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Total therapy 3 (TT3), incorporating bortezomib up-front into a tandem transplant regimen for newly diagnosed multiple myeloma (MM), effected 2-year complete response (CR) estimates >90%, which appeared superior to results reported for total therapy 2 (TT2). With median follow-up times of 2 years with TT3 and 5 years with TT2, the clinical outcomes of 303 patients in the former and 668 in the latter trial were compared, including the subset of 607 patients with gene expression profiling (GEP) data. With similar baseline prognostic factors, event-free survival (EFS) (P = 0·0002) and CR duration (P = 0·003) were superior with TT3 vs. TT2 with a strong trend noted also for improved overall survival (OS) (P = 0·16). In the GEP-defined FGFR3 subgroup, TT3 imparted significantly superior OS, EFS and CR duration vis-à-vis TT2. Matching 300 patients each by standard prognostic factors, TT3 yielded superior EFS and CR duration and borderline superior OS. The advantage of TT3 still pertained when the comparison was limited to patients who completed TT2 consolidation rapidly within 24 months. Our data strongly suggest that the addition of bortezomib in TT3 was accountable for its superior performance rather than greater compliance with protocol completion as a result of greater dose-density in TT3 vs. TT2.
Complete remission (CR) has long been considered a necessary but not sufficient first step toward achieving long-term disease control in systemic malignancies including multiple myeloma (MM). Owing to a marked dose–response effect for melphalan (MEL) that could be exploited safely with the use of autologous transplantation, CR rates have increased from less than 5% with standard melphalanprednisone (MP) to 50% range, especially with tandem transplants as reported for total therapy (TT) protocols (Barlogie et al, 1997, 2006a) and the Intergroupe Francophone du Myelome (IFM) trials (Attal et al, 2003; Moreau et al, 2006). Despite translating into significant prolongation of overall survival (OS), such high CR rates have not been sustained in the majority of patients, as reflected by median CR durations of 3 years with total therapy 1 (TT1) and 4·5 years with total therapy 2 (TT2) although a plateau emerged at nearly 20% beyond 10 years in TT1 (Barlogie et al, 2006b).
Recent trials with new agents in combination, such as MPT (melphalan, prednisone, thalidomide) (Facon et al, 2006; Palumbo et al, 2006a), REV-DEX (lenalidomide, dexamethasone) (Rajkumar et al, 2005), MPR (melphalan, prednisone, lenalidomide) (Palumbo et al, 2006b), VMP (bortezomib, melphalan, prednisone) (Mateos et al, 2006) and especially VMPT (Palumbo et al, 2007), but also with PAD (bortezomib, doxorubicine, dexamethasone) (Oakervee et al, 2005; Orlowski et al, 2005) and VAD (bortezomib, doxil, dexamethasone) (Orlowski et al, 2006) have all reported frequencies of CR and near-CR (n-CR, immunofixation positive) that approached results obtained with autotransplant-supported high-dose MEL, although follow-up is lacking regarding the durability of such new agent-induced remissions.
We have recently reported on the results of the total therapy 3 (TT3) trial, which incorporated bortezomib into the up-front therapy of patients with MM utilizing multiagent VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) for induction prior to and consolidation after high-dose melphalan-based tandem autotransplants (Barlogie et al, 2007). The VDT-PACE combination was developed based on the marked efficacy of the VTD regimen (bortezomib, thalidomide, dexamethasone) in advanced and refractory MM (Barlogie et al, 2004) and, more recently, in untreated patients (Wang et al, 2005); the PACE component (cisplatin, doxorubicin, cyclophosphamide, etoposide) integrated the components of CAD (cyclophosphamide, doxorubicin, dexamethasone) and DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin) employed previously for induction therapy of TT2 (Barlogie et al, 2006a). As we had observed a high 90% CR rate sustained at 2 years (Barlogie et al, 2007), this report provides a follow-up of our TT3 results, which were compared with TT2 outcomes in the context of both standard prognostic factors (SPF) and of gene expression profiling (GEP) data, available in 351 of 668 patients enrolled in TT2 and in 275 of 303 patients accrued to TT3.
