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In this report, the authors describe their collective experience with melphalan-based autotransplants since the inception of their program at the University of Arkansas for Medical Sciences in 1989.
The authors evaluated the clinical outcomes of 3077 successive patients with multiple myeloma (MM) who underwent at least 1 melphalan-based autotransplantation at the University of Arkansas. Of these, 1078 patients were enrolled on front-line Total Therapy (TT) protocols (TT-P) TT1, TT2, and TT3; 1104 patients were entered on protocols for newly diagnosed or previously treated patients (non-TT-P); and 895 patients were treated off protocol (non-P).
The 10-year overall survival (OS) rates after first transplantation were 41%, 19%, and 11% (P < .001) for the TT-P, non-TT-P, and non-P groups, respectively. In the TT-P group, the median OS was 72 months on TT1, was not reached at ≥7 years on TT2, and was 88% at 2 years on TT3. Among 2683 patients with complete baseline data, absence of hypodiploidy/chromosome 13 deletion, β-2-microglobulin <3.0 mg/L, C-reactive protein <6 mg/L, albumin ≥3.0 g/dL, and platelet count ≥100,000/μL all were associated independently with superior OS (P < .001), event-free survival (P < .001), and duration of complete remission (P < .001).
The results from this large, single-institution experience demonstrated that >10-year OS was accomplished in >40% of all patients enrolled on TT-P, whereas such success was observed in only 15% of the remaining patients (including 25% in the presence of all 5 good-risk features). Superior outcomes with protocol-based, primary transplant regimens such as TT-P draw attention to the importance of applying the best available therapies upfront.
Substantial progress has been achieved in the treatment of patients with multiple myeloma (MM) ever since the marked dose-response effect of melphalan (MEL) could be exploited safely as a result of autologous hematopoietic stem cell support, especially using peripheral blood stem cells (PBSC).1-3 Indeed, the majority of randomized and historically controlled clinical trials have demonstrated that, by increasing stringently defined complete response (CR) rates up to a range from 40% to 50% (rates that are achievable readily with “tandem transplants”), event-free survival (EFS) and overall survival (OS) durations have been extended beyond 3 years and 6 years, respectively.4-9 Thus, MM has become the primary indication for autotransplantation in both the U.S. and Europe. Although the advent of novel agents, such as thalidomide, lenalidomide, and bortezomib employed either alone or in combination with dexamethasone, each other, or standard-dose melphalan, has resulted in high CR rates approaching those achieved with MEL-transplants, currently, follow-up is too short to comment on the durability of such remissions.10-12
Therefore, it is important periodically to update autotransplantation results, especially from large, MM-specialized centers such as ours, to provide MM physicians and patients alike with long-term results against which new agent combinations will have to be measured. Herein, we report our collective experience with MEL-based autotransplants since the inception of our program at the University of Arkansas for Medical Sciences in 1989.
Three thousand seventy-seven patients were identified from our MM database who underwent their first MEL-based autotransplantation between 1989 and December 2006 at our institution. Patients were divided into 3 groups according to whether they were enrolled on Total Therapy (TT) protocols (TT-P) TT1, TT2, and TT38,9,13-16 for newly diagnosed patients or on other protocols for newly diagnosed or previously treated patients (non-TT-P).17,18 A third group included patients who were treated off protocol (non-P) for reasons of ineligibility, insurance denial, or patient/physician preference. All protocols had been reviewed and approved by the Institutional Review Board. Protocol patients signed an informed consent specific for the trial prior to enrollment, whereas patients who were treated off protocol signed a general informed consent stating the anticipated risks and potential benefit of the proposed therapies.
