Bortezomib retreatment is effective in relapsed multiple myeloma patients - real-life clinical practice data.

Nowadays, bortezomib, a proteasome inhibitor, is widely used in treatment of newly diagnosed or relapsed multiple myeloma. The aim of this study was to analyze efficiency of bortezomib retreatment in patients with relapsed or refractory multiple myeloma. From 2004 to 2016, 283 patients were retrospectively evaluated at all hematological centers in the Czech Republic. Bortezomib was administered at the standard dosing and in combined therapy with corticosteroids, chemotherapy or thalidomide. Before bortezomib retreatment, 61% of patients received previous lenalidomide treatment, 40.6% autologous transplantation, and median number of prior lines of therapy was three. In total, 21% of patients were refractory to the first bortezomib treatment. In bortezomib retreatment, overall response rate was 34.5%, median progression-free survival was 7.8 months (95% CI: 6.7-8.9), median duration of response was 10.5 months (95% CI: 8.0-13.0) and median overall survival was 20.3 months (95% CI: 17.9-22.7). Grade 3-4 adverse events included thrombocytopenia, neutropenia, anemia and infection. Neuropathy grade 2 or higher occurred in 19.4% of patients. We conclude that bortezomib retreatment is an effective and safe therapeutic alternative for relapsed or refractory multiple myeloma patients.

Methodology and results of real-world cost-effectiveness of carfilzomib in combination with lenalidomide and dexamethasone in relapsed multiple myeloma using registry data.

OBJECTIVE: To predict the real-world (RW) cost-effectiveness of carfilzomib in combination with lenalidomide and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) in relapsed multiple myeloma (MM) patients after one to three prior therapies. METHODS: A partitioned survival model that included three health states (progression-free, progressed disease and death) was built. Progression-free survival (PFS), overall survival (OS) and time to discontinuation (TTD) data for the Rd arm were derived using the Registry of Monoclonal Gammopathies in the Czech Republic; the relative treatment effects of KRd versus Rd were estimated from the phase 3, randomised, ASPIRE trial, and were used to predict PFS, OS and TTD for KRd. The model was developed from the payer perspective and included drug costs, administration costs, monitoring costs, palliative care costs and adverse-event related costs collected from Czech sources. RESULTS: The base case incremental cost effectiveness ratio for KRd compared with Rd was €73,156 per quality-adjusted life year (QALY) gained. Patients on KRd incurred costs of €117,534 over their lifetime compared with €53,165 for patients on Rd. The QALYs gained were 2.63 and 1.75 for patients on KRd and Rd, respectively. CONCLUSIONS: Combining the strengths of randomised controlled trials and observational databases in cost-effectiveness models can generate policy-relevant results to allow well-informed decision-making. The current model showed that KRd is likely to be cost-effective versus Rd in the RW and, therefore, the reimbursement of KRd represents an efficient allocation of resources within the healthcare system.

Lenalidomide and dexamethasone in treatment of patients with relapsed and refractory multiple myeloma - analysis of data from the Czech Myeloma Group Registry of Monoclonal Gammopathies.

Lenalidomide (LEN) is an immunomodulator with clinical activity against myeloma cells. Based on the pivotal phase 3 trials MM-009 and MM010, the combination of lenalidomide and dexamethasone(DEX) was approved for patients with multiple myeloma who received at least one prior therapy. Here, we evaluated LEN/DEX therapy in unselected population and subsequently in selected sub-groups of patients with relapsed/refractory multiple myeloma followed in the Registry of Monoclonal Gammopathies of the Czech Myeloma Group. Altogether 858 patients were treated with LEN/DEX in the Czech Republic and Slovakia until end of 2017. The analyzed sub-groups were defined as patients with high risk cytogenetic aberrations and patients with relapsed and refractory MM. The overall response rate (ORR; partial remission or better response, PR) in the whole group of patients was 46.3% for all lines of therapy, 26.4% for high-risk group and 32.1% for relapsed and refractory group. Medians of overall survival (OS) in the same cohorts were as follows: 25.6, 15.7 and 18.5 months, progression free survival (PFS) was: 11.2, 6.4 and 9.0 months respectively. The most common adverse events were hematologic and infectious. In conclusion we found that our results correlated with those found in other studies in terms of response rates, survival measures, and also of treatment toxicity.

Simplified novel prognostic score for real-life older adults with multiple myeloma-registry-based analysis.

