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Originally published as JCO Early Release 10.1200/JCO.2007.12.3463 on September 4 2007 © 2007 American Society of Clinical Oncology. Melphalan, Prednisone, and Lenalidomide Treatment for Newly Diagnosed Myeloma: A Report From the GIMEMA—Italian Multiple Myeloma Network
From the Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliera S. Giovanni Battista, Torino; Divisione di Ematologia, Istituto Nazionale Tumori, Milano; UO Ematologia e Trapianto di Cellule Staminali, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo; Cattedra di Ematologia, Ospedale Ferrarotto, Catania; Cattedra e UO Ematologia e Trapianti midollo, Università degli Studi di Parma, Parma; Sezione Ematologia, Università di Brescia, Spedali Civili, Brescia; Servizio di Epidemiologia dei Tumori dell'Università di Torino, Azienda Ospedaliera S. Giovanni Battista, Torino, e CPO Piemonte; UO di Ematologia e Trapianto di Cellule Staminali, CROB - Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture; Dipartimento di Biotecnologie e Ematologia, Università La Sapienza, Roma, Italy; and the Celgene Corporation, Summit, NJ Address reprint requests to Antonio Palumbo, MD, Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliera S. Giovanni Battista, Via Genova 3, 10126 Torino, Italy; e-mail: appalumbo{at}yahoo.com
Purpose Lenalidomide has shown significant antimyeloma activity in clinical studies. Oral melphalan, prednisone, and thalidomide have been regarded as the standard of care in elderly multiple myeloma patients. We assessed dosing, efficacy, and safety of melphalan, prednisone, and lenalidomide (MPR) in newly diagnosed elderly myeloma patients. Patients and Methods Oral melphalan was administered in doses ranging from 0.18 to 0.25 mg/kg on days 1 to 4, prednisone at a 2-mg/kg dose on days 1 to 4, and lenalidomide at doses ranging from 5 to 10 mg on days 1 to 21, every 28 days for nine cycles, followed by maintenance therapy with lenalidomide alone. Aspirin was given as a prophylaxis for thrombosis. Results Fifty-four patients were enrolled and evaluated after completing the assigned treatment schedule. The maximum tolerated dose was defined as 0.18 mg/kg melphalan and 10 mg lenalidomide. With these doses, 81% of patients achieved at least a partial response, 47.6% achieved a very good partial response, and 23.8% achieved a complete immunofixation-negative response. In all patients, 1-year event-free and overall survival rates were 92% and 100%, respectively. At the maximum tolerated dose, grade 3 adverse events included neutropenia (38.1%), thrombocytopenia (14.2%), febrile neutropenia (9.5%), vasculitis (9.5%), and thromboembolism (4.8%); grade 4 adverse events were neutropenia (14.2%) and thrombocytopenia (9.5%). Conclusion Oral MPR therapy is a promising first-line treatment for elderly myeloma patients. Hematologic adverse events were frequent but manageable. A low incidence of nonhematologic adverse events was noted. Aspirin appears to provide adequate antithrombosis prophylaxis.
Multiple myeloma is a malignant plasma cell disorder that accounts for approximately 15,000 new diagnoses each year in Europe.1 In the past 50 years, several combination chemotherapy regimens have been assessed, but none was better than the original melphalan and prednisone (MP) schema.2-4 In the past 10 years, high-dose melphalan with hematopoietic stem-cell support has been the only option that has significantly increased the rate of complete response (CR) and has extended event-free and overall survival rates.5-7 New drugs, such as thalidomide, lenalidomide, and bortezomib, are now changing the therapeutic paradigm of multiple myeloma and offer hope for better outcomes.8-15 In preclinical models, lenalidomide was 300-fold more potent than thalidomide in inhibiting myeloma cell proliferation.16-19 In relapsed myeloma, the combination of lenalidomide plus dexamethasone increased the CR rate and significantly prolonged outcomes in comparison with dexamethasone alone.11,12 Neutropenia and thrombocytopenia are the most frequently observed adverse events.20 The incidence of deep vein thrombosis (DVT) increases in newly diagnosed patients compared with those with relapsed and refractory disease, especially when lenalidomide is given with high-dose steroids or doxorubicin. Aspirin prophylaxis has reduced the incidence of DVT.21-23 Sedation, constipation, and peripheral neuropathy are uncommon, but moderate-to-severe skin rashes have been observed.20 In two independent randomized studies, the oral combination of melphalan, prednisone, and thalidomide (MPT) was more effective than MP in newly diagnosed multiple myeloma.13,24 MPT is now considered the standard of care in elderly patients. In a recent phase II study, the combination of bortezomib, melphalan, and prednisone (VMP) also appeared superior to standard MP.25 No data are available on the clinical use of lenalidomide in combination with MP, which may represent an alternative approach. These observations provided the rationale for this phase I/II, multicenter trial. The primary goal of the study was to identify the most appropriate dose of lenalidomide in combination with MP (MPR), and to determine its safety, tolerability, and efficacy.
