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Originally published as JCO Early Release 10.1200/JCO.2005.03.0551 on November 7 2005 © 2005 American Society of Clinical Oncology. High-Dose Therapy and Autologous Blood Stem-Cell Transplantation Compared With Conventional Treatment in Myeloma Patients Aged 55 to 65 Years: Long-Term Results of a Randomized Control Trial From the Group Myelome-AutogreffeFrom the Immuno-Hematology Unit and Department of Biostatistics, Hôpital Saint Louis; Epidemiology Unit, Hôpital Bichat; Rheumatology Unit, Hôpital Lariboisière; Hôpital Kremlin-Bicêtre; Hematology Unit, Hôpital Pitié; Hematology Unit, Hôpital Necker; Hematology Unit, Hôpital Cochin, Paris; Hematology Unit, Hôpital Henri Mondor, Créteil; Hematology Unit, Centre R. Huguenin, Saint Cloud; Hematology Unit, Centre Hospitalier, Amiens; and Hematology Unit, Centre Hospitalier, Caen, France Address reprint requests to J.P. Fermand, MD, Service d'Immuno-Hématologie, Hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75475 Paris cédex 10, France; e-mail: jpfermand{at}yahoo.fr
PURPOSE: To study the impact of high-dose therapy (HDT) with autologous stem-cell support in patients with symptomatic multiple myeloma (MM) between the ages of 55 and 65 years. PATIENTS AND METHODS: One hundred ninety patients between 55 and 65 years old who had newly diagnosed stage II or III MM were randomly assigned to receive either conventional chemotherapy (CCT; ie, monthly courses of a regimen of vincristine, melphalan, cyclophosphamide, and prednisone) or HDT and autologous blood stem-cell transplantation (using either melphalan alone 200 mg/m2 intravenous [IV] or melphalan 140 mg/m2 IV plus busulfan 16 mg/kg orally as pretransplantation cytoreduction). RESULTS: Within a median follow-up of 120 months, median event-free survival (EFS) times were 25 and 19 months in the HDT and CCT groups, respectively. Median overall survival (OS) time was 47.8 months in the HDT group compared with 47.6 months in the CCT group. A trend to better EFS (P = .07) was observed in favor of HDT, whereas OS curves were not statistically different (P = .91). The period of time without symptoms, treatment, and treatment toxicity (TwiSTT) was significantly longer for the HDT patients than for the CCT patients (P = .03). CONCLUSION: With a median follow-up time of approximately 10 years, this randomized trial confirmed a benefit of HDT in terms of EFS and TwiSTT but did not provide evidence for superiority of HDT over CCT in OS of patients aged 55 to 65 years with symptomatic newly diagnosed MM.
High-dose therapy (HDT) with autologous stem-cell rescue is presently considered the treatment of choice for patients with multiple myeloma (MM) and good performance status.1,2 HDT is feasible in patients who are 65 years of age or even older,3,4 but its actual benefit, compared with conventional chemotherapy (CCT), has not been formally established in the higher age brackets. Indeed, in most reports of phase II studies of HDT, the median age of patients who received transplantations did not exceed 52 years.3,5-8 Pair-mate analyses provided some evidence for the superiority of HDT compared with CCT, including for patients up to 75 years of age,4,9,10 but these results are questionable because of potential selection bias and because the CCT patients in these studies were taken from historical series. Two randomized studies conducted by the Intergroupe Français du Myelome (IFM) and the Medical Research Council (MRC) provided evidence for a survival benefit of HDT compared with CCT.11,12 Although both studies were designed to recruit patients less than 65 years of age, the median ages of included patients were 57 and 55 years, respectively. In addition, in the IFM study, the high-dose strategy yielded better results than conventional treatment only in patients less than 60 years of age.11 To address the issue of patient age when HDT should be recommended, we conducted a prospective randomized trial in which previously untreated MM patients between 55 and 65 years of age were randomly assigned to receive either HDT supported by autologous blood stem-cell transplantation or CCT.
Patients Eligibility criteria included age between 55 and 65 years and symptomatic MM. Patients were not included if they had stable stage I MM (Durie and Salmon classification), had received cytotoxic chemotherapy (other than one course of corticosteroids and/or alkylating agents) or radiotherapy (other than local irradiation), or had renal failure (serum creatinine level > 300 µmol/L) or severe cardiac, hepatic, or pulmonary dysfunctions. The study was approved by the Institutional Ethics Committee of Saint Louis Hospital (Paris, France). All patients gave informed consent. After enrollment, patients were randomly assigned to the HDT group or the CCT group. In the HDT group, a second random assignment defined the protocol of the HDT regimen, comparing a regimen including the radiomimetic drug busulfan with a standard high-dose melphalan treatment. Both random assignments were stratified according to center and were carried out by telephone.
