Comparative efficacy of tandem autologous versus autologous followed by allogeneic hematopoietic cell transplantation in patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background: Despite advances in understanding of clinical, genetic, and molecular aspects of multiple myeloma (MM) and availability of more effective therapies, MM remains incurable. The autologous-allogeneic (auto-allo) hematopoietic cell transplantation (HCT) strategy is based on combining cytoreduction from high-dose (chemo- or chemoradio)-therapy with adoptive immunotherapy. However, conflicting results have been reported when an auto-allo HCT approach is compared to tandem autologous (auto-auto) HCT. A previously published meta-analysis has been reported; however, it suffers from serious methodological flaws.

Methods: A systematic search identified 152 publications, of which five studies (enrolling 1538 patients) met inclusion criteria. All studies eligible for inclusion utilized biologic randomization.

Results: Assessing response rates by achievement of at least a very good partial response did not differ among the treatment arms [risk ratio (RR) (95% CI) = 0.97 (0.87-1.09), p = 0.66]; but complete remission was higher in the auto-allo HCT arm [RR = 1.65 (1.25-2.19), p = 0.0005]. Event-free survival did not differ between auto-allo HCT group versus auto-auto HCT group using per-protocol analysis [hazard ratio (HR) = 0.78 (0.58-1.05)), p = 0.11] or using intention-to-treat analysis [HR = 0.83 (0.60-1.15), p = 0.26]. Overall survival (OS) did not differ among these treatment arms whether analyzed on per-protocol [HR = 0.88 (0.33-2.35), p = 0.79], or by intention-to-treat [HR = 0.80 (0.48-1.32), p = 0.39] analysis. Non-relapse mortality (NRM) was significantly worse with auto-allo HCT [RR (95%CI) = 3.55 (2.17-5.80), p < 0.00001].

Conclusion: Despite higher complete remission rates, there is no improvement in OS with auto-allo HCT; but this approach results in higher NRM in patients with newly diagnosed MM. At present, totality of evidence suggests that an auto-allo HCT approach for patients with newly diagnosed myeloma should not be offered outside the setting of a clinical trial.

Figure 1

Flow-diagram depicting the identification and selection of eligible studies for inclusion in the systematic review.

Figure 2

A through 2C: Forest plot for response rates. Overall (A), complete (B) or at least very good partial response (C). The summary estimate (risk ratio) from individual studies is indicated by rectangles with lines representing the 95% confidence intervals (CIs). The summary pooled estimate from all studies is represented by the diamond and the stretch of the diamond indicates the corresponding 95% CI.

Figure 3

A and 3B: Forest plot for event-free survival according to intent-to-treat analysis (A) and overall survival (B). The summary estimate (hazard ratio) from individual studies is indicated by rectangles with lines representing the 95% confidence intervals (CIs). The summary pooled estimate from all studies is represented by the diamond and the stretch of the diamond indicates the corresponding 95% CI.

Figure 4

A through 4C: Forest plot for non-relapse mortality (A), grade II-IV graft versus-host disease (B) and chronic graft versus-host disease (C). The summary estimate (risk ratio/proportions) from individual studies is indicated by rectangles with lines representing the 95% confidence intervals (CIs). The summary pooled estimate from all studies is represented by the diamond and the stretch of the diamond indicates the corresponding 95% CI. For the proportional meta-analysis the diamond represents the pooled summary estimates and the 95% CI is indicated by the line.