Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis

Abstract

Purpose Lenalidomide maintenance therapy after autologous stem-cell transplantation (ASCT) demonstrated prolonged progression-free survival (PFS) versus placebo or observation in several randomized controlled trials (RCTs) of patients with newly diagnosed multiple myeloma (NDMM). All studies had PFS as the primary end point, and none were powered for overall survival (OS) as a primary end point. Thus, a meta-analysis was conducted to better understand the impact of lenalidomide maintenance in this setting. Patients and Methods The meta-analysis was conducted using primary-source patient-level data and documentation from three RCTs (Cancer and Leukemia Group B 100104, Gruppo Italiano Malattie Ematologiche dell'Adulto RV-MM-PI-209, and Intergroupe Francophone du Myélome 2005-02) that met the following prespecified inclusion criteria: an RCT in patients with NDMM receiving ASCT followed by lenalidomide maintenance versus placebo or observation with patient-level data available and achieved database lock for primary efficacy analysis. Results Overall, 1,208 patients were included in the meta-analysis (605 patients in the lenalidomide maintenance group and 603 in the placebo or observation group). The median PFS was 52.8 months for the lenalidomide group and 23.5 months for the placebo or observation group (hazard ratio, 0.48; 95% CI, 0.41 to 0.55). At a median follow-up time of 79.5 months for all surviving patients, the median OS had not been reached for the lenalidomide maintenance group, whereas it was 86.0 months for the placebo or observation group (hazard ratio, 0.75; 95% CI, 0.63 to 0.90; P = .001). The cumulative incidence rate of a second primary malignancy before disease progression was higher with lenalidomide maintenance versus placebo or observation, whereas the cumulative incidence rates of progression, death, or death as a result of myeloma were all higher with placebo or observation versus lenalidomide maintenance. Conclusion This meta-analysis demonstrates a significant OS benefit and confirms the PFS benefit with lenalidomide maintenance after ASCT in patients with NDMM when compared with placebo or observation.

Figures

Fig 1.

Progression-free survival (PFS) analysis (intent-to-treat population). For analyses of PFS, patients who started another antimyeloma therapy before documented disease progression or patients with missing assessments are censored. (A) Kaplan-Meier estimates of PFS. (B) Hazard ratios (HRs) for PFS by individual study. (C) HRs for PFS by subgroup. (*) The size of each blue box corresponds to the size of the individual study. The CI is a function of the overall sample size. (†) Age at random assignment was available and used for the Cancer and Leukemia Group B (CALGB) 100104 study and the Intergroupe Francophone du Myélome (IFM) 2005-02 study. Only age at diagnosis was available for the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) RV-MM-PI-209 study. (‡) The International Staging System (ISS) stage was based on β2-microglobulin and albumin at diagnosis for the GIMEMA and IFM studies and at registration for the CALGB study. (§) Upon central review, four patients did not meet the criteria for stable disease (SD). ASCT, autologous stem-cell transplantation; CR, complete response; Len, lenalidomide; PR, partial response; VGPR, very good partial response.

Fig 2.

Overall survival (OS) analysis (intent-to-treat population). (A) Kaplan-Meier estimates of OS. (B) Hazard ratios (HRs) for OS by subgroup. (C) HRs for OS by prior induction subgroup. (D) HRs for OS by individual study. (*) Age at random assignment was available or used for the Cancer and Leukemia Group B (CALGB) 100104 study and the Intergroupe Francophone du Myélome (IFM) 2005-02 study. Only age at diagnosis was available for the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) RV-MM-PI-209 study. (†) The International Staging System (ISS) stage was based on β2-microglobulin and albumin at diagnosis for the GIMEMA and IFM studies and at registration for the CALGB study. (‡) Upon central review, four patients did not meet the criteria for stable disease (SD). (§) All patients in the GIMEMA study received lenalidomide-based induction, which could be used in combination with any other drug. The size of each blue box corresponds to the size of the individual study. The CI is a function of the overall sample size. ASCT, autologous stem-cell transplantation; CR, complete response; Len, lenalidomide; NR, not reached; PR, partial response; TD, thalidomide and dexamethasone; VAD, vincristine, doxorubicin, and dexamethasone; VD, bortezomib and dexamethasone; VGPR, very good partial response.

Fig 3.

Second primary malignancy and mortality analyses. (A) Cumulative incidence curve of time to hematologic second primary malignancy (SPM) onset (as-treated population). Patients who were randomly assigned but not treated with lenalidomide maintenance are included in the control group. (B) Cumulative incidence of time to solid tumor SPM onset (as-treated population). Patients who were randomly assigned but not treated with lenalidomide maintenance are included in the control group. (C) Cumulative incidence curves of time to disease progression and time to invasive SPM onset before disease progression. (D) Kaplan-Meier (KM) curve of time to death by cause of death. AE, adverse event; Len, lenalidomide; MM, multiple myeloma; PD, progressive disease.