Patients From January through October 2005, 54 patients were enrolled in 10 Italian centers. Inclusion criteria were: newly diagnosed multiple myeloma patients  65 years, or younger if ineligible for high-dose therapy; measurable disease; Karnofsky performance status 60%; platelet count 75 x 109/L; absolute neutrophil count 1.5 x 109/L; corrected serum calcium  3.5 mmol/L (14 mg/dL); serum hepatic aminotransferase levels 2.5-fold of the upper limit of normal (ULN); total bilirubin 1.5-fold of the ULN; and creatinine clearance 20 mL/min. Exclusion criteria were the presence of another cancer, amyloidosis, or psychiatric disease. Patients agreed to use contraception. The institutional review board at each participating center approved the study in accordance with the Declaration of Helsinki. All patients provided written informed consent.
Study Design and Treatment
Lenalidomide dose reduction (from 10 mg to 5 mg) was applied if toxicities occurred. Grade 4 neutropenia 7 days despite G-CSF administration, any other grade 4 hematologic toxicities, or any grade 3 nonhematologic toxicities required immediate withholding of treatment and subsequent dose reduction at the start of the following cycle. A new cycle was allowed if the neutrophil count was 1 x 109/L, platelet count was 50 x 109/L, and nonhematologic adverse events were grade 2. A delay of 2 weeks was allowed without any dose modification. A new cycle delay beyond a maximum of 2 weeks required dose reduction.
Assessment of Efficacy and Safety Treatment response was monitored by the measurements of protein in both serum and urine at each participating center, using the response criteria of the European Group for Blood and Marrow Transplantation.26 Briefly, CR required the disappearance of myeloma protein in both serum and urine by immunofixation. Partial response (PR) required at least a 50% reduction of myeloma protein in serum and a 90% decrease in urine. A very good partial response (VGPR), a subcategory of PR, required at least a 90% reduction of myeloma protein in serum. A minimal response was defined as a reduction of myeloma protein in serum of 25% to 49%. A reduction in myeloma protein of 24% or less was classified as no response. Event-free survival was calculated from the time of enrollment until the date of progression, relapse, death, or the date the patient was last known to be in remission. Overall survival was calculated from the time of enrollment until the date of death or the date the patient was last known to be alive. All adverse events were assessed at each visit and graded according to the National Cancer Institute Common Toxicity Criteria (version 3.0).27 All data were monitored by an independent/external contract research organization.
Fluorescence In Situ Hybridization Analysis
End Points and Statistical Analysis The maximum tolerated dose was defined as the highest dose level at which less than 33% of patients experienced dose-limiting toxicities. All patients meeting the eligibility criteria who had received the first cycle of therapy were evaluated for response, toxicity, and survival. Time-to-event analysis was performed using the Kaplan-Meier method.30 The analyses were performed using SAS software, version 8.2 (SAS Institute, Cary, NC).
Patient Characteristics and Responses Table 1 presents patient characteristics. In the MPR group, the median age was 71 years. Fifty-four patients were enrolled in the protocol as planned. One patient has not been included in the response and toxicity evaluation because of the presence of exclusion criteria (cardic amyloidosis). A total of 53 patients were evaluated for safety and efficacy.