The main goal was to find a simple prognostic to evaluate overall survival of patients older than 65 years of age with myeloma. Retrospective registry-based analysis from the Registry of Monoclonal Gammopathies was conducted. Patients over 65 years with symptomatic myeloma were included. The four major parameters with impact on survival were identified: male gender, age > 75, creatinine > 152 µmol/L, and ECOG performance status 2-4. The patients were scored as good (0 points), intermediate good (1 point), intermediate poor (2 points), poor (3-4 points). Patients (1410 MM) were included. Median OS (months) was 65.7 (95% CI 49.8-81.7) for good, 51.0 (44.1-57.8) for intermediate good, 32.2 (26.2-38.2) for intermediate poor, and 18.9 (15.1-22.7) for poor. The differences in OS were statistically significant (p < 0.0001). Good score was used as reference for hazard ratios, which for each other score were 1.43 (1.09-1.84) for intermediate good, 2.58 (2.00-3.33) for intermediate poor, and 3.88 (2.94-5.10) for poor. Time to progression showed medians (months) 20.5 (17.4-62.4) for good, 19.3 (17.0-21.7) for intermediate good, 19.6 (16.2-23.0) for intermediate poor, and 13.0 (10.8-15.2) for poor. The suggested scoring system provides readily available information about the prognosis of MM patients above 65 years.

[MicroRNA Analysis for Extramedullary Multiple Myeloma Relapse]. / Analýza mikroRNA u extramedulárního relapsu mnohocetného myelomu.

INTRODUCTION AND AIMS: Multiple myeloma (MM) is the second most common hematooncological disease. Patient survival has been greatly improved by the introduction of new drugs into clinical practice, but survival is negatively affected by the so-called extramedullary relapse (EM), caused by the loss of plasma cell dependence on the bone marrow microenvironment and their migration out of the bone marrow. The nature and causes of this process are currently unclear. MicroRNAs (miRNAs) are short, non-coding RNA molecules involved in many physiological and pathological processes. Their significance in the pathogenesis of MM has been demonstrated by several studies. We assume that they are also involved in the development of the EM. The aim of this study was to analyze different miRNA expression between MM and EM patients. MATERIAL AND METHODS: Using next generation sequencing, we analyzed 39 samples of bone marrow cells from MM patients at diagnosis and 9 bone marrow plasma samples of EM patients. RESULTS: In total, 2,278 miRNA were sequenced, but only 658 miRNAs were analyzed as they were expressed in all samples and had at least 20 reads. Expression data were generated using the Chimira tool from fastq data. All sequences were mapped using miRBase v20. Further analyses were performed using the R/Bioconductor package. The Bayesian procedure was used for normalization of expression. P values were adjusted using the Benjamini-Hochberg method. Analysis found 10 miRNA (p < 0.0005) that are statistically significantly expressed in EM vs. MM patients - these are miR-26a-5p, miR-26b-5p, miR-30e-5p, miR-424-3p, miR-503-5p, miR-767-5p, miR-105-5p, miR-5695-5p, miR-450b-5p and miR-92b-3p. These miRNAs will be further verified by qPCR method on a larger set of MM and EM patients. CONCLUSION: Our pilot study has shown that there are differentially expressed miRNAs between MM and EM patients.Key words: multiple myeloma - microRNA - carcinogenesis - next generation sequencing The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papersThis work was supported by grant MZ CR AZV 17- 29343A. Submitted: 17. 3. 2018Accepted: 20. 3. 2018.

Whole Exome Sequencing of Aberrant Plasma Cells in a Patient with Multiple Myeloma Minimal Residual Disease.

Multiple myeloma is a plasma cell dyscrasia. It is the second most common hematological malignancy which is characterized by proliferation of clonal plasma cells producing harmful monoclonal immunoglobulin. Despite treatment modalities greatly evolved during the last decade, small amount of aberrant residual cells reside in patients after therapy and can cause relapse of the disease. Characterization of the residual, resistant clones can help to reveal important therapeutic targets for application of effective and precious treatment. We use CD38, CD45, CD56 and CD19 sorted aberrant plasma cells to perform next generation sequencing of their exome. Among the 213 genes in which at least one variant was present, the most interesting was found gene NRAS, one of the most often mutated gene in multiple myeloma, and homologs of 88 gene panel previously used for multiple myeloma sequencing among which was a gene previously identified as gene meaningful in bortezomib resistance. Nevertheless, the results of next generation exome sequencing need to be interpreted with caution, since they rely on bioinformatical analysis, which is still being optimized. The results of next generation sequencing will also have to be confirmed by Sanger sequencing. Final results supported by larger cohort of patients will be published soon.Key words: multiple myeloma - minimal residual disease - exome - next generation sequencing.