The regimen details have recently been published (Barlogie et al, 2006a, 2007) and their essential features are summarized in Fig 1. Briefly, TT3 employed abbreviated induction and consolidation therapies with two rather than four cycles each in TT2, on the assumption that the addition of bortezomib to DT-PACE in VDT-PACE would be highly synergistic so that comparable anti-tumour activity would be delivered with two rather than four cycles. As a result, we anticipated and indeed accomplished higher compliance with both transplants so that the intended therapies could be delivered to a higher proportion of patients. Drug-free phases of TT2 were ‘bridged’ by thalidomide-dexamethasone (THAL-DEX) in an effort to suppress the potentially MM-stimulatory signals associated with postchemotherapy haematopoietic recovery. Finally, bortezomib was combined with THAL-DEX in VTD, which was applied in monthly cycles during the first year of maintenance, followed by THAL-DEX for 2 more years. In TT2, maintenance comprised interferon with added DEX pulsing during the first year; in case of randomization to THAL, the drug was continued indefinitely until disease progression or untoward toxicity.
Protocol-directed laboratory monitoring for response and toxicities was applied with both trials as reported previously (Barlogie et al, 2006a, 2007). Standard laboratory studies included haemogram and multi-chemical scans. Cardiac evaluations were done by Multiple Gated Acquisition (MUGA) scan or echocardiogram; pulmonary status was evaluated by the forced expiratory volume in 1 s (FEV1) and carbon monoxide diffusing capacity (DLCO) analyses; these tests had to be within the institutional normal range before entry and each of the two transplant regimens. Standard skeletal surveys and magnetic resonance imaging studies were also performed. Cytogenetic abnormalities (CA) were detected by metaphase analysis of Giemsa-banded chromosomes in typically 20 cells (Sawyer et al, 1995). GEP analysis was performed on CD138-purified plasma cells using the Affymetrix platform (Zhan et al, 2002) and applying a 70 gene-based risk score (Shaughnessy et al, 2007) and 7-subgroup designations as recently published (Zhan et al, 2006).
Response and relapse definitions employed criteria similar to those reported by Blade et al (1998). CR required the absence of M-protein in serum and urine on immunofixation analysis as well as normal bone marrow aspirate and biopsy by microscopy and flow cytometry (absence of aneuploidy and monoclonal cytoplasmic light chain); in addition, metaphase CA had to be absent. Response criteria had to be documented on at least two subsequent occasions at least 2 months apart. Relapse from CR implied the re-appearance of M-protein in serum or urine on immunofixation, reappearance of monoclonal bone marrow plasmacytosis or of CA, the development of extramedullary disease or of new bone lesions recognized on at least annually performed magnetic resonance imaging or skeletal survey. Non-secretory relapses in the absence of M-protein recurrence also constituted relapse, such as new focal lesions on magnetic resonance imaging or positronemission tomography scan, re-emergence of bone marrow monoclonal plasmacytosis or extramedullary disease often associated with elevated levels of lactate dehydrogenase (LDH).
The Kaplan–Meier method was used to estimate event-free survival (EFS), overall survival (OS) and CR duration (Kaplan & Meier, 1958); group comparisons were made using the logrank test. EFS was defined as the time from the date of registration to death from any cause, disease progression, or relapse. Patients experiencing no event were censored at the time of last contact. OS was defined from the date of registration until death from any cause; survivors were censored at the time of last contact. CR duration was measured from the onset of CR until relapse or death from any cause. The cumulative incidence of CR was estimated using the method outlined by Gooley et al (1999). Results of different trials were compared using the log-rank test. Multivariate models of prognostic factors were carried out using Cox regression (Cox, 1972). Pair-mate analysis was used to compare TT2 and TT3 patients based on standard prognostic factors found to be significant in TT2. Pair-mate analysis was also used on the subset of patients with GEP information available based on their risk score.
Both TT3 and TT2 protocols had been approved by the Institutional Review Board and the Food and Drug Administration. Patients signed an informed consent indicating that they understood the investigative nature of the trials along with treatment alternatives, in keeping with Institutional Review Board, National Institutes of Health and Food and Drug Administration policies.
Response and toxicity details had been monitored by an independent certified audit team that reviewed the data on 248 of 303 patients enrolled in TT3 and on 310 of 668 patients enrolled in TT2. A Safety and Monitoring Board reviewed the data twice and gave permission for manuscript submission.
