Biology of Blood and Marrow Transplantation 12: (2006) 2006 American Society for Blood and Marrow Transplantation

Transcription

1 Biology of Blood and Marrow Transplantation 12: (2006) 2006 American Society for Blood and Marrow Transplantation /06/ $32.00/0 doi: /j.bbmt New Staging Systems Can Predict Prognosis of Multiple Myeloma Patients Undergoing Autologous Peripheral Blood Stem Cell Transplantation as First-Line Therapy Hawk Kim, 1 Hee-Jung Sohn, 2 Shin Kim, 2 Kihyun Kim, 3 Jae Hoon Lee, 4 Soo-Mee Bang, 4 Dong-Hwan Kim, 5 Sang Kyun Sohn, 5 Je-Jung Lee, 6 Cheolwon Suh 2 1 Division of Hematology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea; 2 Division of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 3 Department of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 4 Department of Hematology/Oncology, Gil Medical Center, Gachon Medical School, Incheon, Korea; 5 Department of Hematology/Oncology, Kyungpook National University Hospital, Kyungpook National University, Daegu, Korea; 6 Department of Hematology/Oncology, Chonnam National University Hospital, Chonnam National University, Gwangju, Korea Correspondence and reprint requests: Cheolwon Suh, MD, PhD, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Pungnap-2dong, Songpa-gu, Seoul , Korea ( csuh@amc.seoul.kr). Received December 25, 2005; accepted April 17, 2006 ABSTRACT Staging systems for multiple myeloma (MM) include the Southwest Oncology Group (SWOG) staging system, the International Staging System (ISS), and the Durie-Salmon (DS) staging system. We evaluated whether staging at the time of diagnosis could predict survival in MM patients undergoing autologous peripheral blood stem cell transplantation (APBSCT) as first-line treatment. Between November 1996 and June 2005, 152 MM patients were treated with induction VAD (vincristine, adriamycin, dexamethasone) chemotherapy, followed by APBSCT at 6 institutions in Korea. Median follow-up times were 22.6 months (range, months) from the day of diagnosis and 14.1 months (range, months) from the day of APBSCT. Progression-free survival (PFS) from the day of diagnosis was predicted by the SWOG staging system (P.0129) and ISS (P.0299), but not by the DS staging system at diagnosis (P.1074). In addition, overall survival (OS) from the day of diagnosis could be predicted by the SWOG staging system (P.0207) and ISS (P.0105), but not by the DS staging system (P.2542). PFS from day of APBSCT was not predicted by the DS staging system (P.5731), SWOG staging system (P.2817), or ISS (P.1167). OS from day of APBSCT could be predicted by the SWOG staging system (P.0392) and ISS (P.0198), but not by the DS staging system (P.5426). Our findings indicate that PFS and OS in association with APBSCT can be predicted by stages assessed by the SWOG and ISS systems, but not by the DS system. Moreover, staging by the SWOG and ISS systems at the time of diagnosis was better correlated with survival than was staging at the time of APBSCT American Society for Blood and Marrow Transplantation KEY WORDS Staging Multiple myeloma Durie-Salmon Southwest Oncology Group International Staging System Autologous peripheral blood stem cell transplantation INTRODUCTION Despite its many complex criteria, the Durie- Salmon (DS) staging system has been the standard staging tool for patients with multiple myeloma (MM). Recently, the Southwest Oncology Group (SWOG) published a new, simplified staging system, focusing on 2 common measures with prognostic importance in MM: serum beta2-microblobulin (beta2m) and serum albumin [1]. The SWOG staging system was found to correlate well with survival and DS staging. 837

2 838 H. Kim et al. More recently, the International Staging System (ISS) was introduced. The ISS is similar to the SWOG staging system in that serum beta2m and albumin are the main determinants of staging; however, the ISS has 3 stages rather than the 4 stages of the SWOG staging system [2]. The DS staging system was developed based on the clinical manifestations of a small number of patients, whereas both the SWOG staging system and the ISS are based on prognostic studies of larger populations. Autologous peripheral blood stem cell transplantation (APBSCT) has become a standard therapeutic modality for MM to prolong disease-free interval [3,4]. The existence of 3 major