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Multiparameter Flow Cytometry Evaluation of Plasma Cell DNA Content and Proliferation in 595 Transplant-Eligible Patients with Myeloma Included in the Spanish GEM2000 and GEM2005<65y Trials
Instituto de Investigación Biomédica de Salamanca, Salamanca, SpainServicio General de Citometría and Department of Medicine, Universidad de Salamanca, Salamanca, Spain
The incorporation of high-dose therapy/autologous stem cell transplantation (HDT/ASCT) and novel agents has significantly improved survival in patients with multiple myeloma (MM), but whether this improvement also benefits patients harboring poor prognostic features, such as nonhyperdiploid MM (NH-MM) and a high proliferation index, remains largely unknown. We analyzed the DNA content and proliferation index of bone marrow plasma cells (PCs) by multiparameter flow cytometry in 595 newly diagnosed transplant-eligible patients with MM included in two consecutive PETHEMA/GEM trials: GEM2000 [VBMCP/VBAD (vincristine, carmustine, melphalan, cyclophosphamide, prednisone/vincristine, bischloroethylnitrosourea, adriamycin, and dexamethasone) followed by HDT/ASCT; n = 319] and GEM2005<65y (randomized induction with VBMCP/VBAD/bortezomib or thalidomide/dexamethasone or bortezomib/thalidomide/dexamethasone followed by HDT/ASCT; n = 276). Of the 595 patients, 295 were classified as NH-MM (49.6%) and 336 (56.5%) as high-proliferative MM (≥1% PCs in S-phase). Detection of NH-MM DNA content and ≥1% PCs in S-phase were of independent prognostic value for overall survival. Treatment with bortezomib-based regimens abrogated the inferior overall survival of patients with ≥1% PCs in S-phase but not of patients with NH-MM. Finally, a comparative analysis of PC proliferation index at diagnosis versus disease progression showed a twofold increase at relapse in 44 of 52 patients (85%) analyzed at both time points. NH-MM and a high proliferation index assessed by multiparameter flow cytometry remain as independent prognostic factors in MM, but the latter may be overcome by incorporating novel agents in the HDT/ASCT setting.
The incorporation of high-dose therapy/autologous stem cell transplantation (HDT/ASCT) and novel therapeutic agents
Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis.
have markedly changed the landscape of multiple myeloma (MM). Overall, MM is mainly divided into two major categories: hyperdiploid (H-MM; usually harboring multiple numerical chromosomal alterations) and nonhyperdiploid (NH-MM; typically enriched for IgH translocations),
Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe Francophone du Myelome.
However, in-depth analysis through microarray gene expression profiling (GEP) has shed significant light on the molecular heterogeneity of MM plasma cells (PCs), with up to 10 patient subgroups being identified.
Since the MMSET molecular subgroup is intrinsically associated with t(4;14) and this abnormality can be systematically evaluated by fluorescence in situ hybridization (FISH) analysis, important data are emerging suggesting that the poor outcome of patients harboring t(4;14) may be partially overcome by some regimens.
Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.
Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines.
Reduction in plasma cell proliferation after initial therapy in newly diagnosed multiple myeloma measures treatment response and predicts improved survival.
Multiparameter flow cytometry (MFC) immunophenotyping is a widely available tool in routine laboratories. It provides not only rapid measurement of PC proliferation but also simultaneous assessment of PC total DNA content.
Importantly, we recently observed in elderly patients with MM receiving novel agents during induction and maintenance that the poor prognosis of NH-MM was not abrogated,
Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance.
but whether survival of transplant-eligible patients with NH-MM and high PC proliferation is improved by the incorporation of novel agents up front remains largely unknown.