Asymptomatic and Treatment-requiring Multiple Myeloma - Data from the Czech Registry of Monoclonal Gammopathies.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) are premalignant stages of multiple myeloma (MM). MM is a malignancy of plasma cells, which is associated with a median overall survival of 5 to 7 years. MM accounts for approximately 10% of hematological malignancies. PATIENTS AND METHODS: Descriptive analysis of data from 19 Czech centres collected in the Registry of Monoclonal Gammopathies (RMG) was performed. RESULTS: Over the last 10 years of prospective collection of data, together with retrospectively recorded data on patients diagnosed before the registry establishment, data on 7,467 patients with either asymptomatic or symptomatic form of MM have been gathered. Validation criteria for the analysis were met by 2,506 MGUS patients, 400 SMM patients and 4,738 MM patients. The median duration of follow-up was 4.3 years in MGUS patients and 2.4 years in SMM patients. The overall risk of progression from MGUS to malignancy was 1.7% per year. The risk of progression from SMM to MM was highest in the 1st years after diagnosis: overall, this risk was 16.6% per year. The median duration of follow-up was 2.8 years in MM patients. The median overall survival from the diagnosis was 5.7 years. The median OS from treatment initiation/progression-free survival decreased from 60.5/21.0 months in the 1st line therapy to 34.3/12.4 months in the 2nd line therapy, 22.6/8.9 months in the 3rd line therapy and 13.8/5.8 months in the 4th or higher line therapies. Thanks to the availability of novel drugs for MM treatment in the Czech Republic, treatment strategies have changed dramatically over the last decade. CONCLUSION: RMG is a registry designated for the collection of data on diagnosis, treatment, treatment results and survival of patients with monoclonal gammopathies in the long-term follow-up. RMG is a valuable source of data from real clinical practice.Key words: registries - monoclonal gammopathy of undetermined significance - smouldering multiple myeloma - multiple myeloma - progression - treatment - survival.

A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS).

This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4-14.4) vs 10.0 months (95% CI 7.7-12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760-1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.

[Assessment of Heavy/ Light Chain Pairs of Immunoglobulin (Hevylite assay) -  Benefit for Stratification of Multiple Myeloma?]. / Vysetrení páru tezkých/ lehkých retezcu imunoglobulinu (Hevylite assay) -  prínos pro stratifikaci mnohocetného myelomu?

BACKGROUND: The aim of the study was the comparison of two novel stratification models in multiple myeloma (MM), ie. according to Avet- Loiseau (A L) and according to Ludwig (L), based on the HLC r index (ratio of serum levels of involved- HLC/ uninvolved HLC, ie. HLC κ/ HLC  λ assessed using ie. nephelometric/turbidimetric technique using specific polyclonal antibodies on a Binding Site SPA(PLUS)) technique) and ß(2) microglobulin (ß(2) M) with selected prognostic factors (PF) of MM and staging systems according to Durie- Salmon (D S) and International Staging System (ISS). PATIENTS AND METHODS: In a cohort of 132 patients (94 with IgG and 38 with IgA type of MM) at the time of dia-gnosis, we assessed HLC r, select-ed PF and D S, ISS, A L and L stratification systems. RESULTS: Unlike in IgA isotype, in IgG isotype we found a significant relationship of HLC r to stratification according to D S and ISS with the difference between A and B substages according to D S (p = 0.049) and between ISS stages 1 vs. 3 (p = 0.001). In the IgG group, there was highly significant relationship of the depth of Hb and albumin decrease and ß(2) M increase to the results of stratification according to ISS, A L and L model (p < 0.0001), increase of LDH in the ISS system and A L, and creatinine according to ISS and L but not the relationship of the stages according to any of the stratification systems to the values of FLC r (ratio of serum free light chains κ/ λ of immunoglobulin), thrombocytes and Ca. In the IgA type, there was a significant relationship of the depth of the decrease of Hb, thrombocytes, albumin and increase of ß(2) M to the results of stratification according to ISS, A L and L and increase of creatinine in the case of ISS, but not of the values of FLC r, Ca and LDH in the case of any of the stratification systems. The degree of correlation of selected PF, especially of Hb, albumin and ß(2) M, event. of thrombocytes, LDH and creatinine to the stages according to ISS and to stage 1-3 according to A L and L model was in IgG vs IgA isotype significantly different (p < 0.0001- 0.030). Staging system according to ISS had proportional distribution of stages 1- 3, whereas in the A L model prevailed in IgA and IgG isotype risk category 2, ie. intermediate-risk (47.3 and 44.7%) and in the L model prevailed risk category 3, ie. high-risk (41.5 and 52.6%) with low count of category 1, ie. low- risk category (23.4 and 10.5%). McNemar- Bowker test of symmetry showed in both types of MM the highest concordance between the stratification according to D S and L in category 3, ie. high-risk (31.9 vs. 28.9%) with overall accord only in 53.2 and 42.1% and with significant shift in the case of IgG isotype only (p = 0.036). In IgG and IgA isotype there was an overall concordance in the distribution of categories 1- 3 according to ISS vs. A L (62.4 and 63.2%) but with significant shift of the stratification (p = 0.002 and 0.028). In the case of IgG and IgA isotype there was a close relationship between the models A L and L (64.5 and 81.6%) with significant stratification shift (p < 0.0001 and 0.030). CONCLUSION: The new stratification models for MM according to A L and L are easily practically applicable, with close relationship to principal PF but they need separate assessment of IgG and IgA isotypes of MM. The choice of optimal model for routine practice needs a validation study aimed at progression free survival and overall survival.

