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Blood, 1 November 2005, Vol. 106, No. 9, pp. 2977-2981. Prepublished online as a Blood First Edition Paper on July 14, 2005; DOI 10.1182/blood-2005-02-0691. This Article Abstract Full Text (PDF) All Versions of this Article: 2005-02-0691v1 106/9/2977    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Richardson, P. G. G. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Richardson, P. G. G. Articles by Anderson, K. C. Related Collections Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma Paul Gerard Guy Richardson, Bart Barlogie, James Berenson, Seema Singhal, Sundar Jagannath, David Irwin, S. Vincent Rajkumar, Teru Hideshima, Hugh Xiao, Dixie Esseltine, David Schenkein, Kenneth C. Anderson, for the SUMMIT Investigators From the Dana-Farber Cancer Institute, Boston, MA; University of Arkansas for Medical Sciences, Little Rock, AR; Cedars-Sinai Medical Center, Los Angeles, CA; Northwestern Memorial Hospital, Chicago, IL; St Vincent's Comprehensive Cancer Center, New York, NY; Alta Bates Cancer Center, Berkeley, CA; Mayo Clinic, Rochester, MN; and Millenium Pharmaceuticals, Inc., Cambridge, MA.    Abstract Top Abstract Introduction Patients, materials, and methods Results Discussion Appendix References   Bortezomib, a potent and reversible proteasome inhibitor, affects the myeloma cell and its microenvironment, resulting in down-regulation of growth and survival signaling pathways and durable responses in patients with relapsed and refractory myeloma. Potential associations between baseline parameters and outcomes with bortezomib were explored in 202 patients who received bortezomib 1.3 mg/m2 twice weekly for 2 weeks every 3 weeks for up to 8 cycles in a phase 2 trial. Using European Group for Blood and Marrow Transplantation criteria, the response rate (complete or partial response) to bortezomib alone was 27% and was not associated with sex, race, performance status, isotype, chromosome 13 deletion, number or type of previous therapies, or concentration of hemoglobin or 2-microglobulin. By multivariate analysis, factors associated with lower response were being age 65 or older versus younger than 65 (19% vs 32%; P < .05) and plasma-cell infiltration in bone marrow greater than 50% versus 50% or less (20% vs 35%; P < .05). Factors that may be indicative of tumor burden (bone marrow plasma-cell infiltration greater than 50%, hypoalbuminemia, thrombocytopenia) were predictive of overall survival. Chromosome 13 deletion and elevated 2-microglobulin, generally considered poor prognostic factors, were not predictive of poor outcome with bortezomib in this study.    Introduction Top Abstract Introduction Patients, materials, and methods Results Discussion Appendix References   Prognostic factors may be useful to help select patients with multiple myeloma who are more likely to benefit from certain types of therapy. Factors that have been identified as predictive of a poor outcome in patients with multiple myeloma at presentation are listed in Table 1.1-12 At relapse, adverse prognostic factors have included increased age,13,14 elevated creatinine (177 µM; 2 mg/dL),14 chromosome 13 deletion or other cytogenetic abnormalities,13-15 increased plasma-cell labeling index,15 and elevated levels of 2-microglobulin and C-reactive protein.13,15 View this table: [in this window] [in a new window]   Table 1.. Factors previously reported to be associated with poor outcomes in patients with MM at presentation   Bortezomib, a potent, specific, and reversible inhibitor of the proteasome, offers a novel approach to the treatment of multiple myeloma.16 In an open-label, phase 2 clinical trial (Study of Uncontrolled Myeloma Managed with Proteasome Inhibition Therapy [SUMMIT]), 202 patients with relapsed and refractory myeloma were treated with bortezomib.17 Durable responses were reported in this heavily pretreated population who had received a median of 6 previous therapies. The response rate (complete response [CR] + partial response [PR]) was 27%, and the median time to response (TTR) was 1.3 months (approximately 2 cycles).17 With extended follow-up, the median duration of response (DOR) was 12.7 months, median time to progression (TTP) among all patients was 7.0 months, and median overall