J Clin Oncol 23: by American Society of Clinical Oncology INTRODUCTION

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1 VOLUME 23 NUMBER 36 DECEMBER JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T 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-Autogreffe Jean-Paul Fermand, Sandrine Katsahian, Marine Divine, Veronique Leblond, Francois Dreyfus, Margaret Macro, Bertrand Arnulf, Bruno Royer, Xavier Mariette, Edouard Pertuiset, Coralie Belanger, Maud Janvier, Sylvie Chevret, Jean Claude Brouet, and Philippe Ravaud From 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. Submitted June 10, 2005; accepted September 30, 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, Authors disclosures of potential conflicts of interest are found at the end of this article. Address reprint requests to J.P. Fermand, MD, Service d Immuno- Hématologie, Hôpital Saint-Louis, 1, avenue Claude Vellefaux, Paris cédex 10, France; jpfermand@ yahoo.fr. A B S T R A C T 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/m 2 intravenous [IV] or melphalan 140 mg/m 2 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. J Clin Oncol 23: by American Society of Clinical Oncology 2005 by American Society of Clinical Oncology X/05/ /$20.00 DOI: /JCO INTRODUCTION 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 9227

2 Fermand et al 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 AND METHODS 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 mol/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 In patients included in the HDT group, autologous peripheral-blood stem-cell (PBSC) collection was most often performed after one course of high-dose corticosteroids (methylprednisolone 400 mg/d intravenous [IV] on days 1 to 4). PBSCs were initially mobilized by a reinforced regimen of cyclophosphamide 1,500 mg/m 2 on day 1, doxorubicin 90 mg/m 2 on day 1, vincristine 1.4 mg/m 2 on day 1, and prednisone orally 80 mg/m 2 on days 1 to 4. A granulocyte colony-stimulating factor (G-CSF; 5 g/kg from day 6 through the last day of leukapheresis initiated on recovery of leukocytes to /L) was added to the chemotherapeutic regimen after the first inclusions. Collection and quantification of PBSCs were performed as previously described. 13 After PBSC collection, patients received three or four courses of vincristine 0.4 mg/d administered as a continuous 24-hour infusion, doxorubicin 9 mg/m 2 /d, and IV methylprednisolone 0.4 g/d on days 1 to 4 (VAMP). 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/m 2 IV on day 2; MLP 200 arm) or combined busulfan (4 mg/kg/d orally on days 6to 3) and melphalan (140 mg/m 2 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 Patients included in the CCT group received monthly courses of vincristine 1.4 mg/m 2 IV on day 1, melphalan 6 mg/m 2 orally on days 1 to 4, cyclophosphamide 600 mg/m 2 IV on day 1, and prednisone 80 mg/m 2 orally on days 1 to 4 (VMCP). In the patients who achieved at least a partial response (PR), VMCP courses were pursued until a stable plateau phase was reached (see Criteria for Response subsection). 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 Treatment with recombinant interferon-alfa (IFN; 3 MU subcutaneously three times weekly) was proposed in both arms to all patients in HDT- or CCT-induced remission. IFN was discontinued at the physician s discretion when it induced persisting side effects. Pamidronate (90 mg IV, every 4 weeks) was systematically administered to patients of both groups from time of relapse to death. Criteria for Response The response to HDT and VMCP was determined according to previously described criteria. 5 Briefly, PR was defined as a 50% or more decrease in the monoclonal immunoglobulin (MIg) serum level and/or as a 75% or more decrease in urinary Bence Jones protein levels. Complete response (CR) was defined as no MIg measurable in serum and 50 times concentrated urine by immunofixation analysis and as 5% or fewer plasma cells of normal morphology on bone marrow smears. A stable plateau phase was considered to exist in patients who achieved at least PR when three consecutive measurements of MIg concentration 2 months apart varied by less than 20%. Relapse was defined by the reappearance of MIg, by a 25% or more increase in the level of MIg, or by other unequivocal signs of disease progression such as hypercalcemia or plasma cell tumor. Statistical Analysis The main end point was overall survival (OS) from the initial random assignment, whatever the cause of death. Secondary end points were treatment response, event-free survival (EFS), and time without symptoms, treatment, and treatment toxicity (TwiSTT) adapted from Cole et al, 14 as previously described. 15 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 9228 JOURNAL OF CLINICAL ONCOLOGY

