Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR.

The randomized phase 3 study ENDEAVOR demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (MM). We conducted a preplanned subgroup analysis of ENDEAVOR to evaluate Kd vs Vd by cytogenetic risk. Of 785 patients with known cytogenetics, 210 (27%) had high-risk cytogenetics (Kd, n=97 (25%); Vd, n=113 (28%)) and 575 (73%) had standard-risk cytogenetics (Kd, n=284 (75%); Vd, n=291 (72%)). Median PFS in the high-risk group was 8.8 months for Kd vs 6.0 months for Vd (hazard ratio (HR), 0.65; 95% confidence interval (CI), 0.45-0.92; P=0.0075). Median PFS in the standard-risk group was not estimable for Kd vs 10.2 months for Vd (HR, 0.44; 95% CI, 0.33-0.58; P<0.0001). Overall response rates were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved ⩾CR. This preplanned subgroup analysis found that Kd was superior to Vd in relapsed or refractory MM, regardless of cytogenetic risk.

Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study.

The randomized phase 3 ENDEAVOR study (N=929) compared carfilzomib and dexamethasone (Kd) with bortezomib and dexamethasone (Vd) in relapsed multiple myeloma (RMM). We performed a subgroup analysis from ENDEAVOR in patients categorized by number of prior lines of therapy or by prior treatment. Median progression-free survival (PFS) for patients with one prior line was 22.2 months for Kd vs 10.1 months for Vd, and median PFS for patients with ⩾2 prior lines was 14.9 months for Kd vs 8.4 months for Vd. For patients with prior bortezomib exposure, the median PFS was 15.6 months for Kd vs 8.1 months for Vd, and for patients with prior lenalidomide exposure the median PFS was 12.9 months for Kd vs 7.3 months for Vd. Overall response rates (Kd vs Vd) were 81.9 vs 65.5% (one prior line), 72.0 vs 59.7% (⩾2 prior lines), 71.2 vs 60.3% (prior bortezomib) and 70.1 vs 59.3% (prior lenalidomide). The safety profile in the prior lines subgroups was qualitatively similar to that in the broader ENDEAVOR population. In RMM, outcomes are improved when receiving treatment with carfilzomib compared with bortezomib, regardless of the number of prior therapy lines or prior exposure to bortezomib or lenalidomide.

[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.

[Heart transplantation and the subsequent treatment of AL amyloidosis]. / Transplantace srdce a následná lécba AL-amyloidózy.

UNLABELLED: Severe damage to the heart caused by AL amyloid deposits is a contraindication of high-dose chemotherapy with autologous haematopoietic stem cell transplantation. Severe heart damage caused by AL amyloid results in frequent life-threatening complications, even during the course of the classical chemotherapy treatment and it often makes keeping to the treatment schedule impossible. Scheduling heart transplantation before the treatment of AL amyloidosis will significantly improve the patients overall condition and enable them to undergo the intensive AL amyloidosis treatment with the hope that a long-term complete remission may be achieved. CASE DESCRIPTIONS: Transplantations of heart damaged by AL amyloid deposits were conducted in three patients; two men, age 48 and 54, and one woman, age 63. In the interval of 3-6 months from the heart transplantation before the scheduled AL amyloidosis treatment was initiated, an examination of bone marrow, the concentration of monoclonal immunoglobulin and free light chains was carried out. Both men had more than 10% of plasma cells in the bone marrow after the heart transplantation and the concentrations of the λ free light chains were pathologically increased. During the first-line therapy, autologous haematopoietic stem cells were harvested from peripheral blood after mobilizaton with granulocyte growth factor (filgrastim) at the dose of 5 µg/kg twice a day. During the administration of filgrastim until the end of the haematopoietic stem cell harvest, the combined immunosuppressive treatment was reduced and a corticosteroid dose was compensatory increased. The prophylactic antiviral drug valganciclovir was discontinued during the haematopoietic stem cell harvest. High-dose chemotherapy (melphalan 100 mg/m2) with autologous haematopoietic stem cell transplantation followed. In the interval from administering melphalan until the rise in neutrophil count over 2 x 109/l, antiviral prophylaxis was discontinued again, the immunosuppressive drug doses were reduced and corticoid doses were slightly increased. High-dose chemotherapy with melphalan at the of 100 mg/m2 was tolerated without major complications and without mucositis; however, in neither of the male patients did it lead to a complete haematological remission. Consequently, the second-line therapy followed using bortezomib combined with dexamethasone and also with cyclophosphamide or doxorubicin. One of these two patients reached a complete haematological remission after the bortezomib therapy; the values of free light chains were normal, immunofixation was negative, and clonal plasma cells were absent in the bone marrow. In the case of the other patient, the bortezomib therapy only induced partial remission. In this case, the third-line therapy followed, applying a combination of lenalidomide, dexamethasone and cyclophosphamide. This therapy significantly reduced the values of free light chains; however, their ratio remained pathological. To conclude, the latter response can be described as a very good partial remission. Both men currently show no signs of disease activity and are in a good clinical condition 28 and 30 months after the heart transplantation. The third heart transplantation, due to severe heart damage by AL amyloid deposits, was conducted in a woman aged 63. An examination of this woman three months after the heart transplantation showed that the original pathological values of free light chains became normal. The woman had approx. 8% of clonal plasma cells before the heart transplantation. Three months after the heart transplantation the bone marrow contained only 3% of polyclonal plasma cells. In this case, the immunosuppressive treatment with corticosteroids after the heart transplantation probably induced a complete haematologic remission. The woman is in a complete AL amyloidosis remission seven months after the heart transplantation. CONCLUSION: It was beneficial to perform the heart transplantation first and to initiate the AL amyloidosis treatment no sooner than three months after the heart transplantation in patients with severe heart damage caused by AL amyloid deposits. If the patients are in a good clinical conditions, autologous haematopoietic stem cells can be harvested after the heart transplantation and high-dose chemotherapy can be offered to the patients. If this intensive treatment does not induce remission, it is necessary to apply additional alternative treatments.