At dose levels 1 and 2, no dose-limiting toxicities were observed. At dose level 3, one patient experienced grade 4 neutropenia for 7 days despite the use of G-CSF and grade 3 hyperuricemia. At dose level 4, one patient experienced a treatment delay due to persistent neutropenia; one patient experienced pulmonary embolism and treatment delay; and one patient experienced febrile neutropenia and grade 3 cutaneous macular eruption. Dose level 3 (0.18 mg/kg melphalan and 10 mg lenalidomide) was therefore defined as the maximum tolerated dose. At dose level 4, seven dose-limiting toxicities were observed during cycles one to three, and two dose-limiting toxicities were observed during subsequent cycles four to six. Given the significant reduction in dose-limiting toxicities during cycles four to six, the protocol was amended and 15 additional patients were evaluated at both dose levels 3 and 4. At the time of analysis, all patients had completed the assigned induction treatment schedule. After a median of 6.2 months, 16 of 53 MPR patients did not complete the assigned nine cycles because of adverse events: delays of therapy because of hematologic toxicity (eight patients); grade 3 cutaneous toxicity (two patients); grade 3 osteonecrosis of the jaw (two patients); grade 3 fatigue (one patient); grade 3 depression (one patient); grade 3 diarrhea (one patient); and withdrawal of consent (one patient).
Efficacy
The median follow-up from study entry was 14.6 months (range, 10.8 to 21.8 months) for survivors. Relapse (six patients) or death from disease progression (one patient) occurred in seven of 53 MPR patients (13.2%). In all 53 MPR patients, the 1-year event-free survival was 92.3% (95% CI, 85.1 to 99.5; Fig 2A). In the 21 patients who received the maximum tolerated dose, the 1-year event-free survival was 95.2% (95% CI, 93.2 to 97.3). The 1-year overall survival was 100% in all MPR patients (95% CI, 91.8% to 100%; Fig 2B).
By exploratory subgroup analyses, the 1-year event-free survival among the 20 patients who achieved CR or VGPR was 100% compared with 88% in the 33 patients who achieved PR or minimal response only (P = .034); the 1-year event-free survival was 100% in the 23 patients with ß2-microglobulin serum levels lower than 3.5 mg/L and 86% in the 30 patients with higher levels (P = .02). The 1-year event-free survival was 85% in the 20 patients with chromosome 13 abnormalities and 95% in the 22 patients without (P = .18). The 1-year event-free survival was 83% in the eight patients with the translocation (4;14) and 87.5% in the 12 patients without (P = .49).
Safety
At the maximum tolerated dose, grade 3/4 neutropenia was reported in 11 patients (52.4%), thrombocytopenia was reported in five patients (23.8%), and anemia was reported in one patient (4.8%). Nine patients (42.8%) received G-CSF support, one patient (4.8%) received a platelet transfusion, and one patient (4.8%) received RBC support. Delay to restart therapy was reported in four patients (19%) due to neutropenia and thrombocytopenia; the lenalidomide dose was reduced in three patients (14.3%), and the drug was discontinued for six patients (28.6%) because of neutropenia, thrombocytopenia, cutaneous reactions, consent withdraw, and osteonecrosis of the jaw. No grade 4 nonhematologic adverse events were reported. All early infections occurred in patients with a high tumor burden, whereas all late infections occurred in poor responders. Dermatologic events were typically mild to moderate and were manageable with lenalidomide dose modification and corticosteroid therapy. One pulmonary embolism was reported during the first cycle. DVT was noted in two patients after aspirin discontinuation, both during cycle 7 and maintenance therapy. Aspirin prophylaxis was withheld because of concomitant thrombocytopenia (platelet count < 70 x 109/L) in 18 patients (34%). Peripheral neuropathy was never observed.
