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The purpose of this study was to update outcomes of autotransplantation trials for myeloma conducted by the Intergroupe Francophone du Myelome (IFM), the Southwest Oncology Group, and the University of Arkansas for Medical Sciences (Total Therapy [TT]).
IFM90 (N = 194), IFM04 (N = 402), IFM9902 (N = 692), IFM9904 (N = 197), S9321 (N = 817), TT1 (N = 231), TT2 (N = 668), and TT3 (N = 303) were updated, and results were compared with original reports.
Superior survival with single transplantation versus standard therapy in IFM90 was confirmed (P = .004), and a trend in favor of tandem versus single transplantation was maintained in IFM94 (P = .08). S9321 data were validated, with comparable survival in single transplantation and standard treatment arms (P = .35). A survival benefit from thalidomide maintenance in IFM9902 was not confirmed (P = .39) but emerged for the thalidomide arm of TT2 (P = .04). On multivariate analysis, survival was superior in TT2, TT3, and IFM9902 (all P < .001); tandem transplantations were superior to both single transplantations and standard therapies (P < .001), as were tandem transplantations with added thalidomide versus trials without thalidomide (P < .001). Postrelapse survival (PRS) was superior when initial event-free survival (EFS) exceeded 1280 days and when tandem transplantations had been administered, whereas PRS was shorter when EFS lasted 803 days or less and when trials had included thalidomide and bortezomib.
These long-term follow-up data of transplantation trials provide a crucial framework of reference for outcome reporting of novel agent–based trials reportedly exhibiting remarkable short-term efficacy approaching high-dose therapy results.
Survival of patients with multiple myeloma has been extended markedly as a result of autotransplantation-supported high-dose melphalan therapy1–5 and the availability of novel agents.6–11 The results of clinical trials are usually reported in line with original statistical objectives focusing on differences in complete response rate and event-free survival (EFS) between treatment arms or vis-à-vis historical controls. In the initial report on Total Therapy (TT) 2, overall survival (OS) was not prolonged in patients randomly assigned to the experimental arm with thalidomide, although both complete response and EFS were superior to results obtained on the control arm.5 With an additional 38 months of follow-up (now at 80 months), however, OS is also significantly extended (P = .04) despite discontinuation of thalidomide for toxicity reasons by nearly 80% within 2 years.12 This observation motivated us to update the results of major transplantation trials conducted by the authors of this report to determine whether earlier outcome estimates could be confirmed.
Eight trials are covered in this report. Intergroupe Francophone du Myelome (IFM) trial IFM90 compared a single transplantation with standard chemotherapy.1 IFM94 compared tandem and single transplantation.3 IFM9902, which studied standard-risk myeloma, used tandem transplantation and randomly assigned patients to one of three maintenance arms (none, pamidronate, or pamidronate plus thalidomide).13 IFM9904, which studied high-risk myeloma (high β2-microglobulin [B2M] and deletion 13), evaluated tandem transplantations with a higher melphalan dose of 220 mg/m2 and added anti–interleukin-6 monoclonal antibody.14 Southwest Oncology Group trial S9321 randomly assigned patients to either single transplantation in support of melphalan plus total-body irradiation or the M2 regimen after vincristine, doxorubicin, and dexamethasone induction.15 TT1 was a phase II study of tandem transplantation followed by interferon maintenance.16 TT2 randomly assigned patients up front to receive or not to receive thalidomide and, compared with TT1, added consolidation chemotherapy after tandem transplantation and applied dexamethasone pulsing for the first year of maintenance with interferon.5 TT3 was a phase II trial building on TT2 with bortezomib added to the thalidomide arm of TT2 but with two instead of four cycles each of induction and consolidation therapy before and after tandem transplantations, whereas maintenance included bortezomib-thalidomide-dexamethasone in the first year and thalidomide-dexamethasone in years 2 and 3.17 Cancer Research and Biostatistics received data updates of IFM trials as of July 2008, of S9321 as of February 2009, and of all three TT trials as of April 2009. The individual protocols had been reviewed and approved by both centralized and individual institutional review boards. All patients had signed a written informed consent before protocol enrollment, in keeping with the Helsinki Declaration.
