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1.
Haematologica ; 109(7): 2239-2249, 2024 07 01.
Article in English | MEDLINE | ID: mdl-38299578

ABSTRACT

The primary and prespecified updated analyses of ICARIA-MM (clinicaltrial gov. Identifier: NCT02990338) demonstrated improved progression-free survival (PFS) and a benefit in overall survival (OS) was reported with the addition of isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma. Here, we report the final OS analysis. This multicenter, randomized, open-label, phase III study included patients who had received and failed ≥2 previous therapies, including lenalidomide and a proteasome inhibitor. Between January 10, 2017, and February 2, 2018, 307 patients were randomized (1:1) to isatuximab-pomalidomide-dexamethasone (Isa-Pd; N=154) or Pd (N=153), stratified based on age (<75 vs. ≥75 years) and number of previous lines of therapy (2-3 vs. >3). At data cutoff for the final OS analysis after 220 OS events (January 27, 2022), median follow-up duration was 52.4 months. Median OS was 24.6 months (95% confidence interval [CI]: 20.3-31.3) with Isa-Pd and 17.7 months (95% CI: 14.4- 26.2) with Pd (hazard ratio=0.78; 95% CI: 0.59-1.02; 1-sided P=0.0319). Despite subsequent daratumumab use in the Pd group and its potential benefit on PFS in the first subsequent therapy line, median PFS2 was significantly longer with Isa-Pd versus Pd (17.5 vs. 12.9 months; log-rank 1-sided P=0.0091). In this analysis, Isa-Pd continued to be efficacious and well tolerated after follow-up of approximately 52 months, contributing to a clinically meaningful, 6.9-month improvement in median OS in patients with relapsed/refractory multiple myeloma.


Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Dexamethasone , Multiple Myeloma , Thalidomide , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Multiple Myeloma/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dexamethasone/administration & dosage , Thalidomide/analogs & derivatives , Thalidomide/administration & dosage , Male , Aged , Female , Middle Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Aged, 80 and over , Adult , Drug Resistance, Neoplasm , Treatment Outcome , Recurrence , Survival Analysis
2.
Haematologica ; 106(11): 2799-2812, 2021 Nov 01.
Article in English | MEDLINE | ID: mdl-34261295

ABSTRACT

According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and <60%, and absence of any myeloma-defining event. Active multiple myeloma is preceded by SMM, with a median time to progression of approximately 5 years. Cases of SMM range from the extremes of "monoclonal gammopathy of undetermined significance-like", in which patients never progress during their lifetimes, to "early multiple myeloma", in which transformation into symptomatic disease, based on genomic evolution, may be rapid and devastating. Such a "split personality" makes the prognosis and management of individual patients challenging, particularly with regard to the identification and possible early treatment of high-risk SMM. Outside of clinical trials, the conventional approach to SMM generally remains close observation until progression to active multiple myeloma. However, two prospective, randomized trials have recently demonstrated a significant clinical benefit in terms of time to progression, and of overall survival in one of the two studies, for some patients with higher-risk SMM treated with lenalidomide ± dexamethasone, raising the question of whether such an approach should be considered a new standard of care. In this paper, experts from the European Myeloma Network describe current biological and clinical knowledge on SMM, focusing on novel insights into its molecular pathogenesis, new prognostic scoring systems proposed to identify SMM patients at higher risk of early transformation, and updated results of completed or ongoing clinical trials. Finally, some practical recommendations for the real-life management of these patients, based on Delphi consensus methodology, are provided.


