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Myeloma survival varies markedly with International Staging System (ISS) classification, presence of cytogenetic abnormalities (CA) and, especially, gene expression profiling (GEP)-based risk and delTP53 status, whose collective impact has not been examined in the context of specific therapies.
We examined overall survival (OS), event-free survival (EFS) and complete response duration (CRD) in Total Therapy 2 (TT2) with randomization to a control or thalidomide arm and in Total Therapy 3 (TT3) with added bortezomib. Among 612 patients with complete data sets, multivariate analyses were employed to investigate the relative contributions to OS, EFS and CRD of ISS stage, CA and GEP-derived risk and delTP53 status, in the context of the 3 TT regimens.
Whereas GEP risk segregated outcomes within all 3 ISS stages, ISS-3 conferred inferior prognosis only in low-risk myeloma while the grave prognosis of high-risk disease was ISS-independent. After adjusting for GEP-defined high-risk and delTP53 in multivariate analysis, ISS-3 and CA both retained independent adverse implications for OS, EFS and CRD. Among the 86% with low-risk disease, CA and delTP53 both affected all 3 endpoints negatively while the ISS-3 effect was limited to OS. TT3 improved survival outcomes beyond results obtained with TT2.
In the genomic era, standard laboratory variables, such as ISS stage and CA, continue to impact survival after adjusting for GEP-risk and delTP53 status, providing a basis for stratification in our current practice of GEP risk-based treatment assignment.
We previously reported that, in comparison with predecessor protocol Total Therapy 2 (TT2) (1), Total Therapy 3 (TT3) incorporating bortezomib markedly improved clinical outcomes of the approximately 85% of patients presenting with gene expression profiling (GEP)-defined low-risk myeloma (2). Although the adverse implications of GEP-defined high-risk were dominant in both protocols (3), standard prognostic parameters such as beta-2-microglobulin (B2M), albumin and International Staging System (ISS) classification (derived from these 2 variables) (4), along with lactate dehydrogenase (LDH) and the presence of metaphase cytogenetic abnormalities (CA), retained, to varying degrees, predictive power for overall survival (OS), event-free survival (EFS) and often complete response duration (CRD) (5). Given the increasing focus in myeloma trials and outcome analyses on genomics, we herein examined the relative contributions of the various baseline features in the context of essentially 3 different treatment regimens (TT2 without thalidomide [TT2−], TT2 with thalidomide [TT2+] and TT3). Our overall approach was geared toward distilling weak spots of outcome prediction not sufficiently encompassed by the fundamentally very powerful genomic predictors.
Both TT2 and TT3 trials employed 4 phases of therapy comprising induction, melphalan-based tandem transplantation, consolidation, and maintenance. TT2 enrolled 668 patients who were randomized up-front to a control versus thalidomide arm, whereas the phase 2 TT3 trial accruing 303 patients added bortezomib to induction, consolidation and maintenance phases, in addition to thalidomide. A further distinguishing feature of TT3 was the reduction from 4 to 2 cycles each of induction prior to and consolidation after transplantation, in an effort to improve patients’ compliance with the intended treatment. Both trials had been approved by the Institutional Review Board in keeping with institutional and federal guidelines and the Helsinki Declaration. All patients had signed a written informed consent prior to initiation of therapy. An independent federally accredited investigator team audited nearly 80% of patients’ records for protocol compliance, response and toxicity information.
Extensive baseline laboratory studies were performed and included standard prognostic variables plus metaphase cytogenetics in virtually all subjects. Among the approximately one-third displaying CA, we also denoted some specific abnormalities of previously recognized prognostic significance, such as abnormalities of chromosomes 1 and 13 (CA-1, CA-13) and hypodiploidy (CA-hypodiploidy) (6). GEP baseline studies were available for 351 patients in TT2 and 275 in TT3. With few exceptions (see below), patient baseline characteristics, including GEP-defined risk (3), were similar in both trials (2, 3).
The median follow-up times of live patients are 87 months for TT2 and 47 months for TT3. The Kaplan-Meier method was used to generate survival distribution graphs (8) and comparisons were made using the log-rank test (9). Multivariate analyses applied stepwise selection and Cox proportional hazard regression modeling (10).
Significant differences in baseline characteristics between the 3 TT regimens pertained only to age and albumin levels (Table 1). Other variables of recognized prognostic significance were comparable, i.e. presence of CA and CA subgroups, GEP-defined variables (high-risk designation, delTP53 status), ISS stage distribution and elevation of serum levels of B2M and LDH. We also examined the relationship between the specific variables addressed in this report, i.e. GEP-defined risk, presence of CA and ISS stage (Figure 1). The Venn diagram portrays the overlap between these 3 risk factors among the 286 patients displaying at least one adverse feature. Of the 86 subjects with GEP high-risk myeloma, only 11 (12.8%) had no other adverse characteristic; in the case of ISS-3, 41.5% of 130 exhibited no other high-risk parameter; and as to the presence of CA present in 207 subjects, 51.7% had no other high-grade label. The proportion of patients with high-risk GEP increased significantly with advancing ISS stage regardless of CA status; conversely, those with low risk progressively were progressively inderrepresented in the subset without CA (Table 2).