survival (OS) was 17.0 months.18 New therapies for myeloma with novel mechanisms of action may have the ability to change the course of the disease or to be active in patients in whom other therapies fail. Importantly, their use should be prioritized in patients most likely to benefit from them. The objective of this study was to perform an analysis of baseline demographic and disease parameters to determine their value in predicting outcome for patients with relapsed and refractory multiple myeloma being treated with bortezomib. Univariate analyses were used to identify single factors that appeared to be associated with outcome, then multivariate analyses were used to eliminate factors that may confound univariate analysis.19    Patients, materials, and methods Top Abstract Introduction Patients, materials, and methods Results Discussion Appendix References   Patients Patients with multiple myeloma who had relapsed after initial chemotherapy and who had been refractory to their most recent salvage chemotherapy were enrolled into the SUMMIT trial, the methodology of which has been previously published.17 Main inclusion criteria were Karnofsky performance score (KPS) of 60 or greater, hepatic transaminases within 3 times the upper limit of normal (ULN), serum total bilirubin concentration within 2 times ULN, creatinine clearance greater than or equal to 0.5 mL/s (exceptions were allowed for levels < 0.5 but 0.7 mL/s if caused by significant myelomatous involvement of the kidney), platelet count greater than or equal to x109/L (or 30 x 109/L if extensive bone marrow infiltration by myeloma was present), hemoglobin level greater than or equal to 80 g/L (8 g/dL), and absolute neutrophil count greater than or equal to 1.0 x 109/L (except where the bone marrow was extensively infiltrated and absolute neutrophil count 0.5 x 109/L was allowed). All patients provided written informed consent before entering the study, which was performed in accordance with the Declaration of Helsinki and was approved by the institutional review board at each participating center. Treatment and evaluation of outcome Bortezomib 1.3 mg/m2 was administered by intravenous bolus over 3 to 5 seconds on days 1, 4, 8, and 11 of a 21-day cycle for up to 8 cycles. Patients with a suboptimal response, defined as progressive disease after 2 cycles or no change after the first 4 cycles of bortezomib, could receive oral dexamethasone 20 mg on the day of and day after bortezomib treatment. Responses were categorized according to the criteria of the European Group for Blood and Marrow Transplantation,20 with the addition of a near CR category (stable bone disease, normal serum calcium levels, and 100% disappearance of M-protein by electrophoresis but immunofixation positive). The response rate (CR + PR) to bortezomib alone was examined in 193 evaluable patients because 9 of the 202 patients enrolled into the SUMMIT trial were excluded from the intent-to-treat population for efficacy analyses. These patients were excluded because they were enrolled in the study with nonmeasurable disease, and a priori the statistical analysis plan specified that only patients with measurable disease would be included in the intent-to-treat population given that the internal review committee could not assess response. DOR was assessed only in patients who responded to bortezomib alone (n = 53). TTR and TTP were assessed for patients receiving bortezomib alone, whereas OS was assessed for all patients, regardless of the addition of dexamethasone. For each of these outcomes, the following factors were assessed: age (younger than 65 years, 65 years or older), sex, race (white, black, other), body surface area ( 2 m2, > 2 m2), KPS ( 70, 80, 90), number of previous therapies ( 5, 6), previous treatment with thalidomide (yes, no), previous stem-cell transplantation (yes, no), percentage of plasma-cells in bone marrow biopsy ( 50%, > 50%), abnormal cytogenetics, chromosome 13 deletion by conventional cytogenetics, hemoglobin concentration (< 105 g/L [10.5 g/dL], 105 g/L [10.5 g/dL]), and M-protein isotype (immunoglobulin G [IgG], IgA, light chain). Serum levels of 2-microglobulin, albumin, platelets, and C-reactive protein were assessed as continuous variables without specific cutoff values. The effect