Total Therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy

Abstract

The impact of cumulative dosing and premature drug discontinuation (PMDD) of bortezomib (V), thalidomide (T), and dexamethasone (D) on overall survival (OS), event-free survival (EFS), time to next therapy, and post-relapse survival in Total Therapy 3 were examined, using time-dependent methodology, relevant to induction, peritransplantation, consolidation, and maintenance phases. Univariately, OS and EFS were longer in case higher doses were used of all agents during induction, consolidation (except T), and maintenance (except V and T). The favorable OS and EFS impact of D induction dosing provided the rationale for examining the expression of glucocorticoid receptor NR3C1, top-tertile levels of which significantly prolonged OS and EFS and rendered outcomes independent of D and T dosing, whereas T and D, but not V, dosing was critical to outcome improvement in the bottom-tertile NR3C1 setting. PMDD of V was an independent highly adverse feature for OS (hazard ratio ‫؍‬ 6.44; P < .001), whereas PMDD of both IntroductionThe superiority of Total Therapy 3 (TT3) 1,2 to Total Therapy 2 (TT2) 3 was limited to the approximately 85% of patients presenting with gene expression profiling (GEP)-defined lowrisk myeloma. 4,5 As a consequence of shortened induction before and consolidation after melphalan-based tandem transplantations in TT3 versus TT2, the compliance with intended protocol steps was improved which, along with the incorporation of bortezomib, affected prognosis favorably. 6 TT3 applied 2 cycles of VTD-PACE (bortezomib, thalidomide, dexamethasone; 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide) as induction before and, at reduced doses, as consolidation after melphalan-based tandem transplantation. Thalidomide and dexamethasone were given at 50 mg/day and 20 mg/day for 4 days every 28 days to "bridge" drug-free intervals between induction cycles, whereas thalidomide dosing was 100 mg/day with dexamethasone 20 mg/day for 4 days every 28 days between transplantations and consolidation cycles. Maintenance therapy comprised VTD (bortezomib [V], thalidomide [T], and dexamethasone [D]) in year 1 and TD without V in years 2 and 3.Here, we examined whether cumulative dosing of VTD components and their premature drug discontinuation (PMDD) impacted overall survival (OS), event-free survival (EFS), time to next therapy (TNT), and postrelapse survival (PRS) in the context of baseline variables and completion of second transplantation and both cycles of consolidation therapy. MethodsTrial details have been reported previously. 1,2,4,5 Briefly, TT3 accrued 303 newly diagnosed patients with symptomatic or progressive myeloma between February 2004 and July 2006. GEP analysis of CD138-enriched plasma cells was performed in a subset of 275 patients. 7 GEP parameters considered included risk designation (high vs low), 4 molecular subgroups (hyperdiploidy, low bone disease, CCND1 without CD-1 and with CD20 coexpression, MAF/MAFB, MMSET/FGFR3, myeloid, proliferation), 8 and delTP53 status. 9,1...

Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data

“…The protocol details have been described previously, 20,21 as have imaging parameters for MBS, MRI and PET. 10,14 All radiographic studies were evaluated by radiologists who specialize in imaging of MM, each with more than a decade of experience in their respective field.…”

“…Interestingly, four genes associated with high-risk disease (related to cell cycle and metabolism) were linked to counts of focal lesions detected by magnetic resonance imaging and positron emission tomography. The purpose of this study was to examine, among patients with newly diagnosed MM enrolled in the Total Therapy 3 (TT3) clinical trial, 20,21 the mutual correlation between MBS-OL counts and FL counts (defined by MRI and PET), and their associations with baseline prognostic variables.…”

Can multiple myeloma become a curable disease?

“…Our position is that the philosophy for a cure should be based on the knowledge of those treatments that have demonstrated efficacy, and the investigation of optimal combinations, sequences, and of novel agents, instead of looking for soft replacements of equivalent efficacy that do not improve survival. Examples of this strategy are the results reported by Cavo et al, 23 and the total therapy programs developed by the Arkansas group 17,24 that integrate all treatment tolls through induction, consolidation and maintenance. This approach has resulted in a 4-year CR duration estimated at 89% in patients defined as low-risk by GEP, equivalent to Editorials and Perspectives haematologica | 2011; 96 (9)an estimated cure rate of 50%.…”

Stem Cell Transplantation for Multiple Myeloma: Current and Future Status

“…24 This group demonstrated that long-term disease control was feasible in myeloma and that cytogenetic abnormalities and baseline beta 2 microglobulin levels could predict long-term outcomes. 27,28 The recent experience with Total Therapy II and Total Therapy III has underscored the feasibility and efficacy of intensive induction followed by consolidation and maintenance as a strategy of obtaining high rates of CR and durable remissions in patients with standard-risk cytogenetic abnormalities. 27,28 Of particular interest has been defining risk groups according to gene-expression profiling that, if validated by others, will allow a more rational use of therapies in myeloma patients to achieve the overarching goal of maximum benefit with minimum burden of therapy.…”

“…27,28 The recent experience with Total Therapy II and Total Therapy III has underscored the feasibility and efficacy of intensive induction followed by consolidation and maintenance as a strategy of obtaining high rates of CR and durable remissions in patients with standard-risk cytogenetic abnormalities. 27,28 Of particular interest has been defining risk groups according to gene-expression profiling that, if validated by others, will allow a more rational use of therapies in myeloma patients to achieve the overarching goal of maximum benefit with minimum burden of therapy. 29 However, what remains to be determined is whether such intensive induction therapy and posttransplantation consolidation is warranted for all patients with myeloma, or if it should be relegated to patients with specific risk categories.…”