Efficacy Of Bortezomib-Based Regimens With Or Without An Immunomodulatory Agent In Older Adults With Multiple Myeloma: A Systematic Review and Meta-Analysis
Authors: Atkins Jordan , Fowler Susan A , Tuuli Methodius , James Aimee S , Wildes Tanya M 
Published: October 2019

Abstract

Introduction
Multiple myeloma (MM) is an incurable disease within older adults, caused by the malignant proliferation of plasma cells and destruction of skeletal structure, with subsequent end-organ dysfunction. In the elderly and transplant ineligible population, chemotherapeutic regimens that include novel and conventional drugs are currently being employed to attain optimal response and survival outcomes. We performed a systematic review and meta-analysis to investigate the efficacy of the proteasome inhibitor bortezomib, in combination with an immunomodulatory drug (IMiD) versus bortezomib-containing regimens alone in improving overall survival, progression-free survival, and response in patients aged 65 and older ineligible for stem cell transplant.

Methods
We searched Pubmed/Medline, Embase, Scopus, CENTRAL, DARE, and clinicaltrials.gov databases for randomized controlled trials (RCTs) published from January 1946 until March 2013 using search terms such as: “bortezomib” “thalidomide/analogs and derivatives” and “lenalidomide.” Primary outcomes such as overall survival “OS” and progression-free survival “PFS” were harvested from standard indexes and on-topic articles. We abstracted data from relevant studies for analysis. Heterogeneity was assessed using Cochrane's Q and Higgin's I2 with p<0.1 considered significant. Pooled risk ratios (RR) and hazard ratios (HR) were estimated using DerSimonain and Laird random effect models.

Results
We identified 762 studies, 201 of which were duplicates that were excluded. Of these studies, 561 met initial inclusion criteria. After screening and systematic review, we found a majority of the articles originated from sub-analyses or reviews of 2 major studies which fully met inclusion criteria: 1) bortezomib-melphalan-prednisone-thalidomide (VMPT) versus bortezomib-melphalan-prednisone (VMP) [Palumbo JCO 2010] and 2) bortezomib-thalidomide-prednisone (VTP) versus VMP [Mateos Lancet Onc 2010). Of the two studies included, 384 patients received thalidomide and bortezomib-containing regimens (VMPT or VTP), and 387 patients received VMP. Thalidomide-containing combinations were associated with improvement in complete response (pooled RR 1.55 [95% Confidence intervals 1.23-1.95]) and very good partial response (pooled RR 1.19 [95% Confidence intervals 1.04-1.38]). There was no evidence of significant heterogeneity associated with either of these outcomes across the studies (I2=0; p=0.559 and I2=0; p=0.600). There were no significant differences in partial response (pooled RR 1.08; 95% CI 0.98-1.19), overall survival (pooled HR 1.04; 95% CI 0.65-1.44), or progression-free survival (pooled HR 0.91; 95% CI 0.29-1.42). There were also no significant differences in toxic side effects (Table).

Conclusion
Based on the limited data included in this meta-analysis, we found that the addition of thalidomide to a bortezomib-based regimen was associated with improved complete response and very good partial response, but no improvement in overall or progression-free survival. Larger studies of thalidomide and other immunomodulatory agents are required to further clarify the role of adding IMiDs to bortezomib-based regimens in the treatment of MM.

Disclosures:
No relevant conflicts of interest to declare.