staging systems for MM raises the question of which staging system has the most prognostic value for patients undergoing APBSCT. In addition, the prognosis of patients with MM can depend not only on staging at diagnosis, but also on stage just before APBSCT and the response to initial therapy. Therefore, it is important to determine whether staging just before APBSCT is more predictive of prognosis than staging at diagnosis. Consequently, we compared these 3 staging systems in patients undergoing APBSCT and also evaluated the best time point at which to estimate prognosis. METHODS Data Collection We collected basic information and staging scores of patients with MM who underwent APBSCT at 6 institutions in Korea between November 1996 and June All patient data were obtained retrospectively from case report form questionnaires. Each questionnaire contained information about patient age, sex, date of diagnosis, immunoglobulin subtype, staging scores (DS, SWOG, and ISS) at the time of diagnosis and at the time of APBSCT, conditioning regimen, disease status at APBSCT, date of APBSCT, response to APBSCT, date of response to APBSCT, date of last follow-up, survival status, and date of progression. For patients who underwent tandem APBSCT, we evaluated the data for the first APBSCT. Patients excluded from the initial database included those who did not undergo APBSCT, those who did not undergo APBSCT as first-line therapy, and those for whom we had no data on serum albumin or serum beta2m concentration at diagnosis and/or time of APBSCT. Disease MM was diagnosed by the presence of monoclonal gammopathy, the presence of 10% plasma cells among bone marrow nuclear cells, and impairment of a related organ or tissue, including an osteolytic bone lesion, anemia, or azotemia. Patients were initially classified by DS stage and later reclassified by SWOG/ISS. After 3 or more cycles of VAD (vincristine, adriamycin, dexamethasone) chemotherapy, patients underwent APBSCT regardless of their response to VAD. Each patient gave written informed consent to undergo APBSCT. APBSCT Peripheral blood hematopoietic stem cells were mobilized with cyclophosphamide and hematopoietic growth factor (HPGF), with the latter consisting of either granulocyte-colony stimulating factor or granulocyte-monocyte colony stimulating factor. Infusion of at least CD34 cells/kg among the collected mononuclear cell (MNC) was recommended. Neither CD34-positive selection nor purging was applied. The conditioning regimen was melphalan 100 mg/m 2 for 2 days. HPGF support was given until hematologic engraftment occurred, with hematologic engraftment defined as the first day of absolute neutrophil count (ANC) 500 cells/ L for 3 consecutive days. After disease progression, salvage therapy was done at the discretion of the attending physician. Stage Classification Until 2003, DS stage was used to classify MM patients at the time of diagnosis. There are 3 DS stages (I, II, and III), each of which is divided into Table 1. Basic Characteristics of MM Patients Characteristic No. of Patients (%) Total 152 (100) Sex Male 82 (54.2) Female 70 (45.8) Age >50 years 96 (63.2) Immunoglobulin type IgG/kappa 51 (33.6) IgG/lambda 23 (15.1) IgA/kappa 18 (11.8) IgA/lambda 13 (8.6) IgD/lambda 11 (7.2) Free kappa 13 (8.6) Free lambda 15 (9.9) Others 5 (3.3) Disease status at APBSCT First CR 36 (23.7) Initial PR 100 (65.8) Primary refractory 16 (10.5) Responses to APBSCT Continued CR 36 (23.7) Induced CR 50 (32.9) Induced or continued PR 55 (36.2) Stable disease 3 (2) Progressive disease 2 (1.3) Not evaluated 6 (3.9)

3 New Staging Systems after APBSCT in Multiple Myeloma 839 Table 2. Staging of MM Patients According to the DS Staging System Stage at APBSCT Stage at Diagnosis I II III Total I 8 (5.3%) 3 (2.0%) 3 (2.0%) 14 (9.2%) II 9 (5.9%) 1 (.7%) 1 (.7%) 11 (7.2%) III 26 (17.1%) 16 (10.5%) 85 (55.9%) 127 (83.6%) Total 43 (28.3%) 20 (13.2%) 89 (58.6%) 152 (10%) subclasses A and B according to serum creatinine level. Patients were sorted into DS stage I, II, or II regardless of subclass to simplify the analysis. The patients were reclassified by SWOG stage according to their serum albumin and beta2m levels at the time of diagnosis and at the time of APBSCT, with SWOG stage I defined as beta2m 2.5 mg/l; stage II, as 2.5 beta2m 5.5 mg/l; stage