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Bruno Paiva,
Joaquin Martinez-Lopez,
Maria-Belen Vidriales, Maria-Victoria Mateos,
Maria-Angeles Montalban,
Elena Fernandez-Redondo,
Lourdes Alonso,
Albert Oriol,
Ana-Isabel Teruel,
Raquel de Paz,
José-Garcia Laraña,
Enrique Bengoechea,
Alejandro Martin,
Joaquin Diaz Mediavilla,
Luis Palomera,
Felipe de Arriba,
Joan Bladé,
Alberto Orfao,
Juan-Jose Lahuerta,
Jesus F San Miguel
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Jesús F San Miguel,
Rudolf Schlag,
Nuriet K Khuageva,
Meletios A Dimopoulos,
Ofer Shpilberg,
Martin Kropff,
Ivan Spicka,
Maria Teresa Petrucci,
Antonio Palumbo,
Olga S Samoilova, [......],
Michel Delforge,
Bin Jiang, Maria-Victoria Mateos,
Kenneth C Anderson,
Dixie-Lee Esseltine,
Kevin Liu,
William Deraedt,
Andrew Cakana,
Helgi van de Velde,
Paul G Richardson
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ABSTRACT: PURPOSEThis final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies. PATIENTS AND METHODS
In all, 682 patients received up to nine 6-week cycles of VMP or MP and were then observed every 12 weeks or less. Data on second primary malignancies were collected by individual patient inquiries at all sites from 655 patients.ResultsAfter median follow-up of 60.1 months (range, 0 to 74 months), there was a 31% reduced risk of death with VMP versus MP (hazard ratio [HR], 0.695; P < .001; median OS 56.4 v 43.1 months). OS benefit with VMP was seen across prespecified patient subgroups (age ≥ 75 years, stage III myeloma, creatinine clearance < 60 mL/min). Sixty-three percent of VMP patients and 73% of MP patients had received subsequent therapy. Time to next therapy (median, 30.7 v 20.5 months; HR, 0.557; P < .001) was longer with VMP than with MP. Among patients who received subsequent therapies, survival from start of subsequent therapy was similar following VMP (median, 28.1 months) or MP (median, 26.8 months; HR, 0.914). Following VMP/MP, incidence proportions of hematologic malignancies (1%/1%) and solid tumors (5%/3%) and exposure-adjusted incidence rates (0.017/0.013 per patient-year) were similar and were consistent with background rates. CONCLUSIONVMP resulted in a significant reduction in risk of death versus MP that was maintained after 5 years' follow-up and despite substantial use of novel-agent-based salvage therapies. There is no emerging safety signal for second primary malignancies following VMP.
Journal of Clinical Oncology 12/2012; · 18.37 Impact Factor
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Roberto J Pessoa-Magalhaes,
Maria-Belen Vidriales,
Bruno Paiva,
Carlos Fernandez Gimenez,
Ramon Garcia-Sanz, Maria Victoria Mateos,
Norma Gutierrez,
Quentin Lecrevisse,
Juan F Blanco,
Jose Hernandez, [......],
Monica Roig,
Elaine Sobral da Costa,
Enrique Ocio,
Martin Perez-Andres,
Angelo Maiolino,
Marcio Nucci,
Javier Delarubia,
Juan Jose' Lahuerta,
Jesus F San Miguel,
Alberto Orfao
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ABSTRACT: Background. Multiple myeloma remains largely incurable. However, a few patients experience ≥10-years relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with complete response, since some revert into an MGUS profile. Design and Methods. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of long-term disease control multiple myeloma (n=28) vs. both newly-diagnosed MGUS (n=23) and symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Results. Similarly to MGUS and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8+T-cells and NK-cells. However, bone marrow Tregs were reduced in long-term disease control vs. symptomatic multiple myeloma. Noteworthy, B-cells were depleted in MGUS and symptomatic multiple myeloma, while recovered in long-term disease control patients in both bone marrow and peripheral blood, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B-cells. The number of bone marrow dendritic cells and tissue macrophages significantly differed between long-term disease control and symptomatic multiple myeloma with a recovery trend in the former patient population towards levels similar to those found in healthy adults.Conclusions. In summary, our results indicate that long-term disease control multiple myeloma patients have a constellation of unique immune changes favoring both immune cytotoxicity and recovery of B-cell production and homing, suggesting an improved immunesurveillance.Keywords: myeloma, long term follow-up, immunesurveillance, T-cells, Tregs, B-cells.