3 High-Dose v Conventional Therapy in Myeloma 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. RESULTS 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 beta 2 - microglobulin ( 2M) 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 Table 1. Main Baseline Characteristics of the 190 Randomly Assigned Patients According to Treatment Group Characteristic HDT (n 94) No. of Patients % CCT (n 96) No. of Patients % Age, years Median th to 75th percentile Male Durie-Salmon stage I II III M component (Ml/g) IgG IgA IgD BJ protein only None Hb, g/l g/l Serum calcium, mmol/l mmol/l Serum albumin, g/l Serum creatinine, mol/l mol/l BM plasmocytosis, % Serum 2 -microglobulin, mg/l mg/l CRP, mg/l mg/l Abbreviations: HDT, high-dose therapy; CCT, conventional chemotherapy; Mlg, monoclonal immunoglobulin; BJ, Bence Jones; Hb, hemoglobin; BM, bone marrow; CRP, C-reactive protein. All progressive (see text). Fig 1. Trial profile. (*) The cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) course was usually preceded by a 4-day course of methylprednisolone (400 mg/d; see text). CCT, conventional chemotherapy; HDT, high-dose therapy; PBSC, peripheral-blood stem cell; VAMP, vincristine, doxorubicin, and methylprednisolone; VMCP, vincristine, melphalan, cyclophosphamide, and prednisone; HDM 200, high-dose melphalan 200 mg/m 2 IV; HDM-BUS, high-dose melphalan plus busulfan. 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

4 Fermand et al 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 At the reference date of December 15, 2004, the median follow-up time was 120 months. On an intent-to-treat basis, 79 and 80 patients died in the HDT and CCT groups, respectively. The hazard ratio of death in the CCT group compared with the HDT group was estimated at 0.98 (95% CI, 0.72 to 1.34; log-rank test, P.91; Fig 2A). Median OS time was 47.8 months in the HDT group compared with 47.6 months in the CCT group (Table 2). Among the 23 patients in the HDT group who could not receive transplantation, one was still alive at analysis 14 years after enrollment, whereas the other patients had died, some early (nine deaths during the first year after random assignment), others late (eight deaths 5 years after random assignment). In terms of EFS, there was a trend for benefit of HDT compared with CCT (P.07; Fig 2B). In the HDT group, relapse or death had occurred in 88 patients, and the median EFS time was 25.3 months (95% CI, 23.5 to 29 months). Results were similar in both protocols of the HDT regimen (melphalan alone or combined with busulfan; data not shown). At relapse, seven patients received a second high-dose treatment, whereas the other patients were treated with various CCT regimens. 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/m 2 ) 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 The variables significantly influencing OS on univariate analysis of presentation features for the whole group of patients were serum 2M, creatinine, calcium, hemoglobin, and ISS stage (data not shown). In the multivariable model using these characteristics, in addition to age and random assignment group, a stepwise selection procedure isolated only 2M serum level (P.0001) as influencing prognosis. There was no interaction between treatment effect and age, creatinine level, 2M 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 Fig 2. (A) Overall survival according to treatment group. (B) Comparison of the event-free survival (EFS) of the two groups. CCT, conventional chemotherapy; HDT, high-dose therapy. P, probability JOURNAL OF CLINICAL ONCOLOGY

5 High-Dose v Conventional Therapy in Myeloma Table 2. Summary of Results According to Random Assignment Result HDT (n 94) CCT (n 96) P OS, years Median Range Year OS, % Median Range EFS, years Median Range Year EFS, % Median Range TwiSTT, months Median Range Early deaths, 9 months No % Toxicity No. 5 2 % 5 2 Progressive disease No. 4 8 % Disease response MRD CR No % PR No % Minimal response No % Resistant or progressive disease No % HDT not done No. 23 % 24 Early toxic death, No. 2 Abbreviations: HDT, high-dose therapy; CCT, conventional chemotherapy; OS, overall survival; EFS, event-free survival; TwiSTT, time without symptoms, treatment, and treatment toxicity; MRD, minimal residual disease; CR, complete response; PR, partial response. Four deaths occurred after peripheral-blood stem-cell mobilization, and one death occurred after HDT. See Figure 1. 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). DISCUSSION 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 data 22 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

6 Fermand et al Fig 3. Partitioning of Kaplan-Meier overall survival of (A) the high-dose therapy group and (B) the conventional chemotherapy (CCT) group. The areas between the curves and the vertical line at 120 months (median follow-up) represent estimates of duration between events, namely treatment duration (dark grey), time without symptoms and treatment toxicity (TwiSTT; white), and time between relapse (REL) and death (light grey). P, probability. 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/m 2 with autologous stem-cell support proved to be safe and effective in patients up to 75 years of age. 10 Recently, Palumbo et al 23 reported the superiority of tandem melphalan 100 mg/m 2 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 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/m 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 frontline 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 Acknowledgment 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 JOURNAL OF CLINICAL ONCOLOGY

7 High-Dose v Conventional Therapy in Myeloma Appendix The Appendix is included in the full-text version of this article, available online at It is not included in the PDF (via Adobe Acrobat Reader ) version. Authors Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 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: , Barlogie B, Shaughnessy J, Tricot G, et al: Treatment of multiple myeloma. Blood 103:20-32, 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. 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