III, as beta2m 5.5 mg/l and albumin 3 g/dl; and stage IV, as beta2m 5.5 mg/l and albumin 3 g/dl. The patients were also reclassified by ISS stage, with ISS stage I defined as beta2m 3.5 mg/l and albumin 3.5 g/dl; stage II, as all patients not assorted into stage I or III; and stage III, as beta2m 5.5 mg/l. Stage at diagnosis was compared with stage just before APBSCT and categorized as improved, no change, or aggravated. Response Evaluation Protein electrophoresis and immunofixation electrophoresis in serum and/or urine was used to evaluate response and progression. Simple X-ray, computed tomography, or magnetic resonance imaging was used for imaging evaluation. Positron emission tomography was not used to determine progression. Disease status at APBSCT was categorized as first complete remission (CR), initial partial remission (PR), or primary refractory. Response to therapy was based on criteria in patients with MM treated with high-dose therapy and hematopoietic stem cell transplantation (Blade criteria) [5]. Response to APBSCT was classified as continued CR, induced CR, induced or continued PR, stable disease, progressive disease, or not evaluated. Survival Data Progression-free survival (PFS) was calculated as the time interval between the starting point and the date of first progression after APBSCT. If a patient did not progress, then the end point for PFS was the date of last follow-up, and the patient was censored. Overall survival (OS) was calculated as the time interval between the starting point and the date of last follow-up. Patients alive at last follow-up were censored from analysis of OS. Any death was defined as an event regardless of cause. On progression or relapse, the second-line therapy was instituted at the discretion of the attending physician. Statistical Analysis The 2 test was used to compare nonnumerical variables among groups. The start dates of all time variables were day of diagnosis and day of APBSCT. All 4 time intervals were used for the 3 staging systems: OS from day of diagnosis, OS from day of APBSCT, PFS from day of diagnosis, and PFS from day of APBSCT. Stage at time of diagnosis was evaluated by OS or PFS from day of diagnosis, whereas stage at time of APBSCT was evaluated by OS or PFS from day of APBSCT. The Kaplan-Meier method was used to assess OS and PFS, and 2-tailed log-rank tests were used to compare OS and PFS curves. Quantitative variables are reported as medians (range), and qualitative variables are reported as number of patients (percentage) unless specified otherwise. A P value.05 was considered significant. Hazard ratios (HRs) were calculated using the Cox regression model. Table 3. Staging of MM Patients According to the SWOG Staging System Stage at APBSCT Stage at Diagnosis I II III IV Total I 25 (16.4%) 11 (7.2%) 1 (.7%) 0 (.0%) 37 (24.3%) II 32 (21.1%) 35 (23.0%) 4 (2.6%) 2 (1.3%) 73 (48.0%) III 4 (2.6%) 8 (5.3%) 13 (8.6%) 0 (.0%) 25 (16.4%) IV 3 (2.0%) 11 (7.2%) 2 (1.3%) 1 (.7%) 17 (11.2%) Total 64 (42.1%) 65 (42.8%) 20 (13.2%) 3 (2.0%) 152 (10%)

4 840 H. Kim et al. Table 4. Staging of MM Patients According to the ISS Stage at APBSCT Stage at Diagnosis I II III Total I 35 (23.0%) 4 (2.6%) 3 (2.0%) 42 (27.6%) II 47 (30.9%) 17 (11.2%) 4 (2.6%) 68 (44.7%) III 12 (7.9%) 16 (10.5%) 14 (9.2%) 42 (27.6%) Total 94 (61.8%) 37 (24.3%) 21 (13.8%) 152 (10%) RESULTS Patient Characteristics Data were collected from initial questionnaires on 211 patients who underwent APBSCT, with the data locked as of November 12, Data on 12 patients were ineligible because of a second APBSCT. We also excluded 7 patients who underwent APBSCT after relapse and 1 patient in whom poor mobilization disturbed completion of APBSCT. SWOG/ISS staging was not available for 15 patients at the time of diagnosis, for 29 patients at the time of APBSCT, and at either time point for 4 patients. Thus, data on 152 patients were deemed eligible for analysis. Of these 152 patients, 82 (53.9%) were men and 70 (46.1%) were women. Their median age was 54 years (range, years). The most common immunoglobulin type was IgG/ (n 51; 33.6%). The date of APBSCT was between November 23, 1996 and June 15, More than half of the patients (56.6%) were either continued CR or induced PR as a response to APBSCT. Patient characteristics are summarized in Table 1. Stages At