Refining “total therapy” for myeloma

High-dose therapy followed by hematopoietic stem cell support (ASCT) is an essential component in the treatment of younger patients with multiple myeloma (MM). In fact, MM is currently the most frequent indication for ASCT in Europe and the United States. The greatest survival benefit is observed in patients achieving immunofixation (IFE)–negative complete remission (CR) after transplantation, the sensitivity to the initial therapy being the most important predictor of CR after ASCT. With the use of conventional induction regimens, the posttransplantation CR rate is about 35%, the median survival 6 years, and the proportion of patients in continued CR beyond 10 years—“operational” cures—from ASCT is less than 10%.¹  The introduction of novel drugs such as thalidomide, lenalidomide, and bortezomib has provided the frame for improving the results of ASCT in MM.¹  In this regard, the association of thalidomide and dexamethasone (TD) and bortezomib and dexamethasone (VD) have been investigated as novel pretransplantation induction regimens. It seems that TD is suboptimal because of its limited efficacy in patients with high-risk cytogenetics as well as in those with extramedullary involvement.^2,3  Although VD can overcome the poor prognostic impact of high-risk cytogenetics, the posttransplantation CR rate is at most 35% and long-term results are not yet available. From the current data, it seems that triple regimens such as bortezomib-adriamycin-dexamethasone (PAD) and bortezomibthalidomide-dexamethasone (VTD) with pretransplantation and posttransplantation CR rates ranging from 19% to 31% and from 43% to 52%, respectively, will result in outcomes superior to those with pretransplantation TD or VD.

The Arkansas group has developed the so-called Total Therapy programs during the past 20 years by using all the available drugs throughout all the up-front treatment steps. Thus, the main components of Total Therapy 1 were induction with VAD, tandem ASCT with MEL-200, and interferon maintenance. Total Therapy 2 included the new drug thalidomide in both induction and maintenance, whereas Total Therapy 3 incorporated bortezomib in the VTD-PACE induction followed by tandem ASCT, 1 year of VTD consolidation, and 2 years of TD maintenance. Each program resulted in outcome superior to that of its predecessor, particularly in gene-expression profiling (GEP)–defined low-risk disease. The improved results of Total Therapy 3 versus Total Therapy 2 were attributed to the incorporation of bortezomib up front.⁴ 

In this issue of Blood, Nair et al⁵  report the results of Total Therapy 3 compared with those obtained in the Arkansas subsequent trial with identical design except that the 3 years of VTD/TD consolidation/maintenance were replaced by 3 years of VRD consisting of monthly cycles of bortezomib at 1 mg/m² on days 1, 4, 8, and 11 for 1 year followed by a weekly administration during years 2 and 3 along with lenalidomide and dexamethasone for all 3 years. Despite a significantly higher incidence of adverse prognostic features (ie, higher proportion of ISS stages 2 and 3 and high-risk GEP as well as lower incidence of favorable GEP) in the most recent study compared with Total Therapy 3, the results on EFS and duration of CR and OS were super-imposable with the 2 protocols, which was attributed to a superior consolidation/maintenance, including long-term bortezomib and the incorporation of lenalidomide in the more recent trial. However, the 15% of patients with high-risk GEP usually still had unsustained CRs resulting in a short survival. For this reason, the Arkansas group is exploring whether a more continued treatment with fewer dose-intensity strategies (Total Therapy 5) can prevent the relapses observed during the treatment-free intervals in the previous Total Therapy programs.⁵ 

There is no doubt that the achievement of IFE-negative CR is the first step for a long-lasting response and prolonged survival after ASCT in MM.¹  However, with the current treatment possibilities and with the availability of novel technologies, the achievement of a serologic response should no longer be the ultimate goal in the treatment of MM. In this regard, the Arkansas group has recently reported, applying a time-dependent methodology, on the importance of not only achieving CR but also of sustaining CR, in patients included in Total Therapies 1, 2, and 3.⁶  On the other hand, sequential minimal residual disease (MRD) measurements with multi-parameter flow cytometry (MFC)⁷  or molecular studies⁸  could be crucial to determine from what level of MRD further treatment is or not needed. Ideally, in 2010, the so-called Total Therapy should include a triple-agent induction regimen such as VTD, ASCT with MEL-200, consolidation with VRD or VRD-like regimens, and maintenance incorporating novel agents along with sequential MRD studies to determine for how long treatment is still of benefit. Our immediate goal should be that the 55% predicted “cure fraction” for patients with low-risk MM included in Total Therapy 3⁵  is achieved with even more refined “total therapy” approaches and that it becomes not only an estimated but an actual cure rate.