Melphalan and Prednisone (MP) Versus Melphalan, Prednisone and Thalidomide (MPT) as Initial Therapy for Previously Untreated Elderly and/or Transplant Ineligible Patients with Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials.

Trials comparing efficacy of standard melphalan prednisone (MP) therapy with MP plus thalidomide (T) in the transplant ineligible, elderly patients with multiple myeloma have provided conflicting evidence. While there is greater agreement with regard to superior response rates (RR) with the addition of T to MP in elderly patients, the impact on progression free survival (PFS) and overall survival (OS) is less clear with some trials showing an improvement in PFS and/or OS with MPT and others demonstrating no difference in outcomes. We performed a systematic review to integrate the existing outcome data related to the efficacy of MP vs. MPT using a meta-analytic approach.

A comprehensive search of electronic database through July 31^st, 2009 was performed for publications, abstracts and presentations to identify randomized controlled trials (RCTs) comparing MP with MPT. A meta-analysis was performed by pooling results on clinical endpoints of RR, PFS and OS reported in all the identified RCTs under a random effects model. We did not have access to individual patient data from these trials.

Overall, five prospective RCTs (3 published articles and 2 abstracts) comparing MP with MPT regimen and comprising a total of 1571 patients were identified. For the endpoints of OS and PFS, data were extractable only from 4 RCTs (abstract by Gulbrandsen et al. was excluded). The Bregg and Egger funnel plot for OS demonstrated a symmetric distribution (P = 0.6) indicating no significant publication bias. The test of heterogeneity among all RCTs was statistically significant in the estimate of RR (tau²=0.21; chi²=16.33; p=0.003 (df=4); I² = 75.5%), but not significant for the estimates of PFS (tau²=0.01; chi²=4.61; p=0.2 (df=3); I² = 34.9%), and OS (tau²=0.02; chi²=5.53; p=0.14 (df=3); I² = 45.8%). As expected, the pooled odds ratio of responding to treatment with MP versus MPT was 0.307 (P<0.001) indicating that MP was worse than MPT in achieving at least a partial response. The pooled hazard ratios (HR) for PFS and OS were 1.59 (p<0.001) and 1.34 (p=0.006), respectively (see table for forest plots) in favor of MPT.

Our meta-analysis implies that in previously untreated, transplant ineligible elderly patients with multiple myeloma, the addition of thalidomide to melphalan-prednisone demonstrates improved RR, PFS and OS compared with the use of melphalan-prednisone alone. Although the results from a comprehensive individual patient data pooled analysis would give a more precise estimate, our analysis suggests that MPT is superior to MP in terms of response and survival.

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Dispenzieri:Celgene: Research Funding. Gertz:Celgene: Honoraria. Kumar:celgene, genzyme, millennium, novartis, bayer: Research Funding; genzyme: Membership on an entity's Board of Directors or advisory committees.