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Integrated analysis of randomized controlled trials evaluating bortezomib + lenalidomide + dexamethasone or bortezomib + thalidomide + dexamethasone induction in transplant-eligible newly diagnosed multiple myeloma
Rosiñol, L., Hebraud, B., Oriol, A., Colin, A. L., Ríos Tamayo, R., Hulin, C., Blanchard, M. J., Caillot, D., Sureda, A., Hernández, M. T., et al
Frontiers in oncology. 2023;13:1197340
Abstract
OBJECTIVE Providing the most efficacious frontline treatment for newly diagnosed multiple myeloma (NDMM) is critical for patient outcomes. No direct comparisons have been made between bortezomib + lenalidomide + dexamethasone (VRD) and bortezomib + thalidomide + dexamethasone (VTD) induction regimens in transplant-eligible NDMM. METHODS An integrated analysis was performed using patient data from four trials meeting prespecified eligibility criteria: two using VRD (PETHEMA GEM2012 and IFM 2009) and two using VTD (PETHEMA GEM2005 and IFM 2013-04). RESULTS The primary endpoint was met, with VRD demonstrating a noninferior rate of at least very good partial response (≥ VGPR) after induction vs VTD. GEM comparison demonstrated improvement in the ≥ VGPR rate after induction for VRD vs VTD (66.3% vs 51.2%; P = .00281) that increased after transplant (74.4% vs 53.5%). Undetectable minimal residual disease rates post induction (46.7% vs 34.9%) and post transplant (62.4% vs 47.3%) support the benefit of VRD vs VTD. Treatment-emergent adverse events leading to study and/or treatment discontinuation were less frequent with VRD (3%, GEM2012; 6%, IFM 2009) vs VTD (11%, IFM 2013-04). CONCLUSION These results supported the benefit of VRD over VTD for induction in transplant-eligible patients with NDMM. The trials included are registered with ClinicalTrials.gov (NCT01916252, NCT01191060, NCT00461747, and NCT01971658).
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Lenalidomide and dexamethasone with or without ixazomib maintenance tailored by residual disease status in myeloma
Rosiñol, L., Oriol, A., Ríos-Tamayo, R., Blanchard, M. J., Jarque, I., Bargay, J., Hernandez Garcia, M. T., Cabañas, V., Carrillo-Cruz, E., Sureda, A., et al
Blood. 2023
Abstract
From November 2014 to May 2017, 332 patients homogeneously treated with VRD induction, ASCT and VRD consolidation were randomized to receive maintenance therapy with RD (161 patients) vs IRD (171 patients). RD consisted of lenalidomide 15 mg/d from days 1-21 plus dexamethasone 20 mg/d on days 1-4 and 9-12 at 4-weeks intervals while in the IRD arm oral ixazomib at a dose of 4 mg on days 1,8, and 15 was added. MRD negative patients after 24 cycles were discontinued while those who were MRD positive remained on maintenance with RD for 36 more cycles. The MRD negativity from baseline increased from 50.9% to 71.8% with RD and from 59.6% to 72.4% with IRD at 2 years. After a median follow-up of 69 months from the initiation of maintenance, the PFS was similar in both arms, median not reached in either arm with a 6-years PFS rate of 61.3% and 55.6% for RD and IRD, respectively (HR 1.136 [95% CI 0.809 - 1.603]). No significant differences in PFS between RD and IRD were observed in any prognostic subgroup. After 2 years of maintenance, treatment was discontinued in 163 patients who were MRD negative while 63 MRD positive patients were continued on RD therapy. Maintenance discontinuation in MRD negative patients resulted in a low progression rate (17.2% at 4 years), even in patients with high-risk features. In summary, our results show the efficacy of RD maintenance and support the safety of maintenance discontinuation in MRD negative patients at 2 years. This trial is registered at ClinicalTrials.gov (NCT02406144) and EudraCT (2014-00055410).
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3.
Circulating Tumor Cells for the Staging of Patients With Newly Diagnosed Transplant-Eligible Multiple Myeloma
Garcés, J. J., Cedena, M. T., Puig, N., Burgos, L., Perez, J. J., Cordon, L., Flores-Montero, J., Sanoja-Flores, L., Calasanz, M. J., Ortiol, A., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022;:Jco2101365
Abstract
PURPOSE Patients with multiple myeloma (MM) may show patchy bone marrow (BM) infiltration and extramedullary disease. Notwithstanding, quantification of plasma cells (PCs) continues to be performed in BM since the clinical translation of circulating tumor cells (CTCs) remains undefined. PATIENTS AND METHODS CTCs were measured in peripheral blood (PB) of 374 patients with newly diagnosed MM enrolled in the GEM2012MENOS65 and GEM2014MAIN trials. Treatment included bortezomib, lenalidomide, and dexamethasone induction followed by autologous transplant, consolidation, and maintenance. Next-generation flow cytometry was used to evaluate CTCs in PB at diagnosis and measurable residual disease (MRD) in BM throughout treatment. RESULTS CTCs were detected in 92% (344 of 374) of patients with newly diagnosed MM. The correlation between the percentages of CTCs and BM PCs was modest. Increasing logarithmic percentages of CTCs were associated with inferior progression-free survival (PFS). A cutoff of 0.01% CTCs showed an independent prognostic value (hazard ratio: 2.02; 95% CI, 1.3 to 3.1; P = .001) in multivariable PFS analysis including the International Staging System, lactate dehydrogenase levels, and cytogenetics. The combination of the four prognostic factors significantly improved risk stratification. Outcomes according to the percentage of CTCs and depth of response to treatment showed that patients with undetectable CTCs had exceptional PFS regardless of complete remission and MRD status. In all other cases with detectable CTCs, only achieving MRD negativity (and not complete remission) demonstrated a statistically significant increase in PFS. CONCLUSION Evaluation of CTCs in PB outperformed quantification of BM PCs. The detection of ≥ 0.01% CTCs could be a new risk factor in novel staging systems for patients with transplant-eligible MM.