[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.

[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.

[The comparison of serum levels of selected biomarkers in monoclonal gammopathy of undetermined significance and multiple myeloma]. / Srovnání sérových hladin vybraných biologických pusobku u monoklonální gamapatie nejistého významu a mnohocetného myelomu.

BACKGROUND: The aim of the study was the evaluation of serum levels of 12 selected biomarkers in monoclonal gammopathy of undetermined significance (MGUS) and in initial, asyptomatic phase of multiple myeloma, especially from the view of potential differentiation of these conditions in clinical practice. METHODS AND RESULTS: Analyzed group of 268 individuals consisted of 89 individuals with MGUS and 179 patients with MM examined in time of diagnosis before treatment initiation. For evaluation of serum levels were used following methods: radioenzymatic method (thymidinekinase), enzymatic immunoassay (beta2-M, IL-6R, ICAM-1, VCAM-1, ICTP, PINP and OPG) and quantitative sandwich enzymatic immunoassay (HGF, VEGF, syndecan-1/CD138 and Fas). Pearson's chi2-test and test according to Mann-Whitney were used for statistical evaluation (p < 0.05). Wide statistic differences in serum levels of analyzed markers in MGUS vs. MM were detected in case of beta2-M, TK, ICTP, OPG, HGF and syndecan-1 (p < 0.0001), lower differences in case of VCAM-1, PINP and VEGF (p = 0.003, 0.001 and 0.04), and without difference in case of Fas. Except for thymidinekinase (p = 0.014) and syndecan-1 (p = 0.001) was not detected statistically important contrast of measured values in MGUS individuals and in patients with initial, asymptomatic phase of MM (stage 1), but these markers cannot be used in clinical practice due to significant overlap of serum values. Continuous downgrade of serum values of VEGF due to degree of MM progression (stages 1-3 according to Durie-Salmon) was unexpected. RESULTS: Although the significant differences in 9 of 12 evaluated serum levels of selected biomarkers in groups of MGUS and MM were seen, the results revealed that these markers are unprofitable to bring discriminatory potential capable of being used to distinguish between MGUS and initial, asymptomatic phase of MM.

Low-dose thalidomide regimens in therapy of relapsed or refractory multiple myeloma.