of disease stage on outcome according to the new International Staging System was assessed in the univariate and multivariate settings using the following classification: stage I, 2-microglobulin less than 3.5 mg/L and serum albumin more than or equal to 3.5 g/dL; stage II, 2-microglobulin less than 3.5 mg/L and albumin less than 3.5 g/dL, or 2-microglobulin 3.5 to less than 5.5 mg/L; stage III, 2-microglobulin more than or equal to 5.5 mg/L.19 Statistical analyses In the univariate analysis assessing response rate (CR + PR), Fisher exact test was performed for categoric factors, and logistic regression was performed for continuous variables (2-microglobulin level, serum albumin level, platelet count, and C-reactive protein level). In the univariate analysis assessing TTR, DOR, TTP, and OS, the Cox proportional hazards model was applied to calculate a hazard ratio to determine the relative risk of an event at any point in time associated with a 1-unit change in the variable. A hazard ratio greater than 1 indicated increased risk, whereas a ratio less than 1 indicated decreased risk. In the Cox regression analyses assessing TTR, TTP, and OS, a backward elimination method was used to derive the final analysis model. In the analysis of DOR (n = 53), a forward stepwise model selection method was used. In the multivariate analysis assessing response rate, logistic regression was performed for all factors to determine the relative contribution of each in predicting response. All factors were analyzed in a stepwise model selection procedure to determine a minimal set of prognostic factors. In the multivariate analysis assessing TTR, DOR, TTP, and OS, the Cox proportional hazards model was used to analyze all factors to determine the relative contribution of each factor. All factors were analyzed through a model selection procedure to determine a minimal set of prognostic factors. P less than .05 was considered statistically significant, and P greater than or equal to .05 but less than .10 was considered marginally significant.    Results Top Abstract Introduction Patients, materials, and methods Results Discussion Appendix References   The 202 patients enrolled in SUMMIT had been heavily pretreated with a median of 6 previous therapies (range, 2-15), and 91% were refractory to their last therapy before bortezomib. Previous therapy included steroids in 99.5% of patients, alkylating agents in 92%, thalidomide in 83%, anthracyclines in 81%, and stem-cell transplantation in 64%. Ninety-two percent of the patients were treated with 3 or more therapies, excluding stem-cell transplantation.17 Response rate Of 202 patients, 193 patients had measurable disease and were included in the analyses of response to bortezomib monotherapy. The response rate (CR + PR) was 27% (53 of 193 patients).17 In univariate analysis, the only factors that were associated with a significantly lower response rate to bortezomib were bone marrow plasma-cell infiltration greater than 50% compared with 50% or less (20% vs 35%; P = .030) and abnormal cytogenetics compared with normal cytogenetics (19% vs 35%; P = .047), but not chromosome 13 deletion. Although there was no significant association between response rate and light-versus heavy-chain disease (9 [33%] of 27 vs 44 [27%] of 163; P = .49), 8 of the 9 responses in patients with light-chain disease were CRs, whereas 11 of the 44 responses in patients with heavy-chain disease were CRs. Marginal significance was noted for age 65 (19% vs 32%; P = .064) and white race (24% white vs 48% black and 33% other; P = .064). The response rate to bortezomib was not significantly affected by sex, body surface area, KPS, number or type of previous therapy, myeloma type, chromosome 13 deletion, and hemoglobin or 2-microglobulin concentration (Table 2). By multivariate analysis (Table 3), only 2 factors—age greater than or equal to 65 years (P = .03) and bone marrow plasma-cell infiltration greater than 50% (P = .03)—were significantly associated with a lower response rate to bortezomib after stepwise selection analysis. View this table: [in this window] [in a new window]   Table 2.. Effect of demographic variables, disease characteristics, and previous treatment on response (CR + PR) to bortezomib in univariate analysis   View this