Currently, management of MM remains challenging and relapse of MM and disease progression is common even after achievement of complete remission. With many novel agents available to treat RRMM patients, there is a need to identify the optimal combinations to achieve an appropriate balance between efficacy and safety. Immunomodulatory drugs in combination with dexamethasone have shown great clinical benefit in patients with RRMM (12, 30). The main goal of this meta-analysis was to systematically analyze the efficacy and toxicity of triple combinations specifically containing dexamethasone and an immunomodulatory in treatment for RRMM. Our results suggested that triple combinations containing dexamethasone and an immunomodulatory significantly increased ORR and, importantly, improved PFS and OS, indicating a survival advantage with an added treatment agent. These findings are fully congruent with Dimopoulos et al. (2018) (23) who used a Bayesian approach to a meta-analysis and found that triplet therapies were superior to doublet therapies. The focus of that study was distinct in that they used immunomodulatory treatment in at least two arms within the same study as a criterion, whereas we focused on the combination of dexamethasone and an immunomodulatory. Using classical statistics, our study confirms their finding that adding a third agent (specifically daratumumab in their study) to an immunomodulatory and dexamethasone was most efficacious – an identical finding to that of both Botta et al. (2017) (21) and van Beurden-Tan et al. (2017) (22). Thus, our results are in line with current guidelines and treatment recommendations for RRMM.
Similar to Botta et al. (2017) (21), this study also assessed adverse effects, though their work compared bortezomib-containing versus immunomodulatory-containing regiments. With the focus on dexamethasone and an immunomodulatory, we found the incidence of ≥ grade 3 diarrhea and fatigue were significantly higher in the triplet combination group. There was a trend toward increased incidence of ≥ grade 3 neutropenia, thrombocytopenia, thromboembolism, and peripheral neuropathy in the triplet therapy group, but these did not reach statistical significance compared to doublet therapy. Cautious interpretation is advised here as these studies may have been under powered; thus, while more trials and patients are needed to determine whether the trends underly reality, it appears as though these adverse effects are more likely to be observed in patients on triplet therapies including dexamethasone and an immunomodulatory. Interestingly, we found that triplet therapy had a lower rate of anemia compared to doublet therapy. Anemia is a typical symptom of MM, so the lower rate of anemia may reflect better efficacy of the triplet therapy.
This meta-analysis had some limitations. The work was based on published studies, not an analysis of individual patient data, which limited time-to-event analyses. Our analysis was also limited to the available published data, which omits unpublished or ongoing trials and is subject to a reasonable risk of reporting bias. This study is underpowered for assessment of publication bias by current statistical approaches (31). Despite these limitations, our meta-analysis includes a comprehensive search for eligible studies, the careful consideration of study quality, and a rigorous analytical approach.
The focus on studies that included only dexamethasone and immunomodulatory drug treatments for comparisons allows for informed treatment decisions based on these two standard therapies. This last point is a key difference between this study and that of Sun et al. (2017). Sun et al. (2017) also included a report that compared treatments with bortezomib and dexamethasone along with studies that included treatments with immunomodulatory agents and dexamethasone(20). While survival outcomes were similar between the two studies, a clear difference was observed for one major adverse outcome: anemia. Our analysis suggests triplet therapy including an immunomodulatory and dexamethasone may reduce the occurrence of anemia over doublet therapy. This is the first meta-analysis of RCTs in patients with RRMM suggesting that triplet combinations that include dexamethasone and an immunomodulatory drug have a favorable risk-benefit profile compared with treatments that only include dexamethasone and an immunomodulatory drug. This is completely consistent with a recent report from Alahmadi et al. (2019), who found that adding cyclophosphamide to lenalidomide and dexamethasone had clinical benefit with manageable toxicities(32), and Attal et al.(2019), who found that adding isatuximab to pomalidomide and dexamethasone enhanced PFS(33). Given the high degree of variability of real patient populations and treatment outcomes in RRMM(34), our study provides additional evidence for clinicians as they consider whether immunomodulatory and dexamethasone-based combinations are the best treatment options for their patients.