Contributions
Abstract: EP1015
Type: E-Poster Presentation
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
In patients with newly diagnosed multiple myeloma, early intensive consolidation with high dose therapy-autologous hematopoietic cell transplantation (HDT-AHCT) leads to a superior progression-free survival (PFS) compared to standard dose therapy (SDT). However, whether patients with high-risk cytogenetics benefit from early HDT-AHCT remains unclear. To answer this question, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing consolidation with HDT-AHCT versus SDT in the era of proteasome inhibitor (PI) and/or immunomodulatory drug (IMiD)-based induction therapy.
Aims
The primary objective of this study was to evaluate the association of HDT-AHCT with PFS in newly diagnosed high-risk myeloma, with overall survival (OS) being the secondary objective.
Methods
Standard electronic databases were searched for citations of phase 3 RCTs comparing HDT-AHCT with SDT in newly diagnosed myeloma. High-risk myeloma was defined as subjects with adverse-risk cytogenetics, as specified by individual study protocol. Efficacy data was extracted using hazard ratios (HRs) for PFS and OS. We used DerSimonian-Laird random effects model to pool log HRs, and applied Hartung-Knapp adjustment as the total number of trials was small. Heterogeneity was assessed using the Cochran Q and the I2 statistic.
Results
After screening all citations, a total of 17 RCTs were retrieved, of whom, 4 RCTs were deemed eligible for inclusion in the meta-analysis. An additional RCT was included after searching conference abstracts and grey literature. The included RCTs were as follows: IFM 2009 (Attal et al. NEJM. 2017), EMN02/HOVON 95 (Cavo et al. Lancet Haem. 2020 and Cavo et al. ASH 2020), RV-MM-EMN-441 (Gay et al. Lancet Oncol. 2015), RV-MM-PI-209 (Palumbo et al. NEJM. 2014), and FORTE (Gay et al. ASH. 2020). The induction regimens used were VRD (bortezomib-lenalidomide-dexamethasone; n=1), KRD (carfilzomib-lenalidomide-dexamethasone; n=1), VCD (bortezomib-cyclophosphamide-dexamethasone; n=1), and RD (lenalidomide-dexamethasone; n=2). Patients underwent a single HDT-AHCT in 2 trials, tandem in 2 trials and a combination of single or tandem in 1, with the conditioning regimen being melphalan 200 mg/m2 in all RCTs. Three RCTs (IFM 2009, EMN02/HIVON95, and RV-MM-EMN-441) included post-transplant lenalidomide maintenance in all patients and 2 RCTs (RV-MM-PI-209 and FORTE) randomized patients to lenalidomide versus observation or carfilzomib-lenalidomide respectively. Early intensive consolidation with HDT-AHCT led to superior PFS compared to SDT, with the benefit consistent in both high-risk (Pooled HR, 0.50 [0.27-0.94]) and standard-risk (Pooled HR, 0.58 [0.46-0.73]) subrgoups (p-value for interaction=0.32). A subset of 3 RCTs (EMN02/HOVON95, RV-MM-EMN-441, and RV-MM-PI-209) reported OS in cytogenetic risk subgroups. Patients with high-risk cytogenetics had a greater OS benefit with early HDT-AHCT (Pooled HR, 0.59 [0.47-0.74]) compared to standard-risk (Pooled HR, 0.82 [0.63-1.07]) patients (p-value for interaction<0.01).
Conclusion
In patients with newly diagnosed myeloma undergoing induction therapy with PIs +/- IMiDs, early intensive consolidation with HDT-AHCT is associated with a superior PFS compared to SDT, with benefit being consistent in both high-risk and standard-risk subgroups. Furthermore, although HDT-AHCT leads to an OS benefit overall, high-risk patients derive greater benefit compared to standard-risk. HDT-AHCT should not be delayed in patients with high-risk myeloma outside of well designed clinical trials.
Keyword(s):
Abstract: EP1015
Type: E-Poster Presentation
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
In patients with newly diagnosed multiple myeloma, early intensive consolidation with high dose therapy-autologous hematopoietic cell transplantation (HDT-AHCT) leads to a superior progression-free survival (PFS) compared to standard dose therapy (SDT). However, whether patients with high-risk cytogenetics benefit from early HDT-AHCT remains unclear. To answer this question, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing consolidation with HDT-AHCT versus SDT in the era of proteasome inhibitor (PI) and/or immunomodulatory drug (IMiD)-based induction therapy.
Aims
The primary objective of this study was to evaluate the association of HDT-AHCT with PFS in newly diagnosed high-risk myeloma, with overall survival (OS) being the secondary objective.
Methods
Standard electronic databases were searched for citations of phase 3 RCTs comparing HDT-AHCT with SDT in newly diagnosed myeloma. High-risk myeloma was defined as subjects with adverse-risk cytogenetics, as specified by individual study protocol. Efficacy data was extracted using hazard ratios (HRs) for PFS and OS. We used DerSimonian-Laird random effects model to pool log HRs, and applied Hartung-Knapp adjustment as the total number of trials was small. Heterogeneity was assessed using the Cochran Q and the I2 statistic.
Results
After screening all citations, a total of 17 RCTs were retrieved, of whom, 4 RCTs were deemed eligible for inclusion in the meta-analysis. An additional RCT was included after searching conference abstracts and grey literature. The included RCTs were as follows: IFM 2009 (Attal et al. NEJM. 2017), EMN02/HOVON 95 (Cavo et al. Lancet Haem. 2020 and Cavo et al. ASH 2020), RV-MM-EMN-441 (Gay et al. Lancet Oncol. 2015), RV-MM-PI-209 (Palumbo et al. NEJM. 2014), and FORTE (Gay et al. ASH. 2020). The induction regimens used were VRD (bortezomib-lenalidomide-dexamethasone; n=1), KRD (carfilzomib-lenalidomide-dexamethasone; n=1), VCD (bortezomib-cyclophosphamide-dexamethasone; n=1), and RD (lenalidomide-dexamethasone; n=2). Patients underwent a single HDT-AHCT in 2 trials, tandem in 2 trials and a combination of single or tandem in 1, with the conditioning regimen being melphalan 200 mg/m2 in all RCTs. Three RCTs (IFM 2009, EMN02/HIVON95, and RV-MM-EMN-441) included post-transplant lenalidomide maintenance in all patients and 2 RCTs (RV-MM-PI-209 and FORTE) randomized patients to lenalidomide versus observation or carfilzomib-lenalidomide respectively. Early intensive consolidation with HDT-AHCT led to superior PFS compared to SDT, with the benefit consistent in both high-risk (Pooled HR, 0.50 [0.27-0.94]) and standard-risk (Pooled HR, 0.58 [0.46-0.73]) subrgoups (p-value for interaction=0.32). A subset of 3 RCTs (EMN02/HOVON95, RV-MM-EMN-441, and RV-MM-PI-209) reported OS in cytogenetic risk subgroups. Patients with high-risk cytogenetics had a greater OS benefit with early HDT-AHCT (Pooled HR, 0.59 [0.47-0.74]) compared to standard-risk (Pooled HR, 0.82 [0.63-1.07]) patients (p-value for interaction<0.01).
Conclusion
In patients with newly diagnosed myeloma undergoing induction therapy with PIs +/- IMiDs, early intensive consolidation with HDT-AHCT is associated with a superior PFS compared to SDT, with benefit being consistent in both high-risk and standard-risk subgroups. Furthermore, although HDT-AHCT leads to an OS benefit overall, high-risk patients derive greater benefit compared to standard-risk. HDT-AHCT should not be delayed in patients with high-risk myeloma outside of well designed clinical trials.
Keyword(s):