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Predicting mortality after autologous transplant: Development of a novel risk score
Berro, M., Chhabra, S., Pinana, J. L., Arbelbide, J., Rivas, M. M., Basquiera, A. L., Vitriu, A., Requejo, A., Milovic, V., Yantorno, S., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
There have been several efforts to predict mortality after autologous stem cell transplantation (ASCT), such as the Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI), described for allogeneic-SCT and validated for ASCT, however there is no composite score in the setting of ASCT combining comorbidities with other clinical characteristics. Our aim is to describe a comprehensive score combining comorbidities with other clinical factors and to analyze the impact of this score on non-relapse mortality (NRM), overall survival (OS) and early morbidity end-points (mechanical ventilation, shock or dialysis) after ASCT. For the training cohort, we retrospectively reviewed data of 2068 adult patients who received an ASCT in Argentina (10/2002-06/2017) for multiple myeloma or lymphoma. For the validation cohort, we analyzed 2168 ASCT performed in the Medical College of Wisconsin and Spanish stem cell transplant group (GETH) (01/2012-12/2018). We first performed a multivariate analysis for NRM in order to select and assigned weight to the risk factors included in the score (male patients, age 55-64 and ≥65 years, HCT-CI ≥3, HL and NHL). The hazard ratio for NRM increased proportionally with the score. Patients were grouped as low risk (LR) with a score 0-1 (686, 33%), intermediate risk (IR) score 2-3 (1109, 53%), high risk (HR) score 4 (198, 10%) and very high risk (VHR) score ≥5 (75, 4%). The score was associated with a progressive increase in all the early morbidity endpoints. Moreover, the score was significantly associated with early NRM (day 100: 1.5% vs 2.4% vs 7.6% vs. 17.6%) as well as long term (1-3 years 1.8-2.3% vs. 3.8-4.9% vs. 11.7-14.5% vs. 25.0-27.4% respectively, p<0.0001) and OS (1-5 years 94-73% vs. 89-75% vs. 76-47% vs. 65-52% respectively, p<0.0001). The score was validated in an independent cohort (N=2168) and was significantly associated with early and late events. In conclusion, we developed and validated a novel score predicting NRM and OS in two large cohorts of more than 2000 autologous transplant patients. This tool can be useful for tailoring conditioning regimens or defining risk for transplant programs decision-making.
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5.
Measurable Residual Disease by Next-Generation Flow Cytometry in Multiple Myeloma
Paiva, B., Puig, N., Cedena, M. T., Rosinol, L., Cordon, L., Vidriales, M. B., Burgos, L., Flores-Montero, J., Sanoja-Flores, L., Lopez-Anglada, L., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019;:Jco1901231
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Abstract
PURPOSE Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG). PATIENTS AND METHODS In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 x 10(-6). Patients received maintenance (lenalidomide +/- ixazomib) according to the companion PETHEMA/GEM2014MAIN trial. RESULTS Overall, 205 (45%) of 458 patients had undetectable MRD after consolidation, and only 14 of them (7%) have experienced progression thus far; seven of these 14 displayed extraosseous plasmacytomas at diagnosis and/or relapse. Using time-dependent analysis, patients with undetectable MRD had an 82% reduction in the risk of progression or death (hazard ratio, 0.18; 95% CI, 0.11 to 0.30; P < .001) and an 88% reduction in the risk of death (hazard ratio, 0.12; 95% CI, 0.05 to 0.29; P < .001). Timing of undetectable MRD (after induction v intensification) had no impact on patient survival. Attaining undetectable MRD overcame poor prognostic features at diagnosis, including high-risk cytogenetics. By contrast, patients with Revised International Staging System III status and positive MRD had dismal progression-free and overall survivals (median, 14 and 17 months, respectively). Maintenance increased the rate of undetectable MRD by 17%. CONCLUSION The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM.