Details of the TT1, TT2, and TT3 regimens have been published previously.8,9,15 Non-TT-P trials for previously treated patients included induction with dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide (DT-PACE)18 followed by intended tandem transplants either with MEL at a dose of 200 mg/m2 (MEL200) or with MEL at a dose of 140 mg/m2 (MEL140) in patients with renal insufficiency who had creatinine levels >3 mg/dL or in patients with advanced age (>70 years).19,20 Other patients received a MEL-DT-PACE hybrid regimen with MEL140 plus DT-PACE.21 If a partial response (PR) was not achieved after the first transplant, then the second transplant regimen included MEL140 plus either total body irradiation (TBI), or high-dose cyclophosphamide, or the carmustine, etoposide, cytosine arabinoside, melphalan (BEAM) regimen.22,23 More recently, in the non-P setting, MEL was applied in 3 equal fractions of up to 100 mg/m2 (total dose, 300 mg/m2)24 after bortezomib on Days 1, 4, and 7 along with thalidomide and dexamethasone25 to exploit the potential synergy between MEL and bortezomib demonstrated in experimental settings.26
Table 1 shows that all 3077 patients underwent a MEL-based first transplantation, including 898 patients who underwent a single transplantation (MEL200 in 69%; MEL140 with or without TBI in 21%; and other MEL-based combination regimens, such as BEAM, in 10%) and 1927 patients who underwent 2 transplantations (MEL200 × 2 in 63%; MEL200 followed by either MEL140 plus TBI or BEAM in 10% each; MEL200 followed by an allogeneic transplantation in 5%; MEL140 × 2 with or without TBI in 4%; and other MEL-based combination regimens, such as MEL140-DTPACE, in 8%). Of 233 patients who underwent 3 transplantations, MEL200-based tandem transplants were followed by BEAM in 21%, further MEL200 in 18%, an allotransplantation in 17%, MEL140 in 12%, and other regimens in the remaining 32%. There were 19 patients who underwent 4 transplantations, all of whom received MEL200 as their initial tandem transplant. PBSCs had been obtained with chemotherapy regimens and hematopoietic growth factors, which also were applied as the sole means of PBSC mobilization.
All patients underwent full pretransplantation staging of their MM along with a thorough assessment of all organ functions and thorough laboratory evaluation with multichemical scans, hemograms, and MM parameters. MM response criteria of Blade et al. were applied.27 The time from first therapy to first transplantation was computed from the available referral information.
The results presented here are based on follow-up as of April 2007. The median follow-up was 38 months (range, 0.6–201 months). The Kaplan-Meier method28 was used to estimate EFS and OS, and comparisons were made by using the log-rank test.29 EFS and OS were measured from the first day of MEL administration until disease recurrence or death. CR was defined only for patients with secretory disease and was based on serum and urine measurements in accordance with the criteria of Blade et al.27 CR duration was measured from the onset of CR until disease recurrence or death. For patients who were in CR at the time of their first transplantation, duration of CR was measured from the date of first transplantation. Relapse criteria from CR and PR have been reported previously.7,9,27 The cumulative incidence of CR was estimated according to the method of Gooley et al.30 with death treated as a competing risk. Cox regression analysis31 was used to examine multivariate models of prognostic factors using a stepwise method to select the 5 pretransplantation factors associated most strongly with EFS, OS, and duration of CR. CR and application of a second transplant also were considered as time-dependent covariates.32
Patient characteristics in the 3 principal treatment groups are depicted in Table 2. The 3 groups were similar with regard to prognostic factors, including immunoglobulin subtype, lactate dehydrogenase levels, race, and sex. Higher proportions of patients on non-P and non-TT-P regimens had low hemoglobin, platelet, and albumin levels and high creatinine, β-2-microglobulin (B2M), and C-reactive protein (CRP) concentrations, as expected. High-risk cytogenetic abnormalities (CA) of the hypodiploidy/deletion 13 variety (CA13/hypodiploidy) were observed more frequently in the non-P group. Eighty-three percent of patients in the TT-P group, 71% of patients in the non-TT-P group, and 56% of patients in the non-P group completed a second transplantation (P < .001). Pretransplantation CR rates were higher in the TT-P group than in the other 2 groups. Post-transplantation CR rates, which were computed on an intent-to-treat basis, were highest with TT-P regimens (62%), intermediate with non-TT-P regimens (46%), and lowest with non-P regimens (44%).
Figure 1 depicts Kaplan-Meier plots of the durations of OS, EFS, time to CR, and CR duration for the 3 groups. OS and EFS were superior with TT-P regimens followed by non-TT-P and non-P regimens; CR and CR duration were significantly higher and longer, respectively, with TT-P regimens compared with the other regimens. Among the TT-P regimens, TT2 outcomes were superior to outcomes with TT1; compared with TT2, TT3 produced both increased CR and EFS (Fig. 2). With the non-TT-P regimens, there was a significant improvement in OS among patients who were from 1994 onward; EFS improved significantly during the third 4-year interval, and there was a strong trend toward ongoing improvement from 2004 onward; and CR duration improved overall from 1989 onward (Fig. 3). Such progress was not apparent with the non-P regimens (Fig. 4).