table: [in this window] [in a new window]   Table 3.. Factors significantly predictive of outcome with bortezomib in multivariate analysis   TTR, DOR, TTP, and OS By univariate analysis, the only factors associated with longer TTR were older age (P = .042) and abnormal cytogenetics (P = .047) but not chromosome 13 deletion (Table 4). By multivariate analysis, however, abnormal cytogenetics dropped out, whereas older age (P = .009) and bone marrow plasma-cell infiltration greater than 50% (P = .021) were found to be associated with longer TTR. An increased C-reactive protein concentration was marginally significant by multivariate analysis (P = .050). View this table: [in this window] [in a new window]   Table 4.. Factors significantly associated with TTR, DOR, TTP, and OS in univariate analysis   Factors were assessed to determine their association with DOR in this patient population. Previous treatment with thalidomide (P = .033), hypoalbuminemia (P = .001), low KPS (P = .004), and abnormal cytogenetics (P = .035), but not chromosome 13 deletion, were associated with shorter DOR in the univariate analysis. Factors that remained significantly associated with shorter DOR in the multivariate assessment were hypoalbuminemia (P = .003) and low KPS (P = .01). Similarly, factors associated with shortened TTP were assessed by univariate analysis. Patients with bone marrow plasma-cell infiltration greater than 50% (P = .009), increased 2-microglobulin concentration (P = .02), thrombocytopenia (P = .025), increased C-reactive protein concentration (P = .037), anemia (P = .005), abnormal cytogenetics (P < .001), higher stage (P = .024), and chromosome 13 deletion (P = .013) had shorter TTP. Factors associated with shortened TTP that remained significant when assessed by multivariate analysis were increased C-reactive protein concentration (P = .011) and abnormal cytogenetics (P = .02), but not chromosome 13 deletion. Although many factors were found to be associated with shorter OS by univariate analysis, only 4 were significantly associated with shorter survival in the multivariate analysis: bone marrow plasma-cell infiltration greater than 50% (P = .028), hypoalbuminemia (P < .001), thrombocytopenia (P = .024), and low KPS (P = .034).    Discussion Top Abstract Introduction Patients, materials, and methods Results Discussion Appendix References   Bortezomib can induce objective responses in patients with relapsed and refractory multiple myeloma. Results of the multivariate analysis confirmed that the following baseline factors did not influence clinical response rate with bortezomib: number or type of previous therapies, sex, body surface area, chromosome 13 deletion, and hemoglobin and 2-microglobulin concentrations. Although the overall response rate was similar in patients with light- and heavy-chain disease, most of the responses in patients with light-chain disease were CRs. It is important to note that the detection of free light chains in urine depends on renal function and on the sensitivity of the method used. Therefore, although it appears that patients with light-chain disease achieved a higher CR rate, this conclusion is difficult to confirm. Conversely, the lack of effect of chromosome 13 abnormalities on response to bortezomib is noteworthy because this cytogenetic abnormality has been shown to be an important negative prognostic factor of response in relapsed myeloma treated with certain other agents.15 Advanced age has been associated with poor response to treatment in patients with relapsed multiple myeloma who were treated with thalidomide.13 Age was also predictive of response to bortezomib but did not affect DOR, TTP, or OS. These results suggest that age alone should not represent a barrier to treatment with bortezomib. Although older patients may take longer to respond, the data suggest that elderly patients who do respond may achieve DOR, TTP, and OS benefits similar to those of younger patients. The other significant factor in the multivariate analysis of response rate was greater than 50% plasma-cell infiltration in the bone marrow. In general, factors that correlate with high tumor burden (ie, hypoalbuminemia, bone marrow plasma-cell infiltration greater than 50%, and thrombocytopenia) were associated with shorter