Subject(s)
Monoclonal Gammopathy of Undetermined Significance , Multiple Myeloma , Smoldering Multiple Myeloma , Disease Progression , Humans , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Monoclonal Gammopathy of Undetermined Significance/therapy , Multiple Myeloma/drug therapy , Multiple Myeloma/therapy , Prospective Studies , Risk Factors , Smoldering Multiple Myeloma/diagnosis , Smoldering Multiple Myeloma/therapy
3.
J Pathol ; 245(1): 61-73, 2018 05.
Article in English | MEDLINE | ID: mdl-29464716

ABSTRACT

The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukaemia (CLL) due to Epstein-Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B-cell lymphoma (DLBCL), seven (23%) showed EBV expression. In contrast to EBV- tumours, EBV+ DLBCLs derived predominantly from IGVH-hypermutated CLL, and they also showed CLL-unrelated IGVH sequences more frequently. Intriguingly, despite having different cellular origins, clonally related and unrelated EBV+ DLBCLs shared a previous history of immunosuppressive chemo-immunotherapy, a non-germinal centre DLBCL phenotype, EBV latency programme type II or III, and very short survival. These data suggested that EBV reactivation during therapy-related immunosuppression can transform either CLL cells or non-tumoural B lymphocytes into EBV+ DLBCL. To investigate this hypothesis, xenogeneic transplantation of blood cells from 31 patients with CLL and monoclonal B-cell lymphocytosis (MBL) was performed in Rag2-/- IL2γc-/- mice. Remarkably, the recipients' impaired immunosurveillance favoured the spontaneous outgrowth of EBV+ B-cell clones from 95% of CLL and 64% of MBL patients samples, but not from healthy donors. Eventually, these cells generated monoclonal tumours (mostly CLL-unrelated but also CLL-related), recapitulating the principal features of EBV+ DLBCL in patients. Accordingly, clonally related and unrelated EBV+ DLBCL xenografts showed indistinguishable cellular, virological and molecular features, and synergistically responded to combined inhibition of EBV replication with ganciclovir and B-cell receptor signalling with ibrutinib in vivo. Our study underscores the risk of RT driven by EBV in CLL patients receiving immunosuppressive therapies, and provides the scientific rationale for testing ganciclovir and ibrutinib in EBV+ DLBCL. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Subject(s)
Cell Transformation, Neoplastic/drug effects , Herpesvirus 4, Human/drug effects , Immunosuppressive Agents/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Adult , Aged , B-Lymphocytes/drug effects , B-Lymphocytes/pathology , Cell Transformation, Neoplastic/pathology , Epstein-Barr Virus Infections/drug therapy , Epstein-Barr Virus Infections/pathology , Female , Herpesvirus 4, Human/genetics , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Male , Middle Aged
4.
Haematologica ; 103(5): 880-889, 2018 05.
Article in English | MEDLINE | ID: mdl-29545347

ABSTRACT

Protein analysis in bone marrow samples from patients with multiple myeloma has been limited by the low concentration of proteins obtained after CD138+ cell selection. A novel approach based on capillary nano-immunoassay could make it possible to quantify dozens of proteins from each myeloma sample in an automated manner. Here we present a method for the accurate and robust quantification of the expression of multiple proteins extracted from CD138-purified multiple myeloma samples frozen in RLT Plus buffer, which is commonly used for nucleic acid preservation and isolation. Additionally, the biological and clinical value of this analysis for a panel of 12 proteins essential to the pathogenesis of multiple myeloma was evaluated in 63 patients with newly diagnosed multiple myeloma. The analysis of the prognostic impact of CRBN/Cereblon and IKZF1/Ikaros mRNA/protein showed that only the protein levels were able to predict progression-free survival of patients; mRNA levels were not associated with prognosis. Interestingly, high levels of Cereblon and Ikaros proteins were associated with longer progression-free survival only in patients who received immunomodulatory drugs and not in those treated with other drugs. In conclusion, the capillary nano-immunoassay platform provides a novel opportunity for automated quantification of the expression of more than 20 proteins in CD138+ primary multiple myeloma samples.