Haematologica 07/2012; · 6.42 Impact Factor
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ABSTRACT: INTRODUCTION: Several novel proteasome inhibitors (PIs) and immunomodulatory agents (IMIDs) with similar, but not exactly the same, mechanisms of action than their predecessors have been developed in the last years with three different aims: to increase the efficacy; to overcome the resistance and to exhibit a better toxicity profile. AREAS COVERED: This review summarizes the mechanism of action of novel PIs (carfilzomib, ONX-0912, MLN-9708, marizomib and CEP-18770) and IMIDs (pomalidomide), stressing the similarities and differences with their parental drugs. It also reviews their most updated clinical results. A search of the recent literature in published papers and abstracts from the most important oncology scientific meetings (ASCO and ASH) has been performed. EXPERT OPINION: Novel PIs and IMIDs show clinical activity as single agents and in combination with dexamethasone, with similar or even higher efficacy than their predecessors; moreover, they may even overcome resistance to their parental drugs, indicating that there are some differences in their mechanisms of action and resistance. The investigation of these mechanisms of resistance and ways to overcome it would allow the optimization of the sequential use of these agents, and the design of novel therapeutic strategies and more appropriate scientifically based combinations.
Expert Opinion on Investigational Drugs 05/2012; 21(8):1075-87. · 5.27 Impact Factor
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ABSTRACT: Increased risk of acute myeloid leukemia/myelodysplastic syndromes following treatment has been reported in multiple myeloma, but whether dysplastic features are already present at diagnosis remains to be investigated. Using multiparameter flow cytometry, we analyzed the distribution and phenotype of bone marrow hematopoietic cells from 47 multiple myeloma patients (15 symptomatic and 32 high-risk smoldering). From the 32 smoldering myeloma patients, 18 were studied at baseline and 22 after nine cycles of lenalidomide/dexamethasone treatment following the QUIREDEX trial (including 8 from baseline). Phenotypic alterations of bone marrow cells of 7 (47%) symptomatic and 6 (33%) smoldering myeloma patients were detected at baseline; there was no difference in the frequency and extent of phenotypic alterations between symptomatic versus smoldering cases. Likewise, no difference was seen between smoldering myeloma patients studied at baseline versus after lenalidomide/dexamethasone treatment. Our results suggest that phenotypic alterations of bone marrow hematopoietic cells are often present in newly diagnosed symptomatic and smoldering multiple myeloma patients. QUIREDEX trial (NCT00480363).
Haematologica 04/2012; 97(10):1608-1611. · 6.42 Impact Factor
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ABSTRACT: Melphalan-prednisone (MP) was introduced for the treatment of MM in late 1960s. In the subsequent 30 years, the treatment improvements remained stagnant, since more complex chemotherapy combinations, such as vincristine, doxorubicin, and dexamethasone (VAD), or with the addition of BCNU (VBAD) or melphalan and cyclophosphamide (VCMP), only led to small increases in the overall response rate but without differences in survival, as assessed in a large meta-analysis that included over 6000 patients. The next step forward was the use of high-dose melphalan followed by stem cell support (autologous stem cell transplant - ASCT) for young myeloma patients, which resulted in a significant improvement in disease free survival and overall survival. However, for elderly patients MP remained as the standard of care. From year 2000, a revolution in the treatment armamentarium of MM has emerged with the availability of new agents with singular mechanism of action such as thalidomide and lenalidomide (Revlimid®), both immunomodulatory drugs and the proteasome inhibitor bortezomib (Velcade®).
