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Multiple myeloma (MM) is characterized by malignant plasma cell infiltration of the bone marrow. In extramedullary multiple myeloma (EMD), a subclone of these cells migrates out of the bone marrow. Out of 4 985 MM patients diagnosed between 2005 and 2017 in the Czech Republic, we analyzed 234 secondary EMD patients to clarify risk factors of secondary EMD development. We found younger age [65 years; odds ratio (OR) 4·38, 95% confidence interval (CI): 2·46-7·80, P 0·0001], high lactate dehydrogenase (LDH) levels (5 μkat/l; OR 2·07, 95% CI: 1·51-2·84, P 0·0001), extensive osteolytic activity (OR 2·21, 95% CI: 1·54-3·15, P 0·001), and immunoglobulin A (IgA; OR 1·53, 95% CI: 1·11-2·11, P = 0·009) or the non-secretory type of MM (OR 2·83; 95% CI: 1·32-6·04, P = 0·007) at the time of MM diagnosis to be the main risk factors for secondary EMD development. Newly diagnosed MM (NDMM) patients with subsequent EMD had inferior median progression-free (PFS) and overall (OS) survival when compared to NDMM patients without future EMD [mPFS: 13·8 months (95% CI: 11·4-16·3) vs 18·8 months (95% CI: 17·7-19·9), P = 0·006; mOS: 26·7 months (95% CI: 18·1-35·4) vs 58·7 months (95% CI: 54·8-62·6), P 0·001]. We found that NDMM patients with specific risk factors associated with secondary EMD development have a more aggressive disease course before secondary EMD develops.

[Aim]: To evaluate the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma in routine clinical practice. Patients & methods: Patient-level data from the global, observational INSIGHT MM and the Czech Registry of Monoclonal Gammopathies were integrated and analyzed., [Results]: At data cut-off, 263 patients from 13 countries were included. Median time from diagnosis to start of IRd was 35.8 months; median duration of follow-up was 14.8 months. Overall response rate was 73%, median progression-free survival, 21.2 months and time-to-next therapy, 33.0 months. Ixazomib/lenalidomide dose reductions were required in 17%/36% of patients; 32%/30% of patients discontinued ixazomib/lenalidomide due to adverse events., [Conclusion]: The effectiveness and safety of IRd in routine clinical practice are comparable to those reported in TOURMALINE-MM1., This work was supported by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Introduction Risk stratification tools provide valuable information to inform treatment decisions. Existing algorithms for patients with multiple myeloma (MM) were based on patients with newly diagnosed disease, and these have not been validated in the relapsed setting or in routine clinical practice. We developed a risk stratification algorithm (RSA) for patients with MM at initiation of second-line (2L) treatment, based on data from the Czech Registry of Monoclonal Gammopathies. Methods Predictors of overall survival (OS) at 2L treatment were identified using Cox proportional hazards models and backward selection. Risk scores were obtained by multiplying the hazard ratios for each predictor. The K-adaptive partitioning for survival (KAPS) algorithm defined four groups of stratification based on individual risk scores. Results Performance of the RSA was assessed using Nagelkerke’s R2 test and Harrell’s concordance index through Kaplan–Meier analysis of OS data. Prognostic groups were successfully defined based on real-world data. Use of a multiplicative score based on Cox modeling and KAPS to define cut-off values was effective. Conclusion Through innovative methods of risk assessment and collaboration between physicians and statisticians, the RSA was capable of stratifying patients at 2L treatment by survival expectations. This approach can be used to develop clinical decision-making tools in other disease areas to improve patient management. Funding Amgen Europe GmbH. Electronic supplementary material The online version of this article (10.1007/s40487-019-00100-5) contains supplementary material, which is available to authorized users.

Objective: The treatment of relapsed and refractory multiple myeloma (RRMM) remains challenging. The outcomes in highly pretreated populations are unsatisfactory and there is urgent need for novel and safe therapeutic approaches. Recently, daratumumab has been approved for RRMM with promising results even in monotherapy. The aim of this study was to assess the efficacy of single agent daratumumab outside a clinical trial. Patients and Methods: 14 patients with RRMM and significant pretreatment (median 4.5 previous lines) entered a specific healthcare program and received treatment with single agent daratumumab. They were followed for therapeutic response based on IMWG criteria, and incidence of adverse events. The data were collected using the Registry of Monoclonal Gammopathies. Results: The overall response rate was 38.5%. 23.1% of patients reached very good partial response, 15.4% reached partial remission, 15.4% had minimal response, 38.5% had stable disease and 7.7% had progressive disease. The median progression free survival was 4.6 months and median overall survival was not achieved. The toxicities were mostly mild, only infectious complications and hematological toxicity reached grade III. Conclusion: We conclude that daratumumab has significant activity in highly pretreated RRMM even as a single agent, with an acceptable toxicity profile and survival impact.