HDT Group After the VAMP courses, whatever the disease response, a second random assignment procedure defined the protocol of the HDT regimen, which either consisted of melphalan alone (200 mg/m2 IV on day –2; MLP 200 arm) or combined busulfan (4 mg/kg/d orally on days –6 to –3) and melphalan (140 mg/m2 IV on day –2; MLP-BUS arm). In both cases, PBSCs were reinfused at day 0, and growth factor was not systematically used. HDT was administered in protected units.
CCT Group In case of progression or resistance to VMCP and at relapse in responders, patients were treated with the VAMP regimen or by restarting alkylating agents. HDT as rescue treatment was not scheduled and was not recommended.
Other Treatments
Criteria for Response
Statistical Analysis The study was conducted as a sequential trial to minimize the number of patients needed, and a triangular test was used.16 The accumulated data were examined after every 10 deaths. The study was designed to have a type I error of 0.05 with a power of 0.80 to detect an increased survival benefit from HDT compared with CCT, expressed by a hazard ratio of 0.60 (ie, to detect a difference in median survival times from 3 years with CCT to 5 years with HDT). Analysis was performed on an intent-to-treat basis using December 15, 2004, as the reference date. Baseline and response rate comparisons were made using the Fisher's exact test and the nonparametric Wilcoxon rank sum test. Survival curves were estimated by the Kaplan-Meier method and compared by the log-rank test. Survival comparison was adjusted for either imbalanced or prognostic baseline covariates using a Cox model. Treatment-covariate interactions were tested by the Gail and Simon test.17 Hazard ratios were estimated with 95% CIs. Analysis used the SAS 8 (SAS Inc, Cary, NC) and S-plus 1000 (Statistical Sciences, Seattle, WA) software packages.
Patient Characteristics Accrual in the trial began in November 1991 and was stopped in September 1998 after the eighth sequential analysis based on the results of the triangular test. One hundred ninety patients from 14 centers were enrolled (94 and 96 patients in the HDT and CCT groups, respectively). Figure 1 displays the trial profile. Baseline characteristics of the HDT and CCT groups were similar (Table 1), with a median age of 61 years, approximately 80% of patients with stage III disease, and an initial serum beta2-microglobulin (ß2M) level of 3 mg/L or more in 56% of patients. Repartition of the patients according to the International Staging System (ISS)18 was similar in the two groups.
Completion of Allocated Treatment In the HDT group, four patients did not proceed to PBSC mobilization because of retracted consent (n = 2) or fulminant disease (n = 2). Failure of the PBSC collection, whatever the cause (complications of the mobilizing chemotherapy or insufficient number of collected stem cells), was observed in 16 patients (18%), including seven of the 23 patients who were mobilized before the use of G-CSF. Seventy-one patients (ie, 75% of all patients included in the HDT group) actually received transplantion, of whom 38 received the MLP 200 protocol and 33 received the MLP-BUS protocol as a pretransplantation cytoreductive regimen (Fig 1). In the CCT group, the median number of VMCP courses was 12 (range, one to 26 courses). Four patients died early because of progressive disease (n = 2), infectious complications, or sudden death (Fig 1). IFN was used in 20 patients (21%) and 14 patients (15%) in the HDT and CCT groups, respectively. Median duration of IFN therapy was 9.5 months for patients in the HDT group and 14 months for patients in the CCT group (P = .13).
OS, EFS, and TwiSTT
In the CCT group, median EFS time was 18.7 months (95% CI, 15.7 to 23.2 months). At the reference date, 79 patients either had died or had received a second-line treatment because of refractory or relapsing disease. Twenty-one of these patients (ie, 22% of all patients included in the CCT group) received a salvage high-dose regimen (usually melphalan 200 mg/m2) without any transplantation-related mortality. Salvage high-dose treatments were usually administered to patients of less than 60 years of age with a good performance status. In addition, these patients usually had resistant (primary or secondary) or relapsing (in second or third relapse) but stabilized disease. Using a cutoff of 120 months, the average TwiSTT was 25.1 months (95% CI, 19.2 to 31.1 months) and 16.6 months (95% CI, 11.5 to 21.7 months) in the HDT and CCT groups, respectively (Student's t test, P = .033; Fig 3).