DOR and OS with bortezomib. Clinical outcome with bortezomib was independent of the number of previous lines of treatment. Based on the Mayo Clinic experience in patients with relapsed myeloma, irrespective of the type of treatment, DOR steadily decreases with each successive treatment regimen, ranging from 10 months with the first therapy to approximately 3 months with 6 or more previous therapies.2 Patients who received bortezomib in the SUMMIT trial had received a median of 6 previous lines of therapy and had a DOR of approximately 13 months, but neither the type nor the number of previous treatments influenced DOR. Indeed, TTP with bortezomib was 2 to 4 times longer in duration than that reported with the last therapy before enrolling patients in the study.17 The importance of prognostic factors in the pretreatment evaluation of myeloma has gained even more significance with the creation of the new International Staging System (ISS).19 The new system uses only 2 factors for staging patients at diagnosis: serum albumin as a correlate of rapid myeloma growth, and 2-microglobulin as a marker of tumor burden. In the univariate analysis, shorter DOR and OS were individually associated with lower albumin, and shorter TTP and OS were associated with higher 2-microglobulin, but response rate, TTR, and DOR with bortezomib treatment were independent of stage as defined by the ISS using albumin and 2-microglobulin. In the univariate analysis, stage was predictive of TTP and OS. The ability to generally predict response, TTR, DOR, TTP, and OS is meaningful for the physician and the patient in making treatment decisions. In a phase 3 randomized trial, Assessment of Proteasome Inhibition for Extending Remissions (APEX), in which bortezomib therapy was compared with high-dose dexamethasone in patients who had received 1 to 3 previous lines of therapy, bortezomib demonstrated significantly greater benefit in terms of TTP and OS at the preplanned interim analysis, resulting in an independent committee decision to recommend early closure of the dexamethasone arm and to allow all patients access to bortezomib.21 Prognostic factors and the prognostic value of certain genetic markers will be further explored in APEX. A fascinating research focus derived from this work has been the exploration of genetic markers that may aid in identifying patients with a high potential for response to specific therapies.22 Genetic markers from pretreatment bone marrow aspirates of myeloma cells are being studied by microarray analysis in subsets of patients treated with bortezomib in phase 2 and 3 studies to validate this methodology as a promising tool in targeted therapy. Initial research from SUMMIT has shown the feasibility of this approach, and preliminary data suggest that a highly significant gene expression signature can distinguish responders from nonresponders.23 These data may provide yet another valuable method to identify patients with the potential to obtain clinical benefit from bortezomib. Positive clinical outcomes in patients with relapsed and refractory multiple myeloma treated with bortezomib appeared to be independent of many patient and disease factors historically considered to be adverse prognostic factors in myeloma. Importantly, the type or number of previous therapies and an increased baseline 2-microglobulin were not associated with poor response to bortezomib or to unfavorable changes in time-to-event parameters. Although older patients had a lower response rate to bortezomib in this study, their duration of response and survival were not negatively affected. It is recognized that the analyses and models used for each of the several dependent variables (response rate, TTP, OS, TTR, DOR) should be considered exploratory, and the conclusions are subject to confirmation by further clinical studies of bortezomib in this patient population. Ongoing studies will provide further understanding regarding the use of prognostic factors to identify patients most likely to benefit from bortezomib therapy. Pharmacogenomics in conjunction with these clinical factors may provide insight not only into response to bortezomib but also into rational designs for combinations.    