Plasma cell leukaemia (PCL) is a rare and very aggressive plasma cell disorder. Preventing a dismal outcome of PCL requires early diagnosis with appropriate analytical tools. Therefore, the investigation of 33 patients with primary and secondary PCL was done when the quantity of circulating plasma cells (PCs) using flow cytometry (FC) and morphology assessment was evaluated. The phenotypic profile of the PCs was also analysed to determine if there is an association with clinical outcomes and to evaluate the prognostic value of analysed markers. Our results revealed that FC is an excellent method for identifying circulating PCs as a significantly higher number was identified by FC than by morphology (26 center dot 7% vs. 13 center dot 5%, P = 0 center dot 02). None of secondary PCL cases expressed CD19 or CD20. A low level of expression with similar positivity of CD27, CD28, CD81 and CD117 was found in both PCL groups. A decrease of CD44 expression was detected only in secondary PCL. Expression of CD56 was present in more than half of PCL cases as well as cytoplasmic nestin. A decreased level of platelets, Eastern Cooperative Oncology Group score of 2-3 and lack of CD20(+) PC were associated with a higher risk of death. FC could be incorporated in PCL diagnostics not only to determine the number of circulating PCs, but also to assess their phenotype profile and this information should be useful in patients' diagnosis and possible prognosis.

The definition of complete disease response (CR) in multiple myeloma (MM) continues to be reevaluated. The last widely accepted model of response assessment was proposed by the International Myeloma Working Group (IMWG) in 2016.1 Urine immunofixation (uIFE), one of the CR parameters, is being frequently omitted from CR evaluation in routine clinical practice. Patients with missing uIFE are then reported as having very good partial response (VGPR).2 It has been recently suggested in retrospective analysis by Lahuerta et al3 that patients with intact immunoglobulin myeloma (IIMM) who lack uIFE examination present with the very same prognosis as the patients with negative uIFE and therefore uIFE might not be necessary for CR definition in such patients.

Despite the high efficacy of current induction regimens, most multiple myeloma (MM) patients relapse over time. The link between changes in the immune system and the prognosis of the disease is still not entirely clear. Therefore, we analyzed whether the pattern of bone marrow (BM) lymphocytes during routine BM examination after autologous stem cell transplant (ASCT) is related to disease prognosis or MRD negative complete remission. From 2009 to 2018, 98 MM patients underwent routine BM testing after the first ASCT. Using multi-parametric flow cytometry, twelve BM lymphocyte subtypes were analyzed. In 60% of patients who achieved a complete response (CR), MRD by flow cytometric analysis (sensitivity threshold 10-6) was evaluated. We found an association of relative proportion of BM lymphocyte subtypes with treatment response, progression-free survival (PFS), overall survival (OS), and minimal residual disease (MRD) negativity. Higher relative proportion of memory B cells was associated with inferior median PFS [HR 1.089 (95% CI: 1.023-1.160), p = 0.008] and median OS [HR 1.170 (95% CI: 1.074-1.274), p < 0.001]. In non-responding patients (minimal response and worse), higher proportion of memory B cells was found when compared to patients achieving CR [3.8% (range 0.5-35.0) vs. 1.0% (range 0.1-12.5); p = 0.001]. No significant association of BM lymphocyte subtypes proportion with MRD negative CR was found. Our results show that changes in BM lymphocyte subsets including memory B cells may have prognostic value in MM patients after ASCT.

Background Plasma cell leukemia (PCL) is a rare and very aggressive plasma cell (PC) disorder characterized by the presence of circulating plasma cells (cPC) in peripheral blood (PB). Dismal outcome of PCL requires early diagnosis with appropriate analytical tools. Development of flow cytometry (FC) together with some newly analysed antigens may reveal some marker affecting the prognosis of PCL patients. Aim Analysis of phenotypic profile of cPC/PCs to find association with clinical outcomes and to evaluate the prognostic value of analyzed markers. Methods Total of 33 primary and secondary PCL patients were investigated. PCs quantity and phenotype profile was analysed by polychromatic FC in PB and bone marrow (BM). Results Flow cytometry is an excellent method for cPCs identification as a significantly higher number was identified by FC than by morphology. Thus FC should be incorporated as a diagnostic method for preventing late diagnosis of PCL. Although the phenotypic profile of both PCLs did not differ too much, with low level of CD19, CD20, CD27, CD28, CD81 and CD117 expression, some heterogeneously expressed antigens (CD44, CD56, CD200, nestin etc.) may contribute to identification of patients with later extramedullary involvement, high risk of progression and shortened survival. Conclusions FC should be incorporated in PCL diagnostics as not only exact method providing number of cPCs, which is surprisingly overcoming morphology assessment. Moreover, PCL phenotype profile could be connected to patient’s diagnosis and possible prognosis as well. Funding Supported by grant AZV NV18-03-00203.

Background Multiple myeloma (MM) is a heterogeneous plasma cell (PC) malignancy. These malignant PC are dependent on the bone marrow (BM) microenvironment. However, a subclone of PCs can escape the BM microenvironment and infiltrate soft tissues and organs in the so-called extramedullary disease (EMD). This subclone may also escape to peripheral blood; if there are more than 20% of circulating PC (cPC), the disease is reclassified as plasma cell leukemia (PCL). All cells in the BM microenvironment release exosomes. Exosomes are small membranous vesicles that originate from internal multivesicular bodies; they are found in all body fluids, including peripheral blood, breast milk, etc. Exosomes are important in intercellular communication, and they have been implicated in disease relapse, resistance to chemotherapy and many other processes important for tumorigenesis. They contain proteins and nucleic acids, such as microRNAs (miRNAs) - short non-coding RNA molecules that are involved in many physiological and pathological processes. Aims The aim of this work was to analyze expression of exosomal miRNAs in BM plasma samples of MM, EMD and PCL patients. Methods Exosomes were isolated using qEV columns. MiRNAs were isolated from exosomes using qEV original Size Exclusion Columns, following miRNA isolation using miRNeasy Micro Kit. For next generation sequencing (NGS), 8 MM, 7 EMD and 8 PCL samples were used. Results from NGS were validated on 40 MM, 25 EMD and 21 PCL samples by RT-qPCR using Taqman Advanced MiRNA Assays. Results NGS analysis showed 1128 different miRNAs that were present in analyzed samples. Out of these, 239 miRNAs were found in at least 8 samples and had more than 1 read per million; thus, they were included in subsequent analysis. Out of these miRNAs, there are 6 miRNAs (p Conclusions Using NGS, we showed that they are differentially expressed exosomal miRNAs between MM, EMD and PCL patients suggesting their role in pathogenesis of these diseases. This work was supported by AZV 17-29343A and AZV 18-003-00203.