Subject(s)
Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Immunoassay/methods , Multiple Myeloma/metabolism , Nanotechnology/methods , RNA, Messenger/genetics , Syndecan-1/metabolism , Humans , Multiple Myeloma/diagnosis , Multiple Myeloma/genetics , Prognosis , Survival Rate
5.
Lancet Oncol ; 17(8): e328-e346, 2016 08.
Article in English | MEDLINE | ID: mdl-27511158

ABSTRACT

Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Multiple Myeloma/drug therapy , Neoplasm, Residual/diagnosis , Practice Guidelines as Topic/standards , Consensus , Humans , Neoplasm, Residual/chemically induced
6.
Ann Hematol ; 95(12): 2033-2041, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27738789

ABSTRACT

Bortezomib-melphalan-prednisone (VMP) is a standard-of-care for previously untreated, transplant-ineligible multiple myeloma (MM). Here, we compared outcomes between VMP regimens in the VISTA trial (9-cycle VMP schedule, including 4 cycles of twice weekly bortezomib) and the PETHEMA/GEM05 trial (less intensive 6-cycle VMP schedule with 1 cycle of twice weekly and 5 cycles of weekly bortezomib, then bortezomib-based maintenance). A total of 113 patient pairs matched by propensity score (estimated using logistic regression and incorporating eight exposure/outcome-related parameters) were included in this retrospective analysis. Median cumulative bortezomib dose was higher in PETHEMA/GEM05 than VISTA (49.6 vs 37.0 mg/m2); median dose intensity was lower (2.0 vs 5.1 mg/m2/month). Median progression-free survival (PFS) and time-to-progression (TTP) were significantly longer in PETHEMA/GEM05 than VISTA (PFS, 30.5 vs 20.0 months, p = 0.0265; TTP, 33.8 vs 24.2 months, p = 0.0049) after a median follow-up of 77.2 and 26.0 months, respectively. Median overall survival (OS) was similar (61.3 vs 61.0 months, p = 0.6528; median follow-up, 77.6 vs 60.1 months). Post-induction complete response rate was lower in PETHEMA/GEM05 than VISTA (19 vs 31 %; p = 0.03318); on-study (including maintenance) rate was similar (30 vs 31 %; p = 0.89437). This analysis suggests that the less-intensive PETHEMA/GEM05 VMP regimen plus maintenance may improve PFS and TTP, but not OS, compared with the VISTA VMP regimen. TRIAL REGISTRATIONS: NCT00111319, NCT00443235.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bortezomib/administration & dosage , Melphalan/administration & dosage , Multiple Myeloma/drug therapy , Prednisone/administration & dosage , Aged , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Male , Matched-Pair Analysis , Multiple Myeloma/diagnosis , Retrospective Studies , Time Factors , Treatment Outcome
7.
Lancet Oncol ; 14(11): 1055-1066, 2013 Oct.
Article in English | MEDLINE | ID: mdl-24007748

