|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2006.10.2509 on May 7 2007 © 2007 American Society of Clinical Oncology. Prospective, Randomized Study of Single Compared With Double Autologous Stem-Cell Transplantation for Multiple Myeloma: Bologna 96 Clinical Study
From the Istituto di Ematologia ed Oncologia Medica [Seràgnoli], Università di Bologna, Bologna; Clinica Ematologia, Università di Udine, Udine; Cattedra di Ematologia, Università di Catania, Catania; Servizio di Ematologia, Avellino; Sezione di Ematologia, Università di Modena, Modena; Unità Operativa di Ematologia, Cagliari; Servizio di Ematologia, Reggio Emilia; Divisione di Ematologia, Università Federico II, Napoli; Divisione di Ematologia e Trapianti, Università di Siena, Siena; and Oncologia Medica ed Ematologia, Piacenza Address reprint requests to Michele Cavo, MD, [Seràgnoli] Institute of Hematology and Medical Oncology, via Massarenti 9, 40138, Bologna, Italy; e-mail: mcavo{at}med.unibo.it
Purpose We performed a prospective, randomized study of single (arm A) versus double (arm B) autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM). Patients and Methods A total of 321 patients were enrolled onto the study and were randomly assigned to receive either a single course of high-dose melphalan at 200 mg/m2 (arm A) or melphalan at 200 mg/m2 followed, after 3 to 6 months, by melphalan at 120 mg/m2 and busulfan at 12 mg/kilogram (arm B). Results As compared with assignment to the single-transplantation group (n = 163 patients), random assignment to receive double ASCT (n = 158 patients) significantly increased the probability to attain at least a near complete response (nCR; 33% v 47%, respectively; P = .008), prolonged relapse-free survival (RFS) duration of 18 months (median, 24 v 42 months, respectively; P < .001), and significantly extended event-free survival (EFS; median, 23 v 35 months, respectively; P = .001). Administration of a second transplantation and of novel agents for treating sequential relapses in up to 50% of patients randomly assigned to receive a single ASCT likely contributed to prolong the survival duration of the whole group, whose 7-year rate (46%) was similar to that of the double-transplantation group (43%; P = .90). Transplantation-related mortality was 3% in arm A and 4% in arm B (P = .70). Conclusion In comparison with a single ASCT as up-front therapy for newly diagnosed MM, double ASCT effected superior CR or nCR rate, RFS, and EFS, but failed to significantly prolong overall survival. Benefits offered by double ASCT were particularly evident among patients who failed at least nCR after one autotransplantation.
Advances in the treatment of multiple myeloma (MM) had been modest for almost 30 years since the introduction of oral melphalan and prednisone.1 Although the addition of other agents failed to extend median survival beyond the modest value of only 3 years,2 dose escalations of intravenous melphalan to the level requiring autologous stem-cell transplantation (ASCT) increased the frequency of complete response (CR) into the 20% to 30% range3 and prolonged both event-free survival (EFS) and overall survival (OS) when examined in randomized trials compared with conventional chemotherapy.4,5 Based on the in vivo existence of a dose-response effect for melphalan, further pursuit of the cytotoxic dose intensification stimulated the exploration of double ASCT.6,7 The Intergroupe Francophone du Myelome (IFM) was the first to demonstrate that two sequential autotransplantations doubled 7-year EFS and OS rates in comparison with a single ASCT.7 Preliminary data from other randomized trials designed to address this issue have conflicted, though the follow-up was too short to draw definite conclusions.8-10 In 1996, we launched a prospective randomized trial of double versus single ASCT in younger patients with newly diagnosed MM, the results of which are reported here (Fig 1).
Patient Eligibility Eligible patients had to have a confirmed diagnosis of symptomatic or progressive MM,11 an upper age limit of 60 years, and to be previously untreated. Cardiopulmonary and hepatic functions had to be adequate; renal failure was not an exclusion criterion. Written informed consent was obtained from all patients. The study was approved by each local ethic committee of all participating centers and was performed in accordance with the precepts established by Helsinki declaration.