In this phase I/II study, we evaluated dosing, efficacy, and safety of an oral MPR combination in newly diagnosed myeloma patients. Our study shows that MPR is a treatment option for elderly patients. At the recommended dose of 0.18 mg/kg/d melphalan and 10 mg/d lenalidomide, the CR or VGPR rate was 47.6%, and grade 3/4 adverse events were mainly related to neutropenia and thrombocytopenia. In a randomized trial comparing MP with melphalan and dexamethasone, or dexamethasone, or dexamethasone and interferon-alfa, progression-free survival was prolonged in patients who received melphalan and significantly reduced in those who received dexamethasone without melphalan. In addition, severe nonhematologic toxicities were significantly more frequent in patients who received dexamethasone regimens than in patients who received MP.31 These data suggest that melphalan and prednisone may be an ideal combination for new regimens with innovative drugs and specifically designed for elderly patients who are ineligible for autologous transplantation.32 The response rate was similar to that reported in the French and Italian randomized trials with MPT,13,24 as well as in a phase II study with bortezomib, melphalan, and prednisone.25 In the MPR study, all patients achieved at least a minimal response. In contrast, nonresponding patients were 13.2% in the Italian MPT trial, and 11% were nonresponders in the VMP study. The 1-year event-free survival was 92.3% in the MPR group and 78% in the Italian MPT study.13 The 1-year overall survival was 100% in the MPR study and 87.4% in the Italian MPT study.13 Median follow-up was similar in both groups. Even though this comparison was not randomized, and these data should be judged with caution, both event-free survival and overall survival in the MPR group showed an advantage over the MPT group. Cytogenetic abnormalities are the major prognostic factors for multiple myeloma.33,34 In the MPR study, the event-free survival of patients with a chromosome 13 deletion or chromosomal translocation (4;14) was not significantly different from those who did not show such abnormalities. In a recent report, the combination of bortezomib with MP also overcame the negative clinical impact of these chromosomal alterations.25 These preliminary findings need to be validated in a larger series of patients. If these observations are confirmed, therapy may be assigned in light of a given patient-specific chromosomal abnormality. The amount of cytoreduction was also predictive of remission duration. In patients who achieved VGPR, 1-year event-free survival was significantly longer when compared with those who achieved either a PR or minimal response only. The achievement of CR or VGPR is an important predictor of outcome.6,35-37 After the first autologous transplantation, the failure to achieve at least a VGPR suggests the need for a second transplantation.37 In elderly patients, a suboptimal response may similarly influence clinical judgment and suggest the need of further treatment. With MPR no early treatment-related deaths occurred. In the French and Italian MPT or Spanish VMP studies, early deaths were reported as 2.4%, 8.5%, or 7%, respectively.13,24,25 The major adverse effects of lenalidomide were consistent in both type and frequency with those previously described and were mainly related to hematologic toxicity. At the maximum tolerated dose of lenalidomide, the incidence of grade 3/4 neutropenia and thrombocytopenia were 52.4% and 23.8%, respectively. These figures were significantly higher than those reported after MPT,13 but similar to those shown in the VMP study, where the incidence of grade 3/4 neutropenia was 43% and thrombocytopenia was 51%.25 The most frequently reported grade 3/4 nonhematologic adverse events were infections, cutaneous reactions, and thromboembolism (< 10%). In the Italian MPT trial, the frequency of thromboembolism was 12%, frequency of infection was 10%, frequency of neurological adverse effects was 10%, and frequency of cardiac adverse effects was 7%.13 In the VMP study, peripheral neuropathy was reported at a frequency of 17%, infection was reported at a frequency of 16%, diarrhea was reported at a frequency of 16%, and constipation was reported at a frequency of 8%.25 These different safety profiles may suggest different regimens in light of pre-existing comorbidities that are often seen in elderly patients. Lenalidomide may be indicated when pre-existing peripheral neuropathy exists, whereas a