ABSTRACT

BACKGROUND: Few effective treatments exist for patients with refractory or relapsed and refractory multiple myeloma not responding to treatment with bortezomib and lenalidomide. Pomalidomide alone has shown limited efficacy in patients with relapsed multiple myeloma, but synergistic effects have been noted when combined with dexamethasone. We compared the efficacy and safety of pomalidomide plus low-dose dexamethasone with high-dose dexamethasone alone in these patients. METHODS: This multicentre, open-label, randomised phase 3 trial was undertaken in Australia, Canada, Europe, Russia, and the USA. Patients were eligible if they had been diagnosed with refractory or relapsed and refractory multiple myeloma, and had failed at least two previous treatments of bortezomib and lenalidomide. They were assigned in a 2:1 ratio with a validated interactive voice and internet response system to either 28 day cycles of pomalidomide (4 mg/day on days 1-21, orally) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally) or high-dose dexamethasone (40 mg/day on days 1-4, 9-12, and 17-20, orally) until disease progression or unacceptable toxicity. Stratification factors were age (≤75 years vs >75 years), disease population (refractory vs relapsed and refractory vs bortezomib intolerant), and number of previous treatments (two vs more than two). The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01311687, and with EudraCT, number 2010-019820-30. FINDINGS: The accrual for the study has been completed and the analyses are presented. 302 patients were randomly assigned to receive pomalidomide plus low-dose dexamethasone and 153 high-dose dexamethasone. After a median follow-up of 10·0 months (IQR 7·2-13·2), median PFS with pomalidomide plus low-dose dexamethasone was 4·0 months (95% CI 3·6-4·7) versus 1·9 months (1·9-2·2) with high-dose dexamethasone (hazard ratio 0·48 [95% CI 0·39-0·60]; p<0·0001). The most common grade 3-4 haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups were neutropenia (143 [48%] of 300 vs 24 [16%] of 150, respectively), anaemia (99 [33%] vs 55 [37%], respectively), and thrombocytopenia (67 [22%] vs 39 [26%], respectively). Grade 3-4 non-haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups included pneumonia (38 [13%] vs 12 [8%], respectively), bone pain (21 [7%] vs seven [5%], respectively), and fatigue (16 [5%] vs nine [6%], respectively). There were 11 (4%) treatment-related adverse events leading to death in the pomalidomide plus low-dose dexamethasone group and seven (5%) in the high-dose dexamethasone group. INTERPRETATION: Pomalidomide plus low-dose dexamethasone, an oral regimen, could be considered a new treatment option in patients with refractory or relapsed and refractory multiple myeloma. FUNDING: Celgene Corporation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Resistance, Neoplasm/drug effects , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Salvage Therapy , Aged , Dexamethasone/administration & dosage , Female , Follow-Up Studies , Humans , Male , Multiple Myeloma/mortality , Multiple Myeloma/pathology , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prognosis , Survival Rate , Thalidomide/administration & dosage , Thalidomide/analogs & derivatives
9.
Biomed Pharmacother ; 169: 115882, 2023 Dec 31.
Article in English | MEDLINE | ID: mdl-37984300

ABSTRACT

An archetypal anti-inflammatory compound against cytokine storm would inhibit it without suppressing the innate immune response. AG5, an anti-inflammatory compound, has been developed as synthetic derivative of andrographolide, which is highly absorbable and presents low toxicity. We found that the mechanism of action of AG5 is through the inhibition of caspase-1. Interestingly, we show with in vitro generated human monocyte derived dendritic cells that AG5 preserves innate immune response. AG5 minimizes inflammatory response in a mouse model of lipopolysaccharide (LPS)-induced lung injury and exhibits in vivo anti-inflammatory efficacy in the SARS-CoV-2-infected mouse model. AG5 opens up a new class of anti-inflammatories, since contrary to NSAIDs, AG5 is able to inhibit the cytokine storm, like dexamethasone, but, unlike corticosteroids, preserves adequately the innate immunity. This is critical at the early stages of any naïve infection, but particularly in SARS-CoV-2 infections. Furthermore, AG5 showed interesting antiviral activity against SARS-CoV-2 in humanized mice.


Subject(s)
COVID-19 , Cytokine Release Syndrome , Humans , Mice , Animals , Immunity, Innate , SARS-CoV-2 , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
10.
Haematologica ; 97(8): 1187-95, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22371184

ABSTRACT

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is a major complication after allogeneic stem cell transplantation with an adverse effect on both mortality and morbidity. In 2005, the National Institute of Health proposed new criteria for diagnosis and classification of chronic graft-versus-host disease for clinical trials. New sub-categories were recognized such as late onset acute graft-versus-host disease and overlap syndrome. DESIGN AND METHODS: We evaluated the prognostic impact of the new sub-categories as well as the clinical scoring system proposed by the National Institute of Health in a retrospective, multicenter study of 820 patients undergoing allogeneic stem cell transplantation between 2000 and 2006 at 3 different institutions. Patients were retrospectively categorized according to the National Institute of Health criteria from patients' medical histories. RESULTS: As far as the new sub-categories are concerned, in univariate analysis diagnosis of overlap syndrome adversely affected the outcome. Also, the number of organs involved for a cut-off value of 4 significantly influenced both cGVHD related mortality and survival. In multivariate analysis, in addition to NIH score, platelet count and performance score at the time of cGVHD diagnosis, plus gut involvement, significantly influenced outcome. These 3 variables allowed us to develop a simple score system which identifies 4 subgroups of patients with 84%, 64%, 43% and 0% overall survival at five years after cGVHD diagnosis (score 0: HR=15.96 (95% CI: 6.85-37.17), P<0.001; score 1: HR=5.47 (95% CI: 2.6-11.5), P<0.001; score 2: HR=2.8 (95% CI: 1.32-5.93), P=0.007). CONCLUSIONS: In summary, we have identified a powerful and simple tool to discriminate different subgroups of patients in terms of chronic graft-versus-host disease related mortality and survival.


