Transplantation for Myeloma: Work in Progress

Abstract

The introduction of the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib has dramatically changed the management of multiple myeloma. These agents are being incorporated in induction therapies before autologous stem-cell transplantation (ASCT) and in consolidation/ maintenance treatments after ASCT. Outcome improvements associated with these approaches are under investigation. In the article that accompanies this editorial, Sonneveld et al present a phase III trial in which patients who were eligible for transplantation were randomly assigned to receive either vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD) before single or double ASCT. Afterward, 2-year maintenance therapy was administered, which consisted of thalidomide for VAD patients and bortezomib for PAD patients. The incorporation of bortezomib before ASCT resulted in an advantage in response rates, including a complete response rate of 24% with VAD and 36% with PAD (P .001). After ASCT, bortezomib maintenance was better tolerated compared with thalidomide, with a lower rate of treatment discontinuation. As a result of this combined approach, progression-free and overall survival were significantly improved in patients who received ASCT with the bortezomib-containing regimen. Two-drug combinations including dexamethasone plus either thalidomide, lenalidomide, or bortezomib are extensively being used as induction treatment before ASCT. More recently, three-drug approaches, such as the PAD combination used in the study by Sonneveld et al, or bortezomib and dexamethasone plus cyclophosphamide, halidomide, or lenalidomide have further improved response rates. In the absence of thalidomide, lenalidomide, and bortezomib, several studies have raised the question of whether single or double ASCT should be preferred. Two studies suggested that a second ASCT should be performed in patients who failed to achieve a profound cytoreduction after the first ASCT. Today, single ASCT is more commonly used, but to my knowledge, no randomized study has been performed that compared single versus double ASCT and incorporated an effective drug combination. Although not powered to compare single versus double ASCT, Sonneveld et al reported better overall survival in patients who received double ASCT. In this context, future trials that assess the role of single versus double ASCT with effective IMiDs or proteasome inhibitors are warranted. Allogeneic transplantation may be another valuable alternative to achieve longterm disease control. Trials that compare ASCT versus allogeneic transplantation reported conflicting results, and no clear superiority of one approach over the other has been confirmed. On the basis of an international consensus, allogeneic transplantation should be performed infrequently outside clinical trials because it is associated with high treatment-related mortality, although it may cure a minority of patients. Consolidation therapy proved to considerably enhance responses after ASCT, although to my knowledge, no data on progression-free or overall survival are available. In the study of Sonneveld et al, no consolidation was planned after ASCT, and thus, we do not know whether retreatment with PAD after ASCT might have further increased the clinical benefit. This option needs to be further investigated, and is currently under validation in randomized clinical trials. The role of maintenance therapy after ASCT has been addressed in several studies. Thalidomide maintenance consistently improved progression-free survival, but an overall survival advantage was sporadically reported. Maintenance therapy with lenalidomide proved to be a better alternative as a result of the lack of peripheral neuropathy adverse effects. This approach was associated with prolonged progression-free survival in two trials and with an overall survival benefit in one trial. In the article of Sonneveld et al, maintenance therapy with either thalidomide or bortezomib was administered for 2 years. In a landmark analysis, superior outcome was reported with bortezomib, which led to longer progression-free survival and overall survival. However, these results should be interpreted with caution because no random assignment for maintenance was planned, and patients assigned to bortezomib maintenance had already received this drug during induction. The better tolerance of bortezomib during maintenance and the lower discontinuation rate may explain the outcome advantage. The study by Sonneveld et al strengthens the concept that the ideal therapeutic strategy for transplant-eligible patients with myeloma should be a sequential approach that consists of induction with effective drug combinations followed by ASCT and subsequent consolidation/maintenance therapy. Proteasome inhibitors seem to be a better induction choice, whereas IMiDs seem to be a better maintenance option, although head-to-head comparisons of these options are still lacking. In a phase II study, bortezomib-based induction therapy before ASCT followed by lenalidomide as consolidation/maintenance was effective in patients age 65 to 75 years, with a 4-year progression-free survival of 53% and 4-year overall survival of 79%. Randomized studies are currently investigating this sequential strategy. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 24 AUGUST 2