In the present study, we applied MFC to analyze the DNA content and proliferation index of myelomatous PCs from a series of 595 newly diagnosed transplant-eligible patients with MM. These results show that the PC DNA content and proliferation status are independent prognostic factors in MM and that novel agents–based regimens cannot overcome the poor prognosis of NH-MM but rather prolong survival of patients with MM and high proliferation indices. In addition, we investigated which of the commonly assessed cytogenetic abnormalities drives PC proliferation. Finally, we assessed whether there is a difference in individual patients in the proliferative rate of PCs between diagnosis and disease progression.
Materials and Methods
Patients
The study included 595 patients with MM diagnosed according to the International Myeloma Working Group criteria.
Patients were included in two consecutive PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas)/GEM (Grupo Español de MM) trials: GEM2000 [VBMCP/VBAD (vincristine, carmustine, melphalan, cyclophosphamide, prednisone/vincristine, bischloroethylnitrosourea, adriamycin, and dexamethasone) followed by HDT/ASCT and 2 years of maintenance with interferon plus prednisone; n = 319] and GEM2005<65y [randomized induction with the same chemotherapy plus bortezomib in the last two cycles or thalidomide/dexamethasone (TD) or bortezomib/thalidomide/dexamethasone (VTD) followed by HDT/ASCT, and 3 years of maintenance with interferon-a2b or thalidomide or thalidomide/bortezomib; n = 276]. Patients included in the GEM2000 protocol with >65 years, levels of serum calcium >14 mg/dL and/or serum creatinine >2 mg/dL were excluded from the analysis to avoid confounding survival bias. Median follow-up was 38 months (range, 1 to 123 months). All the samples were collected after informed consent was given, and the study was approved by the clinical research ethical committee.
MFC Immunophenotypic DNA Studies
Simultaneous staining for DNA (with propidium iodide) and PC surface antigens (CD38 and CD138) was performed as described elsewhere.
A minimum of 2 × 106 nucleated bone marrow (BM) cells per case were acquired using a FACSCalibur flow cytometer (BD Biosciences, San Jose, CA) using FACSDiva software version 6.0 (BD Biosciences). Total PC DNA content was calculated by dividing the median fluorescence channel of the G0/G1 peak of CD38/CD138hi myelomatous PCs by the median fluorescence channel of G0/G1 residual normal BM cells present in the sample. Patients were considered to be hyperdiploid (H-MM) when the PC DNA content ranged from 1.06 to 1.74; nonhyperdiploid (NH-MM) cases included patients with a PC DNA content <0.95 (hypodiploid), >1.74 (tetraploid/near-tetraploid), and ranging from 0.95 to 1.05 (diploid).
Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance.
after specifically selecting CD38/CD138hi PCs and excluding debris and cell doublets. The PC proliferation index was calculated as the percentage of PCs in S-phase in the whole BM PC compartment.
FISH Analysis
FISH was performed at baseline in immunomagnetically enriched PCs from 325 patients. Patients harboring t(4;14), t(14;16), and/or del(17p13) were classified as having high-risk disease and all other cases as standard risk, according to the International Myeloma Working Group guidelines.
The Mann-Whitney U-test was used to estimate the statistical significance of differences between groups. Progression-free survival (PFS) and overall survival (OS) curves were plotted using the Kaplan-Meier method, and the log-rank test was used to estimate the statistical significance of differences observed between curves. A univariate analysis was conducted to assess the impact of various baseline prognostic factors on PFS and OS (Table 1). The Cox proportional hazards regression model (stepwise regression) was used in a multivariate analysis of PFS and OS, retaining those variables with a significant predictive value (P ≤ 0.05) in the predictive model. For all the statistical analyses, SPSS software version 15.0 (SPSS Inc., Chicago, IL) was used.