Subject(s)
Graft vs Host Disease/mortality , Adolescent , Adult , Aged , Child , Child, Preschool , Chronic Disease , Graft vs Host Disease/epidemiology , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Incidence , Infant , Middle Aged , Prognosis , Retrospective Studies , Transplantation, Homologous , Young Adult
11.
Blood Adv ; 6(4): 1309-1318, 2022 02 22.
Article in English | MEDLINE | ID: mdl-34933328

ABSTRACT

Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, showed deep, durable responses in patients with triple-class exposed, relapsed and refractory multiple myeloma (RRMM) in the phase 2 KarMMa (Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma) trial. We assessed health-related quality of life (HRQoL) among KarMMa patients. The European Organization for Research and Treatment of Cancer Quality of Life C30 Questionnaire and its supplementary 20-item multiple myeloma module, as well as the EuroQol 5-dimension 5-level instrument, were administered at screening, baseline (≤72 hours before or same day as lymphodepletion), day of ide-cel treatment, and after ide-cel treatment. Mean changes from baseline that exceeded the predetermined threshold of minimally important difference were deemed clinically meaningful. The proportions of patients experiencing clinically meaningful changes in HRQoL were assessed using within-patient change thresholds. Time to stable improvement (≥2 consecutive visits with clinically meaningful HRQoL improvements) was analyzed by using the Kaplan-Meier method. A total of 126 (98%) of 128 patients treated with ide-cel were included in the HRQoL analysis. Pretreatment baseline RRMM burden was high and meaningfully worse than that in the age- and sex-weighted general population. Statistically significant and clinically meaningful improvements from baseline were observed by month 1 for pain (-8.9) and disease symptoms (-10.2), and by month 2 for fatigue (-7.2), physical functioning (6.1), cognitive functioning (6.7), and global health status/QoL (8.0). Clinically meaningful improvements in fatigue, pain, and physical functioning were most prominent at months 9, 12, and 18, respectively, and were sustained through 15 to 18 months after ide-cel treatment. For triple-class exposed patients with RRMM with a poor prognosis and few treatment options, a single ide-cel infusion provides early, sustained, statistically significant, and clinically meaningful improvements in HRQoL. This study was registered at Clinicaltrials.gov as #NCT03361748.


Subject(s)
Multiple Myeloma , Receptors, Chimeric Antigen , Fatigue , Humans , Multiple Myeloma/therapy , Pain , Quality of Life , Receptors, Chimeric Antigen/therapeutic use
12.
Lancet Haematol ; 9(2): e143-e161, 2022 Feb.
Article in English | MEDLINE | ID: mdl-35114152

ABSTRACT

Infection remains the leading cause of morbidity and mortality in patients with multiple myeloma because of the cumulative effect of disease, treatment, and host-related factors. Given that infectious risk is cumulative through the course of the disease, preventing infections is paramount. Optimal preventive strategies include vaccination against common pathogens, antimicrobial prophylaxis, infection control measures, and immunoglobulin replacement in a small subset of patients; however, there are no universally accepted guidelines for infection prevention. This Review provides a consensus statement from a panel of 36 experts with global representation, which was convened by The International Myeloma Society to review existing literature and current guidelines, address issues associated with the risk of infection and prevention of infectious complications in multiple myeloma in the context of emerging therapies, and offer recommendations for preventing these complications.