Response to Therapy At 6 months after HDT, 59 of the 71 patients who received transplantation were in remission, including six in CR, 28 with minimal residual disease (MRD), and 25 in PR. Seven patients achieved minimal response, and two patients had resistant disease (Table 2). Three patients died as a result of progressive disease (n = 2) and treatment-related complications (n = 1). Remission rates were 81% (including 42% CR + MRD) and 84% (54% CR + MRD) in the MLP 200 and MLP-BUS arms, respectively. In the CCT group, 56 patients (58%) responded to VMCP. Among these patients, four achieved CR, 15 had MRD (ie, 19.8% CR + MRD), and 37 achieved PR. Eighteen patients achieved minimal response, and 18 patients had refractory disease.
Prognostic Factors for Death There was no interaction between treatment effect and age, creatinine level, ß2M serum level, ISS stage, or period of inclusion. In particular, the OS of the 70 patients treated in the HDT group after the systematic introduction of G-CSF during the mobilization procedure was similar to the OS of the 71 patients treated conventionally during the same period of time (data not shown). Of the 71 patients in the HDT group who actually received HDT, the post-HDT response was not predictive of survival. Median OS time was 59 months (from random assignment) for the 34 patients who achieved a CR or an MRD compared with 40.5 months for the other patients. However, the OS (and EFS) curves of the two groups were not significantly different (P = .22).
Data supporting HDT in MM are strongest for patients younger than 60 years old or even younger than 55 years old. In patients in the seventh decade of life, in whom MM is most frequently diagnosed,19 the relative merits of HDT and CCT are still controversial. The present prospective randomized study was designed to address this issue. Within a median follow-up time of approximately 10 years, this study confirmed a benefit of HDT in terms of EFS and TwiSTT but did not provide evidence for superiority of HDT compared with CCT in OS of patients aged 55 to 65 years with symptomatic newly diagnosed MM. The established superiority of HDT compared with CCT mainly relies on data from the IFM and MRC randomized studies.11,12 Of note, HDT may mainly benefit patients with disease refractory to CCT, as suggested by the absence of any survival difference between the two strategies when administered as a consolidation treatment in responders to an initial standard-dose regimen.20 Like our study, the IFM and MRC trials enrolled previously untreated patients. In both studies, approximately 25% of the patients included in the HDT arm could not receive the designed HDT. For those patients who could proceed to HDT, transplantation-related mortality was low, as it was in most series of patients treated with HDT regimens without high-dose total-body irradiation.8,12 Although we included older patients, we also observed a transplantation exclusion rate and transplantation-related mortality rate of approximately 25% and 1%, respectively. As in our previous studies,15,21 we used blood stem cells that were chemotherapy mobilized nearly front line. This resulted in a tumor contamination much lower than that of marrow stem cells even harvested after a few cycles of induction therapy, as used in the IFM study and, in part, in the MRC study.11,12 CR rates were 44%, 22%, and 8% in the MRC, IFM, and present studies, respectively. These discrepancies were likely a result, at least in part, of the use of less or more stringent response criteria. Post-HDT good response rates (> 90%) were similar (approximately 50%) in the IFM study and the present study. In contrast to the IFM data, we could not demonstrate that achieving such a level of response has a pivotal role for the outcome. Maybe meta-analysis of individual patient data22 will allow a statistical power to be reached that is sufficient enough to solve this issue. In a previous randomized trial designed to assess the optimal timing of HDT and autologous transplantation in young myeloma patients, we observed similar OS whether HDT was performed early (as first-line therapy) or late (as rescue treatment).15 Although this was not scheduled in the present study design, 22% of patients in the CCT group went on to receive a rescue HDT, and this switch might have contributed to equalizing survival in the two groups. Both in the IFM and MRC studies, switch rates were approximately 15%. Intermediate-dose regimens were proposed in an attempt to confer the survival advantage of HDT to elderly patients. Two courses of melphalan 100 mg/m2 with autologous stem-cell support proved to be safe and effective in patients up to 75 years of age.10 Recently, Palumbo et al23 reported the superiority of tandem melphalan 100 mg/m2 when randomly