Chapter 3 – Treatment of transplant-eligible patients

Contributors: Mohamad Mohty, Florent Malard, Jean-Luc Harousseau

3 – Consolidation

The use of short-term consolidation therapy after HDT and auto-SCT aims to improve disease response through the induction of a deeper response. It is widely accepted that consolidation therapy should rely on a highly efficient combination of drugs with limited toxicity, and that it should be administered for a limited period of time. Prior to the introduction of novel agents, a second auto-SCT was used as consolidation therapy (tandem ASCT) following the Arkansas experience [26,27]. The objective was to increase the CR rate. However, currently there is no consensus on the use of tandem auto-SCT since in randomized studies PFS was increased but results regarding OS were less convincing. In the era of new therapies, tandem ASCT might be useful in patients achieving <VGPR after the first ASCT or in cases of high-risk cytogenetic profiles [28]. At present, experiences testing consolidation therapy in myeloma with a combination of novel therapy remain scarce. Initial results suggest that using novel agents after auto-SCT may further increase the rate of high-quality responses and improve both PFS and OS [29]. In patients with a good response after auto-SCT, consolidation therapy has been found not only to increase the CR rate but also to yield molecular remissions, which are associated with longer PFS [30]. Only a few large studies investigating novel agent-based consolidation therapy are available thus far [31–33].

The Italian Myeloma Study Group reported results from a randomized, phase III study that assessed the efficacy of VTD versus TD as induction therapy before, and as, consolidation therapy after double auto-SCT for newly diagnosed myeloma patients [6]. In this randomized study, superior CR/nCR rates and extended PFS were demonstrated with VTD versus TD as induction therapy before, and two cycles of consolidation after, double auto-SCT. A recent per-protocol analysis of 321 patients [31] specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD and TD arms. After consolidation, CR and CR/nCR rates were significantly higher for VTD-treated (n=160) versus TD-treated patients (n=161). VTD consolidation significantly increased CR and CR/nCR rates, but TD did not, and 3-year post-consolidation PFS was significantly longer for the VTD group at 62% compared with 46% in the TD arm (p=0.042). Thus, VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study.

Data from other reports are consistent with the above findings of a clinical benefit of consolidation therapy after auto-SCT. In a retrospective multicenter study, Leleu et al found that two cycles of VTD consolidation therapy (D=dexamethasone orally 40mg weekly) resulted in a significantly lower relapse rate of 21% versus 45% when compared with no consolidation treatment (VTD n=121, no treatment n=96; p=0.001) [32]. In another randomized trial conducted by the Nordic Myeloma Study Group, the use of bortezomib as single-agent consolidation therapy (20 doses during 21 weeks) was compared with no consolidation in a population of bortezomib-naive patients and proved to be a superior approach [33]. In the study, 187 patients received bortezomib single-agent consolidation therapy with an outcome of PFS of 27 months, whereas the bortezomib-naive patients (n=183) only achieved a PFS of 20 months (p=0.05).

Finally, the benefit of a second auto-SCT compared with consolidation therapy and the respective impact of consolidation and maintenance therapies are unknown, and randomized studies addressing these questions are underway [34]. Preliminary data reported in recent meetings lead to controversial conclusions, likely related to the design of the trials.