Thalidomide has been estimated as a useful drug in therapy of refractory or relapsed multiple myeloma. Recently, several studies have shown very good results in therapy combination of thalidomide, cyclophosphamide and dexamethasone, but still high doses of thalidomide associated with serious adverse events have been used. In our study, we performed low-dose thalidomide regimens; the aim of this study was to verify the effect and to assess their toxicity. For younger patients up to 65 years we used a "CTD-junior" regimen, consisting of oral thalidomide 200 mg daily, pulsed intravenous cyclophosphamide 800 mg on day 1 and pulsed oral dexamethasone 40 mg on days 1-4 and 12-15, for every three weeks. For patients over 65 years, the "CTDsenior" regimen was used, with oral thalidomide 50-100 mg daily (according to tolerability), oral cyclophosphamide 50 mg daily and pulsed dexamethasone 20 mg on days 1-4 and 15-18, for every four weeks. From the group of 97 patients with progressive form of multiple myeloma or with resistance to conventional chemotherapy, 85 patients were evaluated. According to the EBMT criteria, we observed in 8% complete remission (CR), in 50% partial response (PR) and in 22% minimal response (MR). Ten patients (12%) were stabilized and seven patients (8%) progressed. Toxicity of both regimens was mild and well manageable, when weakness, obstipation, neuropathy of lower extremities, glycoregulation worsening and mild leucopenia occurred most often. These results showed that low doses of thalidomide are still effective, when combined with other drugs. Both CTD regimens are safe also for patients with advanced and heavily pretreated multiple myeloma.

[Assessment of plasmatic cell proliferation and apoptosis indexes in the course of multiple myeloma]. / Hodnocení proliferacního a apoptotického indexu plazmatických bunek v prubehu mnohocetného myelomu.

INTRODUCTION: The proliferation and apoptosis indexes are a significant prognostic factor in multiple myeloma (MM). The objective of the study was to assess the indexes in the course of MM from the point of view of the disease activity and potential clinical use. METHOD: A sample of 120 patients was studies, of which 49 at diagnosis, 36 in progression and 35 in remission. The proliferation and apoptosis indexes were assessed according to the achieved treatment response and were compared with subsequent progression in patients in remission. The proliferation potential was measured with the propidium-iodide index (PC-PI/CD138), apoptosis was measured with annexine-V (PC-AI/CD138), assessed by the method of flow cytometry. RESULTS: The sample of49 newly diagnosed patients recorded a decrease in PC-PI (M 2.9-2.1, p < 0.0001) and an increase in PC-AI (M 4.7-8.6, p < 0.0001) at remission. Patients without treatment response showed no difference in PC-PI (p = NS), while PC-AI decreased (M 6.2-3.9, p = 0.004). The sample of36 patients in MM progression with treatment response recorded a decrease in PC-PI (M 2.9-2.2, p < 0.0001) and an increase in PC-AI (M 4.6-8.8, p < 0.019). There was no difference in any of the indicators (p = NS) in cases with zero treatment response. 35 patients in remission with developing progression recorded an increase in PC-PI (M 2.3-2.7, p < 0.0001) and a decrease in PC-AI (M 8.3-4.2, p < 0.0001). CONCLUSION: The study has shown that monitoring PC-PI and PC-AI in the course of different phases of MM is beneficial from the point of view of the assessment of changes in the proliferation activity and the degree of apoptosis of myeloma cells. Monitoring the two parametres allows for timely prediction of disease progression.

[Present possibilities of diagnostics and therapy of osteoporosis]. / Soucasné moznosti diagnostiky a lécby osteoporózy.

The occurence of osteoporosis is not so poor in industrial countries, together with advance of socioeconomical level and spreading of human life's lenght, increases the prevalence of osteoporosis, affect about 5-6% of Europe population and also raises the number of the most consequential results--fractures, complications, dramatically deteriorating health state and limiting social self-realization of the pacients. Osteoporosis belongs to metabolic bone diseases with highly clarified mechanisms of bone tissue decrease and comprehensive diagnostic platform, based on combination of imaging and laboratory methods, enabling early disease detection, before occurence of fracture complications. In sequence of disorder etiology, the adequate therapy is known with continualy increasing effectivity and aplication simplicity for pacient, increasing his compliance. Increasing public knowledge and prevention put back not only occurance of complications, but also onset of the disease. Neverthless, the osteoporosis is still hidden danger with serious economic and social impact.