Immunoparesis in MGUS - Relationship of uninvolved immunoglobulin pair suppression and polyclonal immunoglobuline levels to MGUS risk categories.

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic, potentially malignant condition. It has been established that annually approximately 1-2% of MGUS cases transforms into one of the malignant forms of monoclonal gammopathies. Progression risk factors include the quantity and type of M-protein, and namely the ratio of free light immunoglobulin chains (FLC). These factors, enable purposeful stratification of MGUS individuals. Some authors consider suppression of polyclonal immunoglobulin levels to be another progression factor. The aim of the study was to compare polyclonal immunoglobulin (PIg) levels with uninvolved heavy/light chain pair (HLC) levels in order to verify the degree of immunoparesis depending on MGUS risk category (0-3). The analyzed set consisted of 159 serum samples from MGUS patients (102 IgG, 57 IgA), who were stratified into 4 risk groups (0 - low, 1 - low-intermediate, 2 - high-intermediate and 3 - high risk of transformation). The results of analysis showed that with increasing degree of MGUS increases risk of immune paresis defined by decreasing levels of polyclonal immunoglobulins, ie. IgA and IgM in the case of IgG MGUS, respectively, IgG and IgM in case of IgA MGUS. Significant differences were also found when analyzing the levels of uninvolved HLC pairs IgG kappa (resp. IgG lambda) in IgG lambda (IgG kappa) dominant secretion. In the case of MGUS with IgA isotype, the results were similar. Discovery of the connection between the degree of immunosuppression and the level of MGUS risk contributes to our understanding of the relationship between biology, development and potential malignant transformation of MGUS. It is apparent that uninvolved HLC pair assay enables more reliable identification of at-risk MGUS patients than a simple quantitative assay for polyclonal immunoglobulins alone.

[Attainment of complete hematological remission is crucial for extended survival of AL amyloidosis patients with cardiac involvement]. / Dosazení kompletní hematologické remise je zásadní pro prodlouzení prezití nemocných s AL amyloidózou a srdecním postizením.

BACKGROUND: Symptomatic cardiac involvement is the most important prognostic factor in AL amyloidosis patients. Longterm survival is limited not only by cardiac involvement condition, but also by limited choice of treatment with unsatisfactory results. The aim of the present report is to assess the effect of achieved treatment response on survival of AL amyloidosis patients with symptomatic cardiac involvement under conventional treatment. MATERIAL AND METHODS: The monitored patient set consisted of 19 patients with systemic AL amyloidosis and symptomatic cardiac involvement, treated and monitored at the III. Clinic of Internal Medicine between 2004 and 2012. The male : female ratio was 17 : 2, and the age median was 64 (range 48 to 78 years). Thirteen patients died within the monitored period. Functional status was defined according to the NYHA classification, where five patients had class II involvement, 10 patients had class III involvement, and four patients had class IV involvement. Treatment response was assessed by the application of modified IMWG and ISA criteria; all patients were undergoing conventional treatment. Nine patients were treated by a combination of alkylating agents (alkeran, cyclophosphamide), six were treated by a combination treatment with thalidomide, and four were treated by a combination of bortezomib and dexamethasone. Data were analyzed with software SPSS v. 15 (SPSS, Inc., Chicago, USA). Log Rank Test was applied to survival evaluation. RESULTS: The statistical analysis included only 13 patients who underwent at least three months of treatment, where six patients attained complete remission (CR), four patients attained partial remission (PR), and three patients attained only stabilization of disease (SD). Significant difference in patient survival was found to be correlated with attained hematological response, where the patients who attained CR had median survival of 39 months vs 10 months in patients who attained PR or SD (p = 0.005). CONCLUSION: The results indicate that attainment of complete hematological remission is associated with significantly longer survival of AL amyloidosis patients with symptomatic cardiac involvement.