Hematology (Amsterdam, Netherlands) 04/2012; 17 Suppl 1:S3-6. · 1.33 Impact Factor
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ABSTRACT: The current standard of care for elderly patients with newly diagnosed multiple myeloma is melphalan and prednisone (MP) in combination with either bortezomib (VMP) or thalidomide (MPT), with lenalidomide plus dexamethasone increasingly being employed. The addition of bortezomib or thalidomide to the established MP regimen significantly improves outcomes and prolongs survival in elderly and transplant-ineligible patients. However, these benefits are accompanied by increases in treatment-related adverse events (AEs), which may be particularly pronounced in older individuals. Patients receiving bortezomib as part of a VMP regimen commonly experience transient and cyclical thrombocytopenia and neutropenia, along with gastrointestinal AEs. Fortunately, these AEs can be managed with appropriate supportive care and, when necessary, adjustments in dose. Peripheral neuropathy (PN) is the most important side effect of bortezomib, and although it is reversible in a high proportion of patients, it affects their quality of life. Furthermore, PN can require temporary or permanent withholding of bortezomib, which will reduce treatment efficacy. PN is also a common adverse effect of thalidomide; thromboembolic events are also a key concern, requiring thromboprophylaxis in patients receiving thalidomide in combination. For lenalidomide in combination with dexamethasone, the most clinically important adverse effects are hematologic toxicity (particularly neutropenia) and thromboembolic events. Recent phase III studies in newly diagnosed elderly patients are providing further insight into the most appropriate treatment regimens to maximize outcomes and minimize toxicity in individual patients. Of note, once-weekly bortezomib dosing (in combination with MP±T) was shown to reduce the incidence of peripheral neuropathy and gastrointestinal events compared with twice-weekly dosing, while maintaining efficacy. Elderly patients may be less able to withstand the AEs associated with newer treatment regimens and combinations of multiple drugs, and may experience greater declines in quality of life and, subsequently, reduced treatment adherence. It is therefore critical that these patients are closely monitored and any emergent AEs promptly and appropriately managed. For very elderly, frail patients, tailored therapy, reduced intensity regimens, and adverse event management are necessary to encourage treatment adherence and reduce discontinuation. This article will provide practical guidance on the management of bortezomib-, thalidomide-, and lenalidomide-associated AEs, to maximize treatment feasibility and active drug delivered, and thus help minimize toxicity and maximize outcomes.
Blood reviews 07/2011; 25(4):181-91. · 7.19 Impact Factor
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Michel Delforge,
Evangelos Terpos,
Paul G Richardson,
Ofer Shpilberg,
Nuriet K Khuageva,
Rudolf Schlag,
Meletios A Dimopoulos,
Martin Kropff,
Ivan Spicka,
Maria T Petrucci, [......], Maria-Victoria Mateos,
Hila Magen-Nativ,
Hartmut Goldschmidt,
Dixie-Lee Esseltine,
Deborah S Ricci,
Kevin Liu,
William Deraedt,
Andrew Cakana,
Helgi van de Velde,
Jesús F San Miguel
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ABSTRACT: Bone disease is a key presenting feature of myeloma. This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan-prednisone (VMP) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase (ALP), a marker for osteoblast activation, and serum Dickkopf-1 (DKK-1), an inhibitor of osteoblast differentiation, during treatment.
Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m(2) , days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, days 1, 8, 22, 29, cycles 5-9, plus melphalan 9mg/m(2) and prednisone 60mg/m(2) , days 1-4, cycles 1-9; N=344) or MP alone (N=338).
Rates of bisphosphonates use during treatment (73% vs. 82%), progression because of worsening bone disease (3% vs. 11%), and requirement for subsequent radiotherapy (3% vs. 8%) were lower with VMP vs. MP. Median maximum ALP increase was significantly higher with VMP vs. MP overall (49.7% vs. 30.3%, P=0.029), and higher by response group (complete response [CR]: 68.7% vs. 43.9%; partial response [PR]: 41.5% vs. 31.2%). Greater maximum ALP increase was strongly associated with achievement of CR (P≤0.0001) and CR/PR (P≤0.01). Median DKK-1 decreased with VMP by 694.4pg/mL and increased with MP by 1273.3pg/mL from baseline to day 4 (P=0.0069). Available radiologic data revealed evidence of bone healing in 6/11 VMP-treated patients, who achieved best responses of three CR, one PR, and two stable disease.
These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma.