Subject(s)
Infections , Multiple Myeloma , Consensus , Humans , Infections/complications , Multiple Myeloma/complications , Multiple Myeloma/drug therapy
13.
Blood Cancer J ; 11(12): 192, 2021 12 02.
Article in English | MEDLINE | ID: mdl-34857730

ABSTRACT

Primary plasma cell leukemia (PCL) has a consistently ominous prognosis, even after progress in the last decades. PCL deserves a prompt identification to start the most effective treatment for this ultra-high-risk disease. The aim of this position paper is to revisit the diagnosis of PCL according to the presence of circulating plasma cells in patients otherwise meeting diagnostic criteria of multiple myeloma. We could identify two retrospective series where the question about what number of circulating plasma cells in peripheral blood should be used for defining PCL. The presence of ≥5% circulating plasma cells in patients with MM had a similar adverse prognostic impact as the previously defined PCL. Therefore, PCL should be defined by the presence of 5% or more circulating plasma cells in peripheral blood smears in patients otherwise diagnosed with symptomatic multiple myeloma.


Subject(s)
Leukemia, Plasma Cell/diagnosis , Plasma Cells/pathology , Aged , Female , Humans , Leukemia, Plasma Cell/pathology , Male , Multiple Myeloma/diagnosis , Multiple Myeloma/pathology , Prognosis , Retrospective Studies
14.
Leukemia ; 35(1): 18-30, 2021 01.
Article in English | MEDLINE | ID: mdl-32778736

ABSTRACT

Minimal residual disease (MRD) assessment is incorporated in an increasing number of multiple myeloma (MM) clinical trials as a correlative analysis, an endpoint or even as a determinant of subsequent therapy. There is substantial heterogeneity across clinical trials in how MRD is assessed and reported, creating challenges for data interpretation and for the design of subsequent studies. We convened an international panel of MM investigators to harmonize how MRD should be assessed and reported in MM clinical trials. The panel provides consensus on which MM trials should include MRD, the recommended time points for MRD assessment, and expected analytical validation for MRD assays. We subsequently outlined parameters for reporting MRD results implementing the intention-to-treat principle. The panel provides guidance regarding the incorporation of newer peripheral blood-based and imaging-based approaches to detection of residual disease. Recommendations are summarized in 13 consensus statements that should be followed by sponsors, investigators, editors, and reviewers engaged in designing, performing, and interpreting MM trials.


Subject(s)
Multiple Myeloma/epidemiology , Multiple Myeloma/pathology , Neoplasm, Residual/diagnosis , Neoplasm, Residual/epidemiology , Clinical Trials as Topic , Diagnostic Imaging , Disease Management , Drug Collateral Sensitivity , Global Health , Humans , Molecular Diagnostic Techniques/methods , Molecular Diagnostic Techniques/standards , Multiple Myeloma/therapy , Neoplastic Cells, Circulating/metabolism , Neoplastic Cells, Circulating/pathology , Outcome Assessment, Health Care , Population Surveillance , Reproducibility of Results , Smoldering Multiple Myeloma/epidemiology , Smoldering Multiple Myeloma/pathology , Time Factors
15.
Cancer Treat Rev ; 34(3): 283-91, 2008 May.
Article in English | MEDLINE | ID: mdl-18230411

ABSTRACT

The last decade has seen rapid evolution in the management of multiple myeloma. Cytogenetic, molecular, and proteomic techniques have led to a better understanding of the pathophysiology and prognostic markers of this heterogeneous malignancy. New immunomodulatory drugs, such as lenalidomide, which interrupt myeloma growth and survival pathways have entered into clinical usage. Combined with dexamethasone, oral lenalidomide has proved to be highly effective in patients whose disease has become resistant to conventional therapy. Currently, several clinical trials are ongoing in order to define the optimal use of this new agent and its combinations across the spectrum of patients with myeloma. Whether the ultimate outcome of future research will be a single-treatment solution for all patients, or whether treatments will become better-tailored to the individual (based on prognostic markers and pre-existing co-morbidities) has yet to be determined.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Dexamethasone/administration & dosage , Multiple Myeloma/drug therapy , Thalidomide/analogs & derivatives , Clinical Trials as Topic , Humans , Lenalidomide , Models, Biological , Thalidomide/administration & dosage , Thalidomide/adverse effects
17.
Blood Cancer J ; 8(10): 95, 2018 10 04.
Article in English | MEDLINE | ID: mdl-30287814