compared with a combination of oral melphalan and prednisone in patients aged 50 to 70 years (median age, 64 years). In this study, the median OS time was 37 months for patients in the CCT group who received a maximum of 6 monthly courses of melphalan and prednisone. Importantly, this might be not sufficient enough for taking benefit of the slow response that may occur in conventionally treated patients and usually translates in long remission.24 In present study, the standard-dose regimen was maintained until the achievement of a stable plateau phase, and all patients with a progression-free survival of more than 2 years received 12 or more courses of the standard therapeutic regimen (data not shown). In the IFM and MRC studies, a maximum of 12 cycles of standard therapy was delivered, and the median OS times were 44 and 42 months, respectively,11,12 compared with 48 months in the present study. The introduction of novel therapeutic agents, such as thalidomide, lenalidomide, and bortezomib, is changing present views on initial therapy for myeloma patients.25-27 Whether or not combining these drugs with HDT will improve the rate of proceeding to autologous transplantation and the post-HDT outcome is open to question. Moreover, comparing HDT and standard therapy containing novel agents is justified, particularly in elderly patients. Indeed, preliminary results of a large randomized study performed in myeloma patients aged 60 to 75 years showed that a combination of oral melphalan, prednisone, and thalidomide increased response rates compared with both melphalan plus prednisone and tandem melphalan 100 mg/m2.28 For the time being, HDT followed by stem-cell rescue is still the standard form of management of newly diagnosed patients with symptomatic MM. In defining the upper age limit for recommending HDT, the benefit in EFS and TwiSTT duration may lead to choosing HDT as first-line therapy in patients up to 65 years of age. In addition, considering HDT secondarily (ie, in case of failure of a front-line CCT regimen) is likely more and more hazardous as the patient's age increases. Conversely, the advantage of HDT in terms of time without toxicity does not preclude that this strategy may negatively impact patients' quality of life more strongly than CCT, particularly in the higher age brackets, because of more serious and durable adverse effects. Overall, the absence of definite evidence for the superiority of HDT compared with CCT in OS suggests making the treatment choice on an individual basis, taking into account the medical context and patient's preference. In any case, whatever the chosen therapeutic option, present modalities of HDT and/or CCT are not curative, and newly available drugs and/or strategies must be considered. Hopefully, a better understanding of the physiopathology of the disease will open new therapeutic avenues.29
The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF (via Adobe® Acrobat Reader®) version.
The following investigators also participated in the trial: D. Bouscary and M.C. Quarre, Hôpital Cochin, Paris; F. Beaujan, X. Chevalier, and M. Kuentz, Hôpital Henri-Mondor, Créteil; P. Bourgeois, J.P. Marre, and S. Rozenberg, Hôpital Pitié-Salpétrière, Paris; O. Fain, Hôpital Jean Verdier, Bondy; M. Le Porrier and X. Troussard, Centre Hospitalier, and A.M. Penit, Centre A. Baclesse, Caen; C. Gardin, M.F. Kahn, and E. Palazzo, Hôpital Bichat-Beaujon, Paris; T. André and M. Schlienger, Hôpital Tenon, Paris; Y. Kerneis
The authors indicated no potential conflicts of interest.
We thank the patients who participated in the trial, the attending physicians who referred their patients to our centers, the members of the Departments of Hemobiology of our hospitals who performed the peripheral-blood stem-cell collection, and M. Bargis-Touchard for secretarial assistance.
Supported by the Delegation à la Recherche Clinique de l'Assistance Publique of Paris Hospitals. Presented in part at the 41st Annual Meeting of the American Society of Hematology, New Orleans, LA, December 3-7, 1999. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Imrie K, Esmail R, Meyer RM, et al: The role of high-dose chemotherapy and stem-cell transplantation in patients with multiple myeloma: A practice guideline of the Cancer Care Ontario Practice Guidelines Initiative. Ann Intern Med 136:619-629, 2002 2. Barlogie B, Shaughnessy J, Tricot G, et al: Treatment of multiple myeloma. Blood 103:20-32, 2004 3. Sirohi B, Powles R, Mehta J, et al: Complete remission rate and outcome after intensive treatment of 177 patients under 75 years of age with IgG myeloma defining a circumscribed disease entity with a new staging system. Br J Haematol 107:656-666, 1999[CrossRef][Medline] 4. Siegel DS, Desikan KR, Mehta J, et al: Age is not a prognostic variable