Jaroslav Bacovsky

Background: We confirmed the benefit of addition of ixazomib to lenalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma (RRMM) in unselected real-world population. We report the final analysis for overall survival (OS), second progression free survival (PFS-2), and the subanalysis of the outcomes in lenalidomide (LEN) pretreated and LEN refractory patients. Methods: We assessed 344 patients with RRMM, treated with IRD (N = 127) or RD (N = 217). The data were acquired from the Czech Registry of Monoclonal Gammopathies (RMG). With prolonged follow-up (median 28.5 months), we determined the new primary endpoints OS, PFS and PFS-2. Secondary endpoints included the next therapeutic approach and the survival measures in LEN pretreated and LEN refractory patients. Results: The final overall response rate (ORR) was 73.0% in the IRD cohort and 66.8% in the RD cohort. The difference in patients reaching ≥VGPR remained significant (38.1% vs. 26.3%, p = 0.028). Median PFS maintained significant improvement in the IRD cohort (17.5 vs. 12.5 months, p = 0.013) with better outcomes in patients with 1–3 prior relapses (22.3 vs. 12.7 months p = 0.003). In the whole cohort, median OS was for IRD vs. RD patients 40.9 vs. 27.1 months (p = 0.001), with further improvement within relapse 1-3 (51.7 vs. 27.8 months, p ˂ 0.001). The median PFS of LEN pretreated (N = 22) vs. LEN naive (N = 105) patients treated by IRD was 8.7 vs. 23.1 months (p = 0.001), and median OS was 13.2 vs. 51.7 months (p = 0.030). Most patients in both arms progressed and received further myeloma-specific therapy (63.0% in the IRD group and 53.9% in the RD group). Majority of patients received pomalidomide-based therapy or bortezomib based therapy. Significantly more patients with previous IRD vs. RD received subsequent monoclonal antibodies (daratumumab—16.3% vs. 4.3%, p = 0.0054; isatuximab 5.0% vs. 0.0%, p = 0.026) and carfilzomib (12.5 vs. 1.7%, p = 0.004). The median PFS-2 (progression free survival from the start of IRD/RD therapy until the second disease progression or death) was significantly longer in the IRD cohort (29.8 vs. 21.6 months, p = 0.016). There were no additional safety concerns in the extended follow-up. Conclusions: The IRD regimen is well tolerated, easy to administer, and with very good therapeutic outcomes. The survival measures in unsorted real-world population are comparable to the outcomes of the clinical trial. As expected, patients with LEN reatment have poorer outcomes than those who are LEN-naive. The PFS benefit of IRD vs. RD translated into significantly better PFS-2 and OS, but the outcomes must be accounted for imbalances in pretreatment group characteristics (especially younger age and stem cell transplant pretreatment), and in subsequent therapies.

Summary 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...

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. The presentation of cardiac bio-markers assay applications in AL amyloidosis patients at an individual treatment center. 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. 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. 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.

The management of spinal multiple myeloma (MM) is a complex process, including causal treatment (i.e. efforts to suppress the tumor clone), as well as supportive therapy, including surgery. The aim of this article is to present retrospective evaluation of surgical indications in patients with MM or solitary spinal plasmocytoma. A total of 10 patients (8 males and 2 females) aged from 32 to 74 years (the mean age of 53.3) were included in the study. The enrolment criteria were the following: patients operated for MM or solitary spinal plasmocytoma during the past 7-year period, with the minimum follow up period of 6 months. The procedures were indicated for progressing neurological deficit (Frankel score) and for axial spinal pain (VAS classification), not responding to conservative therapy. The extent of the disease was assessed based on plain x-ray, MRI and whole- body 18F-FDG PET/CT. Paliative vertebroplasty was indicated in patients with no neurological deficit to control pain, paliative laminectomy without stabilization in subjects with partial neurological lesions, with transpedicular fixation in concomitant pathological fractures or kyphotizations. More radical approach, i.e. the procedure included somatectomy, was indicated in patients with solitary plasmocytoma and in procedures on cervical or thoracolumbar regions. Control clinical and MRI examinations were performed at 6 weeks, at 6 months and then at yearly intervals. At the end of the study, the authors evaluated effectivity of the employed surgical procedures, based on all control findings, and the data were compared with prognostic scoring systems in surgery for spinal metastases (Tomita score, Tokuhashi modified score and Bauer score). No local relapses of the tumor or stabilization failure were detected. The effect of surgery on pain control and on prevention of neurological dysfunction was maintained over the follow up period. The authors concluded that all surgical procedures and their radicality were adequate in all subjects. The agreement between the authors approach (the procedure's radicality) and the Tomita score, the Tokuhashi modified score and the Bauer score were recorded in 50% of patients, 80% of patients and in 50% of patients, respectively. MM is characterized by increased oseteolysis, which is not followed by new bone formation. Despite successful conservative therapy of MM, the bone defects fail to heal, cause spinal pain and may result in spinal instability. These specific MM signs represent the principal factor in the decision- making process concerning indication for surgery. Furthermore, favourable prognosis, with survival times usually exceeding the required expected minimum survival time of 3-6 months, is yet another reason for indication for surgical therapy in patients with spinal MM. Due to advances in chemotherapy and the use of autologic grafts of peripheral stem cells and radiotherapy, the prognosis of patients have significantly improved in last 10 years. The mean survival time has increased from 2.5 years to 4.5 years. 1. Prevention or improvement of neurological dysfuction and pain control are the main indication criteria for surgery in MM. 2. Surgery should be considered in MM with osteolytic spinal disorder and because of favourable prognosis of the disease when surgery is used. 3. Surgical procedures, including paliative methods resulted in sufficient control of spinal stability in all the study subjects. 4. Using all scoring systems for spinal metastases could result in indications for unnecessary more radical procedures. However, Tokuhashi score appeared to be the most suitable existing prognostic scoring system.