Patient characteristics revealed protocol-specified differences in upper age limit (Table 1). The distribution of patients across prognostic variable cut points varied, so that International Staging System–based stage II and III classification ranged from 44% to 87%. The proportions of patients with low albumin and high B2M levels based on the International Staging System are also portrayed; low albumin (< 3.5 g/dL) was present in 51% of patients enrolled onto IFM9904 and in only 18% enrolled onto TT2; high B2M (> 5.5 mg/dL) was documented in 29% of patients enrolled onto S9321 and in 39% enrolled onto IFM9904 but in only 13% enrolled onto IFM9902. Current median follow-up times were as short as 3.9 years in TT3 and approached 16 years in TT1, for an overall median of 6.1 years. The median times since last follow-up also varied widely, ranging from a short 0.6 months in TT3 to a long 120.5 months in IFM90.
Clinical trial end points included OS and EFS, both of which were dated from initiation of protocol therapy or from treatment random assignment, as indicated. Events included death from any cause in OS and, additionally, relapse in EFS. Patients were censored for OS and EFS when alive and event free, respectively, as of last contact.
Statistical methods included Kaplan-Meier plots of OS and EFS.18 Log-rank statistics were used to compare survival outcomes between treatment and prognostic subgroups.19 Cox regression analysis was applied to determine the relative prognostic implications of baseline variables and treatment protocols in both univariate and multivariate models.20
Figure 1 depicts OS and EFS for all trials reported. In the IFM90, IFM94, S9321, and TT1 trials, survival outcomes extended beyond 10 years. Thus, 10-year OS and EFS estimates were 33% and 14% in TT1, 26% and 9% in IFM94 (both arms combined), 19% and 6% in IFM90 (both arms combined), and 22% and 18% in S9321 (both arms combined), respectively. For the remaining trials, 5-year OS and EFS estimates were 78% and 71% in TT3, 66% and 50% in TT2 (both arms combined), 73% and 34% in IFM9902 (all three arms combined), and 42% and 13% in IFM9904, respectively. Reiterating Kaplan-Meier analyses from early phases through completion of patient accrual and progressively extending follow-up times revealed superimposable OS plots for all trials examined (Data Supplement Fig 1), suggesting consistency of patient characteristics throughout the accrual time periods, patient follow-up, and therapeutic management. Thus, we failed to detect instances where initially more promising results deteriorated with longer follow-up.
Results of individual randomized trials are portrayed in Data Supplement Figure 2. In IFM90, both OS and EFS remain significantly prolonged for the transplantation arm versus standard treatment arm (Data Supplement Fig 2A), whereas trends remain for both OS and EFS in favor of tandem versus single transplantation in IFM94 (Data Supplement Fig 2B). Both arms of S9321 remain virtually superimposable in terms of OS, but a trend has emerged in favor of transplantation for EFS (Data Supplement Fig 2C). Regarding TT2, a significant advantage in favor of the thalidomide arm has now emerged for OS (P = .04; Data Supplement Fig 2D). However, the original OS advantage of thalidomide in IFM9902 is no longer apparent (comparing the two arms without thalidomide v thalidomide-containing maintenance, P = .39; Data Supplement Fig 2E); the current analysis pertains to the 88% of patients who also had interphase fluorescence hybridization data.
Next, we performed univariate and multivariate analyses to determine which pretreatment parameters and which protocols were significantly linked to OS (Table 2). Independent adverse features included advanced age, low albumin and hemoglobin, and high B2M and lactate dehydrogenase (LDH); TT2, IFM9902, and TT3 protocols each conferred lower hazard ratio (HR) values (Table 2). Tandem transplantations as a group yielded superior results compared with single transplantations and standard-dose therapies (HR = 0.61, P < .001), and adding thalidomide to tandem transplantations was superior to tandem transplantations without thalidomide (HR = 0.69, P < .001; Table 3).
To portray individual trial comparisons, protocol patients were matched on the four variables identified as independently affecting OS on multivariate analysis (albumin < 3.5 g/dL, B2M ≥ 3.5 mg/L, LDH ≥ upper limit of normal, and hemoglobin < 10 g/dL), which was accomplished in three sets of 228 patients each, with one set representing the three trials with independently superior OS (TT3, TT2, and IFM9902; Table 2). The best outcomes were recorded in this category (TT3, TT2, and IFM9902), resulting in 8-year OS and EFS estimates of 62% and 31%, respectively, contrasting with similar inferior outcomes of 36% and 20%, respectively, for the two other categories (TT1; and IFM9904, IFM94, IFM90, and S9321; both P < .001; Fig 2).