[The importance of cardiac bio-marker assay for the stratification and monitoring of AL amyloidosis patients -  single center experience]. / Význam stanovení kardiálních bio-markeru ve stratifikaci a sledování nemocných s AL amyloidózou -  zkusenosti jednoho centra.

INTRODUCTION: Cardiac involvement is a dominant prognostic factor in AL amyloidosis patients. A detailed assessment of the presence and degree of cardiac involvement utilizes an array of noninvasive investigation methods, particularly echocardiography and MRI; laboratory parameters include troponins and natriuretic peptides. Cardiac involvement detection aside, cardiac bio-markers are used as a relatively strong stratification and prognostic factor. OBJECTIVE: The presentation of cardiac bio-markers assay applications in AL amyloidosis patients at an individual treatment center. PATIENTS AND METHODS: The monitored patient set consisted of 22 patients with histologically confirmed AL amyloidosis, of whom 18 met the criteria for cardiac involvement. Levels of cardiac bio-markers troponin T (TnT) and Nterminal probrain natriuretic peptide (NT ProBNP) were determined in all patients. Risk stratification of the patients utilized the Mayo staging system which is based on both bio-markers assays; Log Rank Test was applied to survival evaluation. RESULTS: Median survival of patients with cardiac involvement stigmata was 10 months vs 60 months survival of patients without signs of cardiac involvement (p = 0.133). Of the 4 patients without cardiac involvement, 1 has shown positive levels of TnT and 2 positive levels of NT ProBNP. All cardiac involvement patients exhibited abnormal levels of NT ProBNP (median 4,752 ng/ l; 415.7- 35,000) as well as positive levels of TnT (median 0.0815 µg/ l; 0.02- 0.986). The application of the Mayo stratification system to the set had determined 2 patients at stage I, 5 patients at stage II and 15 patients at stage III. The median survival of the Mayo I + II group vs the Mayo III group was 60 vs 6 months (p = 0.015), revealing extremely limited survival of stage III patients. Assessment of TnT and NT ProBNP levels relative to treatment response shows that the degree of decrease in both markers depends on maximum treatment response -  respectively the attainment of a complete hematological remission. CONCLUSION: The results, although obtained from a limited set of patients, confirm a definitive benefit of the application of cardiac bio-markers assay in the diagnostic and therapeutic algorithm of AL amyloidosis patients. The Mayo stratification system utilizing the cardiac indicator values represents a robust tool for risk stratification of AL amyloidosis patients.

[Light chain deposition disease]. / Nemoc z ukládání lehkých retezcu imunoglobulinu (light chain deposition disease).

The aim of the study is to put forward the recent knowledge about a relatively rare clinical condition caused by the deposition of immunoglobulin light chains κ or λ into the parenchyme of kidneys and other vital organs, leading to a progressive loss of their function with terminal organ failure. The paper focuses on the etiopathogenesis of light chain deposition disease, and the differentiation of idiopatic form of the disease from multiple myeloma associated conditions and other B lymphoproliferative disorders. We concentrate on the issue of clinical manifestation, contemporary diagnostic possibilities and differential diagnosis of the disease. Finally, we summarize recent therapeutic approaches using chemo-immunotherapy (bortezomib) and high-dosed chemotherapy with support of autologous peripheral stem cell transplantation that lead to a substantial improvement of the prognosis of this prognostically unfavorable disorder.

Analysis of the serum levels of selected biological parameters in monoclonal gammopathy of undetermined significance and different stages of multiple myeloma.

The aim of the study was to analyze differences in the serum levels of 8 selected biological parameters between monoclonal gammopathy of undetermined significance (MGUS) and different stages of multiple myeloma (MM), potentially beneficial for distinguishing between the two conditions. The analyzed group of 131 subjects comprised 62 individuals with MGUS and 69 MM patients examined at the time of diagnosis. The serum levels were determined by a quantitative immunoradiometric assay (insulin-like growth factor 1, IGF-1) and quantitative sandwich enzyme immunoassay (osteopontin, OPN; endostatin, ES; macrophage inflammatory proteins 1α/ß, MIP-1α/ß; angiogenin, ANG; and interleukin 17, IL-17). The analysis showed a statistically significant difference in serum concentrations between MGUS and the symptomatic form of MM using the Durie-Salmon (D-S) staging system only in the cases of OPN and stages II and III (0.001 and MM. More benefit may be expected from analyses using multiparametric immunophenotyping of plasma cells and molecular biology methods including gene expression analysis and proteomics.