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

PURPOSE OF STUDY: The study focuses on evaluation of differences in serum levels of selected biological indicators in monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM), primarily from the viewpoint of potential asset to clinical practice. PATIENTS AND METHODOLOGY: The analyse set of 96 patients consisted of 30 individuals with MGUS and 66 patients with MM examined in the context of the disease diagnosis before therapy commencement. Serum levels of the assessed parameters were examined with the help of radio-enzymatic method (thymidinkinase), radioimmunoanalysis (beta2-micro-globulin, ICTP, PINP), enzymoimmunoessay method (sIL-6R, sVCAM-1, sICAM-1, sOPG and sRANKL) and the technique of quantitative sandwich enzymatic immunoessay (sHGF, sVEGF, bFGF, syndecan-1/CD138 and sFas). Statistical examination was performed by Pearson and Fischer test, chi2-test, or nonparametric U-test pursuant to Mann-Whitney (p < 0.05). RESULTS: Statistically significant differences were found between MGUS and MM in the case of serum level comparisons of sIL-6R (p = 0.02), ICTP (p = 0.001), sHGF (p = 0.001) and syndecan-1/sCD138 (p = 0.001), while no statistically significant differences were present in the case of sVCAM-1, sICAM-1, PINP, sOPG, sVEGF and sFas. During the analysis of frequency of occurrence of abnormal values in the MM and MGUS groups, significant differences were found not only in the case of standard parameters, such as beta2-microglobulin, thymidinkinase, creatinin and albumin, but also in the case of sIL-6R, ICTP, sHGF and syndecan-1, but not in comparisons of the levels of sVCAM-1, sICAM-1, PINP, sOPG, sVEGF and sFas. Attempts at examination of serum levels of sRANKL and soluble form of bFGF failed as too low values were measured. CONCLUSION: The analysis of behaviour of the 10 parameters, mostly intimately related to biological properties of clonal plasmatic cells or to changes of microclimate of bone marrow, effectively contributed to distinction between MGUS and MM only in the case of serum levels of sIL-6R, ICTP, sHGF and syndecan-l (sCD138), i.e. indicators with demonstrable relevance for MM prognosis assessment.

[Contribution to the evaluation of the relationship between angiogenic cytokines, selected biological parameters and prognostic factors in multiple myeloma]. / Príspevek k hodnocení vztahu angiogenních cytokinu a vybraných biologických ukazatelu k prognostickým faktorum mnohc'etného myelomu.

BACKGROUND: Multiple myeloma is an unusually heterogeneous disease with individually different clinical course, sensitivity to therapy and prognosis. The undoubted limitation of contemporary diagnostic stratification systems is the insufficient credit of those parameters that express the intrinsic biological properties of myeloma cells and the microenvironment of the bone marrow. The aim of this study was to evaluate the relationship of 10 biological parameters to 6 fundamental prognostic factors of multiple myeloma. METHODS AND RESULTS: The analysed group consisted of 66 individuals examined at the time of diagnosis before the start of therapy. For the estimation of serum levels of investigated molecules there were used following methods: REA RIA, ELISA and the technique of quantitative sandwich enzyme immunoassay. For the analysis of proliferative and apoptotic properties of myeloma cells we used propidium iodide (PC-PI) and annexin-V (PC-AI) indices. The statistical estimation was carried out with the help of Pearson and Spearman test, eventually with the help of U-test according to Mann-Whitney. Increased incidence of abnormal serum levels of examined parameter was registered in the case of S-beta2-microglobulin (95.5%), S-thymidinekinase (57.5%), S-sVCAM-1 (78.5%), S-ICTP (87.0%), S-solubile osteoprotegerin (sOPG 76.5%), S-sSyndecan-1 (56.5%) and low index of plasma cell apoptosis (PC-AI, 78.0%). The statistical analysis (Pearson's test) revealed the mutual relationship of serum levels of: S-beta2-microglobulin to sVCAM-1, (r = 0.39, p = 0.002), sICAM-1 (r = 0.33, p = 0.011), sOPG (r = 0.53, p = 0.001), sHGF (r = 0.34, p = 0.006), sSyndecan-1 (r = 0.38, p = 0.003) and sFas (r = 0.42, p = 0.001); S-albumin to sVCAM-1 (r = -0.29, p = 0.036), ICTP (r = -0.33, p = 0.016), sOPG (r = -0.63, p = 0.000), sHGF (r = -0.39, p = 0.003), sSyndecan-1 (r = -0.29, p = 0.042); S-thymidinekinase to sSyndecan-1 (r = 0.46, p = 0.000) and sFas (r=0.29, p = 0.019). There was no relationship of PINP and VEGF to any of the evaluated prognostic factors. There was no relationship found between either of the analysed parameters to PC-PI and PC-AI. With the help of U-test there was found the relationship of sIL-6R to S-beta2-microglobulin (p = 0.001), albumin (p = 0.002) and PC-PI (p = 0.046). CONCLUSIONS: The presented study implies that the traditional algorithm of parameters used in clinical practice for individual characteristics of MM should be enriched with sOPG, sHGF, sSyndecan-1 and sFas.