European Journal Of Haematology 03/2011; 86(5):372-84. · 2.61 Impact Factor
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Paul Richardson,
Rudolf Schlag,
Nuriet Khuageva,
Meletios Dimopoulos,
Ofer Shpilberg,
Martin Kropff,
Marie-Christiane Vekemans,
Maria Teresa Petrucci,
Viktor Rossiev,
Jian Hou,
Tadeusz Robak, Maria-Victoria Mateos,
Kenneth Anderson,
Dixie-Lee Esseltine,
Andrew Cakana,
Kevin Liu,
William Deraedt,
Helgi van de Velde,
Jesús F San Miguel
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ABSTRACT: Although haematological toxicities, such as anaemia, are common in multiple myeloma (MM), no clear consensus exists on the use and impact of erythropoiesis-stimulating agents (ESA) on outcomes in MM. This analysis characterizes haematological toxicities and associated interventions in the phase III VISTA (Velcade(®) as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) study of bortezomib plus melphalan/prednisone (VMP, n = 344) versus MP (n = 338) in previously untreated MM patients ineligible for high-dose therapy, and evaluates the impact of ESA use or red-blood-cell (RBC) transfusions on outcomes and thromboembolic risk. Incidence of haematological toxicities was similar with VMP and MP; similar rates of interventions and associated complications (e.g. bleeding, febrile neutropenia) were observed. Two hundred thirty three patients received ESA; 204 had RBC transfusions. Frequency of thromboembolic events was low and not affected by ESA use. Median time-to progression (TTP) was similar between ESA/non-ESA [hazard ratio: 1·03 (95% confidence interval 0·76-1·39); P = 0·8478] in both arms (VMP: 19·9/not reached; MP: 15·0/17·5 months). Three-year overall survival (OS) rates were similar between ESA/non-ESA in each arm. Patients receiving RBC transfusions had significantly shorter OS (P < 0·0001) versus non-RBC-transfusion patients. In conclusion, bortezomib did not add to melphalan haematological toxicity. Concomitant ESA use with VMP/MP in previously untreated MM patients did not adversely affect TTP or OS, or increase thromboembolic risk. However, RBC transfusion was associated with significantly shorter survival.
British Journal of Haematology 03/2011; 153(2):212-21. · 4.94 Impact Factor
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Bruno Paiva,
Joaquin Martinez-Lopez,
Maria-Belen Vidriales, Maria-Victoria Mateos,
Maria-Angeles Montalban,
Elena Fernandez-Redondo,
Lourdes Alonso,
Albert Oriol,
Ana-Isabel Teruel,
Raquel de Paz,
José-Garcia Laraña,
Enrique Bengoechea,
Alejandro Martin,
Joaquin Diaz Mediavilla,
Luis Palomera,
Felipe de Arriba,
Joan Bladé,
Alberto Orfao,
Juan-Jose Lahuerta,
Jesus F San Miguel
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ABSTRACT: To investigate the impact of immunophenotypic response (IR) versus complete response (CR) and CR plus normal serum free light chain (sFLC) ratio (stringent CR) in elderly patients with multiple myeloma (MM) treated with novel agents.
From a total of 260 elderly patients newly diagnosed with MM included in the GEM05>65y trial, 102 patients achieving at least a partial response with ≥ 70% reduction in M-component after the six planned induction cycles were simultaneously analyzed by immunofixation, sFLC, and multiparameter flow cytometry (MFC) immunophenotyping; this population is the focus of this study.
Forty-three percent of patients achieved CR, 30% achieved stringent CR, and 30% achieved IR. Patients in stringent CR showed no significant survival advantage compared with those in CR, whereas patients in IR showed significantly increased progression-free survival (PFS) and time to progression (TTP) compared with those in stringent CR or CR; this was confirmed by multivariate analysis (hazard ratio, 4.1; P = .01 for PFS). Discrepancies between the three techniques were relatively common. Notably, in all seven patients achieving IR but remaining immunofixation positive, the M-component disappeared in follow-up analysis. In contrast, MFC-positive patients who were immunofixation negative (n = 20) showed a tendency toward early reappearance of the M-component (median, 3 months). Similarly, in five of 11 stringent CR but MFC-positive patients, symptomatic disease progression was recorded at a median of 13 months after induction.
Achieving an IR translates into superior PFS and TTP compared with conventional CR or stringent CR. These techniques provide complementary information and thus, an effort should be made to refine response criteria in MM.
Journal of Clinical Oncology 03/2011; 29(12):1627-33. · 18.37 Impact Factor
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ABSTRACT: Genetic aberrations detected in multiple myeloma (MM) have also been reported in the premalignant conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Our aim was to investigate in depth the level of clonal heterogeneity of recurrent genetic abnormalities in these conditions.