IgM myeloma is a rare hematologic malignancy for which the clinicopathological features and patient outcomes have not been extensively studied. We carried out a multicenter retrospective study in patients with diagnosis of IgM myeloma defined by >10% marrow involvement by monoclonal plasma cells, presence of an IgM monoclonal paraproteinemia of any size, and anemia, renal dysfunction, hypercalcemia, lytic lesions and/or t(11;14) identified by FISH. A total of 134 patients from 20 centers were included in this analysis. The median age at diagnosis was 65.5 years with a male predominance (68%). Anemia, renal dysfunction, elevated calcium and skeletal lytic lesions were found in 37, 43, 19, and 70%, respectively. The median serum IgM level was 2,895 mgdL(-1) with 19% of patients presenting with levels >6,000 mgdL(-1). International Staging System (ISS) stages 1, 2, and 3 were seen in 40 (33%), 54 (44%), and 29 (24%) of patients, respectively. The malignant cells expressed CD20 (58%) and cyclin D1 (67%), and t(11;14) was the most common cytogenetic finding (39%). The median overall survival (OS) was 61 months. Higher ISS score was associated with worse survival (P=0.02). Patients with IgM myeloma present with similar characteristics and outcomes as patients with more common myeloma subtypes.

Monoclonal gammopathy of undetermined significance (MGUS) is a known precursor of more serious cancers, such as multiple myeloma (MM), Waldenstrom macroglobulinemia (MW) and other lymphoproliferative disorders. Using 18F-FDG PET/CT, we aimed to evaluate its benefit in early detection of various accompanying disorders and illnesses in MGUS patients. We prospectively analyzed the diagnostic relevance of 18F-FDG PET/CT in 390 newly diagnosed MGUS patients. On 18F-FDG PET/CT scans, the presence of focal or diffuse areas of detectable increased tracer uptake was recorded in 37 (9.5%) MGUS patients. The most frequent pathology was lymphadenopathy (3.8%), followed by thyroid diseases (2.1%), rheumatic diseases (1.8%), and other solid malignancies (1.5%). These results have major implications for confirmed associations of MGUS with numerous malignant and non-malignant disorders. We believe that 18F-FDG PET/CT imaging in newly diagnosed MGUS patients may be useful in early detection of other serious pathologies, not only in predicting progression of MGUS to active MM, and should be strongly recommended if available.

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.

The combination of lenalidomide and dexamethasone is the current gold standard for treatment of relapsed multiple myeloma. This study analyzes the efficiency of repeated lenalidomide treatment in patients with relapsed and refractory multiple myeloma. A total of 41 patients were prospectively evaluated at the University Hospital Brno. Lenalidomide was administered at standard dosing and in combination with corticosteroids and/or chemotherapy. The maximum cumulative dose of lenalidomide was limited to 4,200 mg because of Czech health insurance rules. Before the second lenalidomide treatment, all patients were refractory to the last treatment; previously, 95% of patients had bortezomib treatment, 48% had autologous transplantation and the median number of prior therapy lines was three. A partial 14.2% or better response was achieved with the second lenalidomide treatment. The median progression-free survival was 4.8 months, and median overall survival was 11.9 months. Unfortunately, predicting risk factors in lenalidomide retreatment proved unsuccessful. Although our treatment results were significantly affected by limited Czech health care system coverage for lenalidomide, we established that its repeated treatment is an effective therapeutic alternative for heavily pretreated patients with relapsed and refractory multiple myeloma.

Multiple myeloma is the second most common hematological malignancy characterized by focal lesions of malignant plasma cells in the bone marrow. These lesions contain subclones that directly influence survival of patients. Bone marrow biopsies are single‐site biopsies and thus cannot contain all information about the tumor. In contrast, liquid biopsies analyze circulating cells and molecules that are secreted from all sites of the tumor. Long noncoding RNA molecules are one class of these molecules. We performed a two‐phase biomarker study investigating lncRNA expression profiles in exosomes of peripheral blood serum of newly diagnosed multiple myeloma (MM) patients, monoclonal gammopathy of undetermined significance (MGUS) patients in comparison with healthy donors (HD). Surprisingly, this analysis revealed dysregulation of only one exosomal lncRNA PRINS in MM vs HD. Overall, MM and MGUS patients were distinguished from HD with sensitivity of 84.9% and specificity of 83.3%. Our study suggests a possible diagnostic role for exosomal lncRNA PRINS in monoclonal gammopathies patients.

We have performed a face to face comparison of all-oral triplet ixazomib, lenalidomide and dexamethasone (IRD) versus lenalidomide and dexamethasone (RD) in patients with relapsed and refractory multiple myeloma (RRMM) in the routine clinical practice. The primary endpoint was progression free survival (PFS), secondary end points included response rates and overall survival (OS).