history of thromboembolism may contraindicate its use. In the MPR patients, neutropenic fever emerged as the most frequent nonhematologic adverse event, whereas pneumonia was reported in only one patient. A more careful assessment of fevers of unknown origin and the prompt institution of antibiotic prophylaxis should reduce their incidence. The introduction of aspirin prophylaxis appears to significantly reduce the risk of thromboembolism. No DVT was reported during aspirin prophylaxis. However, one patient suffered pulmonary embolism despite taking aspirin and two patients developed DVT after aspirin discontinuation because of thrombocytopenia. In a recent trial with lenalidomide, dexamethasone, and aspirin, the incidence of DVT was 3%.14 In other trials with lenalidomide and dexamethasone, but without aspirin, a significantly increased incidence of DVT was noted.11,12 These data clearly show the need for anticoagulant prophylaxis. Larger trials will assess the best anticoagulant prophylaxis and its appropriate duration. Our results demonstrate that MPR is an active combination in newly diagnosed multiple myeloma patients. At the maximum tolerated dose, the CR or VGPR rate was 48%, grade 3/4 adverse events were primarily hematologic, and the nonhematologic adverse effects were less than 10% using aspirin prophylaxis. Remarkable is the 1-year overall survival of 100% that is unprecedented in a newly diagnosed multiple myeloma trial. This phase I/II trial represents the basis for an ongoing, large international randomized trial comparing MP, MPR, and MPR therapies followed by lenalidomide maintenance treatment.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Robert Knight, Celgene Corp (C); Jerome B. Zeldis, Celgene Corp (C) Consultant or Advisory Role: Antonio Palumbo, Celgene Corp (C); Pellegrino Musto, Celgene Corp (C); Mario Boccadoro, Celgene Corp (C) Stock Ownership: Robert Knight, Celgene Corp; Jerome B. Zeldis, Celgene Corp Honoraria: Antonio Palumbo, Celgene Corp; Pellegrino Musto, Celgene Corp; Mario Boccadoro, Celgene Corp Research Funding: None Expert Testimony: None Other Remuneration: None
Conception and design: Antonio Palumbo, Robert Knight, Jerome B. Zeldis, Mario Boccadoro, Maria Teresa Petrucci Provision of study materials or patients: Paolo Corradini, Antonietta Falcone, Francesco Di Raimondo, Nicola Giuliani, Claudia Crippa, Maria Teresa Ambrosini, Francesca Gay, Sara Bringhen, Pellegrino Musto, Robin Foà, Robert Knight, Jerome B. Zeldis, Maria Teresa Petrucci Collection and assembly of data: Patrizia Falco Data analysis and interpretation: Antonio Palumbo, Patrizia Falco, Giovannino Ciccone, Paola Omedè, Maria Teresa Ambrosini, Francesca Gay, Sara Bringhen Manuscript writing: Antonio Palumbo, Patrizia Falco, Paolo Corradini, Antonietta Falcone, Pellegrino Musto, Robin Foà, Robert Knight, Jerome B. Zeldis, Mario Boccadoro, Maria Teresa Petrucci
We thank Letizia Canepa, Fortunato Morabito, and Alessandro Gozzetti, for participating in this study; Giulia Benevolo, Mariella Grasso, Annalisa Luraschi, and Andrea Nozza who referred patients to our institution; patients, nurses, and the clinical trial office staff (Tiziana Marangon, Federica Leotta, and Francesca D'Agostino).
published online ahead of print at www.jco.org on September 4, 2007. Sponsored by the Università degli Studi di Torino, Italy, and supported in part by research funding from Celgene Corporation (Summit, NJ; to M.B.) and by Fondazione Neoplasie Sangue Onlus, Associazione Italiana Leucemie, Compagnia di S. Paolo, Associazione per lo Studio e la Cura delle Malattie del Sangue, Fondazione Cassa di Risparmio di Torino, Ministero Università Ricerca Scientifica e Tecnologia (MIUR), and Consiglio Nazionale delle Ricerche (CNR). Presented in part in abstract format at European Hematology Association, Amsterdam, the Netherlands, June 15-18, 2006; American Society of Clinical Oncology, Atlanta, GA, June 4-6, 2006; American Society of Hematology, Atlanta, GA, December 10-13, 2005; and the American Society of Hematology, Orlando, FL, December 9-12, 2006. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Boyle P, Ferlay J: Cancer incidence and mortality in Europe, 2004. Ann Oncol 16:481-488, 2005 2. Myeloma Trialists’ Collaborative Group: Combination chemotherapy versus melphalan and prednisone as treatment of multiple myeloma: An overview of 6,633 patients from 27 randomized trials. J Clin Oncol 16:3832-3842, 1998 3. Boccadoro M, Marmont F, Tribalto M, et al: Multiple myeloma: VMCP/VBAP alternating combination chemotherapy is not superior to melphalan and prednisone even in high-risk patients. J Clin Oncol 9:444-448, 1991[Abstract] 4. 