Immunoglobulin heavy chain (IGH) translocations, 13q14 and 17p13 deletions, and 1q21 gains using FISH were evaluated in 90 MGUS, 102 high-risk SMM, and 373 MM. To this end, we not only purified plasma cells (PC) for the FISH analysis (purity > 90%), but subsequently, we examined the correlation between the proportion of PC with cytogenetic changes and the number of clonal PC present in the same sample, as measured by multiparametric flow cytometry.
We observed a significant difference between the proportion of clonal PC with specific genetic abnormalities in MGUS compared with SMM and in SMM compared with MM. Thus, the median proportion of PC with IGH translocations globally considered, t(11;14) and 13q deletions was significantly lower in MGUS than in SMM, and in SMM than in MM [IGH translocations: 34% vs. 57% vs. 76%; t(11;14): 38% vs. 61% vs. 81%; and 13q deletion: 37% vs. 61% vs. 74% in MGUS, SMM, and MM, respectively]. For t(4;14), the difference was significant in the comparison between MGUS/SMM and MM and for 1q between MGUS and SMM/MM.
This study demonstrates that the progression from MGUS to SMM, and eventually to MM, involves a clonal expansion of genetically abnormal PC.
Clinical Cancer Research 02/2011; 17(7):1692-700. · 7.74 Impact Factor
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Meletios A Dimopoulos, Maria-Victoria Mateos,
Paul G Richardson,
Rudolf Schlag,
Nuriet K Khuageva,
Ofer Shpilberg,
Martin Kropff,
Ivan Spicka,
Antonio Palumbo,
Ka Lung Wu,
Dixie-Lee Esseltine,
Kevin Liu,
William Deraedt,
Andrew Cakana,
Helgi Van De Velde,
Jesús F San Miguel
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ABSTRACT: This subanalysis of the phase 3 VISTA trial aimed to assess the frequency, characteristics and reversibility of, and prognostic factors for, bortezomib-associated peripheral neuropathy (PN) in newly diagnosed patients with multiple myeloma ineligible for high-dose therapy who received bortezomib plus melphalan-prednisone.
Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m(2), days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, and days 1, 8, 22, 29, cycles 5-9; melphalan 9 mg/m(2), days 1-4, cycles 1-9; and prednisone 60 mg/m(2), days 1-4, cycles 1-9).
Overall, 47% of patients receiving VMP developed PN, including 19% grade 2 and 13% grade ≥ 3 (<1% grade 4). The PN incidence was dose-related and reached a plateau at a cumulative bortezomib dose of approximately 45 mg/m(2). Median time to PN onset was 2.3 months. Bortezomib-associated PN was reversible; 79% of events improved by at least one NCI CTCAE grade within a median of 1.9 months and 60% completely resolved within a median of 5.7 months, with reversibility similar in responding and non-responding patients. By multivariate analysis, baseline neuropathy was the only consistent risk factor for any PN [hazard ratio (HR) 1.785, P=0.0065], grade ≥ 2 PN (HR 2.205, P=0.0032), and grade ≥ 3 PN (HR 2.438, P=0.023); age, pre-existing diabetes, International Staging System stage, obesity, and creatinine clearance did not affect the overall rate of PN.
Rates of bortezomib-induced PN in the frontline setting were similar to those in relapsed patients and resolved in most cases.
European Journal Of Haematology 01/2011; 86(1):23-31. · 2.61 Impact Factor
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Jean-Luc Harousseau,
Antonio Palumbo,
Paul G Richardson,
Rudolf Schlag,
Meletios A Dimopoulos,
Ofer Shpilberg,
Martin Kropff,
Alain Kentos,
Michele Cavo,
Anatoly Golenkov,
Mieczyslaw Komarnicki, Maria-Victoria Mateos,
Dixie-Lee Esseltine,
Andrew Cakana,
Kevin Liu,
William Deraedt,
Helgi van de Velde,
Jesús F San Miguel
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ABSTRACT: The phase 3 Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone study in newly diagnosed multiple myeloma patients ineligible for high-dose therapy demonstrated that bortezomib-melphalan-prednisone (VMP) was superior to melphalan-prednisone across all efficacy end points. We assessed the prognostic impact of response on time-to-event parameters in the intent-to-treat population. Patients received nine 6-week cycles of treatment. Time to progression, time to next therapy, and treatment-free interval were associated with quality of response. When European Group for Blood and Marrow Transplantation criteria were used, complete response (CR) was associated with significantly longer time to progression (hazard ratio [HR] = 0.45, P = .004), time to next therapy (HR = 0.46, P = .0004), and treatment-free interval (HR = 0.38, P < .0001) versus partial response, but there was no significant difference in overall survival (HR = 0.87, P = .54); similar differences were seen with CR versus very good partial response by uniform criteria. Quality of response improved with prolonged VMP treatment, with 28% of CRs achieved during cycles 5-9. CR duration appeared similar among patients with "early" (cycles 1-4) and "late" CRs (cycles 5-9) and among patients receiving 9 versus < 9 cycles of bortezomib within VMP. These results highlight that CR is an important treatment goal and support prolonged VMP therapy to achieve maximal response. This study is registered at http://www.clinicaltrials.gov as NCT00111319.