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.Descriptive analysis of data from 19 Czech centres collected in the Registry of Monoclonal Gammopathies (RMG) was performed.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.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.

Aims: Treatment of multiple myeloma (MM) in relapsed and refractory setting (RRMM) has been a challenge. The best outcomes have been observed in triplet combination of novel drugs. However, most combinations require weekly parenteral administration thus degrading patients´adherence to therapy, especially when treatment is scheduled "until progression". The introduction of fully oral triplet combination ixazomib, lenalidomide and dexamethasone (IRD) showed an outstanding efficacy in the Tourmaline-MM1 trial. Our aim is to determine the efficacy and safety of IRD regimen outside clinical trials. Patients and methods: A cohort of 127 RRMM patients from the Czech and Slovak Republic were treated with IRD regimen within a Named Patient Program between 2016 and 2018. The M/F ratio was 1.2:1 with median age 66 years (41-84). The representation of M-protein and light chain types as well as ISS stage was standard. The data for cytogenetics were recorded only at the time of diagnosis in 71% of patients with 15 patients having high-risk features - t(4;14), t(14;16) and del17, and 41 patients having standard risk features. In 34 patients we were not able to determine the risk status as at least one abnormality was missing and none was positive. The presence of extramedullary plasmocytoma was recorded in 15% of patients. Most patients received IRD for their 1st relapse (58.5%), followed by 2nd (23.7%) and 3rd relapse (7.6%) with significant portion of patients being treated in ≥4th relapse (10.1%). The pretreatment with individual drugs was as follows: bortezomib (BTZ) 94.5%, thalidomide (THAL) 40.9%, lenalidomide (LEN) 18.9% and carfilzomib 5.5%. 62.2% of patients underwent previous autologous stem cell transplant. Altogether 25.2% of patients were refractory to at least 1 drug with 18.9% being BTZ refractory and 7.9% LEN refractory. Data were analyzed from the Czech Registry of Monoclonal Gammopathies. Data were described by absolute and relative frequencies of categorical variables and mean (standard deviation), median (minimum-maximum) of quantitative variables. Survival measures were plotted using Kaplan-Meier methodology at 95% confidence interval, log-rank test was used to estimate the statistical significance at P Results: The overall response rate to IRD regimen (≥ partial response, PR) was 67.1% with clinical benefit rate (≥ minimal response, MR) of 77.2%. The rate of individual responses was as follows: complete response (CR) in 11.4%, very good partial response (VGPR) in 16.5%, PR in 39.2%, MR in 10.1%, stable disease (SD) in 13.9% and progressive disease (PG) in 8.9%. The median overall survival was not reached after median follow up of 9.4 months. Median progression free survival (PFS) was 23.1 months. PFS was significantly decreasing with number of previous lines (not reached after 1 previous lines, 23.1 after 2 lines, 8.7 after 3 lines and 4.6 after ≥4 lines, p = 0,006). As expected, the best PFS increased with deeper therapeutic response (SD+PD = 4.1 months, MR = 9.0 months, PR = 15.1 months, VGPR = 13.2 months, and CR = median PFS not reached). There were limited information regarding the high risk features. Still, we confirmed adverse impact of the presence of extramedullary disease (PFS 5.5 vs 23.1 months, p = 0.001). Similarly, patients did worse when being pretreated by both proteasome inibitor and an IMiD versus solely proteasome inhibitor (PFS 10.0 vs 23.1 months, p = 0.001). The outcomes of high-risk cytogenetics were beyond statistical significance. Most toxicities were grade ≤2. Only hematological toxicity and infection reached grade 3 or higher, as follows: neutropenia in 35.1%, thrombocytopenia in 22.8%, anemia in 12.3% and infection in 19.3%. Conclusions: IRD regimen is very effective in RRMM. We confirmed its efficacy even in highly pretreated population (≥4 prior regimens) and in patients refractory to BTZ or LEN, which were exclusion criteria for the Tourmaline trial. The fully oral combination is well tolerated, with manageable side effects and easy management of dose modifications. Unlike the original trial our data show better results in patients with less pretreatment. The presence of extramedullary plasmocytoma deteriorates the prognosis of patients on IRD regimen. We thank to Takeda for enabling the Named Patient Program. With support of AZV 17-29343A, MH CZ - DRO (FNOl, 00098892) Disclosures Maisnar: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding.