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Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplantation in multiple myeloma
Rosinol, L., Oriol, A., Rios, R., Sureda, A., Blanchard, M. J., Hernandez, M. T., Martinez-Martinez, R., Moraleda, J. M., Jarque, I., Bargay, J., et al
Blood. 2019
Abstract
Achieving and maintaining high-quality response is the treatment goal for patients with newly diagnosed multiple myeloma (NDMM). The phase 3 PETHEMA/GEM2012 study, in 458 patients {less than or equal to} 65 years old with NDMM, is evaluating bortezomib (subcutaneous) + lenalidomide + dexamethasone (VRD) for 6 cycles followed by autologous stem cell transplant (ASCT) conditioned with intravenous busulfan + melphalan vs melphalan and posttransplant consolidation with 2 cycles of VRD. We present grouped response analysis of induction, transplant, and consolidation. Responses deepened over time; in patients who initiated cycle 6 of induction (n = 426), the {greater than or equal to} very good partial response rates were 55.6% by cycle 3, 63.8% by cycle 4, 68.3% by cycle 5, and 70.4% after induction. The complete response rate of 33.4% after induction in the intent-to-treat (ITT) population, which was similar in the 92 patients with high-risk cytogenetics (34.8%), also deepened with further treatment (44.1% after ASCT and 50.2% after consolidation). Rates of undetectable minimal residual disease (median 3 x 10(-6) sensitivity) in the ITT population also increased from induction (28.8%) to transplant (42.1%) and consolidation (45.2%). The most common grade {greater than or equal to} 3 treatment-emergent adverse events during induction were neutropenia (12.9%) and infection (9.2%). Grade {greater than or equal to} 2 peripheral neuropathy (grouped term) during induction was 17.0%, with a low frequency of grade 3 (3.7%) and grade 4 (0.2%) events. VRD is an effective and well-tolerated regimen for induction in NDMM with deepening response throughout induction and over the course of treatment. This trial was registered at ClinicalTrials.gov (NCT01916252) and EudraCT (2012-005683-10).
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Advantages of non-cryopreserved autologous hematopoietic stem cell transplantation against a cryopreserved strategy
Sarmiento, M., Ramirez, P., Parody, R., Salas, M. Q., Beffermann, N., Jara, V., Bertin, P., Pizarro, I., Lorca, C., Rivera, E., et al
Bone marrow transplantation. 2018
Abstract
Autologous stem cell transplantation (auto-HSCT) is an effective treatment strategy for hematological malignancies. The standard mode of handling hematopoietic progenitors for the autologous procedure (CRYO) consists on its collection and freezing with dimethyl sulfoxide (DMSO) and its subsequent thawing and re-infusion. This process is toxic and expensive. Non-cryopreserved (non-CRYO) is a less expensive mode of auto-HSCT. We designed a comparative study between both strategies performed in two different centers to analyze the short-term complications. In total 111 auto-HSCT were performed from January/2015 to October/2016 (42 non-CRYO and 74 CRYO). There were 74 males and 69 (62%) patients had the underlying diagnosis of multiple myeloma. No differences were seen on the characteristics of the apheresis products and their viability. Engraftment was significantly faster in the non-CRYO group (p = 0.001). Febrile neutropenia and severe mucositis were lower in the non-CRYO group (40% vs 92% p = 0.0001 and 11% vs 64%, p = 0.001, respectively). In addition, length of hospitalization was 5 days shorter in the non-CRYO group (p = 0.0001). Overall responses and transplantation outcomes were similar. Our data demonstrate a clear advantage of the non-CRYO over CRYO auto-HSCT with faster engraftment, lower incidence of febrile neutropenia and shorter hospital stay after the transplantation procedure. These data are especially relevant for centers with high transplant activity or with limited resources.
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High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma
Paiva, B., Gutierrez, N. C., Rosinol, L., Vidriales, M. B., Montalban, M. A., Martinez-Lopez, J., Mateos, M. V., Cibeira, M. T., Cordon, L., Oriol, A., et al
Blood. 2012;119(3):687-91
Abstract
The achievement of complete response (CR) after high-dose therapy/autologous stem cell transplantation (HDT/ASCT) is a surrogate for prolonged survival in multiple myeloma; however, patients who lose their CR status within 1 year of HDT/ASCT (unsustained CR) have poor prognosis. Thus, the identification of these patients is highly relevant. Here, we investigate which prognostic markers can predict unsustained CR in a series of 241 patients in CR at day +100 after HDT/ASCT who were enrolled in the Spanish GEM2000 (n = 140) and GEM2005 < 65y (n = 101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median overall survival 39 months). The presence of baseline high-risk cytogenetics by FISH (hazard ratio 17.3; P = .002) and persistent minimal residual disease by multiparameter flow cytometry at day +100 after HDT/ASCT (hazard ratio 8.0; P = .005) were the only independent factors that predicted unsustained CR. Thus, these 2 parameters may help to identify patients in CR at risk of early progression after HDT/ASCT in whom novel treatments should be investigated.