[Contribution of whole-body magnetic resonance in the diagnostics of monoclonal gammopathy of undetermined significance, multiple myeloma, and the assessment of Durie-Salmon Plus staging system]. / Prínos celotelové magnetické rezonance v diagnostice monoklonální gamapatie nejistého výnamu, mnohocetného myelomu a stanovení stadia pokrocilosti nemoci s pomocí systému Durie-Salmon Plus.

BACKGROUND: The aim of the study was to assess the contribution of the whole body MRI (WB-MRI) in the diagnostics of monoclonal gammopathy of undetermined significance (MGUS) and initial, asymptomatic form of multiple myeloma (MM), as well as the evaluation of practical usefulness of the Durie-Salmon Plus staging system (D-S Plus). MATERIALS AND METHODS: The analyzed 86-patient cohort consisted of 28 patients with MGUS and 54 patients with newly diagnosed multiple myeloma and 4 patients with solitary plasmocytoma (SP). WB-MRI was evaluated using Magnetom Avanto 1.5 T with the use of virtual whole body coil with sequential acquisition on 7 levels and 2 sequentions--T2 STIR and T1. Based on the number of lesions and the degree of diffuse involvement we assessed the D-S Plus stage, and compared it to the results of standard staging systems according to Durie Salmon (D-S) and International Staging System (ISS). Statistical estimation was done using the Cohen kappa test and McNemara-Bowker test at p < 0.05. RESULTS: In the group of 28 individuals with MGUS, there were 17 (61%) patients fulfilling the IMWG criteria and/orWB-MRI criteria of incipient MM. In 4/17 (23%) patients we described a more advanced stage when comparing D-S Plus to D-S. Nine out of fourteen (64%) patients with MGUS transforming into MM with negative radiological assessment had positive findings on WB-MRI. The character of WB-MRI findings lead in 9/17 (53%) of the patients to the initiation of induction treatment. Stratification according to D-S Plus divided the 54 newly diagnosed patients with MM into stage 1 (16.7%), stage 2 (33.3%) and stage 3 (50%). In 22% there was a shift into a higher stage using DS-Plus in comparison with D-S, in 9% of the patients the shift lead to downstaging. When comparing the results of ISS vs D-S Plus we found that the system based on WB-MRI showed in 41% of the patients higher stage and only in 9% of the patients lower stage. In 13% of MM patients we described extramedulary masses of the tumor, especially in paraspinal region. In 1 of the 4 SP patients the WB-MRI changed the diagnosis into multifocal plasmocytoma. CONCLUSION: WB-MRI is a very contributive imaging method with substantially higher resolution than conventional radiography. It is able to evaluate the grade and the extent of myeloma bone disease. It improves the diagnostic approach in the differentiation of stable MGUS from the phase of malignant transformation into MM. The D-S Plus system proved to be contributive and is competent to become a routine part of diagnostic and stratification algorithms in MGUS and MM.

[18F-FDG PET/CT and 99mTc-MIBI scintigraphy in evaluation of patients with multiple myeloma and monoclonal gammopathy of unknown significance: comparison of methods]. / 8F-FDG PET/CT v diagnostice mnohocetného myelomu a monoklonální gamapatie nejistého významu: srovnání s 99mTc-MIBI scintigrafií.

BACKGROUNDS: Newer imaging modalities, such as 18F-FDG PET/CT and 99mTc-MIBI scintigraphy, have been recently introduced to assess the activity and extent of disease in patients with multiple myeloma (MM) and gammopathy of undetermined significance (MGUS). The aim of our study was to compare the impact of these imaging modalities in the evaluation of MM and MGUS patients. MATERIALS AND METHODS: A total of 101 patients with MM (81 patients) and MGUS (20 patients) were enrolled in the study (21 newly diagnosed and 44 relapsed patients with symptomatic MM, 16 with asymptomatic MM and 20 with MGUS). All patients were without therapy and underwent 18F-FDG PET/CT and 99mTc-MIBI scintigraphy within a maximum interval of 14 days. The scans were classified as normal (N), diffuse (D), and focal or combined (F-FD) pattern. RESULTS: There was no significant difference in the detection of newly diagnosed MM and relapsed patients between the compared methods. 18F-FDG PET/CT performed better than 99mTc-MIBI scintigraphy in the detection of focal lesions (p < 0.039), whereas 99mTc-MIBI scintigraphy was superior in the visualization of diffuse disease (p = 0.042). 18F-FDG PET/CT visualised significantly more focal lesions than 99mTc-MIBI scintigraphy (p = 0.002), both generally in the cohort and when comparing the number of focal lesions per patient. Both the imaging modalities singly or in combination influenced the subsequent clinical management in 17% of patients. In our study, 18F-FDG PET/CT predicted asymptomatic MM and MGUS transformation into more aggressive forms with the necessity to start therapy more often than 99mTc-MIBI scintigraphy. CONCLUSION: 18F-FDG PET/CT appeared to be a better imaging technique than 99mTc-MIBI scintigraphy in the detection of focal lesions in patients with symptomatic MM. 99mTc-MIBI was superior in the visualization of diffuse disease. On the other hand, despite its limited capacity in detecting focal lesions, 99mTc-MIBI scintigraphy still remains the most rapid and inexpensive technique for whole-body evaluation and may be an alternative option when a PET/CT facility is not available.