Introduction: Multiple myeloma patients over the age of 65 represent the majority of myeloma population. The main goal was to evaluate treatment outcomes in terms of overall survival for elderly patients based on initial choice of anti-myeloma drugs, and to find potential factors affecting survival. Patients and Methods: This is a retrospective registry based analysis from the Registry of monoclonal gammopathies of the Czech Myeloma Group. Patients with multiple myeloma diagnosed between 2007-2016 over the age of 65 with symptomatic myeloma were included in the analysis. Basic demographic data and disease characteristics were obtained. The Kaplan-Meier estimates were completed by the Greenwood confidence interval. The log-rank test was used to estimate the statistical significance of the difference between the curves. The Cox proportional hazards model was performed to explore the univariate significance of risk factors. Results: Data from 1410 MM patients were obtained. Gender [HR 1.316 (1.124-1.541), p=0.001], age [above 75 vs. 66-75, HR 1.437 (1.221-1.692), p< 0.001], creatinine levels [at cutoff 152 µmol/L, HR 1.613 (1.365-1.905), p< 0.001] and ECOG performance status [0-1 vs. 2-4, 1.869 (1.594-2.191), p< 0.001] were found to significantly affect overall survival. Moreover these risk factors have cumulative effect on overall survival of the patients. Overall survival of patients regardless to above mentioned risk factors treated with upfront bortezomib (N = 880) was median OS 40.4 months (CI: 36.1-44.7), patients treated with upfront thalidomide (N = 370) had median OS 48.1 months (CI: 41.0-55.2), for lenalidomide (N = 64) median overall survival was 53.2 months (CI: 44.6-61.8) and for combination of bortezomib and thalidomide (N = 46) 32.2 months (CI: 26.6-37.8). When any of these risk factors was present the OS in each group shortened. In the group of patients with no risk factors (N = 255) the median OS for bortezomib (N = 126) was not reached, for thalidomide (N = 96) the median OS was 66.3 months (CI: 43.1-89.6), for lenalidomide (N = 17) 71.1 months (CI: 44.8-97.4) and for combination of bortezomib and thalidomide (N=8) was not reached. In the group of patients with 1 risk factor (N = 514) the median OS for bortezomib (N = 303) was 46.1 months (CI: 36.2-56.1), for thalidomide (N = 141) 56.2 months (CI: 47.5-64.9), for lenalidomide (N = 29) 49.0 months (CI: 9.7-88.2) and for combination of bortezomib and thalidomide (N=20) was not reached. In the group of patients with 2 risk factors (N = 420) the median OS for bortezomib (N = 288) was 34.0 months (CI: 24.7-43.4), for thalidomide (N = 87) 31.9 months (CI: 22.8-40.9), for lenalidomide (N = 14) 33.2 months (CI: 0.0-67.6) and for combination of bortezomib and thalidomide (N=20) 29.4 months (CI: 7.6-51.1). In the group of patients with 3-4 risk factors (N = 221) the median OS for bortezomib (N = 163) was 19.2 months (CI: 14.9-23.5), for thalidomide (N = 46) 18.9 months (CI: 13.0-24.7), for lenalidomide (N = 4) 6.1 months (CI: 0.0-63.0) and for combination of bortezomib and thalidomide (N=3) 14.3 months (CI:-). Conclusion: The overall survival of patients above the age of 65 shows promising results with the use of novel agents. The treatment outcomes seem to be generally affected by overall condition, age and gender of the patient rather than treatment modality used upfront. Figure. Figure. Disclosures Hajek: Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Maisnar:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

Background Multiple myeloma (MM) is the second most common hematological malignancy characterized by plasma cell (PC) infiltration of the bone marrow. Unfortunately, better imaging techniques convey multiple reports about increased incidence of the so-called extramedullary disease of MM (EM), an aggressive, mostly resistant entity with poor prognosis for patients. EM probably develops because of 'bone marrow escape' of PC subclone that migrates out of the BM infiltrating soft tissues losing dependence on the BM microenvironment, either partially or completely. There are two types of EM - primary, found at the time of MM diagnosis, and secondary, found at the time of MM relapse. However, there are very few reports about EM. Aims This study aims to analyze risk factors connected to EM development. Methods Data from the Registry of Monoclonal Gammopathies (RMG) were analyzed. The RMG represents a database for collection of clinical data concerning diagnosis, treatment and follow-up of Czech MM and other monoclonal gammopathies patients. In total, data of 4985 MM patients were collected into the RMG database between 2007 and June 2017. Our analysis compared patients who developed EM at initiation of first or higher line of therapy with patients without EM during at least 5-year-long follow-up (patients who died earlier included). Logistic regression analysis was used to assess the association of baseline characteristics at MM diagnosis with EM occurrence at first line and relapse, respectively. Results In total, 4985 MM patients data were collected into the RMG database between 2007 and 2017. Patients were treated with bortezomib, lenalidomide, thalidomide, pomalidomide, ixazomib and daratumumab. Regardless of treatment, EM patients responded worse than MM patients did to any form of treatment. While primary EM patients had similar PFS as MM patients, OS was significantly worse (48.7 vs 60.6 months, resp.). Secondary EM patients did even worse, with PFS 8.7 months and OS 23.8 months only. We found 543 MM patients (10.9%) who developed EM during the entire follow-up. Out of these EM patients, we found 309 patients who were diagnosed with primary EM at initiation of first line of therapy. At initiation of 2nd line of treatment, we found 111 secondary EM patients. At 3rd, 4th and 5th, we found 61, 39 and 23 EM patients, resp. Finally, 309 patients who developed EM at initiation of 1st line and 234 patients who developed EM at initiation of further treatments were compared to 2092 patients who did not develop EM during the entire course of the disease. Overall, occurrence of EM at 1st or higher lines of treatment was associated with younger age, male sex, low ISS, D-S substage A, low B2 microglobulin, low creatinine, high hemoglobin, elevated thrombocytes, other types of M-Ig than IgG and presence of bone lesions. For EM cases found only at initiation of 1st line (primary EM), we found association with high ECOG status, low LDH, low M-protein quantity and low % of plasma cells infiltration in the bone marrow. For EM cases found at MM relapse (secondary EM), we found association with high D-S stage, high LDH, high CRP, high Ca, del13q and gain1q. Conclusion EM remains an aggressive disease with poor prognosis regardless of use of novel drugs. Surprisingly, in our group of patients, most EM disease developed early in the course of the disease - more than 60% at first relapse. We analyzed risk factors connected to development of EM and found that LDH, hemoglobin, thrombocytes and M-Ig status were associated with EM development. We suggest that in such patients, PET/CT or whole body MRI should be performed regularly to ensure early detection of EM. Grant support: AZV 17-29343A. Disclosures Maisnar: BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

