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.

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.

Comparison of autologous hematopoietic cell transplantation performed in tandem and in disease relapse in multiple myeloma patients.

Multiple myeloma is a malignant hemato-oncological malignancy that affects up to 600 people in the Czech Republic every year. Treatment options are under constant improvement and the autologous hematopoietic cell transplantation (Tx) remains a part of treatment protocols. Despite modern drug administration, the autologous Tx keeps its irreplaceable position and when ensuring two autologous Tx, the studies confirm a survival time more than twice as long as in non-transplant patients. However, there are no standardized procedures specifying the period in between the transplantations in more detail. Within our group, we compared the total of 66 patients who were administered a double transplant. One group underwent both planned tandem autologous Tx within a median of six months and mostly achieved just partial remission (PR) and less after the first transplant and out of disease progression. The other group only underwent the second Tx within a median of up to 14 months during a progression period or disease relapse. Both groups were comparable as far as basic parameters are concerned (age, type of induction therapy and cytogenetic risk). A significantly better treatment free survival (TFX) and overall survival (OS) were observed in the group where tandem Tx was administered. TFS was 18 months and median OS was not reached for the group of patients who received tandem Tx, while TFS was 10 months (p=0.04) and median OS was 57 months (p=0.005) for those who received delayed second Tx. In the group of patients who received second Tx during relapse, we observed that TFS and OS were shorter in those with a higher paraprotein level, thus suggesting the potential role of paraprotein level as a prognostic marker. The TFS in the subgroup with a high initial level was 4 months vs. 11 months (p=0.0016) and OS 44 months vs. 65 months (p=0.03).

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.

Prognostic factors to predict outcome of reduced intensity allogeneic haematopoietic cell transplantation for chronic lymphocytic leukemia.

Despite advances in immunochemotherapy CLL remains an incurable disease.. Allogeneic haematopoietic cell transplantation (HCT) has proven curative potential with ability to overcome adverse prognostic factors, however due to its toxicity it is generally perceived as the last option. We performed retrospective study to explore the outcomes and possible determinants of survival in the unselected consecutive cohort of 68 CLL patients (median age 59 years) receiving reduced intensity HCT as a part of salvage therapy in 2 Czech centers. The median interval from diagnosis to HCT was 69 months with median 3 of prior regimens, all patients were refractory to purine analogues. 49% of patients were transplanted with advanced (i.e. refractory or progressive disease or CR/PR>3), 38% had high risk cytogenetics. With median follow-up of 35 months the 3-year Kaplan-Meier survival probability for OS and PFS were 39% and 26%, respectively. Altogether 18 patients (26%) have relapsed or progressed. During the follow-up 41 patients died, 32 (78%) of transplant related factors (NRM), the others of relapse or disease progression.Univariate analysis failed to identify any clinical and pre- or post-transplant variables having clear prognostic significance for OS or PFS. The marginal OS advantage favoring HCT performed recently was detected (3-year OS: 31% for HCT until 2006 and 47% thereafter, p=0.0923). In multivariable hazards model only the female donors were associated with shorter OS (HR 2.278, p=0.016) whereas transplanted T-cell> 2.75x108/kg predicted inferior PFS(HR 1.957, p=0.035). No prognostic impact of donor type, age of donor and recipient, HLA mismatch, disease status pre-HCT, number of previous therapy lines, interval from dg. to HCT and number of transplanted hematopoietic cells was found. Our findings support the conclusion that alloHCT is able to overcome well known negative cytogenetic prognostic factors and that preferring male to female donors could be beneficial.

[The incidence of malignancies and surveillance of hematopoietic stem cells donors--the results of the Haemato-Oncology Department University Hospital in Plzen (Pilsen) and Czech National Marrow Donors Registry observation]. / Výskyt malignit a dispenzarizace dárcu krvetvorných bunek--výsledky sledování Hematologicko-onkologického oddelení FN Plzen a Ceského národního registru dárcu drene

BACKGROUNDS: Granulopoesis colony-stimulating factor filgrastim is used to mobilize peripheral stem cells but there are concerns regarding an elevated risk of haematological malignancies. We analyzed the incidence of malignancies and the system of haematopoietic stem cells donor surveillance. PATIENTS AND METHODS: prospective observation of sibling donors of the Haemato-Oncology Department University Hospital in Plzen (Pilsen) and of unrelated donors of the Czech National Marrow Donors Registry (CNMDR) in 2001-2010. RESULTS: No malignancy was observed in a group of 344 unrelated CNMDR donors, providing 753 person-years; one case of chronic lymphocytic leukaemia manifested 6 years after bone marrow donation, with leukaemia clone retrospectively detected by DNA analysis in blood samples taken prior to the marrow donation. Acute myeloid leukaemia, non-Hodgkin lymphoma, renal and colorectal carcinoma were observed in a group of 84 peripheral stem cells sibling donors, providing 337 person-years observation. The respective incidence of the two haematologic malignancies was 593 cases and the expected incidence rate was 143 per 100,000. The sibling (related) donors age was significantly higher: 48 (16-75) vs. 31 (20-42) years, (p<0.0001). Significantly more lost-to-follow-up donors were among the related donors (32% vs. 3%, p<0.0001), even though active surveillance system was implemented. CONCLUSION: The development of malignancies in hematopoietic stem cells donors can naturally be expected. Related (sibling) donors are at higher risk because of their generally older age, and higher susceptibility to haematological malignancies developed within the family. The contribution of filgrastim exposure needs to be further investigated. The follow-up cooperation with related (sibling) donors is limited.

[Alemtuzumab in chronic lymphocytic leukemia treatment: retrospective analysis of outcome according to cytogenetics]. / Alemtuzumab v terapii chronické lymfocytárni leukemie: retrospektivní analýza a hodnoceni lécebné odpovidi podle cytogenetickiho rizika.

UNLABELLED: Alemtuzumab in chronic lymphocytic leukemia treatment: retrospective analysis of outcome according to cytogenetics SUMMARY: Alemtuzumab is effective in B-cell chronic lymphocytic leukemia (CLL) with 17p deletion, which responds poorly to chemotherapeutic agents. Our retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced CLL, categorized by cytogenetic profile. Data were collected from 74 consecutive who had received alemtuzumab. Median of previous therapies was 2. The incidence of cytogenetic abnormalities was: trisomy 12, 10%; 13q deletion, 13%; 11q deletion 25%; 17p deletion, 26%; none of these, 26%. The overall response rate was 65% (11% complete remission, 54% partial remission) in the whole cohort. From start of alemtuzumab therapy, median progression-free survival was 217 days, median time to alternative treatment was 287 days, and median overall survival was 999 days in the total cohort, respectively. Alemtuzumab was effective across all cytogenetic categories evaluated. There were no statistically significant differences between subgroups in the level of efficacy.