Table 1Baseline Disease Features with a Significant Effect on PFS and/or OS (Univariate and Multivariate Analyses)
PC DNA Content and Its Relationship with Disease Characteristics and Patient Survival
Of the 595 patients included in the present study, 295 were classified as having NH-MM (49.6%) and the remaining 300 as having H-MM (50.4%). As expected, patients with NH-MM showed an increased frequency of t(4;14) (20% versus 9%, P = 0.008), t(11;14) (28% versus 5%; P < 0.001), t(14;16) (5% versus 1%; P = 0.055), and del(13q14) (50% versus 33%, P = 0.002) but not del(17p13) (5% versus 7%, P = 0.37). Moreover, NH-MM showed more frequently advanced disease (International Staging System stage III, 21% versus 13%; P = 0.03) and higher BM PC infiltration by MFC (16% versus 9%; P = 0.008).
As expected, patients with NH-MM had significantly inferior median PFS (34 versus 44 months; P = 0.004; Figure 1A) and OS (67 versus 84 months; P = 0.005; Figure 1B) than those with H-MM. We detected the presence of two different clones of myelomatous PCs (with different DNA content) in 34 of the 595 patients (5.7%) by MFC (Figure 2), and although the number is small, this subgroup had a dismal outcome compared with patients in whom only one PC clone was detected (median PFS and OS of 26 and 52 months, respectively; P ≤ 0.005). After this analysis in the overall MM population, we specifically looked at whether the outcome of NH-MM versus H-MM differed according to the trial: GEM2000 and GEM2005<65y. As occurred in the overall series, patients with NH-MM included in the GEM2000 trial had a significantly inferior PFS (34 versus 42 months, P = 0.04; Figure 3A) and a trend toward decreased OS (63 versus 79 months, P = 0.11; Figure 3B). Likewise, significant differences emerged for PFS (40 months versus not reached; P = 0.03; Figure 3C) and OS (both medians not reached; P = 0.004; Figure 3D) for patients included in the GEM2005<65y trial according to the NH-MM versus H-MM classification.
Figure 1PFS (A) and OS (B) of patients with symptomatic MM treated with HDT/ASCT grouped according to the presence of H-MM (n = 300) and NH-MM (n = 295) PC DNA content assessed by MFC at diagnosis. The median PFS was 44 months in the H-MM group and 34 months in the NH-MM group. The median OS was 84 months in the H-MM group and 67 months in the NH-MM group.
Figure 2Bivariate dot plot histograms illustrating the detection of two different PC clones (with different DNA content) by MFC in the BM of three newly diagnosed patients with myeloma. A represents a case with diploid and tetraploid PC clones, whereas on B and C, two hyperdiploid PC clones coexist.
Figure 3PFS and OS of patients with symptomatic MM treated with HDT/ASCT grouped according to the presence of H-MM and NH-MM PC DNA content assessed by MFC at diagnosis. A and B: PFS and OS of patients with MM included in the GEM2000 protocol (n = 319). C and D: PFS and OS of patients with MM included in the GEM2005<65y trial (n = 276).
PC Proliferation Index and Its Relationship with Disease Characteristics and Patient Survival
The median percentage of PCs in S-phase in the whole series was 1.14% (range, 0% to 13%). When we looked for a specific association between the percentage of PCs in S-phase and other baseline parameters, no significant correlations were found (data not shown), except for an inferior proliferation index in patients with NH-MM versus those with H-MM (1.00% versus 1.23%; P = 0.008). We then investigated the potential association between specific cytogenetic alterations and PC proliferation. Patients harboring t(11;14) showed a significantly decreased percentage of PCs in S-phase (0.7% versus 1.2%, P < 0.001), but no significant differences were recorded for t(4;14), t(14;16), del(13q14), and del(17p13). Accordingly, the presence or absence of high-risk cytogenetics was not associated with different PC proliferation, irrespective of whether we looked in all patients (1.12% versus 1.16%, respectively; P = 0.33) or specifically in patients with NH-MM versus H-MM (see Supplemental Table S1 at http://ajp.amjpathol.org).
