Consolidation therapy in myeloma: a consolidated approach?

The use of a short consolidation treatment after autologous transplantation increases the complete response rate and relapse-free survival.

Survival in multiple myeloma has significantly increased in the past decade and this has been mainly due to the introduction of novel agents, such as immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib).^1,2  However, how to optimally use these agents through the different phases of the disease has yet to be determined. In this issue of Blood, Cavo et al show that consolidation therapy with VTD (bortezomib, thalidomide, and dexamethasone) after double autologous stem cell transplantation (ASCT) is significantly associated with improved complete response rate (CR) and progression-free survival (PFS) compared with TD consolidation.³  This benefit was confirmed in the multivariate regression analysis, because VTD consolidation was identified as an independent variable favorably influencing PFS. Moreover, the toxicity was acceptable in consonance with the use of low-dose thalidomide (100 mg) and bortezomib (weekly schedule). In fact, only 1 patient with pre-existing neuropathy developed grade neuropathy.

A potential pitfall of this study is that patients who received VTD consolidation had already received VTD as induction while those allocated to TD consolidation were induced with TD. Therefore, it may be difficult to dissect the benefit of consolidation versus induction therapies. To overcome this potential bias Cavo et al performed a per-protocol analysis (excluding patients who discontinued treatment because of disease progression—more frequent in the TD arm—or because of adverse events). Using this approach, the CR rates after the second ASCT were not significantly different in the VTD and TD arms (P = .13); in contrast, after consolidation the CR rate was significantly higher with VTD compared with TD (P = .012)

In younger myeloma patients, the treatment goal for cooperative groups and large institutions should be to investigate curative treatment approaches.⁴  This implies integrating the best therapy for induction, consolidation, and maintenance. The evolving total therapy programs pioneered by the Arkansas group represent an example of this philosophy.⁵  Consolidation therapy here means a short-term treatment given to upgrade the quality of the responses obtained in the previous treatment phases. This goal was achieved in the present trial, particularly in the VTD arm, with 54.8% of patients achieving an upgraded response with consolidation. Unfortunately, the study design did not include minimal residual disease techniques (multiparametric flow cytometry or RQ-PCR) to evaluate the potential benefit of tumor reduction in patients who were already in CR before consolidation.^2,6  It should be noted that this same group has previously reported that achievement of molecular responses after intensification with VTD is associated with long-term, relapse-free survival.⁷  Therefore, although there are long-term survivors who do not achieve CR but revert to a monoclonal gammopathy of undetermined significance–like status, for the majority of patients achieving and maintaining the best response would be a prerequisite for cure.

One of the most important findings of the Cavo et al study is the efficacy of VTD consolidation in patients with high-risk cytogenetics.³  Thus, in the cohort of patients with t(4;14) and/or del17p or just t(4;14), those who received VTD consolidation had a 63% relative reduction in the risk of progression compared with TD-treated patients. Moreover, the PFS curve of high-risk group was almost parallel to that of the standard-risk group, which indicates that VTD not only improves but overcomes the adverse prognosis associated with these cytogenetic abnormalities. It should be noted that this effect should not only be attributed to the consolidation therapy but to the integrated treatment, based on an optimized induction plus double autologous transplantation and consolidation. These positive results deserve 2 additional comments. (1) Although bortezomib appears to be an important drug for treatment of high-risk patients, not all bortezomib-based studies have obtained the same positive results; therefore, attention should be paid to the subtle differences among trials. (2) Optimized treatments should not only be offered to high-risk but also, and particularly, to standard-risk patients because they are the first likely candidates for cure.

A final comment about overall survival: the study by Cavo et al does not show differences in OS between VTD or TD consolidation. This may be due to a short follow-up or to differences in the rescue therapies used (which were not under trial control), or to the emergence of more resistant clones. This latter possibility is unlikely to be the explanation because the treatment duration of consolidation therapy is very short; therefore, the other options are more plausible.

Overall, this article highlights the benefit of VTD consolidation after double ASCT with emphasis in the high-risk population and although additional ongoing trials need to confirm these results, it is possible that “consolidation treatment” will become a “consolidated” part of the therapeutic scheme of younger patients.