[Contribution to the evaluation of serum levels of selected biological parameters in monoclonal gammopathy of undetermined significance and in individual clinical stages of multiple myeloma]. / Príspevek k hodnocení sérových hladin vybraných biologických pusobku u monoklonální gamapatie nejistého výnamu a v jednotlivých klinických stadiích mnohocetného myelomu.

INTRODUCTION: This study aimed to measure serum levels of 12 selected parameters in patients with monoclonal gammopathy of undetermined significance (MGUS) and initial, asymptomatic phase of multiple myeloma (MM) to assess their potential benefit in differentiating both conditions. PATIENT SAMPLE AND METHODOLOGY: The analysed sample of 131 patients consisted of 62 patients with MGUS and 69 patients with MM fulfilling the criteria of the International Myeloma Working Group (IMWG). The following techniques were used to assess serum levels: quantitative immunoradiometry (bone-type alkaline phosphatase - bALP and insulin-like growth factor-1 - IGF-1), chemiluminescent enzyme immunochemical reaction (parathormone--PTH), quantitative sandwich enzyme immunoassay (osteopontin--OPN, endostatin (ES), macrophage inflammatory protein-1alpha/beta--MIP-1alpha/beta, angiogenin--ANG a IL-17). Pearson chi2 test and Mann-Whitney U-test were applied during the statistical analysis. RESULTS: The analysis showed statistically significant differences in serum concentrations between MGUS and symptomatic form of MM (Durie-Salmon (D-S) stage 2-3) for: albumin, beta2-microglobulin (beta2-M) and OPN (p = 0.0001 and < 0.0001); osteocalcin for stage 2 (p = 0.006) and MIP-1alpha for stage 3 patients (p = 0.0002). Using the International Staging System (ISS), statistically significant differences between MGUS and all stages of MM (1-3) were identified for albumin and OPN (p = 0.003 and 0.001 and 0.00009, respectively), stages 2 and 3 for beta2-M and ES (p = 0.015 and 0.0001, respectively), stage 2 for ANG (p = 0.014) and stage 3 for MIP-1alpha (p = 0.00001). Statistically significant differences between MGUS and initial, asymptomatic phase of MM (D-S stage 1) was found only for bALP (p = 0.01) and for albumin (p = 0.004) and OPN (p = 0.003) when ISS was applied. Renal function impairment (D-S substage B) showed in comparison to MGUS significant elevation of serum levels of beta2-M (p < 0.0001), OC (p = 0.011), IGF-1 (p = 0.014), OPN (p = 0.003), ES (p = 0.0001), MIP-1alpha (p = 0.0004) and ANG (p = 0.005) and for albumin (p < 0.0001), beta2-M (p < 0.0001) and OPN (p < 0.0001) only when compared to substage A. CONCLUSION: Only albumin and OPN showed useful even though non-specific potential to differentiate MGUS from all ISS stages of MM, beta2-M and ES for ISS stages 2 and 3, the other parameters differed for stage 2 (ANG), stage 3 (MIP-1alpha) only and stage 1 (bALP), stage 2 (OC) and stage 3 (MIP-1alpha) when D-S stratification was applied.

[Analysis of serum levels of selected biological parameters in monoclonal gammopathy of undetermined significance and multiple myeloma]. / Analýza sérových hladin vybraných biologických ukazatelu u monoklonální gamapatie nejistého významu a mnohocetného myelomu.