In accordance with the median proliferation index of the whole series (1.14%), patients were stratified using a cutoff point of ≥1% versus <1% S-phase PCs, which translated into a significantly different PFS (median of 34 versus 43 months; P < 0.001) and OS (median of 66 versus 93 months; P = 0.001). Moreover, we confirmed that the higher the percentage of S-phase PCs, the worse the associated survival. In particular, a proliferation index ≥3% identified a subgroup of patients (92 of 595, 15.5%) with high-risk disease (median PFS and OS of 22 and 45 months, respectively; P < 0.001; Figure 4). In the group of patients with ≥1% S-phase PCs (n = 336), the complete response rate was slightly higher than that in the remaining patients (45% versus 36%, P = 0.053); however, the duration of the complete response tended to be shorter (PFS at 3 years: 65% versus 80%; P = 0.057). Thereafter, we explored whether the poor prognosis of patients with a high proliferation index (≥1% PCs in S-phase) could be abrogated in the most recent GEM2005<65y trial. The results show that while for patients included in the GEM2000 trial patient stratification into ≥1% versus <1% S-phase PCs predicted for different PFS (33 versus 43 months; P = 0.003; Figure 5A) and OS (61 versus 93 months; P < 0.001; Figure 5B), patients with ≥1% S-phase PCs receiving novel agents up front still showed only slightly inferior PFS (40 months versus not reached; P = 0.09; Figure 5C) and similar OS (both medians not reached; P = 0.99; Figure 5D) compared with patients with <1% PCs in S-phase. Accordingly, it seems that treatment with novel agents overcomes the adverse prognosis of a high proliferation index (≥1% S-phase PCs); however, this applied only to patients treated with either VTD or VBMCP/VBAD/bortezomib (median PFS of 40 and 44 months, respectively) but not to patients who received TD (PFS of 23 months; P = 0.03).
Figure 4PFS (A) and OS (B) of patients with symptomatic MM treated with HDT/ASCT grouped according to the presence of <1% (n = 259), ≥1% to <3% (n = 244), and ≥3% (n = 92) S-phase PCs as assessed by MFC at diagnosis.
Figure 5PFS and OS of patients with symptomatic MM submitted to HDT/ASCT grouped according to the presence of <1% and ≥1% S-phase PCs as assessed by MFC at diagnosis. A and B: PFS and OS of patients with MM included in the GEM2000 protocol (n = 319). C and D: PFS and OS of patients with MM included in the GEM2005<65y trial (n = 276).
Prognostic Factors for PFS and Overall Survival by Univariate and Multivariate Analyses
On univariate analysis, eight factors in addition to the PC DNA content and proliferation index by MFC were identified as having a significant adverse effect on PFS (Table 1): International Staging System disease stage, baseline anemia, serum β2-microglobulin, lactate dehydrogenase, BM PC infiltration by morphology and by MFC, persistence of normal PC levels (>5%) at baseline by MFC, and high-risk cytogenetics. For OS, all the same factors except BM PC infiltration by morphology retained their prognostic value, in addition to patient age.
In the multivariate analysis (Table 1), the presence of high-risk cytogenetics, increased lactate dehydrogenase level, ≥1% S-phase PCs, >15% PCs by MFC, and >5% normal PCs in the BM PC compartment remained as independent prognostic factors for PFS; in turn, for OS, the presence of high-risk cytogenetics, increased lactate dehydrogenase level, ≥1% S-phase PCs, International Staging System disease stage, and NH-MM PC DNA content were selected (Table 1). It should be noted that the prognostic significance of PC proliferation according to ≥3% S-phase PCs was not superior to high-risk cytogenetics in the multivariate analysis (data not shown).
Proliferation Index at Diagnosis Versus Disease Progression
To address the final question on whether there is a difference in the proliferation of PCs between diagnosis and disease progression, we compared the proliferative rate of PCs from 52 patients with paired BM samples at diagnosis and at relapse (see Supplemental Figure S1 at http://ajp.amjpathol.org). Of note, 44 of the 52 patients (84.6%) showed an increased percentage of S-phase PCs at relapse, with a median twofold difference between the proliferative rate at diagnosis versus that at relapse (0.97% versus 2.29%, respectively; P < 0.001).