Study Design and Treatment Phases
Both arms of the study comprised a remission induction therapy with vincristine, doxorubicin, and dexamethasone (VAD), followed by high-dose cyclophosphamide to collect peripheral-blood stem cells in support of a subsequent course of high-dose melphalan at 200 mg/m2. The minimum threshold dose of CD34+ cells to be collected in an attempt to safely perform double ASCT was 4 x 106 per kilogram (kg) of body weight. Three to 6 months after the first autotransplantation, patients randomly assigned to arm B received a second ASCT in support of high-dose melphalan (120 mg/m2) combined with busulfan (12 mg/kg). Maintenance therapy with recombinant interferon alfa (IFN-
Assessment and Criteria of Response Response to therapy was monitored by means of monoclonal (M) protein evaluation, which was performed monthly from the start of therapy to the third month after ASCT(s) and subsequently every 3 months during post-transplantation follow-up. In addition, it was monitored by bone marrow aspirate and biopsy. For patients who completed the entire treatment program, the maximal response achieved after ASCT(s) was calculated. For those patients who failed to complete therapy, the maximal response ever achieved was considered. Patients who died before response could be established were considered as experiencing treatment failures. Criteria for response were those proposed by the European Group for Blood and Marrow Transplant (EBMT).12 A near CR (nCR) category (as defined by the disappearance of M protein at routine electrophoresis, but positive immunofixation) was added to EBMT criteria, based on results of previous studies showing the superiority of single ASCT over conventional chemotherapy in terms of at least nCR rate.4 CR required the absence of M protein on immunofixation analysis and less than 5% plasma cells in the bone marrow. Relapse after CR or nCR was defined as reappearance of M protein on immunofixation or routine electrophoresis, respectively, and/or appearance of new bone lytic lesions. Disease progression required more than 25% increase in M protein from nadir levels (in case of responders) or baseline levels (in case of nonresponders) and/or appearance of new bone lytic lesions.
Statistical Analysis
The primary study end point was CR or nCR rate. For computation of response, all randomly assigned patients were eligible and were analyzed in their assigned arms. Comparison between the two groups was performed using the Secondary study end points included relapse-free survival (RFS), EFS, and OS, which were calculated from the start date of therapy to the relapse or progression date, or the date of any event (including relapse or progression) or death for any cause. Patients lost to follow-up or survivors who experienced no event, including relapse or progression, were censored at the date of last contact. Transplantation-related mortality (TRM) included any death occurring within 90 days and attributable to high-dose therapy. Data were analyzed as of March 31, 2006. Curves of RFS, EFS, OS and postrelapse survival (as calculated from the date of relapse or progression to the date of last contact or death for any cause) were plotted according to the Kaplan-Meier method and were compared using the log-rank test. All statistical tests were two-tailed. Regression covariates for RFS, EFS, and OS were analyzed by the Cox proportional hazards regression model using Statistical Package for the Social Sciences, version 11 (SPSS Inc, Chicago, IL). The study was registered at ClinicalTrials.gov (NCT00378222 [ClinicalTrials.gov] ).
Patient Characteristics at Baseline From January 1, 1996 to December 31, 2001, a total of 321 patients from 32 Italian centers were registered and randomly assigned to receive either a single ASCT (n = 163 patients) or double ASCT (n = 158 patients). Baseline characteristics of the two treatment groups were comparable (Table 2). Data on cytogenetic abnormalities, including the favorable outcome associated with t(11;14) and the adverse prognostic value of t(4;14), were previously reported.13,14
Treatment Received Figure 2 shows the flow of patients through the different treatment phases and off-study reasons. The probability of receiving one ASCT was 85% in arm A and 90% in arm B (P = .20); 65% of patients randomly assigned to the double-transplantation arm received the second ASCT. The median time interval between the first and second ASCT was 4 months; 92% of patients completed two sequential transplantations within 6 months. The mean duration of IFN-  maintenance therapy was 20.2 months (± 16.1 month) in the control group and 23.8 months (± 18.1 month) in the double-transplantation group (P = .10). Disease progression or relapse was the most frequent cause of IFN- discontinuation in both treatment arms (single transplantation at 69% and double transplantation at 50%), followed by toxicity (single transplantation at 25% and double transplantation at 31%).
Rates of Response In comparison with a single transplantation, double ASCT increased the CR or nCR rate from 33% (54 of 163 patients) to 47% (75 of 158 patients), for a P of .008 on an intention-to-treat basis. The corresponding values for patients who completed the assigned therapies were 38% (53 of 139 patients) in arm A and 54% (56 of 103 patients) in arm B (P = .01). In the group of double-transplantation recipients, 26 patients experienced an upgrade of their response status after the second ASCT, including 20 who attained CR or nCR. Patients who responded to VAD had a CR or nCR rate after either single or double ASCT of 52% and 73%, respectively (P = .010). Both of these values were much higher than those observed among patients who did not respond to VAD, whose post-transplantation CR or nCR rate was 11% in arm A and 12% in arm B (P = .20). On multivariate analysis, randomization to double ASCT (P < .001) and partial response to VAD (P < .001) were independent significant predictors of post-transplantation attainment of CR or nCR.