OBJECTIVE:Subcutaneous (SC) application of bortezomib has been recently introduced as a new application route in multiple myeloma (MM) patients. We performed an analysis to compare the outcomes of bortezomib-based therapy in multiple myeloma (MM) patients treated using either intravenous (IV) or subcutaneous (SC) route of administration. PATIENTS AND METHODS:During January 2012 through December 2013, we performed a retrospective analysis of 446 patients with MM treated with bortezomib-based regimens (either once weekly - 63% or twice weekly - 27%) in both, the first line setting, and in relapse, with separate analysis of patients undergoing autologous stem cell transplantation. We assessed the response rates and toxicity profiles in both, IV and SC route of bortezomib administration. RESULTS:The response rates in both IV and SC arm were similar with overall response rate 71.7% vs 70.7%, complete remissions in 13.9% vs 8.6%, very good partial remissions in 30.8% vs 34.5% and partial remissions in 27% vs 27.6%. The most frequent grade ≥ 3 toxicities were anemia, thrombocytopenia and neutropenia, with no significant differences between IV and SC group. There were no significant differences in the rate of peripheral neuropathy (PN). PN of any grade was present in 48% in the IV arm and in 41% in the SC arm. PN grade ≥ 2 was present in 20% vs 18% and PN grade ≥ 3 was present in 6% vs 4%. CONCLUSIONS:We conclude that subcutaneous application of bortezomib has similar therapeutic outcomes and toxicity profile as intravenous route of application. In our cohort there was no difference in the incidence of PN, suggesting that PN is dose dependent and might be reduced by lower intensity schemes rather than by the route of administration.

Introduction: Collection of valid data in patients with hematologic malignancies remains a challenge. Especially low grade malignancies require long term follow-up and valid high quality data. The RMG registry was established in 2007 and has become one of the flagship projects of the Czech Myeloma group. To date, four parts of the registry are active - module for multiple myeloma (MM), monoclonal gammopathies of undetermined significance (MGUS), AL amyloidosis (ALA) and Waldeströms macroglobulinemia. The later two has been started in 2014. Aim: To analyze current status of the registry in terms of amount of contained data. Methods: All patients must sign a written consent before entering their data into the registry. Data concerning diagnosis, demography, treatment and survival are regularly collected and updated into the registry via online system at https://trials.cba.muni.cz/trialdb2/interface_forms/login_rmg.asp. The data from MGUS patients are retrospective and prospective, data from MM patients are only prospective (since 2007). Registry is regularly monitored and data are validated by an external monitor. Results: There are 22 participating centers as of July 2015 (18 from the Czech Republic and 4 from Slovakia). Data from 4549 patients with MM, 2168 with MGUS, 121 patients with WM and 22 with ALA have been collected. Together 6860 patients have been included in the registry as of July 2015. Median follow-up of MGUS patients is 4 years (0-35 years) and median follow-up for MM patients is 2 years (0-32 years). The huge amount of data allowed publication of treatment results of MM patients treated with bortezomid and thalidomide in the Czech Republic and regular analysis of patients treated with lenalidomide. Novel prognostic models for MGUS progression and asymptomatic myeloma have been created based on registry data (manuscripts submitted). Conclusion: The RMG is one of the largest registries in Europe. Its biggest advantage is collection of validated updated data which can be used to create rapid analyses in order to react to changing myeloma field. It helps us to create new guidelines and serves as a potent research tool. It can be also used to negotiate reimbursement with healthcare insurance companies and government regulatory authorities for novel drugs implementation into treatment standards. Supported by The Ministry of Education, Youth and Sports (Specific university research of the Faculty of Medicine, University of Ostrava) project no. SGS01/LF/2014-2015, by the Moravian-Silesian Region - grant no. MSK 02692/2014/RRC, by the Institutional Development Plan of University of Ostrava in 2015, financial resources are allocated by The Ministry of Education, Youth and Sports. Supported by grant NT14575. Disclosures Hajek: Amgen: Honoraria; Celgene: Consultancy; Janssen: Consultancy.

Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is a non-malignant condition associated with a risk of progression to multiple myeloma (MM) or related disorders. There are currently 2 clinical models predicting progression from MGUS to MM. The Mayo Clinic model uses levels and type of serum monoclonal protein (M-protein) and serum free light chain ratio (sFLC). The Spanish PETHEMA model uses flow cytometry of bone marrow plasmocytes (BMPC) and the presence of DNA aneuploidy. Purpose: The primary end point was to estimate the cumulative risk of hematologic disorders occurring during the follow-up of our cohort. The secondary end points were: to validate known clinical models suggested by the Mayo Clinic group and the Spanish PETHEMA group for the risk of progression from MGUS to MM or related malignancies and to establish a new risk model by the Czech Myeloma Group (CMG model) with better prediction of low-risk MGUS group. Group: Data for this study were obtained from the Registry of Monoclonal Gammopathies (RMG) acquired from hematologic centers of the Czech Republic. MGUS diagnosis was made according to IMWG criteria. In total, 2028 persons with MGUS were enrolled in the RMG study from May 2007 to June 2013. A total of 93% (1887/2028) of persons were evaluated. Results: 1887 MGUS persons were followed with median 4 years. Malignancies developed in 8.6% (162/1887) cases; MM occurred in 77.2% (125/162) of persons. The risk of progression was 1.5% at 1 year, 7.6% at 5 years and 16.5% at 10 years after diagnosis. The key predictors factors of progression were as follows: age ≥ 69 years, serum M- protein concentration ≥ 1.5 g/dL, BMPC > 5%, pathological sFLC ratio (< 0.26 or >1.65), immunoparesis of polyclonal immunoglobulins, levels of serum hemoglobin at baseline < 12.0 g/dL and the presence of normal plasma cells (nPC) in bone marrow ≤ 5 % identified by multiparametric flow cytometry techniques. Distribution of MGUS persons according to risk groups based on the Mayo Clinic model confirmed predictive power of Mayo Clinic model based on our data although isotype of M- protein was not found as independent predictor. At 10 years, no-risk group had 4.9% risk of progression compared to 16.3%, 24.6%, and 54.9% in groups with 1, 2 or 3 risk factors, respectively (p< 0.001). MGUS group with 1, 2 and 3 risk factors in comparison to the reference group without any risk factor had HR( 2.59 [95% CI: 1.39- 4.84]; p= 0.003, HR 4.79 [95% CI: 2.56-8.93]; p< 0.001, HR 12.97 [95% CI: 5.52-30.48];p< 0.001), retrospectively. Immunoparesis instead of DNA aneuploidy was used together with the presence of abnormal plasma cells (aPCs) to validate the modified PETHEMA model. The rates of progression at 3 years were 2.5%, 8.1% and 28.0% for groups with neither, one or both risk factors, respectively (p< 0.001). MGUS group with 1 and 2 risk factors in comparison to the reference group without any risk factor had HR (3.98 [95% CI: 1.60-9.91]; p= 0.003, HR 14.23 [95% CI: 2.86-70.76]; p< 0.001), retrospectively. Based on the 5 parameters with independent predictive value in the univariate analysis (immunoparesis, serum M-protein quantity ≥ 1.5 g/dL, BMPC > 5%, abnormal sFLC ratio and serum level of hemoglobin < 12.0 g/dL) we proposed a new CMG model. The created CMG model clearly detected MGUS persons at low risk 86.6% (828/956) with the risk of progression 5.6% at 5 years better than previously described models. As expected, the number of MGUS persons with the highest risk of progression was limited to 3.7% only (35/956), with the risk of progression 31.9% at 5 years. The MGUS group with 5 risk factors had 63 times higher hazard of progression compared to reference MGUS group (HR 63.17 [95% CI: 13.99-285.36]; p< 0.001). Conclusion: In the large cohort of MGUS persons, we confirmed validity of previously considered clinical models for the risk of progression from MGUS to MM by the Mayo Clinic group and the Spanish PETHEMA group (model used for SMM). New CMG model for the risk of progression from MGUS to MM or related malignancies was established with an advantage for better identification of MGUS persons at low risk (87% of persons with risk of progression below 10% in 5 years) as well as few persons at the highest risk of progression. As a consequence, limited evaluation and visits can be planned in majority of MGUS persons in follow-up. Acknowledgments: This work was supported by grants NT13492-4, NT14575-3 and by EU FP7/2007-2013; grant n° 278570. Disclosures No relevant conflicts of interest to declare.

Background Several models predict the progression from smouldering multiple myeloma (SMM) to therapy requiring multiple myeloma (MM). Three models comprise the assessment of tumour mass by different clinical parameters to stratify in risk groups: 1) the Mayo Clinic model uses bone marrow plasma cells percentage (BMPC) and serum monoclonal protein (M-protein), 2) the PETHEMA model uses immunoparesis and the percentage of abnormal plasma cells by flow cytometry, 3) the Heidelberg group assesses tumour mass by either the percentage of malignant plasma using iFISH or the Mayo assessment depicted above, and the presence of chromosomal aberrations associated with adverse prognosis. Besides tumor mass, they find the number of focal lesions in whole body MRI (>1) as strong prognostic factor. Aim To assess a combination of easily accessible clinical factors identifying patients at ≥ 80% risk of progression to MM requiring treatment within two years from the diagnosis of SMM. Methods Data for this study were obtained from the Registry of Monoclonal Gammopathies (RMG) acquired from hematologic centers of the Czech Republic for 287 SMM patients enrolled from May 2007 to June 2013. A cohort comprising 240 SMM patients from Heidelberg, Germany was used for validation (Neben et al. JCO 2013). Results During the follow up period (median 2.4 years; range 0.6 - 18.0) progression to MM was observed in 51.9% (149/287) patients in the study cohort, representing 16% risk of progression at 1 year, 31.2% at 2 years, 54.8% at 5 years and 73.4% at 10 years. In univariate analysis factors significantly associated with progression were as follows: serum free light chain (iFLC/uFLC) ratio > 30 (HR 2.4 [95% CI: 1.4 - 4.1]; p< 0.001) plasma cell infiltration in bone marrow cytology ≥ 15% (HR 2.1 [1.5-3.0]; p< 0.001), immunoparesis (HR 2.0 [1.3-2.9]; p< 0.001), M - protein concentration ≥ 2.3 g/dL (HR 2.00 [1.4-2.7]; p< 0.001), beta2 microglobulin ≥ 2.0 mg/l (HR 1.8 [1.2-2.7]; p= 0.001), and thrombocyte count ≤ 250 x 109/l (HR 1.7 [1.1-2.4]; p= 0.005). In multivariate analysis, 3 parameters showed independent predictive value (immunoparesis, serum M-protein quantity ≥ 2.3 g/dL and iFLC/uFLC > 30). Combining these factors, we proposed a new risk model for SMM patients (CMG model). The risk of progression from SMM to MM at 2 years was 18.5%, 20.9%, 41.9% and 78.7% if 0 (reference group), 1, 2 or 3 risk factors are present (p< 0.001) (Figure 1) with HR of 1.5 [0.7-2.9]; p=0.283, 2.5 [1.3-5.0]; p= 0.008, 6.8 [3.0-15.2]; p Conclusion We propose and validate a new risk model for SMM patients with prediction of 80% (78.7% on our CMG model; 81.3% on data from Heidelberg) risk of progression to therapy requiring myeloma within two years based on easily accessible clinical parameters (CMG model). The model could especially be used to identify high-risk patients to be included in early treatment clinical trials. Acknowledgments: This work was supported by grants NT13492-4, NT14575-3 and by EU FP7/2007-2013; grant n°278570 and “OverMyR”, as well as the Deutsche Forschungs-Gemeinschaft (DFG) SFB/TRR79. Figure 1: CMG risk model: CMG cohort of patients and validation cohort of Heidelberg patients Figure 1:. CMG risk model: CMG cohort of patients and validation cohort of Heidelberg patients Disclosures Seckinger: Novartis: Research Funding.