Discussion
Introduction of HDT/ASCT in the 1990s and the discovery and incorporation of novel agents in the past decade represent a major cornerstone in the treatment of MM.
Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences.
In fact, this contribution opened the debate about whether patients defined in the era of conventional agents as being at high risk (identified by PCLI,
Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines.
Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis.
Prognostic value of immunophenotyping in multiple myeloma: a study by the PETHEMA/GEM cooperative study groups on patients uniformly treated with high-dose therapy.
Accordingly, a growing body of data is emerging regarding the impact of novel agents on survival of high-risk patients carrying cytogenetic abnormalities, such as t(4;14) or del(17p13),
Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance.
Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.
HOVON-65/GMMG-HD4 randomized phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly diagnosed multiple myeloma (MM).
Herein, we report on the prognostic relevance of the PC DNA content and proliferation index assessed by MFC in a large series of transplant-eligible patients, with approximately half of them receiving novel agents up front.
In line with results of previous studies based on conventional cytogenetics,
Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe Francophone du Myelome.
we found that patients with H-MM have increased survival compared with patients with NH-MM. Moreover, in the present series, NH-MM DNA content emerged as an independent prognostic factor for OS but not for PFS, which is also in line with previous observations.
Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance.
Although the molecular mechanisms responsible for these findings remain largely unknown, it should be considered that based on recent observations, patients with a hyperdiploid GEP signature have superior postrelapse survival.
Moreover, NH-MM DNA content was independent of high-risk cytogenetics, stressing that the high-risk factors associated with patients with NH-MM might not be fully captured by FISH cytogenetics. In the present study, we identified a small fraction (5.7%) of patients with two different PC clones with different PC DNA content. High-density genomic tools are now shedding some light on the cytogenetic heterogeneity of clonal PCs in MM,
Second clones in molecularly-defined biclonal multiple myeloma are derived from unrelated B cells, can be present at high frequency and exhibit chromosomal abnormalities.
Herein, we show that patients with clonal heterogeneity potentially relating to increased chromosomal instability can be easily identified by MFC and have a dismal outcome (median PFS and OS of 26 and 52 months, respectively). Specific analysis of the cytogenetic profile of these patients showed no significant differences compared with those with only one PC clone according to the DNA content (data not shown). Altogether, these results require further investigation and validation.
The assessment of PCLI has repeatedly been shown to be a powerful prognostic tool in patients with newly diagnosed myeloma,
but analysis of PC proliferation by fluorescent microscope slide–based methods is labor intensive and time-consuming and, therefore, difficult to incorporate into routine clinical practice.
Reduction in plasma cell proliferation after initial therapy in newly diagnosed multiple myeloma measures treatment response and predicts improved survival.
in which the proliferation index of PCs measured by MFC emerged as a powerful prognostic factor in transplant and nontransplant settings. Herein, patients with a proliferation index greater than the median (>1% of S-phase PCs) had inferior PFS and OS; these results were further confirmed in the multivariate analysis. Moreover, it was also possible to identify a subgroup of patients (≈15%) showing extremely increased proliferation (≥3% of S-phase PCs) associated with a high-risk signature (median OS of <4 years), in accordance with data derived from high-throughput GEP analysis.
The present results do not confirm this, and neither do other associations with cytogenetic abnormalities, such as t(4;14), t(14;16), and del(17p11). In turn, patients with NH-MM and/or t(11;14) showed a significantly lower percentage of S-phase PCs.