Appendix Top Abstract Introduction Patients, materials, and methods Results Discussion Appendix References   The names and affiliations of all individuals comprising the SUMMIT Investigators are as follows: Paul Gerard Guy Richardson, MD, Dana-Farber Cancer Institute, Boston, MA; Bart Barlogie, MD, PhD, University of Arkansas for Medical Sciences, Little Rock, AR; James Berenson, MD, Cedars-Sinai Medical Center, Los Angeles, CA; Seema Singhal, MD, Northwestern Memorial Hospital, Chicago, IL; Sundar Jagannath, MD, St Vincent's Comprehensive Cancer Center, New York, NY; David Irwin, MD, Alta Bates Cancer Center, Berkeley, CA; S. Vincent Rajkumar, MD, Mayo Clinic, Rochester, MN; Gordon Srkalovic, MD, PhD, Cleveland Clinic Foundation, Cleveland, OH; Melissa Alsina, MD, H. Lee Moffitt Cancer Center, Tampa, FL; Raymond Alexanian, MD, M.D. Anderson Cancer Center, Houston, TX; David Siegel, MD, Carol G. Simon Cancer Center, Morristown, NJ; Robert Z. Orlowski, MD, PhD, University of North Carolina, Chapel Hill, NC; David Kuter, MD, Massachusetts General Hospital, Boston, MA; Steven Limentani, MD, Charlotte Medical Clinic, Charlotte, NC; Teru Hideshima, MD, PhD, Dana-Farber Cancer Institute, Boston, MA; Hugh Xiao, PhD, Millennium Pharmaceuticals, Inc., Cambridge, MA; Dixie Esseltine, MD, Millennium Pharmaceuticals, Inc., Cambridge, MA; David Schenkein, MD, Millennium Pharmaceuticals, Inc., Cambridge, MA; and Kenneth C. Anderson, MD, Dana-Farber Cancer Institute, Boston, MA.    Footnotes   Submitted February 18, 2005; accepted June 10, 2005. Prepublished online as Blood First Edition Paper, July 14, 2005; DOI 10.1182/blood-2005-02-0691. A complete list of the members of the Study of Uncontrolled Myeloma Managed with Proteasome Inhibition Therapy (SUMMIT) Investigators appears in the "Appendix." Supported by Millennium Pharmaceuticals, Inc. Several of the authors have declared a financial interest in and/or are employed by Millenium Pharmaceuticals, whose product was studied in the present work. P.G.G.R. is on the Speakers' Bureau and the Advisory Board for Millennium Pharmaceuticals, Inc. J.B. receives grants and honoraria from Speakers' Bureaus and consultant fees from Millennium Pharmaceuticals, Inc., and is on the Advisory Board of Millennium Pharmaceuticals, Inc. S.J. is a consultant on the Speakers' Bureau for Millennium Pharmaceuticals, Inc. S.V.R. has received grant support from Millennium Pharmaceuticals, Inc., to conduct clinical trials in myeloma at the Mayo Clinic. H.X. is a contractor-biostatistician working with Millennium Pharmaceuticals, Inc. D.E. is a full-time employee of and owns stock in Millennium Pharmaceuticals, Inc. D.S. is a full-time employee of and owns stock in Millennium Pharmaceuticals, Inc. K.C.A. receives grant support from Millennium Pharmaceuticals, Inc. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Paul G. G. Richardson, Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney St, Dana 1B02, Boston, MA 02115; e-mail: paul_richardson{at}dfci.harvard.edu.    References Top Abstract Introduction Patients, materials, and methods Results Discussion Appendix References   Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78: 21-33.[Abstract/Free Full Text] Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of patients with relapsed multiple myeloma. Mayo Clin Proc. 2004;79: 867-874.[Abstract/Free Full Text] Desikan R, Barlogie B, Sawyer J, et al. Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities. Blood. 2000;95: 4008-4010.[Abstract/Free Full Text] Greipp PR, Lust JA, O'Fallon WM, Katzmann JA, Witzig TE, Kyle RA. Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma. Blood. 1993;81: 3382-3387.[Abstract/Free Full Text] Facon T, Avet-Loiseau H, Guillerm G, et al. Chromosome 13 abnormalities identified by FISH analysis and serum beta2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy. Blood. 2001;97: 1566-1571.[Abstract/Free Full Text] Fonseca R, Harrington D, Oken MM, et al. Biological and prognostic significance of interphase fluorescence in situ hybridization detection of chromosome 13 abnormalities (delta13) in multiple myeloma: an Eastern Cooperative Oncology Group study. Cancer Res. 2002;62: 715-720.[Abstract/Free Full Text] Rajkumar SV, Mesa RA, Fonseca R, et al. Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis. Clin Cancer Res. 2002;8: 2210-2216.