RFS, EFS, and OS On an intention-to-treat basis, double ASCT significantly prolonged the median duration of RFS (42 v 24 months for the control group; P < .001; Fig 3A) and of EFS (35 v 23 months for the control group; P = .001; Fig 3B) in comparison with a single ASCT. The probabilities of surviving event-free 5 years after start of therapy were 17% in arm A and 29% in arm B (Fig 3B). The median OS was 65 months for patients randomly assigned to treatment arm A and 71 months for those assigned to arm B (P = .90). The 7-year probability of OS was 46% in the single-transplantation group and 43% in the double-transplantation group. Most frequent WHO grade 3 to 4 nonhematologic toxicities registered with a single (arm A) or double (arm B) ASCT included mucositis (25% v 28%, respectively) and infections (21% v 24%, respectively). TRM was 3% in arm A and 4% in arm B (P = .70).
In a multivariate analysis of all 321 patients, variables significantly extending EFS and RFS included the following: CR or nCR, random assignment to double ASCT, baseline platelet count greater than 150.000/µL,15 hemoglobin level greater than 10 g/dL at diagnosis, and younger than 55 years (Table 3). Prolonged OS was significantly related to the following independent variables: baseline hemoglobin concentration greater than 10 g/dL, serum creatinine level less than 177 µmol/L at diagnosis, and CR or nCR (Table 3).
Salvage Therapy At the time of relapse or disease progression, patients on both arms could undergo, at their physician's discretion, additional stem-cell transplantation, which was performed in 43 (33%) of 130 patients on arm A and in 10 (10%) of 99 patients on arm B. Novel agents were offered to 65 patients (50%) on arm A (thalidomide, n = 55, and/or bortezomib, n = 10) and to 54 patients (55%) on arm B (thalidomide, n = 48, and/or bortezomib, n = 6). With a median follow-up of 24 months from the time of relapse or progression, median durations of postrelapse survival were 32 months in arm A and 25 months in arm B (P = .19; Fig 3C).
Patient Outcome According to Response Within 4 Months After One Autologous Transplantation
The Bologna 96 clinical study of single versus double ASCT for newly diagnosed MM was designed to evaluate whether further cytotoxic dose intensification improved the outcome of younger patients in comparison with a single course of high-dose therapy. In light of the pivotal role of M protein disappearance after a single ASCT as predictor of long-lasting response and extended survival,4,16,17 the primary end point of our study was CR or nCR. As compared with the control group, double ASCT induced a significantly higher rate of at least nCR both on an intention-to-treat basis (33% v 47%, respectively; P = .008) and among patients that completed the assigned therapies (38% v 54%, respectively; P = .001). Twenty percent of patients failing at least nCR after the first transplantation achieved CR or nCR after the second planned transplantation. In the presence of at least a partial response to VAD, the post-transplantation rate of CR or nCR was 73% in the double-transplantation arm and 52% in the single-transplantation group (P = .010). Conversely, among patients who failed on VAD, the corresponding CR or nCR rates were 12% and 11%, respectively (P = .20). This finding suggests that sensitivity to alkylating agents at doses requiring ASCT was greater when sensitivity to conventional chemotherapy was preserved; conversely, resistance to conventional chemotherapy conferred a relative degree of resistance even to double ASCT. Other studies of single4,5,18 and double autotransplantation6,19 reported CR or nCR rates similar to those found in both arms of our study. However, conflicting data concern the superiority of double over single ASCT in terms of better quality of response.7-10 Differences among studies with respect to their design, enrollment criteria, baseline patient characteristics, high-dose therapy administered before ASCT, and criteria for response may explain these discrepancies as well. In comparison with the single-transplantation arm, prolongation by 18 months of RFS among patients randomly assigned to double ASCT (P < .001) was linked to the higher CR or nCR rate, a key independent variable favorably affecting the duration of remission (P < .001). As a result of better quality of response, an analysis performed on an intention-to-treat basis revealed that double ASCT prolonged EFS by 1 year (P = .001) in comparison with a single ASCT. The benefit offered