2 = 0%) but not in the consolidation setting (HR 1.01, 95% CI 0.77-1.33, P = 0.935; I2 = 0%). Regarding safety, bortezomib-based consolidation/maintenance therapy significantly increased the risk of grade 3 or 4 peripheral sensory neuropathy and neuralgia (RR 2.09, 95% CI 1.11-3.95, p = 0.022; I2 = 52.64%) compared to observation or regimens without bortezomib. There was a trend toward increased rates of grade 3 or 4 thrombocytopenia (RR 1.54, 95% CI 0.95-2.52, p = 0.08; I2 = 21.67%), GI symptoms (RR 2.54, 95% CI 0.63-10.25, p = 0.19; I2 = 76.72%), vascular events (RR 1.90, 95% CI 0.80-4.53, p = 0.15; I2 = 0.00%), and fatigue (RR 2.10, 95% CI 0.83-5.30, p = 0.12; I2 = 0.00%) with bortezomib-based consolidation/maintenance, but these did not reach statistical significance. Conclusions: Bortezomib-based consolidation/maintenance significantly improves PFS and OS in MM patients following induction therapy +/- ASCT. The OS benefit appears to be limited to the maintenance setting based on a subgroup analysis. Bortezomib-based regimen increases the risk of grade 3 or 4 peripheral sensory neuropathy and neuralgia. Disclosures Bachanova: Gamida Cell: Research Funding; GT Biopharma: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees.

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Efficacy Of Novel Agents As Maintenance Therapy For Multiple Myeloma: A Direct and Network Meta-Analysis

Blood ◽

10.1182/blood.v122.21.1945.1945 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1945-1945

Author(s):

Tea Reljic ◽

Ambuj Kumar ◽

Helen Mahoney ◽

Branko Miladinovic ◽

Mohamed A Kharfan-Dabaja ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Randomized Controlled Trials ◽

Meta Analysis ◽

Novel Agents ◽

Cumulative Probability ◽

Controlled Trials ◽

Randomized Controlled ◽

Mixed Treatment ◽

American Society

Abstract Background Multiple myeloma (MM) accounts for 10% of all hematological malignancies. While MM remains incurable, several life-extending treatments are available including maintenance treatments. The goal of maintenance therapy is to modulate residual MM after an initial response, thereby prolonging progression-free and overall survival by adding additional therapy following induction treatment. The role of maintenance therapies in the management of multiple myeloma is unclear and evidence on efficacy of novel regimens (e.g. bortezomib, lenalidomide, or thalidomide) remains conflicting. We performed a systematic review and network meta-analysis of trials to assess the efficacy of novel agents used as maintenance therapy in management of multiple myeloma. Methods A comprehensive search of MEDLINE (PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and meeting abstracts from American Society of Hematology, American Society of Clinical Oncology, European Society for Medical Oncology and European Hematology Association was conducted to identify all phase III randomized controlled trials (RCTs) of novel agents used as maintenance therapy for multiple myeloma published until May 2013. We extracted data on overall and progression-free survival (OS, PFS). Data were pooled using direct and network meta-analysis. Direct comparisons within trials were combined with indirect evidence from other trials using the Bayesian mixed treatment comparison method under the random-effects model. Indirect comparisons were constructed from trials which have one treatment in common. Results Of 2678 identified references, 23 randomized controlled trials met the inclusion criteria. Of these, 12 studies (4832 patients) contributed data to the network. The network of direct comparisons for all included studies for the outcome of PFS is shown in figure 1A. The results for meta-analysis of novel agents for PFS is shown in figure 1B. The combination of lenalidomide with prednisone was superior to no treatment as well as prednisone alone in addition to lenalidomide as single agent compared with no treatment. Furthermore, combination bortezomib plus thalidomide and dexamethasone plus lenalidomide was superior to no treatment. None of the novel agents except thalidomide plus prednisone compared with prednisone alone showed a significant improvement in OS and therefore an indirect comparison for OS was not conducted. The results of mixed treatment comparisons are illustrated in figure 1C which shows non-superiority of any novel agent. The cumulative probability rank for PFS is shown in Figure 1D. The area under the cumulative probability rank curve was highest for bortezomib+prednisone (0.73), followed by lenalidomide and lenalidomide+dexamethasone (both 0.71). Conclusion This analysis is an important addition to prior direct comparisons of novel agents for maintenance in multiple myeloma. Looking at PFS, use of bortezomib+prednisone, lenalidomide and lenalidomide+dexamethasone appears to be superior to other agents. However, provided the small number of trials between each comparison, current data do not allow for strong conclusions on superiority of any one treatment and direct comparison in a RCT is warranted for more conclusive results. Disclosures: No relevant conflicts of interest to declare.

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