Because of the long time span over which the protocols were executed, we examined postrelapse survival (PRS) to account for greater access to novel agents in more recently conducted trials. Thus, later trials' superior OS may have resulted from the availability of better salvage regimens rather than the impact of the original treatment. The following 5-year PRS estimates were recorded: 35% for IFM9902 and TT1, 29% for S9321, 27% for IFM9904 and TT2, 22% for IFM94, and 14% for IFM90 and TT3 (P < .001; Fig 3). IFM90 and TT1 participants had least access to thalidomide, which became available in 1997, but PRS after TT1 was far superior to PRS after IFM90. Patients in IFM94 and S9321 should have had equal access to thalidomide, perhaps explaining similar PRS. The availability of bortezomib and lenalidomide for salvage treatment around the year 2000 likely benefited patients treated on TT2, IFM9902, and IFM9904. The short PRS in patients who experienced treatment failure after TT3 may be attributable to the up-front use of all myeloma-active treatment ingredients, thus curtailing salvage efforts at relapse.
We also performed a multivariate analysis to capture variables independently linked to PRS, including baseline characteristics (relapse characteristics were only available in TT trials), individual trials, and the length of preceding EFS (Table 3). Older age and higher levels of baseline B2M (> 5.5 mg/L) and LDH had adverse impacts on PRS; preceding EFS equal to or shorter than the median (803 days) was another adverse feature, whereas long EFS (fourth quartile, ≥ 1,280 days) reduced the hazard of PRS. Regarding individual protocols, IFM90 and TT3 both resulted in shorter PRS, whereas IFM9902 trial participation conferred superior PRS. Tandem transplantation significantly reduced the PRS hazard compared with single transplantation and standard chemotherapy, and thalidomide as part of tandem transplantations was an independent favorable feature for PRS. Availability of thalidomide at protocol start (IFM9902, TT2, and TT3) was associated with a low HR (HR = 0.71, P < .001), whereas the availability of bortezomib in TT3 was associated with poor PRS (HR = 2.04, P < .001). Long preceding EFS retained its favorable impact on PRS.
This report represents, to our knowledge, the first international effort at systematically updating trial results reported earlier. Several important observations were made. First, outcomes were remarkablyconsistent when reiterative Kaplan-Meier plots were executed. Second, more recent trials had increased 10-year OS estimates, from 20% to 30% in IFM90, IFM94, S9321, and TT1% to 50% in TT2, which was confirmed by multivariate and pair-mate analyses. On the basis of EFS data showing steep improvements when comparing IFM9902 with TT2 and TT3, further gains in 10-year OS are likely to ensue with TT3. Third, among randomized trials, consistency was observed in OS for S9321 and IFM90 and, trend-wise, for IFM94. In contrast, with longer follow-up, thalidomide's initially observed survival benefit when used as maintenance therapy in IFM9902 could not be confirmed, whereas a significant survival improvement from its up-front use in TT2 emerged with a significant delay of almost 8 years after 80% of patients had discontinued its use. Another trial has also reported on thalidomide's benefit in maintenance therapy,21 which, in the case of the Tunisian study, could not be validated with longer follow-up.22,23 The late manifestation of thalidomide's survival benefit in TT2 remains an enigma but is not unprecedented in cancer therapy, because higher dose equivalents of glucocorticoids in pediatric acute lymphoblastic leukemia have long-ranging cure effects.24 Fourth, we also examined the variables impacting PRS, which was longer when prior EFS was sustained for at least 3.5 years, when tandem transplantations were used, and when thalidomide was included in the trial design (IFM9902, TT2, and TT3); the up-front use of bortezomib in TT3 adversely affected PRS. However, OS from protocol start was favorably affected by tandem transplantations, thalidomide with tandem transplantations, and TT3 that included bortezomib. Finally, in light of the steadily improving outcomes in myeloma, with 10-year survival estimates of 50% or higher as in TT2, the collective impact of successive interventions during induction, consolidation, and maintenance phases of treatment demands longer follow-up than currently practiced for survival effects to be appreciated, especially because complete response rates exceeding 50% can be regularly achieved with novel agent combinations even without transplantation. We hope that our work will encourage other groups to update their results so that the full impact of therapeutic trial interventions can be appreciated.
Supported by the National Cancer Institute, Bethesda, MD.
The funding source had no involvement in study design; collection, analysis, and interpretation of the data; writing of the report; or decision to submit the report for publication.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Bart Barlogie, Millennium Pharmaceuticals, Celgene, Novartis Expert Testimony: None Other Remuneration: None
Conception and design: Bart Barlogie, John Crowley, Brian G.M. Durie, Jean-Luc Harousseau
Provision of study materials or patients: Bart Barlogie, Michel Attal
Collection and assembly of data: Frits van Rhee
Data analysis and interpretation: John Crowley, Jackie Szymonifka, Philippe Moreau