Data presented in Table I show that the prognostically relevant parameters were similar in patients treated on the TT3 and TT2 regimens. Notably, the proportions of patients with CA as the major standard adverse prognostic feature in our TT trials were in the 30% range. GEP-defined high-risk percentages were virtually identical in TT2 and TT3 proto cols. Differences were observed with regard to greater representation of patients in TT3 who were older than 65 years of age, had advanced International Staging System (ISS) stage II, anaemia, elevation of beta-2-microglobulin (B2M) levels and hypoalbuminaemia; higher C-reactive protein (CRP) levels were more frequent in TT2. The median follow-up of live patients on TT3 is 2 years and on TT2, 5 years.
Figure 2 depicts the progression of patients through successive phases of protocol therapies. As intended, higher proportions of patients enrolled in TT3 completed first and second transplants much earlier than was the case with TT2; in addition, the compliance with consolidation and maintenance phases was also higher in TT3 than TT2. There was no difference between the two arms of TT2 with regard to the completion kinetics of protocol phases (data not shown). The cumulative proportions of patients achieving CR on TT3 vs. TT2 are portrayed in Fig 3A. Despite the lack of differences between times of onset and levels of CR between TT3 and TT2 plus thalidomide, 2-year sustained CR rates with TT3 were superior at 92% to 81% with thalidomide (P = 0·005) and 79% without thalidomide in TT2 (P = 0·003) (Fig 3B); no difference was observed in CR duration between the two arms of TT2. EFS with TT3 was superior to both arms of TT2 (Fig 3C), whereas there was a trend for improved OS (Fig 3D).
‘Weak links’ had been observed in the TT2 design, prompting the introduction of ‘bridging therapy’ with thalidomide plus dexamethasone between induction and consolidation cycles and peri-transplant when designing TT3. Figure 4 depicts the relapse kinetics in TT3 and TT2 for each protocol phase. As is readily apparent, significantly higher proportions of patients suffered an event in the first 12 months after each protocol step of TT2 than TT3.
In the subset of patients with GEP data (TT2, n = 351; TT3, n = 275), the above analyses were reiterated in the context of the 70-gene model, distinguishing approximately 15% of patients at high risk in both studies (Shaughnessy et al, 2007). The subsets of patients with GEP data enrolled in TT3 and TT2 protocols had similar pretreatment prognostic variables and outcomes as those without GEP data (results not shown); thus the GEP subsets were representative of the larger overall patient population. CR durations (Fig 5A) were superior with TT3 vs. TT2 (either arm) only among the GEP-defined low-risk group; no difference was noted among the two arms of TT2. EFS was superior with TT3 vs. TT2 in both risk groups, although this was especially prominent in patients with low-risk MM (Fig 5B). A strong trend was observed for superior OS with TT3 vs. TT2 among the high-risk subgroup, whereas such benefit was not apparent for patients with low-risk disease who represented 85% of the entire population (Fig 5C). Applying the 7-subgroup GEP model (Zhan et al, 2006), the FGFR3/MMSET subgroup benefited from TT3 vs. TT2 (both arms combined) in terms of CR duration, EFS and OS (Fig 5D–F), whereas no difference was observed between the two arms of TT2.
Considering the higher compliance with protocol completion in TT3 vs. TT2, we examined the clinical outcomes in the two studies in the subgroup of patients completing posttransplant consolidation early, i.e. entering the maintenance phase 2 years after protocol initiation. While EFS was indeed superior among patients treated with T3 vs. TT2 (Fig 6A), a trend was observed for superior OS with TT3 (Fig 6B). These data strongly suggest that the overall benefit with TT3 vs. TT2 is attributable to the incorporation of bortezomib in TT3 rather than greater compliance with intended therapy steps in TT3.
According to multivariate analyses, OS was adversely affected by the presence of CA, elevated serum levels of LDH and B2M (>5·5 mg/l) and by hypoalbuminaemia (Table II); the TT2 arm without thalidomide was borderline inferior to TT3. In the case of EFS and CR duration, both arms of TT2 were independent, unfavourable variables affecting these two endpoints in addition to baseline parameters. In the context of GEP models, OS, EFS and CR duration were adversely affected by GEP-defined high risk and MS (FGFR3/MMSET) subgroup categories (Table III); TT3 was superior to both arms of TT2 in terms of EFS and CR duration. Matching 300 TT3 with 300 TT2 patients according to four adverse features dominantly affecting OS and EFS in TT2 (CA, LDH >190 U/l, B2M >5·5 mg/l, albumin <35 g/l), TT3 was associated with highly significantly superior CR duration and EFS (Fig 7A and B), and a strong trend was noted for superior OS (Fig 7C).