Blood 11/2010; 116(19):3743-50. · 9.90 Impact Factor
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Juan José Lahuerta, Maria Victoria Mateos,
Joaquin Martínez-López,
Carlos Grande,
Javier de la Rubia,
Laura Rosiñol,
Anna Sureda,
José García-Laraña,
Joaquín Díaz-Mediavilla,
Miguel T Hernández-García,
Dolores Carrera,
Joan Besalduch,
Felipe de Arriba,
Albert Oriol,
Lourdes Escoda,
Javier García-Frade,
Concepción Rivas-González,
Adrían Alegre,
Joan Bladé,
Jesús F San Miguel
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ABSTRACT: The aim of this study was to compare the long-term safety and efficacy of oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) and melphalan 200 mg/m(2) as conditioning regimens for autologous stem cell transplantation in newly diagnosed patients with multiple myeloma in the GEM2000 study.
The first 225 patients received oral busulfan 12 mg/kg plus melphalan 140 mg/m(2); because of a high frequency of veno-occlusive disease, the protocol was amended and a further 542 patients received melphalan 200 mg/m(2).
Engraftment and hospitalization times were similar in both groups. Oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) resulted in higher transplant-related mortality (8.4% versus 3.5%; P=0.002) due to the increased frequency of veno-occlusive disease in this group. Response rates were similar in both arms. With respective median follow-ups of 72 and 47 months, the median progression-free survival was significantly longer with busulfan plus melphalan (41 versus 31 months; P=0.009), although survival was similar to that in the melphalan 200 mg/m(2) group. However, access to novel agents as salvage therapy after relapse/progression was significantly lower for patients receiving busulfan plus melphalan (43%) than for those receiving melphalan 200 mg/m(2) (58%; P=0.01).
Conditioning with oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) was associated with longer progression-free survival but equivalent survival to that achieved with melphalan 200 mg/m(2) but this should be counterbalanced against the higher frequency of veno-occlusive disease-related deaths. This latter fact together with the limited access to novel salvage therapies in patients conditioned with oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) may explain the absence of a survival difference. Oral busulfan was used in the present study; use of the intravenous formulation may reduce toxicity and result in greater efficacy, and warrants further investigation in myeloma patients. (Clinicaltrials.gov identifier: NCT00560053).
Haematologica 11/2010; 95(11):1913-20. · 6.42 Impact Factor
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Maria-Victoria Mateos,
Paul G Richardson,
Rudolf Schlag,
Nuriet K Khuageva,
Meletios A Dimopoulos,
Ofer Shpilberg,
Martin Kropff,
Ivan Spicka,
Maria T Petrucci,
Antonio Palumbo,
Olga S Samoilova,
Anna Dmoszynska,
Kudrat M Abdulkadyrov,
Rik Schots,
Bin Jiang,
Dixie L Esseltine,
Kevin Liu,
Andrew Cakana,
Helgi van de Velde,
Jesús F San Miguel
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ABSTRACT: The purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies.
Previously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338).
With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months.
VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent-based treatment until relapse.