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). 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. 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. 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.

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/β, MIP-1α/β; 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.

Patients with multiple myeloma have a high risk of venous thromboembolism (VTE), especially during the induction chemotherapy. The aim of our observational study was to determine the impact of prophylaxis with low molecular weight heparin (LMWH) on the incidence of thromboembolic complications. We analyzed the incidence of thromboembolic events in 258 patients treated with induction chemotherapy containing vincristin, doxorubicin or idarubicin, and dexamethasone, followed by stimulation chemotherapy with cyclophosphamide and G-CSF, and high-dose chemotherapy with melphalan. Two groups of these patients were compared based on the practice of thromboprophylaxis. Patients in the first group (Control, n = 140) were either not treated or treated with a short duration of anticoagulation therapy while the patients in the second group (Prophylactic, n = 118) underwent standard prophylaxis with LMWH throughout the entire period of induction chemotherapy. A total of 102 patients were selected for a close monitoring of the prophylactic effect of different LMWH doses and to be compared to patients without treatment. Standard prophylaxis with LMWH significantly (p < 0.007) lowered a risk of VTE when compared to patients without such prophylaxis (3.4% versus 12.9%, respectively). Furthermore, analysis of the subgroup of 102 patients revealed that higher LMWH doses (> 70 IU/kg per day) achieved full prophylaxis in 28 patients while lower doses were less effective leading to DVT in 3 (7.7%) out of 39 patients. In contrast, VTE was diagnosed in 5 (14.3%) out of 35 patients without any LMWH prophylaxis. Prophylaxis with LMWH leads to a significant reduction of the risk of thromboembolic complications during the induction chemotherapy in patients suffering from MM. The prophylactic effect of LMWH is dose-dependent.

Technetium-99m 2 methoxyisobutylisonitrile (Tc-99m MIBI) scintigraphy has been used to identify biologic activity and extent of multiple myeloma (MM) and monoclonal gammopathy of unknown significance (MGUS). The examination could also serve both as a prognostic tool and an examination for monitoring the disease course in MM patients. The purpose of this study was to evaluate the prognostic value of different Tc-99m MIBI uptake patterns. Ninety-nine consecutive patients with newly diagnosed symptomatic MM and 18 patients with MGUS underwent baseline Tc-99m MIBI scintigraphy before applying any kind of therapy. The Tc-99m MIBI scans were classified as showing normal, diffuse, and focal or combined (diffuse and focal) patterns of tracer uptake. To evaluate the prognostic value of different Tc-99m MIBI uptake patterns, overall survival (OS) was chosen as an end point. Median of follow-up period was 84 months. Survival according to patterns of Tc-99m MIBI uptake was calculated using the Kaplan-Meier plots. Statistically significant correlation between the baseline patterns of Tc-99m MIBI uptake and OS was found (P < 0.0001). Focal or combined patterns of Tc-99m MIBI uptake indicated significantly worse prognosis with shorter OS than normal or diffuse tracer patterns. Tc-99m MIBI scintigraphy plays the predictive role in the follow-up of patients with MM. Baseline scintigraphic pattern of Tc-99m MIBI uptake seems to be a useful prognostic indicator of OS in MM patients and Tc-99m MIBI scintigraphy could be used as an additional tool for the initial examination in patients with newly diagnosed MM.

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. 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. 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. 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.