the time of diagnosis, most patients were in an advanced stage according to the DS staging system (83.6% in stage III; Table 2) in contrast to SWOG (11.2% in stage IV; Table 3) and ISS (27.6% in stage III; Table 4). Before APBSCT, the number of patients in an advanced stage was reduced not only in SWOG (2% in stage IV) and ISS (13.8% in stage III), but also in DS (83.6% in stage III). According to the DS staging system, many patients showed improvement after APBSCT compared with time of diagnosis (P.001); 51 (33.5%) patients improved, 94 (61.9%) remained the same, and 7 (4.7%) worsened after APBSCT. The same tendency was observed using the SWOG staging system (P.001) and ISS (P.001), although the proportion showing improvement after APBSCT was larger for SWOG and ISS than for the DS staging system. According to the SWOG staging system, 60 (39.5%) patients improved, 74 (48.7%) remained the same, and 18 (11.8%) worsened; whereas according to the ISS, 75 (49.3%) patients improved, 66 (43.4%) remained the same, and 11 (7.2%) worsened. Survival from Day of Diagnosis The median follow-up from day of diagnosis was 22.6 months (range, months), whereas the median follow-up from day of APBSCT was 14.1 months (range, months). None of the 152 patients was lost to follow-up. Progression after ABPSCT was observed in 81 patients (53.3%). As shown in Table 5, PFS from day of diagnosis was not predicted by the DS staging system at diagnosis (P.1074, HR 1.387; Fig 1A), but was predicted by both the SWOG staging system (P.0129, HR 1.335; Fig 1B) and ISS (P.0299, HR 1.379; Fig 1B). Differences in PFS were significant only between stages I and IV according to the SWOG staging system and between stages I and III according to the ISS. Staging at APBSCT was not predictive of PFS from day of diagnosis according to the SWOG system (P.2994, HR 1.152), ISS (P.3120, HR 1.130), or DS staging system (P.116, HR 1.282). As of November 2005, 38 patients (25%) had died, 25 from disease progression, 9 from infection, 1 from Table 5. PFS and OS from Day of Diagnosis When Stages were Evaluated at the Time of Diagnosis Survival System Stage n (Event) Median, Months P PFS DS 1 14 (7) (4) NR (70) SWOG 1 37 (18) (38) (14) (11) ISS 1 42 (17) (39) (25) OS DS 1 14 (4) (2) NR (32) SWOG 1 37 (5) NR (16) (10) (7) ISS 1 42 (5) NR (16) (17) NR, not reached.

5 A p = D p = PFS from day of Diagnosis (Months) PFS from day of APBSCT (Months) B p = 129 E p = 817 V V PFS from day of Diagnosis (Months) PFS from day of APBSCT (Months) C p = 299 F p = PFS from day of Diagnosis (Months) PFS from day of APBSCT (Months) Figure 1. PFS curves of 152 MM patients after APBSCT (Kaplan-Meier curves). A C, PFS from day of diagnosis according to DS staging (A), SWOG staging (B), and the ISS (C) at time of diagnosis. D F, PFS from day of APBSCT according to DS staging (D), SWOG staging (E), and the ISS (F) at time of APBSCT. is represented by the thick solid line; stage II, by the dotted line; stage III, by the solid line; and stage IV, by the thick dotted line. 841

6 842 H. Kim et al. bone marrow aplasia, 1 from suicide, and 2 from other causes. Eighty-one patients (53.3%) had relapsed. OS from day of diagnosis was not predicted by the DS staging system, either at diagnosis (P.2542, HR 1.144) or at APBSCT (P.5426, HR 1.391) (Fig 2A). In contrast, both the SWOG staging system and ISS could predict OS from day of diagnosis, either at diagnosis (P.0207 and.0105, HR and 1.642, respectively; Fig 2B) or at APBSCT (P.0198 and.0054; HR and 1.734, respectively; Fig 2C). OS from day of diagnosis is presented in Table 5. Using these staging systems, only stage I differed from other stages, however. This tendency was amplified when patients were restaged at APBSCT. Survival from Day of APBSCT PFS from day of APBSCT, either at diagnosis or at APBSCT, was not predicted by the DS staging system (P.1644 and.5731; HR and 1.147, respectively; Fig 1D), the SWOG staging system (P.2660 and.2817; HR and 1.198, respectively; Fig 1E), or the ISS (P.2233 and.1167; HR and 1.734, respectively; Fig 1F). In addition, OS from the day of APBSCT either at diagnosis or at APBSCT was not predicted by the DS staging system (P.2542 and.5426; HR 59 and 1.250, respectively; Fig 2D). In contrast, OS from day of APBSCT could be predicted by the ISS from the day of diagnosis (P.0207, HR 1.841) and from the day of APBSCT (P.0198, HR 1.629; Fig 2F). The SWOG staging system was intermediate, in that it could not predict OS from the day of ABPSCT at diagnosis (P.0553, HR 1.506) but could do so at the day of APBSCT (P.0392, HR 1.585; Fig 2E). Survival from the day of APBSCT is summarized in Table 6. We also determined whether stage shift after VAD chemotherapy could alter survival. Comparing patients showing improved stage with patients showing no change or aggravation for PFS and OS revealed nobetween-group differences in PFS from the day of diagnosis, PFS from the day of APBSCT, OS from the day of diagnosis, or OS from the day of APB- SCT, except that the improvement in SWOG staging system was predictive of longer PFS from the day of diagnosis (P.0332). Responses to VAD chemotherapy were not associated with the stage shift in DS stage and SWOG (P.939 and.455, respectively), but improved ISS after VAD exhibited a tendency toward good response (P.094). DISCUSSION In general practice, almost all patients with MM who are under age 65 years undergo APBSCT after initial chemotherapy, (eg, VAD), thus emphasizing the prognostic factors for ASCT. High serum concentrations of beta2m, C-reactive protein, or lactate dehydrogenase and low serum concentrations of albumin have all been associated with poorer outcome [6,7]. The presence of chromosome 13 deletions and other chromosomal abnormalities is also associated with worse survival [8-12]. Both the SWOG staging system and the ISS were based on prognostic analysis of large populations and use serum beta2m and albumin concentrations as prognostic markers. Because their detailed applications are somewhat different, we wished to determine which of these staging systems is better for patients undergoing APBSCT. We found that PFS from the day of diagnosis was predicted by SWOG staging and ISS, but not by DS staging, although longer PFS was observed only for stage I according to the SWOG staging system and ISS. In contrast, PFS from the day of APBSCT was not predicted by any of the 3 staging systems. The DS staging system also was not prognostic of OS, either at time of diagnosis or at time of APBSCT. The OS curves of SWOG stages II and III crossed over, whereas the OS curves of the different ISS stages at the time of diagnosis were distinct. These findings indicate that the ISS, which was simple and well correlated with both PFS and OS, was more prognostic than the DS and SWOG staging systems. Another concern was the significance of staging just before APBSCT. DS staging at time of diagnosis was not correlated with either PFS or OS. In contrast, patients in SWOG or ISS stage I exhibited longer OS at both time of diagnosis and time of APBSCT. OS curves of SWOG and ISS stages II and III at time of APBSCT could not be distinguished from one another, however. Factors associated with significantly shorter OS after APBSCT were lack of CR after transplantation, ISS stage III, and age 60 years at transplantation [13]. The status of disease before ASCT did not significantly affect PFS and OS after transplantation. Patients in SWOG or ISS stage I had longer OS when reevaluated at the time of APBSCT, but stage evaluation at the time of APBSCT was not superior to, and did not provide more information than, stage at diagnosis. Patients in SWOG stages II and III had similar OS curves, indicating that the SWOG staging system was less correlated with PFS and OS compared with the ISS. According to all 3 staging systems, many patients showed improvement at the time of APBSCT compared with the time of diagnosis. Comparing the patients with improved stage with the patients with no change or aggravation in terms of PFS and OS revealed that only improvements in SWOG staging after VAD chemotherapy had a longer PFS from day of diagnosis. In contrast, improved stage after VAD chemotherapy according to the DS staging system and ISS could not be correlated with longer PFS or OS, suggest-

7 Figure 2. Overall survival (OS) curves of 152 MM patients after APBSCT (Kaplan-Meier curves). A C, OS from day of diagnosis according to DS staging (A), SWOG staging (B), and the ISS (C) at time of diagnosis. D F. OS from day of APBSCT according to DS staging (D), SWOG staging (E), and the ISS (F) at time of APBSCT. is denoted by the thick solid line; stage II, by the dotted line; stage III, by the solid line; and stage IV, by the thick dotted line. 843

