The role of bortezomib treatment for patients with multiple myeloma

Background

Multiple myeloma is a type of blood cancer, affecting plasma cells inside the bone marrow. Bortezomib is a type of treatment for myeloma called a proteasome inhibitor. Proteasomes are enzymes found in all cells and play an important role in cell function and growth. Cancer cells are more sensitive to the effects of bortezomib, causing cancer cells to die or not grow any further.

Study characteristics

We wanted to know the benefits and harms from bortezomib treatment for myeloma. We searched medical databases and trial registries until January 2016. We included studies of bortezomib compared to no bortezomib, with either the same or different background therapy or compared to other drugs. Studies of newly diagnosed and relapsed myeloma were included as well as those that compared different doses, ways of administering bortezomib and treatment schedules.

Key results

We found 16 studies involving 5626 myeloma patients. The results of this review suggest that bortezomib can lead to better survival, a longer time without progression and better response rates compared to those not receiving bortezomib. Treatment with bortezomib causes a number of side effects including: low levels of some blood cells; gastro-intestinal effects such as constipation, diarrhoea, nausea and vomiting; nerve pain and tingling in hands and feet, as well as infection. A greater risk of heart problems was seen in one of the comparison groups studied. Risk of death from bortezomib treatment was uncertain in either group analysed. Only four studies assessed quality of life and could not be analysed together.

Quality of the evidence

We judged quality of the evidence as high to moderate for mortality or number of deaths, whereas it was considered low-quality evidence for progression-free survival. the quality of evidence for adverse events was highly variable (low to high). For assessment of treatment-related death, there was no evidence of a difference, with low-quality evidence in one comparison (bortezomib compared to no bortezomib with the same background therapy) and very low-quality evidence in comparison two (bortezomib compared to no bortezomib with different background therapy or compared to other drugs).

Conclusion

Patients receiving bortezomib had better response rates, longer time without progression and appeared to live longer compared to those not receiving bortezomib, however patients receiving bortezomib experienced more side effects. Other proteasome inhibitor drugs have also been developed, therefore further research should focus on whether these newer drugs provide additional benefits and fewer side effects than bortezomib. More studies on health-related quality of life are also needed.

Authors' conclusions: 

This meta-analysis found that myeloma patients receiving bortezomib benefited in terms of OS, PFS and response rate compared to those who did not receive bortezomib. This benefit was observed in trials of bortezomib versus no bortezomib with the same background therapy and in trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s). Further evaluation of newer proteasome inhibitors is required to ascertain whether these agents offer an improved risk-benefit profile, while more studies of HRQoL are also required.

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Background: 

Multiple myeloma is a malignancy of plasma cells accounting for approximately 1% of cancers and 12% of haematological malignancies. The first-in-class proteasome inhibitor, bortezomib, is commonly used to treat newly diagnosed as well as relapsed/refractory myeloma, either as single agent or combined with other therapies.

Objectives: 

We conducted a systematic review and meta-analysis to assess the effects of bortezomib on overall survival (OS), progression-free survival (PFS), response rate (RR), health-related quality of life (HRQoL), adverse events (AEs) and treatment-related death (TRD).

Search strategy: 

We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE (till 27 January 2016) as well as conference proceedings and clinical trial registries for randomised controlled trials (RCTs).

Selection criteria: 

We included randomised controlled trials (RCTs) that compared i) bortezomib versus no bortezomib with the same background therapy in each arm; ii) bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s) and iii) bortezomib dose comparisons and comparisons of different treatment administrations and schedules.

Data collection and analysis: 

Two review authors independently extracted outcomes data and assessed risk of bias. We extracted hazard ratios (HR) and their confidence intervals for OS and PFS and odds ratios (OR) for response rates, AEs and TRD. We contacted trial authors to provide summary statistics if missing. We estimated Logrank statistics which were not available. We extracted HRQoL data, where available.

Main results: 

We screened a total of 3667 records, identifying 16 relevant RCTs involving 5626 patients and included 12 trials in the meta-analyses. All trials were randomised and open-label studies. Two trials were published in abstract form and therefore we were unable to assess potential risk of bias in full.

There is moderate-quality evidence that bortezomib prolongs OS (four studies, 1586 patients; Peto OR 0.77, 95% CI 0.65 to 0.92) and PFS (five studies, 1855 patients; Peto OR 0.65, 95% CI 0.57 to 0.74) from analysing trials of bortezomib versus no bortezomib with the same background therapy in each arm.

There is high-quality evidence that bortezomib prolongs OS (five studies, 2532 patients; Peto OR 0.76, 95% CI 0.67 to 0.88) but low-quality evidence for PFS (four studies, 2489 patients; Peto OR 0.67, 95% CI 0.61 to 0.75) from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s).

Four trials (N = 716) examined different doses, methods of administrations and treatment schedules and were reviewed qualitatively only.

We identified four trials in the meta-analysis that measured time to progression (TTP) and were able to extract and analyse PFS data for three of the studies, while in the case of one study, we included TTP data as PFS data were not available. We therefore did not analyse TTP separately in this review.

Patients treated with bortezomib have increased risk of thrombocytopenia, neutropenia, gastro-intestinal toxicities, peripheral neuropathy, infection and fatigue with the quality of evidence highly variable. There is high-quality evidence for increased risk of cardiac disorders from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or versus other agents. The risk of TRD in either comparison group analysed is uncertain due to the low quality of the evidence.

Only four trials analysed HRQoL and the data could not be meta-analysed.

Subgroup analyses by disease setting revealed improvements in all outcomes, whereas for therapy setting, an improved benefit for bortezomib was observed in all outcomes and subgroups except for OS following consolidation therapy.

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