Table 3 depicts, across TT regimens, univariate and multivariate analyses of baseline parameters significantly associated with OS, EFS and CRD. All of the variables generally recognized to affect OS and EFS were validated univariately. Among patients with CA, CA-del1p, CA-amp1q, CA-13, and CA-hypodiploidy all impacted outcomes in univariate models; however, only the presence of any CA rather than specific CA subgroups survived the multivariate model. Other independently significant adverse variables included ISS stage 3 (OS, EFS, CRD), GEP-defined high-risk disease and delTP53 status (OS, EFS, CRD), elevated serum LDH levels (OS, EFS) and creatinine (EFS). Treatment with TT3 rather than the other regimens resulted in significantly prolonged EFS and CRD with borderline significance for OS. When applied to the majority of patients with GEP-defined low-risk myeloma, the presence of CA was the sole feature adversely affecting all 3 clinical endpoints; ISS-3 and LDH elevation were linked only to OS but not to EFS or CRD (Table 4). Both OS and EFS were shorter in case of GEP-defined delTP53, low platelet levels and creatinine elevation. The favorable impact of having been treated with TT3 was apparent for EFS and CRD, with a trend existing for OS.
The impact of GEP risk classification on clinical outcomes within individual ISS stages is portrayed in Figure 2. OS, EFS and CRD all were inferior, regardless of ISS stage, in case of GEP-defined high-risk myeloma. Although the greatest difference pertained to lower stages ISS-1 (Figure 2a) and ISS-2 (Figure 2b), a statistical difference was still maintained in ISS-3 (Figure 2c). The influence of ISS stage within GEP-defined risk groups is shown in Figure 3. In low-risk myeloma, outcomes in ISS-3 were drastically inferior to those observed in lower stages ISS-1 and ISS-2 with super-imposable Kaplan-Meier plots (Figure 3a); with the exception of superior CRD in ISS-1, OS and EFS both were uniformly poor in high-risk disease regardless of ISS stage (Figure 3b).
We have undertaken comprehensive analyses to examine the contributions especially of ISS and CA status to myeloma prognosis in the context of GEP, now recognized as the most robust discriminator of patients’ outcome in TT2 and TT3 trials (2, 3, 5). Importantly, GEP-risk segregated clinical outcomes within all ISS stages. Conversely, evaluating the role of ISS within risk subgroups revealed that, in low-risk myeloma, only those with ISS-3 fared poorly whereas, in high-risk disease, only CRD was favorably affected by ISS-1, with comparably grave OS and EFS regardless of stage. The proportion of patients with GEP-defined high-risk myeloma increased progressively with advancing ISS stage, from less than 10% in ISS-1 to almost 30% in ISS-3. Despite such link between GEP risk and ISS stage, both variables retained independent adverse consequences for all 3 outcome endpoints on multivariate analysis, along with the presence of CA and delTP53 status, as well as LDH and creatinine. Within low-risk myeloma, CA status dominated the multivariate model for OS, EFS and CRD, with important negative contributions retained for delTP53, platelet count, LDH and creatinine for both OS and EFS. TT3 significantly extended EFS and CRD across risk groups, and a borderline significance was observed for OS. Collectively our data indicate that, after accounting for GEP-derived risk and delTP53 status, especially ISS stage and CA still retain independent prognostic implications.
We are currently using an evidence-based, risk-adapted approach to treatment so that GEP-defined low-risk myeloma is treated with Total Therapy 4 (randomizing patients between a standard arm as in TT3 and an experimental arm with one instead of two cycles each of induction prior to and consolidation after tandem transplants to reduce toxicity) whereas Total Therapy 5 for high-risk disease examines whether greater dose-density and less dose-intensity can reduce myeloma recurrence during previous drug-free phases of TT3. In virtually all cases, GEP information is available within 72 hours of bone marrow sample procurement. Since both ISS stage and the presence of CA contribute to outcome prediction, patients are stratified accordingly.
Inter-phase fluorescence in situ hybridization (FISH) analysis, shown to capture translocations and copy number abnormalities (11, 12), is vastly inferior to GEP in terms of overall risk assessment (3, 11, 13, 14, 15). Offering GEP analyses to the myeloma patient population at large requires access to reference CLIA laboratories and billable services, issues we are presently addressing. Technical advances resulting in significant reduction in required cell number are bringing GEP closer to its becoming a component of the standard of care for patients afflicted with multiple myeloma. Toward eventually capturing a maximum of tumor-cell-associated variability in clinical outcomes, we are currently investigating whether GEP probes can be identified that can substitute for standard prognostic factors still retaining independent significance such as CA, LDH, B2M, albumin and creatinine. Molecular subgroup designations should also be continuously examined for potentially subgroup-unique agents and their possible prognostic implications, as recently suggested for bortezomib in the context of MS-type myeloma (16). Whole genome profiling, rather than targeted approaches involving only selected genes, will become the most appropriate tool for unraveling the fundamental genetic basis of myeloma as a basis for rational therapeutic intervention.
Supported in part by Program project grant CA55819 from the National Cancer Institute Bethesda MD, USA
Author contributions:Designed project: SW, JDS, YA, BN, BB
Contributed patients on clinical trials: SW, FvR, YA, BN, EA, BB
Analyzed data: JS, AH, JC
Wrote paper: SW, BB.
The independent prognostic contribution of gene expression profiling (GEP)-defined high-risk was examined in the context of Total Therapy 2 (with and without thalidomide) and Total Therapy 3 (TT3). Multivariate analyses revealed that International Staging System stage 3 (ISS-3), the presence of cytogenetic abnormalities (CA) and GEP-defined high-risk all affected clinical outcomes adversely; TT3 improved clinical outcomes independent of GEP-risk, CA and ISS stage. (63)
Conflict of Interest: NA