Journal of Clinical Oncology 04/2010; 28(13):2259-66. · 18.37 Impact Factor
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ABSTRACT: Quantification of bone marrow plasma cells in multiple myeloma patients using conventional morphology is of limited prognostic value, while the merit of multiparameter flow cytometry immunophenotyping is still considered unproven. Here we compare the bone marrow plasma cell counts obtained by morphology and multiparameter flow cytometry and explore the potential prognostic impact of both techniques in 765 newly diagnosed, uniformly treated multiple myeloma patients. Although multiparameter flow cytometry generally yields lower plasma cell counts (median percentage of 11% vs. 40%, respectively; p<0.001), there is a significant positive correlation between the two techniques (R =0.46, p<0.001). Regarding prognosis, multivariate analysis selected the bone marrow plasma cell counts obtained by multiparameter flow cytometry as an independent prognostic factor for overall survival (p=0.007), supporting the incorporation of multiparameter flow cytometry immunophenotyping into the routine diagnostic evaluation of multiple myeloma patients and validating the clinical utility of bone marrow plasma cell counting by multiparameter flow cytometry approaches. (clinicaltrials.gov identifier: NCT00560053).
Haematologica 11/2009; 94(11):1599-602. · 6.42 Impact Factor
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Meletios A Dimopoulos,
Paul G Richardson,
Rudolf Schlag,
Nuriet K Khuageva,
Ofer Shpilberg,
Efstathios Kastritis,
Martin Kropff,
Maria T Petrucci,
Michel Delforge,
Julia Alexeeva,
Rik Schots,
Tamás Masszi, Maria-Victoria Mateos,
William Deraedt,
Kevin Liu,
Andrew Cakana,
Helgi van de Velde,
Jesús F San Miguel
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ABSTRACT: PURPOSE To assess bortezomib plus melphalan and prednisone (VMP) and melphalan and prednisone (MP) in previously untreated patients with multiple myeloma (MM) with renal impairment enrolled on the phase III VISTA study, and to evaluate renal impairment reversibility. PATIENTS AND METHODS Patients received nine 6-week cycles of VMP (bortezomib 1.3 mg/m(2), melphalan 9 mg/m(2), prednisone 60 mg/m(2)) or MP. Patients with serum creatinine higher than 2 mg/dL were excluded. Results In the VMP/MP arms, 6%/4%, 27%/30%, and 67%/66% of patients had baseline glomerular filtration rate (GFR) of < or = 30, 31 to 50, and higher than 50 mL/min, respectively. Response rates were higher and time to progression (TTP) and overall survival (OS) longer with VMP versus MP across renal cohorts. Response rates with VMP and TTP in both arms did not appear significantly different between patients with GFR < or = 50 or higher than 50 mL/min; OS appeared somewhat longer in patients with normal renal function in both arms. Renal impairment reversal (baseline GFR < 50 improving to > 60 mL/min) was seen in 49 (44%) of 111 patients receiving VMP versus 40 (34%) of 116 patients receiving MP. By multivariate analysis, younger age (< 75 years; P = .006) and less severe impairment (GFR > or = 30 mL/min; P = .027) were associated with higher reversal rates. In addition, treatment with VMP approached significance (P = .07). In both arms, rates of grade 4 and 5 adverse events (AEs) and serious AEs appeared higher in patients with renal impairment; with VMP, rates of discontinuations/bortezomib dose reductions due to AEs did not appear affected. CONCLUSION VMP is a feasible, active, and well-tolerated treatment option for previously untreated patients with MM with moderate renal impairment, resulting in 44% renal impairment reversal.
Journal of Clinical Oncology 10/2009; 27(36):6086-93. · 18.37 Impact Factor
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Bruno Paiva,
Maria-Belén Vidriales,
Gema Mateo,
Jose J Pérez,
Maria Angeles Montalbán,
Anna Sureda,
Laura Montejano,
Norma C Gutiérrez,
Alfonso García de Coca,
Natalia de las Heras, [......],
Luis Palomera,
Dolores Carrera,
Rafael Martínez,
Javier de la Rubia,
Alejandro Martín,
Yolanda González,
Joan Bladé,
Juan José Lahuerta,
Alberto Orfao,
Jesús F San-Miguel
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ABSTRACT: Multiparameter flow cytometry immunophenotyping allows discrimination between normal (N-) and myelomatous (MM-) plasma cells (PCs) within the bone marrow plasma cell compartment (BMPCs). Here we report on the prognostic relevance of detecting more than 5% residual normal plasma cells from all bone marrow plasma cells (N-PCs/BMPCs) by multiparameter flow cytometry in a series of 594 newly diagnosed symptomatic MM patients, uniformly treated according to the Grupo Español de MM 2000 (GEM2000) protocol. Our results show that symptomatic MM patients with more than 5% N-PCs/BMPCs (n = 80 of 594; 14%) have a favorable baseline clinical prospect, together with a significantly lower frequency of high-risk cytogenetic abnormalities and higher response rates. Moreover, this group of patients had a significantly longer progression-free survival (median, 54 vs 42 months, P = .001) and overall survival (median, not reached vs 89 months, P = .04) than patients with less than or equal to 5% N-PCs/BMPCs. Our findings support the clinical value of detecting residual normal PCs in MM patients at diagnosis because this reveals a good prognostic category that could benefit from specific therapeutic approaches. This trial was registered at www.clinicaltrials.gov as NCT00560053.