by assignment to double ASCT in terms of extended EFS was confirmed in a multivariate analysis (P = .005) and was more evident among double-transplantation recipients (median, 42 v 24 months for the control group; P < .001). These results are consistent with data previously published6 and recently updated,20 supporting the hypothesis that more profound reduction in tumor cell mass results in prolonged duration of response and EFS.21 The lack of a survival benefit for patients randomly assigned to double ASCT, despite their significantly higher CR or nCR rate and superior RFS and EFS, may be due to the long OS of patients assigned to the single-transplantation arm (median, 65 months; 7-year rate of 46%). Although recognizing the difficulty to compare different trials, correspondent values in other studies were lower than those herein reported. For example, in the IFM 904 and the Medical Research Council VII5 randomized trials, probabilities of OS for patients assigned to the single-transplantation arm were 52% after 5 years and 50% after 4 years, respectively. In another study, median OS for patients between age 55 and 65 years that were randomly assigned to receive a single ASCT was 48 months.18 Moreover, in the IFM 94 study demonstrating the superiority of double over single ASCT, median OS in the single-transplantation arm was 48 months and only 21% of these patients had a probability of surviving 7 years after diagnosis.7 Potential factors contributing to prolonging the survival duration of patients assigned to the single-transplantation arm of our study were twofold: approximately a third of patients underwent a second salvage ASCT, obscuring a potential survival benefit of planned double transplantation; and half of the patients were offered novel agents, including thalidomide and/or bortezomib, as salvage therapies. Although this proportion of patients was comparable to that seen for the same class of agents used in arm B, it was much higher than that reported in previous studies demonstrating a survival benefit of double ASCT in comparison with a single ASCT.7 Introduction into the therapeutic armamentarium of MM of new drugs with the potential to reverse resistance to high-dose therapy22-25 could reinduce long-lasting remission and prolong OS.20,26 In support of this latter conclusion, in our trial the estimated 2-year OS rate from the time of relapse was 62% in arm A, thus longer than previously reported in similar studies,7,27 and 51% in treatment arm B. Since most of our patients included in treatment arm A received a second unplanned ASCT and subsequent novel agents for the treatment of sequential relapses, the relative merits of each of these treatment strategies in prolonging the survival duration is difficult to be ascertained. In conclusion, data reported here show that, without suffering increased mortality, double ASCT effected superior CR or nCR rate, RFS, and EFS. Benefits offered by double ASCT in comparison with a single ASCT in terms of improved RFS, EFS, and OS were particularly evident among patients failing at least nCR after one ASCT. Administration of a second ASCT and of novel agents for the treatment of sequential relapses in a sizeable fraction of patients included in the single-transplantation arm likely minimized a potential survival gain offered by double ASCT. Given the availability of newer and highly effective salvage treatments for MM,28,29 OS is not a true reflection of the intended study treatment, so that EFS may be a more valid surrogate for evaluating the efficacy of novel treatments.30 Over the last few years, novel drugs targeting myeloma-stromal cell interactions, such as thalidomide, lenalidomide, and the first proteasome inhibitor, bortezomib, have changed the landscape of MM treatment.31 The main paradigm shift has been the incorporation of these agents into first-line therapy in preparation for subsequent ASCT32-35 or as maintenance therapy after ASCT.36 Among patients who are candidates for ASCT, high CR or nCR rates of 30% to 35% with short-term primary remission induction therapy and in excess of 55% with a single ASCT have been recently reported.33-35 Whether combinations of these agents with a single ASCT or with [old] conventional chemotherapy37,38 will obviate the need for double ASCT, at least in a subset of patients,35 is a still unresolved issue that needs to be properly addressed in the context of prospective, randomized clinical trials.
The author(s) indicated no potential conflicts of interest.