ABSTRACT

Whole Body Low Dose CT (WBLDCT) has important advantages as a first-line imaging modality for bone disease assessment in patients with plasma cell disorders and has been included in the 2014 International Myeloma Working Group (IMWG) criteria for multiple myeloma (MM) definition. Nevertheless, standardization guidelines for the optimal use of WBLDCT in MM patients are still lacking, preventing its more widespread use, both in daily practice and clinical trials. The aim of this report by the Bone Group of the IMWG is to provide practical recommendations for the acquisition, interpretation and reporting of WBLDCT in patients with multiple myeloma and other plasma cell disorders.


Subject(s)
Multiple Myeloma/diagnostic imaging , Multiple Myeloma/pathology , Plasma Cells/pathology , Tomography, X-Ray Computed , Whole Body Imaging , Aged , Female , Humans , Image Interpretation, Computer-Assisted , Image Processing, Computer-Assisted , Male , Osteolysis , Tomography, X-Ray Computed/methods , Whole Body Imaging/methods
18.
Blood Cancer J ; 8(12): 123, 2018 11 23.
Article in English | MEDLINE | ID: mdl-30470751

ABSTRACT

PURPOSE: multiple myeloma is considered an incurable hematologic cancer but a subset of patients can achieve long-term remissions and survival. The present study examines the clinical features of long-term survival as it correlates to depth of disease response. PATIENTS & METHODS: this was a multi-institutional, international, retrospective analysis of high-dose melphalan-autologous stem cell transplant (HDM-ASCT) eligible MM patients included in clinical trials. Clinical variable and survival data were collected from 7291 MM patients from Czech Republic, France, Germany, Italy, Korea, Spain, the Nordic Myeloma Study Group and the United States. Kaplan-Meier curves were used to assess progression-free survival (PFS) and overall survival (OS). Relative survival (RS) and statistical cure fractions (CF) were computed for all patients with available data. RESULTS: achieving CR at 1 year was associated with superior PFS (median PFS 3.3 years vs. 2.6 years, p < 0.0001) as well as OS (median OS 8.5 years vs. 6.3 years, p < 0.0001). Clinical variables at diagnosis associated with 5-year survival and 10-year survival were compared with those associated with 2-year death. In multivariate analysis, age over 65 years (OR 1.87, p = 0.002), IgA Isotype (OR 1.53, p = 0.004), low albumin < 3.5 g/dL (OR = 1.36, p = 0.023), elevated beta 2 microglobulin ≥ 3.5 mg/dL (OR 1.86, p < 0.001), serum creatinine levels ≥ 2 mg/dL (OR 1.77, p = 0.005), hemoglobin levels < 10 g/dL (OR 1.55, p = 0.003), and platelet count < 150k/µL (OR 2.26, p < 0.001) appeared to be negatively associated with 10-year survival. The relative survival for the cohort was ~0.9, and the statistical cure fraction was 14.3%. CONCLUSIONS: these data identify CR as an important predictor of long-term survival for HDM-ASCT eligible MM patients. They also identify clinical variables reflective of higher disease burden as poor prognostic markers for long-term survival.