Blood 09/2009; 114(20):4369-72. · 9.90 Impact Factor
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ABSTRACT: Melphalan-prednisone-thalidomide (MPT) and melphalan-prednisone-bortezomib (MPV) currently appear to be the treatments of choice for a large proportion of elderly multiple myeloma (MM) patients ineligible for autologous stem cell transplantation (ASCT). It seems certain that in the near future cyclophosphamide-thalidomide-dexamethasone, with an attenuated dose of dexamethasone (CTDa), and melphalan-prednisone-lenalidomide (MPR) will also be proved superior to MP, thus providing four therapeutic options in this patient group. These options could lead to more personalized treatment approaches, based on patient comorbidities, as the three novel agents have somewhat different toxicity profiles. MP would be appropriate for only a minority of patients with poor performance status and/or significant comorbidities. Questions regarding the relative efficacy of different melphalan-based regimens or melphalan-based regimens versus dexamethasone-based regimens with low-dose dexamethasone will require further trials. Additionally, the important issue of maintenance treatment needs to be investigated. These new and emerging therapies provide multiple effective treatment options for MM patients and greatly enhanced treatment strategies for clinicians, all offering promise that has been sorely lacking over the past four decades.
Seminars in Hematology 05/2009; 46(2):133-42. · 3.99 Impact Factor
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Juan José Lahuerta, Maria Victoria Mateos,
Joaquin Martínez-López,
Laura Rosiñol,
Anna Sureda,
Javier de la Rubia,
José García-Laraña,
Rafael Martínez-Martínez,
Miguel T Hernández-García,
Dolores Carrera,
Joan Besalduch,
Felipe de Arriba,
José María Ribera,
Lourdes Escoda,
Belén Hernández-Ruiz,
Javier García-Frade,
Concepción Rivas-González,
Adrían Alegre,
Joan Bladé,
Jesús F San Miguel
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ABSTRACT: Complete response (CR) is considered an important goal in most hematologic malignancies. However, in multiple myeloma (MM), there is no consensus regarding whether immunofixation (IF)-negative CR, IF-positive near-CR (nCR), and partial response (PR) are associated with different survivals. We evaluated the prognostic influence on event-free survival (EFS) and overall survival (OS) of these responses pre- and post-transplantation in newly diagnosed patients with MM.
We analyzed 632 patients from the prospective Grupo Español de Mieloma 2000 protocol who were uniformly treated with vincristine, carmustine, cyclophosphamide, melphalan, and predisone/vincristine, carmustine, adryamcine, and dexamethasone induction followed by high-dose therapy and autologous stem-cell transplantation.
Post-transplantation response markedly influenced outcomes. Patients achieving CR had significantly longer EFS (median, 61 v 40 months; P < 10(-5)) and OS (medians not reached; P = .01) versus patients achieving nCR, who likewise had somewhat better outcomes compared with patients achieving PR (median EFS, 34 months, P = .07 v nCR; median OS, 61 months, P = .04). EFS and OS and influence of response were similar among older (age 65 to 70 years) and younger (age < 65 years) patients. Similar findings were observed with pretransplantation response, with trends toward EFS (P = .1; P = .05) and OS (P = .1; P = .07) benefit in patients achieving CR versus nCR and PR, respectively. Post-transplantation response was markedly influenced by pretransplantation response; improvements in response were associated with prolonged survival.
Quality of response post-transplantation, notably CR, is significantly associated with EFS and OS prolongation in newly diagnosed patients with MM. There were trends toward similar associations with pretransplantation response status.
Journal of Clinical Oncology 11/2008; 26(35):5775-82. · 18.37 Impact Factor