One of the major goals of this study was to assess the impact of novel agents–based HDT/ASCT regimens on the survival of patients with NH-MM and a high proliferation index. To answer this question, we compared the outcome of patients stratified according to the GEM2000 and GEM2005<65y trials. Overall, the present results show that patients with NH-MM had inferior PFS and OS than did patients with H-MM, particularly in the GEM2005<65y trial, which may suggest that the survival benefit of incorporating novel agents in the HDT/ASCT setting was mainly favoring patients with H-MM. Regarding the prognostic value of the proliferation index, we observed that the poor outcome detected for patients with ≥1% S-phase PCs included in the GEM2000 trial partially disappeared in the GEM2005<65y trial since their OS was identical to that of patients with <1% S-phase PCs. These findings suggest that HDT/ASCT schemes based on the novel agents may overcome the poor prognosis of patients with a high PC proliferation index. Accordingly, the Mayo Stratification of Myeloma and Risk-Adapted Therapy criteria now consider increased proliferation as an intermediate-risk feature in the era of novel agents.
Finally, an interesting comparison between the PCLI measured at diagnosis and after treatment has been recently reported
Reduction in plasma cell proliferation after initial therapy in newly diagnosed multiple myeloma measures treatment response and predicts improved survival.
in which a reduction in the PCLI after initial therapy predicted improved survival. This led us to investigate the potential role of the proliferation index of PCs in disease progression through the sequential analysis of paired diagnostic and relapse samples from a series of 52 patients; in most of the studied cases (85%), the percentage of S-phase PCs doubles at relapse. These results confirm and expand on previous observations derived by GEP showing an increment of patients with the proliferation signature at relapse,
suggesting that the investigation of novel agents targeting a high-proliferative PC could be of value, particularly in relapsing patients with a high proliferation index.
In summary, the present results show that the PC DNA content and proliferation index by MFC immunophenotyping remain as independent prognostic factors in MM, and that the incorporation of novel agents in the HDT/ASCT setting may improve the survival of patients with a high proliferation index but not that of patients with NH-MM. Moreover, we found that patients show an increased proliferation index at relapse; therefore, the precise mechanisms leading to PC proliferation deserve further investigation.
Acknowledgments
We acknowledge all the participants of the PETHEMA/GEM Cooperative Study Groups: José Francisco Tomas Martinez, Isabel Krsnik Castello, Felipe Prósper Cardoso, Joan Besalduch Vidal, Antonia Sampol Mayol, Inmaculada Fuentes Gutiérrez, Jorge Groiss Buiza, Juan Miguel Bergua Burgués, María Luisa Martín Mateos, Manuel Constenla Figueiras, José Luis Bello López, Jesús Arias Sampedro, Nicolás Díaz Varela, Carmen Albó López, Concha Poderós Baeta, Joaquín Díaz Mediavilla, Rafael Martínez Martínez, Germán las Heras Manso, Pablo Lorente Alegre, Elena Prieto Pareja, Albert Oriol Rocafiguera, Aurelio López Martínez, Joan Bladé Creixentí, Rebeca Cuello García, Alfonso García de Coca, Luis Palomera Bernal, Ana Isabel Teruel Casasus, José María Beltrán de Heredia Oyarzabal, Fernando Marco de Lucas, Juan Carlos García Ruíz, Rafael Flores Cornejo, Esther Jaro Arias, Santiago Jiménez Bravo de Laguna, Alexia Suárez Cabrera, Miguel Granell Gorrochategui, Carlos López Capitan, Rafael Ramos Fernández de Soria, Elena Rámila Herrero, Juan Alfonso Soler Campos, Isabel Navarro Gonzalo, Elena Cabezudo Cabezudo, Eugenia Abella Monreal, José Manuel Calvo Villas, Enrique Bengoechea Nerecan, María Asunción Echeveste Gutiérrez, Carmen Aguilera Sanz, María José Fernández Llavador, María Ángeles Ruíz Guinaldo, Jesús María Ojanguren Bergaz, Inmaculada García Navarro, José