Conception and design: Michele Cavo, Sante Tura, Michele Baccarani Provision of study materials or patients: Francesca Patriarca, Francesco Di Raimondo, Ettore Volpe, Franco Narni, Affra Carubelli, Luciano Masini, Lucio Catalano, Alessandro Gozzetti, Antonio Lazzaro Collection and assembly of data: Michele Cavo, Claudia Cellini, Paola Tacchetti, Sonia Ronconi, Delia Cangini Data analysis and interpretation: Michele Cavo, Patrizia Tosi, Elena Zamagni, Mauro Fiacchini, Antonio de Vivo Manuscript writing: Michele Cavo Final approval of manuscript: Michele Cavo, Sante Tura, Michele Baccarani
The following is a list of additional investigators who participated in the Bologna 96 study: G. Perrone, M. Ceccolini, R.M. Lemoli, M.R. Motta, S. Rizzi (Istituto di Ematologia ed Oncologia Medica [Seràgnoli], Bologna); R. Fanin (Ematologia, Udine); R. Giustolisi (Ematologia, Catania); N. Cantore (Ematologia, Avellino); G. Torelli (Ematologia, Modena); G. Broccia, E. Angelucci (Ematologia, Cagliari); L. Gugliotta (Ematologia, Reggio Emilia); B. Rotoli (Ematologia, Napoli); F. Lauria (Ematologia, Siena); L. Cavanna (Medicina, Piacenza); V.M. Lauta, F. Dammacco (Scienze Biomediche, Bari); M. Offidani, P. Leoni (Ematologia, Ancona); F. Ballerini (Ematologia, Genova); R. Battista (Ematologia, Chioggia); F. Dore (Ematologia, Sassari); P. Gentilini (Oncologia, Forlì); M. Gobbi (Ematologia, Genova); L. Guardigni (Medicina, Cesena); M. Longinotti (Ematologia, Sassari); D. Mamone (Ematologia, Messina); P. Mazza (Ematologia, Taranto); M.G. Michieli (Oncologia Medica, Aviano); A.L. Molinari (Ematologia, Ravenna); F. Ricciuti (Ematologia, Potenza); D. Vertone (Ematologia, Potenza); A. Zaccaria (Ematologia, Ravenna); L. Castagna (Istituto Humanitas, Rozzano); C. Ciabatta (Ematologia, Latina); V. Forcellini (Medicina, Repubblica di San Marino); G. Lalli (Semeiotica Medica, Teramo); A. Ledda (Ematologia, Cagliari); A. Polacco (Ematologia, Mestre); C. Ferrandina (Ematologia, Foggia); F. Gherlinzoni (Ematologia, Treviso); M. Monaco (Ematologia, Foggia); E. Pasquini (Oncologia, Cattolica); F. Russo (Ematologia-Oncologia, Napoli); A. Abbadessa (Ematologia, Napoli); A. Bononi (Oncologia, Rovigo); A. Corvetta (Medicina Interna, Rimini); C. Musolino (Ematologia, Messina).
published online ahead of print at www.jco.org on May 7, 2007. Supported by Università di Bologna, Progetti di Ricerca Fondamentale Orientata (M.C.); Ministero dell'Università e Ricerca Scientifica, progetto FIRB, RBAU012E9A_001 (M.C.); and Fondazione Carisbo. Presented in part at the 46th Annual Meeting of the American Society of Hematology, December 6-9, 2004, San Diego, CA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Myeloma Trialists' Collaborative Group: Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: An overview of 6,633 patients from 27 randomized trials. J Clin Oncol 16:3832-3842, 1998 2. Cavo M, Benni M, Ronconi S, et al: Melphalan-prednisone versus alternating combination VAD/MP or VND/MP as primary therapy for multiple myeloma: Final analysis of a randomized clinical study. Haematologica 87:934-942, 2002 3. McElwain TJ, Powles RL: High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet 2:822-824, 1983[Medline] 4. Attal M, Harousseau 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 5. 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 6. Barlogie B, Jagannath S, Desikan KR, et al: Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 93:55-65, 1999 7. Attal M, Harousseau JL, Facon T, et al: Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 349:2495-2502, 2003 8. Segeren CM, Sonneveld P, van der Holt B, et al: Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: A prospective randomized phase 3 study. Blood 101:2144-2151, 2003 9. Fermand JP: High dose therapy supported with autologous blood stem cell transplantation in multiple myeloma: Long term follow-up of the prospective studies of the MAG group. Haematologica 90:40, 2005 (suppl 1; abstr PL8.05) 10. Goldschmidt H: Single vs. double high-dose therapy in multiple myeloma: Second analysis of the GMMG-HD2 trial. Haematologica 90:38, 2005 (suppl 1; abstr PL8.02) 11. International Myeloma Working Group: Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: A report of the International Myeloma Working Group. Br J Haematol 121:749-757, 2003[CrossRef][Medline] 12. Bladé J, Samson D, Reece D, et al: Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation: Myeloma Subcommittee of the EBMT: European Group for Blood and Marrow Transplant. Br J Haematol 102:1115-1123, 1998[CrossRef][Medline] 13. Soverini S, Cavo M, Cellini C, et al: Cyclin D1 overexpression is a favorable prognostic variable for newly diagnosed multiple myeloma patients treated with high-dose chemotherapy and single or double ASCT. Blood 102:1588-1594, 2003 14. Cavo M, Terragna C, Renzulli M, et al: Poor outcome with front-line ASCT in t(4;14) multiple myeloma: Low complete remission rate and short duration of remission. J Clin Oncol 24:e4-e5, 2006 15. Cavo M, Galieni P, Zuffa E, et al: Prognostic variables and clinical staging in multiple myeloma. Blood 74:1774-1780, 1989 16. Alvares CL, Davies FE, Horton C, et al: Long-term outcomes of previously untreated myeloma patients: Responses to induction chemotherapy and high-dose melphalan incorporated within a risk stratification model can help to direct the use of novel treatments. Br J Haematol 129:607-614, 2005[CrossRef][Medline] 17. Nadal E, Giné E, Bladé J, et al: High-dose therapy/autologous stem cell transplantation in patients with chemosensitive multiple myeloma: Predictors of complete remission. Bone Marrow Transplant 33:61-64, 2004[CrossRef][Medline] 18. Fermand JP, Katsahian S, Divine M, et al: 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. J Clin Oncol 23:9227-9233, 2005 19. Barlogie B, Tricot G, Rasmussen E, et al: Total therapy 2 without thalidomide in comparison with total therapy 1: Role of intensified induction and posttransplantation consolidation therapies. Blood 107:2633-2638, 2006 20. Barlogie B, Tricot GJ, van Rhee F, et al: Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 135:158-164, 2006[CrossRef][Medline] 21. Barlogie B, Tricot G, Anaissie E, et al: Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 354:1021-1030, 2006 22. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999 23. Richardson PG, Sonneveld P, Schuster MW, et al: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487-2498, 2005 24. Dimopoulos MA, Spencer A, Attal M, et al: Study of lenalidomide plus dexamethasone versus dexamethasone alone in relapsed or refractory multiple myeloma (MM): Results of a phase 3 study (MM-010). Blood 106:6a, 2005 (abstr 6)[CrossRef] 25. Richardson PG, Blood E, Mitsiades CS, et al: A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 108:3458-3464, 2006 26. Fassas AB, Barlogie B, Ward S, et al: Survival after relapse following tandem autotransplants in multiple myeloma patients: The University of Arkansas total therapy I experience. Br J Haematol 123:484-489, 2003[CrossRef][Medline] 27. Blade J, Rosinol L, Sureda A, et al: High-dose therapy intensification compared with 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 106:3755-3759, 2005 28. Kyle RA, Rajkumar SV: Multiple myeloma. N Engl J Med 351:1860-1873, 2004 29. Barlogie B, Shaughnessy J, Tricot G, et al: Treatment of multiple myeloma. Blood 103:20-32, 2004 30. Durie BGM: New approaches to treatment for multiple myeloma: Durable remission and quality of life as primary goals. Clin Lymphoma Myeloma 6:181-190, 2005[Medline] 31. Cavo M, Baccarani M: The changing landscape of myeloma therapy. N Engl J Med 354:1076-1078, 2006 32. Cavo M, Zamagni E, Tosi P, et al: Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for ASCT for multiple myeloma. Blood 106:35-39, 2005 33. Rajkumar VS, Hayman SR, Lacy MQ, et al: Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 106:4050-4053, 2005 34. Oakervee HE, Popat R, Curry N, et al: PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol 129:755-762, 2005[CrossRef][Medline] 35. Harousseau JL, Marit G, Caillot d, et al: VELCADE/dexamethasone (Vel/Dex) versus VAD as induction treatment prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM): An interim analysis of the IFM 2005-01 randomized multicenter phase III trial. Blood 108:21a, 2006 (abstr 56) 36. Attal M, Harousseau JL, Leyvraz S, et al: Maintenance therapy with thalidomide improves survival in multiple myeloma patients. Blood 108:3289-32294, 2006 37. Palumbo A, Bringhen S, Caravita T, et al: Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: Randomised controlled trial. Lancet 367:825-831, 2006[CrossRef][Medline] 38. Mateos MV, Hernandez JM, Hernandez MT, et al: Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: Results of a multicenter phase I/II study. Blood 108:2165-2172, 2006 Submitted December 5, 2006; accepted March 22, 2007.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 test. 