[Abstract/Free Full Text] Greipp PR, Kumar S, Blood EA, et al. A simple classification to identify poor-risk untreated myeloma [abstract]. Blood. 2002;100: 598. Jacobson JL, Hussein MA, Barlogie B, Durie BG, Crowley JJ. A new staging system for multiple myeloma patients based on the Southwest Oncology Group (SWOG) experience. Br J Haematol. 2003;122: 441-450.[CrossRef][Medline] [Order article via Infotrieve] Menon H, Kumar K, Ganessan K, et al. Autologous stem cell transplantation (ASCT) in multiple myeloma (MM): analysis of prognostic factors [abstract]. Proc Am Soc Clin Oncol. 2003;22: 608. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma: Intergroupe Francais du Myelome. N Engl J Med. 1996;335: 91-97.[Abstract/Free Full Text] Cavo M, Galieni P, Zuffa E, Baccarani M, Gobbi M, Tura S. Prognostic variables and clinical staging in multiple myeloma. Blood. 1989;74: 1774-1780.[Abstract/Free Full Text] Mileshkin L, Biagi JJ, Mitchell P, et al. Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age. Blood. 2003;102: 69-77.[Abstract/Free Full Text] Zangari M, Barlogie B, Thertulien R, et al. Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival. Clin Lymphoma. 2003;4: 32-35.[Medline] [Order article via Infotrieve] Barlogie B, Desikan R, Eddlemon P, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood. 2001;98: 492-494.[Abstract/Free Full Text] Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999;59: 2615-2622.[Abstract/Free Full Text] Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348: 2609-2617.[Abstract/Free Full Text] Richardson PG, Barlogie B, Berenson J, et al. Survival, duration of response, and time to progression with bortezomib in patients with relapsed and refractory myeloma: an update [abstract]. Hematol J. 2004;5(suppl 2): S128. Greipp PR, San Miguel JF, Durie BGM, et al. A new international staging system (ISS) for multiple myeloma (MM) from the International Working Group [abstract]. Blood. 2003;102: 190. 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. 1998;102: 1115-1123.[CrossRef][Medline] [Order article via Infotrieve] Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethazone for relapsed multiple myeloma. N Engl J Med. 2005;352: 2487-2498.[Abstract/Free Full Text] Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004;64: 1546-1558.[Abstract/Free Full Text] Richardson PG, Barlogie B, Berenson JR, et al. Prognostic factors associated with response in patients with relapsed and refractory multiple myeloma (MM) treated with bortezomib [abstract]. Proc Am Soc Clin Oncol. 2003;22: 581. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. K Kettle, K. L Finkbiner, S. E Klenke, R. D Baker, D. W Henry, and C. B Williams Initial therapy in multiple myeloma: investigating the new treatment paradigm Journal of Oncology Pharmacy Practice, September 1, 2009; 15(3): 131 - 141. [Abstract] [PDF] G. Bianchi, L. Oliva, P. Cascio, N. Pengo, F. Fontana, F. Cerruti, A. Orsi, E. Pasqualetto, A. Mezghrani, V. Calbi, et al. The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition Blood, March 26, 2009; 113(13): 3040 - 3049. [Abstract] [Full Text] [PDF] P. Baumann, S. Mandl-Weber, A. Volkl, C. Adam, I. Bumeder, F. Oduncu, and R. 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[Abstract] [Full Text] [PDF] A. Palumbo, M. T. Ambrosini, G. Benevolo, P. Pregno, N. Pescosta, V. Callea, C. Cangialosi, T. Caravita, F. Morabito, P. Musto, et al. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma Blood, April 1, 2007; 109(7): 2767 - 2772. [Abstract] [Full Text] [PDF] W.-Z. Ying, H.-G. Zhang, and P. W. Sanders EGF Receptor Activity Modulates Apoptosis Induced by Inhibition of the Proteasome of Vascular Smooth Muscle Cells J. Am. Soc. Nephrol., January 1, 2007; 18(1): 131 - 142. [Abstract] [Full Text] [PDF] P. G. Richardson, T. Hideshima, and K. C. Anderson Plasma cell dyscrasias ASH Self-Assessment Program, January 1, 2007; 2007(1): 298 - 327. [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: 2005-02-0691v1 106/9/2977    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Richardson, P. G. G. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Richardson, P. G. G. Articles by Anderson, K. C. Related Collections Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?

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