Next, we examined CR, EFS, and OS durations in the context of pretransplantation parameters by employing both univariate and multivariate regression analyses (Table 3). The results revealed that all 3 clinical endpoints were independently favorably affected by the absence of CA of the deletion 13/hypodiploidy variety (“CA13/hypo”), low B2M and CRP levels, and higher albumin and platelet concentrations; CR and second transplantation (examined as time-dependent variables) prolonged OS and EFS significantly (Table 3). It is noteworthy that, when treatment regimens also were considered, the TT-P group emerged as an independent favorable feature for all 3 clinical endpoints that were considered (Table 3). Among the non-TT group, protocol-based therapy (non-TT-P) was superior to non-P regimens for both OS and EFS (Table 4). Examination by subgroup revealed that albumin and platelet counts were not independently significant variables for OS, EFS, or CR duration in the TT-P cohort (Table 5), and CRP was not significant for EFS or CR duration in either the non-TT-P group (Table 6) or the non-P group (Table 7). CR and second transplantation extended EFS in the TT-P and non-TT-P groups, and a CR effect was observed for both OS and EFS in the non-P cohort of patients.
Figure 5 depicts OS, EFS, and CR durations according to the number of favorable pretransplantation parameters for all patients and in the 3 subgroups. Indeed, when considering all 2683 patients with pertinent information, significant separations of Kaplan-Meier plots were observed between the 5 subgroups: outcomes worsened progressively as the number of good-risk features declined from 5 to 4, to 3 to 2, and to <2. In the TT-P group, the 10-year OS rate was 56% for patients with all 5 favorable parameters and dropped to approximately 20% in patients with <4 favorable parameters; in the other 2 groups, the 10-year OS rates were similar at 25% for the best and 2% for the worst constellation of prognostic factors. The 10-year CR rate was 46% for TT-P patients with 5 favorable features and 0% for patients with <2 favorable features; the corresponding values for patients in the non-TT-P and non-P groups combined were 20% and 5%, respectively.
In this largest single-institution experience with autotransplant-supported, MEL-based, high-dose regimens for patients with MM, we confirmed that scheduled, upfront, tandem transplants such as those applied in the TT regimens produced superior clinical outcomes (Fig. 1) and steady improvement with the transition from the TT1 protocol, to the TT2 protocol, to the TT3 protocol (Fig. 2). The median OS of 92 months and an EFS of 52 months were unprecedented for the TT-P group as were the 12-month CR estimate of 63% and the CR duration of 73 months. The 10-year OS rate was 41% in the TT-P group compared with only 19% in the non-TT-P group and 11% in the non-P group. These profound differences in clinical outcome were related in part to differences in the constellation of pretransplantation parameters, which were significantly more favorable among TT-P patients with regard to CA13/hypodiploidy, B2M, albumin, creatinine, hemoglobin, and platelet counts, and the proportion of patients in CR pretransplantation (Table 2). However, TT-P proved to be an independent, favorable parameter in a multivariate analysis that considered treatment as a variable (Table 3). Similarly, protocol-based therapy for the non-TT patients favored both OS and EFS after adjusting for pretransplantation prognostic factors (Table 4). The inferior outcome of the non-P group could not be traced to any particular features, because the reasons for off-protocol therapy differed widely.
Nevertheless, CA13/hypodiploidy and B2M were associated independently with all 3 endpoints examined with both TT regimens and with non-TT regimens (Tables 5--7).7). According to the constellation of the 5 dominant favorable baseline features identified among the entire patient population (Table 3), the 10-year OS rate varied from a high of 37% in the best constellation of 5 favorable parameters, declined to ~30% with at least 4 favorable, and declined to <5% with ≤2 favorable parameters (Fig. 5). Employing time-dependent variable statistics, both CR and second transplants were independent favorable events toward prolongation of both OS and EFS among all 2683 patients (see Table 3); in the TT-P (Table 5) and non-TT-P cohorts (Table 6), CR and second transplants imparted superior EFS but not OS; in the non-P cohort, CR was meaningful for both OS and EFS (Table 7).
When the calendar year of first transplantation was considered, a significantly improved outcome was observed in later years for the TT-P (Fig. 2) and non-TT-P (Fig. 3) groups, most likely reflecting the availability of new agents such as thalidomide, which has been used widely in our patients’ management since 1999, and bortezomib, which was introduced initially as salvage therapy in 1999 and for front-line management in 2003 as part of TT3.
In the context of contemporary therapies (for review, see Richardson33), the data presented here indicate that, whereas certain prognostic features pertain regardless of the treatment circumstance, a protocol-based approach from the outset as practiced in TT-P assures the best treatment outcome. Dissecting the heterogeneity in survival according to both pretransplantation features and treatment strategies revealed distinct patient subgroups with vastly different potential for 10-year survivorship.
Supported in part by CA55819 from the National Cancer Institute.
We thank the many referring physicians for entrusting us with their patients’ care. The diligence of the Myeloma Institute for Research and Therapy nursing and support staff was crucial to our efforts to care for these patients.