Maintenance Therapy With Immunomodulatory Drugs in Multiple Myeloma: A Meta-Analysis and Systematic Review

Abstract

Background: Immunomodulatory drugs (IMiDs) and proteasome inhibitors have dramatically changed management of multiple myeloma (MM). While MM remains incurable, consolidation and maintenance therapy aimed at improving duration of response can potentially improve survival outcomes. A majority of randomized controlled trials (RCTs) have demonstrated benefit of IMiD-based maintenance therapy in delaying disease progression; however, whether this therapy can lead to improved survival remains controversial.

Methods: PubMed and abstract databases of major hematology and/or oncology meetings were searched for RCTs that studied maintenance therapy with IMiDs in MM. A meta-analysis was conducted to systematically evaluate the impact of IMiD-based maintenance therapy on survival outcomes and serious adverse events associated with the therapy. All statistical tests were two-sided.

Results: Eighteen phase 3 RCTs enrolling 7730 patients were included. IMiD-based maintenance therapy statistically significantly prolonged progression-free survival (PFS; hazard ratio (HR) = 0.62, 95% confidence interval (CI) = 0.57 to 0.67, P < .001) but failed to improve overall survival (OS; HR = 0.93, 95% CI = 0.85 to 1.01, P = .082). Stratified analyses demonstrated that both thalidomide and lenalidomide provided PFS but not OS benefit in transplantation as well as nontransplantation settings. IMiD-based maintenance therapy in MM led to a higher risk of grade 3-4 thromboembolism (risk ratio = 2.52, 95% CI = 1.41 to 4.52, P = .002). Thalidomide maintenance therapy increased the risk of peripheral neuropathy; lenalidomide maintenance therapy increased the risks of myelosuppression and second primary hematological malignancies.

Conclusions: Thalidomide- or lenalidomide-based maintenance therapy improves PFS but not OS in MM and increases risks of grade 3-4 adverse events, including thromboembolism, peripheral neuropathy, neutropenia, and infection.

Figure 1.

Flowchart showing study search, screening and selection. IMiD = immunomodulatory drug; HR = hazard ratio; OS = overall survival; PFS = progression-free survival.

Figure 2.

Forest plots of hazard ratios for (A) progression-free survival and (B) overall survival of immunomodulatory drug-containing groups vs control groups. Hazard ratios (HRs) for each trial are represented by the squares , where the size of the square represents the weight of the trial in the meta-analysis and the horizontal line crossing the square represents the 95% confidence interval (CI). The diamonds represent the subgroup and overall summary HR estimates and 95% CIs. All statistical tests were two-sided. ASCT = autologous stem cell transplantation; IMiD = immunomodulatory drug.

Figure 2.

Forest plots of hazard ratios for (A) progression-free survival and (B) overall survival of immunomodulatory drug-containing groups vs control groups. Hazard ratios (HRs) for each trial are represented by the squares , where the size of the square represents the weight of the trial in the meta-analysis and the horizontal line crossing the square represents the 95% confidence interval (CI). The diamonds represent the subgroup and overall summary HR estimates and 95% CIs. All statistical tests were two-sided. ASCT = autologous stem cell transplantation; IMiD = immunomodulatory drug.