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 5. 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 6. 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 7. 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 8. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999 9. 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 10. Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003 11. 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 106:230a, 2005 (abstr 6) 12. Weber D, Chen C, Niesvizky R, et al: Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): Results of a North American phase III study (MM-009). J Clin Oncol 24:427s, 2006 (suppl; abstr 7521) 13. 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] 14. Rajkumar SV, Hayman SR, Lacy MQ, et al: Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 106:4050-4053, 2005 15. Kyle RA, Rajkumar SV: Multiple myeloma. N Engl J Med 351:1860-1873, 2004 16. Hideshima T, Chauhan D, Shima Y, et al: Thalidomide and its analogues overcome drug resistance of human multiple myeloma cells to conventional chemotherapy. Blood 96:2943-2950, 2000 17. Davies FE, Raje N, Hideshima T, et al: Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 98:210-216, 2001 18. Gupta D, Treon SP, Shima Y, et al: Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: Therapeutic applications. Leukemia 15:1950-1961, 2001[Medline] 19. Bartlett JB, Dredge K, Dalgleish AG: The evolution of thalidomide and its IMiD derivative as anticancer agents. Nat Rev Cancer 4:314-322, 2004[CrossRef][Medline] 20. Hideshima T, Richardson PG, Anderson KC: Current therapeutic uses of lenalidomide in multiple myeloma. Expert Opin Investig Drugs 15:171-179, 2006[CrossRef][Medline] 21. Knight R, DeLap RJ, Zeldis JB: Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med 354:2079-2080, 2006 22. Rajkumar SV, Blood E: Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med 354:2079-2080, 2006 23. Zonder JA, Barlogie B, Durie BG, et al: Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: Benefit of aspirin prophylaxis. Blood 108:403, 2006 24. Facon T, Mary J, Harousseau J, et al: Superiority of melphalan-prednisone (MP) + thalidomide (THAL) over MP and autologous stem cell transplantation in the treatment of newly diagnosed multiple myeloma. J Clin Oncol 24:1s, 2006 (suppl; abstr 1) 25. 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 1/2 study. Blood 108:2165-2172, 2006 26. Blade 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. Br J Haematol 102:1115-1123, 1998[CrossRef][Medline] 27. Cancer Therapy Evaluation Program: Common terminology criteria for adverse events, version 3.0, DCTD, NCI, NIH, DHHS March 31, 2003. http://ctep.cancer.gov 28. Ahmann GJ, Jalal SM, Juneau AL, et al: A novel three-color, clone-specific fluorescence in situ hybridization procedure for monoclonal gamopathies. Cancer Genet Cytogenet 101:7-11, 1998[CrossRef][Medline] 29. Fonseca R, Barlogie B, Bataille R, et al: Genetics and cytogenetics of multiple myeloma: A workshop report. Cancer Res 64:1546-1558, 2004 30. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 31. Facon T, Mary JY, Pegourie B, et al: Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood 107:1292-1298, 2006 32. Orlowski RZ: Initial therapy of multiple myeloma patients who are not candidates for stem cell transplantation. Am Soc Hematol Educ Program 338-347, 2006 33. Jaksic W, Trudel S, Chang H, et al: Clinical outcomes in t(4;14) multiple myeloma: A chemotherapy-sensitive disease characterized by rapid relapse and alkylating agent resistance. J Clin Oncol 23:7069-7073, 2005 34. Chng WJ, Santana-Davila R, Van Wier SA, et al: Prognostic factors for hyperdiploid-myeloma: Effects of chromosome 13 deletions and IgH translocations. Leukemia 20:807-813, 2006[CrossRef][Medline] 35. Barlogie B, Tricot G, Anaissie E, et al: Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 354:1021-1030, 2006 36. Rajkumar SV, Dispenzieri A: Evaluation and monitoring of response to therapy in multiple myeloma. Haematologica 90:1305-1308, 2005 37. Attal M, Harousseau JL, Facon T, et al: For the Intergroupe Francophone du Myelome: Single versus double autologous transplantation for multiple myeloma. N Engl J Med 349:2495-2502, 2003 Submitted April 27, 2007; accepted July 10, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