BACKGROUNDS: The aim of the study was to evaluate the serum levels of 18 selected parameters in monoclonal gammopathy of undetermined significance, and the initial, asymptomatic phase of multiple myeloma, also from the point of view of the potential contribution to the differentiation of these two units. MATERIALS AND METHODS: The analyzed 119-patient group consisted of 59 individuals with monoclonal gammopathy of undetermined significance and 60 patients with multiple myeloma assessed at the time of diagnosis before the start of the treatment. For the evaluation of serum levels we used radioenzyme assay (thymidine kinase), immunoradiometry (IGF-1), enzyme immunoassay (osteocalcin, osteoprotegerin, ICTP), electrochemiluminiscence (PINP), quantitative sandwich enzyme immunoassay (MIP-1 alpha and MIP-1 beta, IL-17, osteopontin, HGF, VEGF, angiogenin, endostatin, syndecan-1/CD138), and for the assessment of serum levels of free light chains kappa and lambda, the Freelite system. Statistical evaluation was done using the Pearson chi-quadrat test and the U-test according to Mann-Whitney (p < 0.05). RESULTS: Statistically significant differences between monoclonal gammopathy of undetermined significance and multiple myeloma were found in the case of serum levels of thymidine kinase (0.0002), ICTP (0.001), MIP-1 alpha (0.002), osteopontin (<0.0001), HGF (< 0.0001), syndecan-1 (<0.0001), and the kappa/lambda ratio (0.0002), while lower significance was found in the case of angiogenin (0.031) and endostatin (0.011). Statistically non-significant differences between multiple myeloma and monoclonal gammopathy of undetermined significance were within the serum levels of IGF-1, osteocalcin, bALP, PINP, OPG, MIP-1 beta, IL-17, parathormon and VEGF. CONCLUSION: Statistical analysis revealed significant differences between monoclonal gammopathy of undetermined significance and multiple myeloma in 9 of the 18 evaluated parameters. However, due to the significant overlapping of the measured values, none of the parameters is unambiguously able to distinguish between the units. A certain contribution in the discrimination of multiple myeloma from monoclonal gammopathy of undetermined significance was found in markedly increased serum levels of thymidine kinase, MIP-1 alpha, osteopontin, HGF and significant pathology of the kappa/lambda index.

The importance of serum levels of selected biological parameters in the diagnosis, staging and prognosis of multiple myeloma.

The study aimed at evaluating the relation of 7 parameters associated with the internal biological properties of myeloma cells and the bone marrow microenvironment to multiple myeloma (MM) stages, distinguishing its initial/asymptomatic phase from monoclonal gammopathy of undetermined significance (MGUS) and assessing their relation to myeloma prognosis. In the studied group comprising 286 individuals (89 MGUS and 179 MM patients), statistically significant differences (Mann-Whitney test) between MGUS and MM at the time of diagnosis were found in the serum levels of HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), ICTP (intercellular - carboxy-terminal telopeptide of type I collagen), PINP (procollagen type I N-terminal propeptide), OPG (osteoprotegerin) and syndecan-1/CD138, but not in Fas. Multivariate analysis (logistic regression) revealed an unsatisfactory potential of all the 7 studied indicators to discriminate between MGUS and MM. A deeper analysis showed statistically significant differences between MGUS and the initial/asymptomatic phase of MM (stage 1 according to the International Staging System) only in the cases of syndecan-1 (p=0.001) and Fas (p=0.008). The assessment of initial values of HGF, VEGF, ICTP, PINP, OPG, syndecan-1 and Fas showed a statistically significant relation (log rank test) to the overall survival (OS) in a group of 132 patients treated with conventional chemotherapy only in the cases of syndecan-1 (p=0.0002) and Fas (p=0.018), but in none of the investigated parameters in a group of 74 patients treated with HDT/ASCT (high-dose therapy/autologous stem cell transplantation). The analysis showed that, despite significant differences in serum levels of 6 of the 7 studied parameters found between MGUS and MM, none of the markers may be included in the spectrum of indicators used to distinguish the two conditions. Despite the positive relation, especially of syndecan-1 and, to a lesser extent, of Fas to the OS in patients treated with conventional chemotherapy, these prognostic factors are not applicable to HDT/ASCT.

Thalidomide and bortezomib overcome the prognostic significance of proliferative index in multiple myeloma.

UNLABELLED: We analyzed proliferative index of myeloma plasmocytes (PC-PI) in acohort of 217 patients with multiple myeloma (MM) treated with conventional chemotherapy and biological agents, thalidomide and bortezomib. In the whole group was adifference between overall survival (OS) favoring patients with PC-PI ven after 40 months (median overall survival 25 vs 10months, p= 0.015), whereas in the group treated with thalidomide and bortezomib was no difference, with medians over 39 months. Even patients with low PC-PI profited from the treatment with novel drugs. Presented results suggest that the treatment of MM with novel agents overcomes the prognostic significance of PC-PI and should be used in all MM patients. KEYWORDS: myeloma -prognostication -proliferative index -biological therapy.