8 844 H. Kim et al. Table 6. PFS and OS from the Day of APBSCT when Stages were Evaluated at the Time of APBSCT Survival System Stage n (Event) Median, Months P PFS DS 1 43 (18) (13) (50) SWOG 1 64 (33) (38) (8) (2) ISS 1 94 (49) (22) (10) OS DS 1 43 (7) NR (5) (26) SWOG 1 64 (9) NR (22) (5) (2) ISS 1 94 (17) NR (14) (7) NR, not reached. ing that stage reevaluation just before APBSCT has no significance for PFS and OS. Although OS is the ultimate end point for any staging system, many factors after APBSCT interfere with interpretation of staging. One limitation of our study was our inability to evaluate other prognostic factors, including chromosome aberrations, and laboratory findings, including S-phase plasma cells, microvessel density, lactic dehydrogenase and C-reactive protein levels, salvage therapy after progression, and gene expression profiles [14-18]. Moreover, we could not perform multivariate analysis for PFS and OS, because our data were limited mainly to stage. Therefore, the prognostic significance in this study should be confined to staging systems. Another pitfall is that median follow-up after transplantation is short; the actual prognosis after APBSCT can change after longer follow-up. Despite this drawback, however, it will be possible to suggest which time point (at the time of diagnosis vs at the time of APBSCT) is more prognostic based on our results. Although our findings may be insufficient to validate various staging systems for MM patients undergoing APBSCT, our study focused only on the prognostic significance of these staging systems for OS and PFS. Our results indicate that the DS staging system is not suitable for MM patients undergoing APBSCT, whereas both the SWOG and ISS staging systems have powerful prognostic value for OS and PFS. Our findings also indicate that the day of diagnosis is optimal for staging evaluation when APBSCT is being considered as an upfront therapy. REFERENCES 1. Jacobson JL, Hussein MA, Barlogie B, et al. A new staging system for multiple myeloma patients based on the Southwest Oncology Group (SWOG) experience. Br J Haematol. 2003;122: Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23: Vesole DH. Transplantation for multiple myeloma: who, when, how often? Patient selection and goals. Blood. 2003;102: Kumar A, Loughran T, Alsina M, et al. Management of multiple myeloma: a systematic review and critical appraisal of published studies. Lancet Oncol. 2003;4: 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. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998;102: Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of multiple myeloma. Blood. 2004;103: 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: Fassas AB, Spencer T, Sawyer J, et al. Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma. Br J Haematol. 2002;118: Shaughnessy J, Jacobson J, Sawyer J, et al. Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with total therapy I: interpretation in the context of global gene expression. Blood. 2003;101: Moreau P, Facon T, Leleu X, et al. Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood. 2002; 100: Calasanz MJ, Cigudosa JC, Odero MD, et al. Hypodiploidy and 22q11 rearrangements at diagnosis are associated with poor prognosis in patients with multiple myeloma. Br J Haematol. 1997;98: Chang H, Sloan S, Li D, et al. The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol. 2004;125: Krejci M, Buchler T, Hajek R, et al. Prognostic factors for survival after autologous transplantation: a single centre experience in 133 multiple myeloma patients. Bone Marrow Transplant. 2005;35: San Miguel JF, Garcia-Sanz R, Gonzalez M, et al. A new staging system for multiple myeloma based on the number of S-phase plasma cells. Blood. 1995;85: Kumar S, Gertz MA, Dispenzieri A, et al. Prognostic value of bone marrow angiogenesis in patients with multiple myeloma undergoing high-dose therapy. Bone Marrow Transplant. 2004;34: Shaughnessy JD Jr. Global gene expression profiling in the study of multiple myeloma. Int J Hematol. 2003;77: Bergsagel PL, Kuehl WM, Zhan F, et al. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005;106: Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood. 2004;104: