Leukemia & Lymphoma | 2019
Current role of high dose chemotherapy in the management of multiple myeloma
Abstract
In this issue of Leukemia & Lymphoma, Su and Sheng [1] report a meta-analysis of 14 trials that compared autologous stem cell transplantation in multiple myeloma to novel agent-based consolidation. They conclude that stem cell transplantation significantly improved progression-free survival and response quality in the novel agent era. Is this data sufficient to lay to rest the argument as to whether stem cell transplantation remains standard of care in the era of novel agents? The quality of a meta-analysis is only as good as the constituent manuscripts included. Unfortunately, the heterogeneity among trials is large, limiting the value of combining the trials. Among the trials that randomized between transplant and lenalidomidebased consolidation therapy, there were 2421 patients. However, half of these patients belonged to a single trial [2], which has only been reported in the abstract. All four trials involving lenalidomide and bortezomib suffer to some degree based on their design. In the Italian trials, the induction and the consolidation were lenalidomide-based and at no time in either arm were patients exposed to bortezomib, which does not reflect current practice where induction is VRD, VTD, VCD, and MPV (bortezomib–lenalidomide–dexamethasone; bortezomib–thalidomide–dexamethasone; cyclophosphamide–bortezomib–dexamethasone; melphalan–prednisone–bortezomib). Arguably, bortezomib is the single most active agent in the treatment of multiple myeloma, so a comparison of outcomes when this agent was never used is problematic. In the Cavo trial, the consolidation represented MPV. MPV has historically been used in the transplantineligible population, and its value in a transplanteligible population remains unclear. In other trials, the comparator arms constituted bortezomib–doxorubicin–dexamethasone with no novel agent exposure in the control arm or used doublet induction, which has been shown to be inferior to triplet induction [3]. As a consequence, the findings reported must be taken as not representing the final word. Nonetheless, there are a number of key findings in this article that argue that early autologous stem cell transplant should represent the standard of care for multiple myeloma. Depth of response was greater in the transplanted group. Depth of response assessed by antisense oligonucleotide-polymerase chain reaction (ASO-PCR) predicts outcome after stem cell transplantation [4]. Although survival has not been demonstrated to be superior in transplanted populations, progression-free survival is correlated with an increase of very good partial or better responses. Progression-free survival, from the patient’s viewpoint, is time spent without myeloma [5]. Deeper responses increase the frequency of patients with minimal residual disease negativity, and this has been associated with superior survival. Minimal residual disease negativity is increased with early stem cell transplantation [6]. The trial of Attal et al. used triplet lenalidomide, bortezomib, and dexamethasone, which demonstrated a reduced relapse rate. Although this trial has not, as yet, demonstrated a survival advantage, given the median survival of myeloma now estimated at eight years for standardrisk patients, means that it will be some time before curve separation can be identified given the outstanding number of salvage regimens that exist [7]. The question of whether or not a transplant is as effective when done early as opposed to being done late has been argued vigorously because it has not been shown that there is a survival advantage for early