Whereas the addition of thalidomide in TT2 improved CR rate and EFS, OS and, not widely appreciated, the 4-year continuous CR estimates were similar in the two study arms (see Fig 3B) (Barlogie et al, 2006a). With TT3, we observed that 92% of patients entering CR sustained such remission at 2 years, whereas with TT2 and TT1 relapses occurred earlier after the onset of CR (Barlogie et al, 1997, 2006a,b). This observation suggested that the addition of bortezomib had ushered in a fundamental shift in the durability of response and prompted a formal analysis of clinical outcomes of patients enrolled on TT3 and TT2, as presented here. Except for higher proportions of patients with advanced age, anaemia, B2M elevation and hypoalbuminaemia and thus higher ISS stage in TT3, the baseline characteristics of patients in the two protocols were similar (see Table I).
As a consequence of shortened induction and consolidation phases and an effort to complete the second autotransplantation within 2–3 months of the first high-dose therapy cycle, the progression through the protocol phases was indeed faster and the proportions of patients completing the intended therapies significantly higher in TT3 than in TT2 (see Fig 2). Thus, as intended, the proportion of patients suffering a relapse was significantly reduced for each of the protocol phases of TT3 vs. TT2 (see Fig 4). Importantly, despite similar times to and levels of CR in TT3 and TT2 plus thalidomide, CR duration was significantly superior in TT3 to TT2 regardless of study arm (see Fig 3B). TT3 also affected superior EFS in comparison with both arms of TT2, whereas the follow-up is too short to comment on OS (see Fig 3C and D). In a pair-mate analysis matching TT3 with TT2 patients on the four key adverse variables identified in TT2, TT3 was superior to TT2 in terms of CR duration and EFS, with a strong trend for OS (see Fig 7A–C).
In the context of the recently reported GEP-defined risk groups (Shaughnessy et al, 2007), it was remarkable to note superiority already for TT3 vs. TT2 in EFS in both low- and high-risk groups (see Fig 5B), with a strong trend emerging for OS in the high-risk subgroup (see Fig 5C). Remarkably, superior Kaplan–Meier plots were observed for CR duration for the low-risk subgroups of TT3 (see Fig 5A), whereas no differences were observed between the two TT2 arms. These observations were supported by the results of multivariate analyses that included protocol assignment, showing superior EFS and CR duration with TT3 versus both arms of TT2 (see Table II). In the context of GEP data, the GEP-defined high-risk category was the dominant baseline feature for both OS and EFS along with the presence of CA and LDH elevation, again with a significant contribution of TT3 for EFS and CR duration (see Table III). When examined in the context of the 7-GEP subgroups (Zhan et al, 2006), patients with FGFR3/MMSET disease benefited significantly from TT3 vs. TT2 in terms of all three endpoints examined (CR duration, EFS, OS) whereas, again, no difference existed between the TT2 arms (see Fig 5E–G).
Finally, to address the issue of whether TT3’s superior performance was related to the addition of bortezomib or the greater protocol compliance in case of TT3, we re-examined OS and EFS in the subgroup of patients entering the maintenance phases of the protocols within 2 years from initiation of therapy. EFS was indeed superior with TT3 vs. TT2, with a trend observed in favour of TT3 for OS (see Fig 6A and B), suggesting an important contribution of bortezomib to the improved outcome of patients receiving TT3.
We conclude from this historical comparison that, unlike with the effects of the addition of thalidomide in TT2, bortezomib in TT3 appeared to significantly prolong CR duration, currently limited to the low-risk subgroup, whereas the traditionally unfavourable FGFR3/MMSET subgroup, which did not benefit from the addition of thalidomide in TT2, experienced significant prolongations of all three clinical endpoints examined, including OS, with TT3.
This work was supported in part by P01 grant CA55819 from the National Cancer Institute, Bethesda, MD.
Author contributionsDesigned project: MPR, JDS, BB. Wrote manuscript: MPR, BB. Contributed to clinical research and provided patient care: MPR, MZ, EA, GT, FvR, BB. Performed statistical analyses: JH, JC.