with autotransplants for multiple myeloma. Blood 93:51-54, 1999 5. Fermand JP, Chevret S, Ravaud P, et al: High-dose chemotherapy and autologous blood stem cell transplantation in multiple myeloma: Results of a phase II trial involving 63 patients. Blood 82:2005-2009, 1993 6. Vesole DH, Tricot G, Jagannath S, et al: Autotransplants in multiple myeloma: What have we learned? Blood 88:838-847, 1996 7. Björkstrand B, Ljungman P, Svensson H, et al: Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: A retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood 88:4711-4718, 1996 8. Barlogie B, Jagannath S, Desikan KR, et al: Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 93:55-65, 1999 9. Barlogie B, Jagannath S, Vesole DH, et al: Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 89:789-793, 1997 10. Palumbo A, Triolo S, Argentino C, et al: Dose-intensive melphalan with stem cell support (MEL100) is superior to standard treatment in elderly myeloma patients. Blood 94:1248-1253, 1999 11. Attal M, Harrousseau JL, Stoppa AM, et al: A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 335:91-97, 1996 12. Child JA, Morgan GJ, Davies FE, et al: High-dose chemotherapy with hematopoietic stem cell rescue for multiple myeloma. N Engl J Med 348:1875-1883, 2003 13. Fermand JP, Levy Y, Gerota J, et al: Treatment of aggressive multiple myeloma by high-dose chemotherapy and total body irradiation followed by blood stem cells autologous graft. Blood 73:20-23, 1989 14. Cole BF, Gelber RD, Anderson KM: Parametric approaches to quality-adjusted survival analysis: International Breast Cancer Study Group. Biometrics 50:621-631, 1994[CrossRef][Medline] 15. Fermand JP, Ravaud P, Chevret S, et al: High dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: Up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood 92:3131-3136, 1998 16. Whitehead J: The Design and Analysis of Sequential Clinical Trials (ed 2). Chichester, United Kingdom, Elis Horwood, 1992 17. Gail M, Simon R: Testing for qualitative interactions between treatment effects and patient subsets. Biometrics 4:361-372, 1985 18. Greipp PR, San Miguel J, Durie BG, et al: International staging system for multiple myeloma. J Clin Oncol 23:3412-3420, 2005 19. Kyle RA, Beard CM, O'Fallon WM, et al: Incidence of multiple myeloma in Olmsted County, Minnesota: 1978 through 1990, with a review of the trend since 1945. J Clin Oncol 12:1577-1583, 1994 20. Blade J, Rosinol L, Sureda A, et al: High-dose therapy intensification versus continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: Long term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood, August 16, 2005, Epub ahead of print 21. Fermand JP, Chevret S, Levy Y, et al: The role of autologous blood stem cells in support of high-dose therapy for multiple myeloma. Hematol Oncol Clin North Am 6:451-462, 1992[Medline] 22. Levy V, Katsahian S, Fermand JP, et al: A meta-analysis on data from 575 patients with multiple myeloma randomly assigned to either high-dose therapy or conventional therapy. Medicine 84:250-260, 2005[CrossRef][Medline] 23. Palumbo A, Bringhen S, Petrucci MT, et al: Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: Results of a randomized controlled trial. Blood 104:3052-3057, 2004 24. Boccadoro M, Pileri A: Diagnosis, prognosis and standard treatment of multiple myeloma. Hematol Oncol Clin North Am 11:111-131, 1997[CrossRef][Medline] 25. Rajkumar SV, Hayman S, Gertz MA, et al: Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 20:4319-4323, 2002 26. Weber D, Rankin K, Gavino M, et al: Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 21:16-19, 2003 27. Richardson PG, Barlogie B, Berenson J, et al: A phase II study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003 28. Facon T, Mary JY, Hulin C, et al: Randomized clinical trial comparing melphalan-prednisone (MP), MP-thalidomide (MP-THAL) and high-dose therapy using melphalan 100 mg/m2 (MEL100) for newly diagnosed myeloma patients aged 65-75 years: Interim analysis of the IFM 99-06 trial on 350 patients. Blood 104:63a, 2004 (abstr 206) 29. Bergsagel PL, Kuehl WM, Zhan F, et al: Cyclin D dysregulation: An early and unifying pathogenic event in multiple myeloma. Blood 106:296-303, 2005 Submitted June 10, 2005; accepted September 30, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, P. Morvan, and G. Philippe, Centre Hospitalier, Pontoise; P. Brice, J.P. Clauvel, C. Hennequin, A. Jaccard, M. Malphettes, and J.P. Marolleau, Hôpital Saint Louis, Paris; B. Rio, Hôtel Dieu, Paris; A. Delmer, Centre Hospitalier, Reims; J. Dumont, J.M. Cosset, A. Fourquet, and J.R. Vilcoq, Institut Curie, Paris; D. Clerc, Hôpital Bicêtre, Paris; F. Lioté, M. Roussel, and J.M. Zini, Hôpital Lariboisière, Paris; R. Delarue, O. Hermine, and B. Varet, Hôpital Necker, Paris, France. 