Subject(s)
Cancer Survivors , Multiple Myeloma/epidemiology , Aged , Aged, 80 and over , Biomarkers , Cancer Survivors/statistics & numerical data , Combined Modality Therapy , Female , Humans , Kaplan-Meier Estimate , Male , Multiple Myeloma/diagnosis , Multiple Myeloma/mortality , Multiple Myeloma/therapy , Neoplasm Staging , Odds Ratio , Population Surveillance , Prognosis , Treatment Outcome
19.
Cancer Treat Rev ; 31(8): 591-602, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16298074

ABSTRACT

Proteasome inhibition is a novel approach to treating malignancy, and bortezomib is the first proteasome inhibitor in this class to be approved for clinical use. In preclinical studies, bortezomib caused cell cycle arrest and apoptosis in myeloma and lymphoma cell lines as well as in other neoplastic cell types. Phase I clinical trials established an optimal dosing strategy and demonstrated a manageable toxicity profile. Cyclical thrombocytopenia and peripheral neuropathy, which generally abate after cessation of treatment, are the most clinically significant toxicities. Two phase II trials, SUMMIT and CREST, demonstrated impressive activity with bortezomib 1.3 mg/m2 monotherapy in relapsed and refractory myeloma, with an impressive 35% response rate (complete+partial+minimal responses) in SUMMIT and a 50% response rate in CREST, using the rigorous European Group for Blood and Marrow Transplantation criteria. A recently completed phase III trial showed the significant clinical benefits of bortezomib over high-dose dexamethasone in patients with relapsed myeloma. Results of ongoing trials with bortezomib in the first-line treatment of myeloma have been extremely encouraging and have demonstrated the benefit of using bortezomib as part of an induction regimen prior to stem cell transplantation. Importantly, two clinical trials with bortezomib as monotherapy in refractory non-Hodgkin's lymphoma have shown impressive response rates, particularly in aggressive mantle cell lymphoma.


Subject(s)
Antineoplastic Agents/therapeutic use , Boronic Acids/therapeutic use , Hematologic Neoplasms/drug therapy , Pyrazines/therapeutic use , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Boronic Acids/pharmacokinetics , Boronic Acids/pharmacology , Bortezomib , Cell Cycle/drug effects , Clinical Trials as Topic , Humans , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Treatment Outcome
20.
Mol Cancer Ther ; 13(2): 504-16, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24431075

ABSTRACT

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth, proliferation, metabolism, and cell survival, and plays those roles by forming two functionally distinct multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Deregulation of the mTOR pathway has been found in different cancers, including multiple myeloma. Agents acting on mTORC1, such as rapamycin and derivatives, are being explored as antitumoral strategies. However, whether targeting mTOR would be a more effective antimyeloma strategy than exclusively acting on the mTORC1 branch remains to be established. In this report, we explored the activation status of mTOR routes in malignant plasma cells, and analyzed the contribution of mTOR and its two signaling branches to the proliferation of myeloma cells. Gene expression profiling demonstrated deregulation of mTOR pathway-related genes in myeloma plasma cells from patients. Activation of the mTOR pathway in myelomatous plasma cells was corroborated by flow cytometric analyses. RNA interference (RNAi) experiments indicated that mTORC1 predominated over mTORC2 in the control of myeloma cell proliferation. However, mTOR knockdown had a superior antiproliferative effect than acting only on mTORC1 or mTORC2. Pharmacologic studies corroborated that the neutralization of mTOR has a stronger antimyeloma effect than the individual inhibition of mTORC1 or mTORC2. Together, our data support the clinical development of agents that widely target mTOR, instead of agents, such as rapamycin or its derivatives, that solely act on mTORC1.


Subject(s)
Multiple Myeloma/metabolism , Multiprotein Complexes/metabolism , TOR Serine-Threonine Kinases/metabolism , Antibiotics, Antineoplastic/pharmacology , Apoptosis/drug effects , Blotting, Western , Cell Cycle Checkpoints/drug effects , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Coculture Techniques , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Imidazoles/pharmacology , Mechanistic Target of Rapamycin Complex 1 , Mechanistic Target of Rapamycin Complex 2 , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Multiprotein Complexes/antagonists & inhibitors , Multiprotein Complexes/genetics , Pyrazines/pharmacology , RNA Interference , Signal Transduction/drug effects , Signal Transduction/genetics , Sirolimus/pharmacology , Stromal Cells/drug effects , Stromal Cells/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/genetics , Tumor Cells, Cultured
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