Mariano Hernández Martín, Fernando Ortega Rivas, Agustín Asensio del Río, Fernando Puente Mangirón, María Blanca Villarubia Lar, Jerónima Ibáñez García, Felipe de Arriba de la Fuente, María José Allegue Vilasó, Abelardo Bárez García, María Jesús Blanchard Blanchard, Antonio Asensio Montoro, Vicente Carrasco Baraja, Luis López Gómez, María José Requena Rodríguez, Joan Bargay Lleonart, José María Guinea de Castro, Carmen Menchaca Echevarría, Yolanda González Montes, Marta Cervera Calvo, Lourdes Escoda Teigell, Juan José Lahuerta Palacios, Bernardo J. González González, Miguel Teodoro Hernández García, Nieves Somolinos de Marcos, Adrián Alegre Amor, Jesús F. San Miguel Izquierdo, Elena Fernández Fontecha, Javier García Frade, Paz Ribas García, Francisco Javier Peñalver Párraga, Javier de la Rubia Comos, Raquel de Paz Arias, Dolores Hernández Maraver, Eulogio Conde García, Pilar Giraldo Castellanos, Araceli Rubio Martínez, Mercedes Gironella Mesa, Pilar Galán Alvarez, Ana Pacheco Onrubia, Monserrat Pérez Sánchez, José María Arguiñano Pérez, María Ángeles Goñi Herranz, Julio Esteban Medina, and Rosa María López López.
We also thank Gloria Ercilla, Isabel Martin, and Maria Teresa Gonzalez for their excellent technical assistance in flow cytometry.
Comparison of plasma cells (PCs) proliferation index in 52 patients with paired bone marrow samples at diagnosis and at relapse. Of note, 44 of the 52 (85%) patients showed an increased percentage of S-phase PCs at relapse (red lines), with a median twofold difference between the proliferative rate at diagnosis versus relapse (0.97% versus 2.29%, respectively; P <.001). The percentage of S-phase PCs at diagnosis versus relapse of all 52 patients is displayed in black notched boxes representing 25th and 75th percentile values; the line in the middle and vertical lines correspond to the median value and both the 10th and 90th percentiles, respectively.
Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis.
Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe Francophone du Myelome.
Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.
Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines.
Reduction in plasma cell proliferation after initial therapy in newly diagnosed multiple myeloma measures treatment response and predicts improved survival.
Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance.
Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences.
Prognostic value of immunophenotyping in multiple myeloma: a study by the PETHEMA/GEM cooperative study groups on patients uniformly treated with high-dose therapy.
HOVON-65/GMMG-HD4 randomized phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly diagnosed multiple myeloma (MM).
Second clones in molecularly-defined biclonal multiple myeloma are derived from unrelated B cells, can be present at high frequency and exhibit chromosomal abnormalities.
Supported by the Cooperative Research Thematic Network (RTICCs RD06/0020/0006, RD06/0020/0005, RD06/0020/0031, RD06/0020/0101, RD06/0020/1056, and G03/136); MM Jevitt, SL firm, Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS: PI060339, 06/1354, 02/0905, 01/0089/01-02, and PS09/01897/01370); and Consejería de Sanidad, Junta de Castilla y León, Valladolid, Spain (557/A/10).
Disclosures: A.O., F.dA., L.P., and J.J.L. have received honoraria from Celgene and Janssen-Cilag. B.P. has received honoraria from, Millennium, Janssen-Cilag, and Celgene. M.V.M. has served on the speaker's bureaus for Millennium, Celgene, and Janssen-Cilag. L.R. and J.B. have received honoraria from and have served on the advisory boards for Janssen-Cilag and Celgene; J.B. has also received grant support from Celgene and Janssen-Cilag. J.F.S.M. has served on the speaker's bureaus and on the advisory boards for and has received honoraria from Millennium, Janssen-Cilag, and Celgene.
High-risk cytogenetics includes any t(4;14), t(14;16), and del(17p); standard-risk cytogenetics includes all other cases.
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