BACKGROUND: The European Commission has granted conditional approval to daratumumab (DARA) as monotherapy in adult patients (pts) with relapsed or refractory multiple myeloma (MM) whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) and who have demonstrated disease progression on the last therapy. DARA was approved under an accelerated assessment based on single-arm phase 2 studies. Outcomes in these heavily pretreated pts in a real-world (RW) setting can provide evidence on the relative treatment efficacy of DARA versus physician's choice (PC). AIMS: To perform an adjusted comparison of overall survival (OS) and progression-free survival (PFS) for DARA monotherapy versus PC, as observed in a RW historical cohort of heavily pretreated and highly refractory MM pts from the Czech Republic using pt-level data. METHODS: Using RW longitudinal pt chart data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group, pts with ≥2 prior lines of therapy previously exposed to both a PI and an IMiD were identified. Pt-level data from the RMG were pooled from pivotal DARA monotherapy studies (pts treated with DARA 16 mg/kg). Pts in the RMG could contribute information to the analysis for multiple lines of therapy, with baseline defined as the date of initiation of the actual treatment line. For the definition of PFS, missing data for the date of disease progression for pts in the RMG who initiated subsequent therapy were replaced by the conservative proxy of the date of initiation of the next treatment. OS and PFS were analysed using a Kaplan-Meier analysis. To adjust for confounding variables, a multivariate Cox proportional hazards regression was developed that included age, gender, beta-2 microglobulin levels (β2M : 5.5 g/L), albumin levels ( RESULTS: From the RMG database, we identified 971 treatment lines in 463 pts previously exposed to both a PI and an IMID (n=206 in third line, n=256 in fourth line, n=203 in fifth line, n=307 in ≥sixth line). The dates of treatment initiation for the RMG pts ranged from March 2006 to March 2015. The most frequent treatment regimens were lenalidomide (33.4%), chemotherapy (18.1%), bortezomib (13.6%), thalidomide (8.0%), and bortezomib+thalidomide (5.3%). The number of pts treated with carfilzomib (2.5%) and pomalidomide (2.4%) was limited. DARA-treated pts (N=148) differed from the RMG cohort in median age (64 vs 62 years), median prior lines of therapy (5 vs 4), prior exposure to carfilzomib (41.2% vs 0.3%) and pomalidomide (55.4% vs 0.6%), thrombocytopenia incidence (46.9% vs 18.0%), and ≥triple refractory status (64.2% vs 5.3%). Median observed PFS and OS for DARA versus PC were 4.0 and 5.6 months, respectively, for PFS and 20.1 and 11.9 months, respectively, for OS. Older age, male sex, low albumin levels, high β2M levels, thrombocytopenia incidence, and double/triple/quadruple refractory status were all independent, statistically significant risk factors for mortality. Albumin levels, β2M levels, thrombocytopenia incidence, and refractory status were also predictive of PFS. The adjusted hazard ratio (95% confidence interval) for OS and PFS for DARA versus PC was 0.35 (0.22-0.56) and 0.79 (0.56-1.12), respectively. Figure 1 represents the predicted survival curves for the RMG cohort that were derived from the multivariate model, comparing observed PFS/OS versus predicted with DARA treatment. CONCLUSIONS: This adjusted treatment comparison suggests a significant improvement in OS and a numerical improvement in PFS for DARA compared to RW historical control data in heavily pretreated/highly refractory MM pts. The lower PFS benefit estimate for DARA compared to OS may be partly explained by limitations in the availability and comparability of data regarding progressive disease in the RMG cohort compared to clinical trial data. Adjusted comparisons between trial data and historical cohorts can provide useful insights to clinicians and reimbursement decision makers on relative treatment efficacies in the absence of head-to-head comparison studies for DARA monotherapy. Disclosures Hájek: Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Spicka:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gatopoulou:Janssen Health Economics & Market Access EMEA: Employment. Vesela:Janssen Cilag s.r.o., Czech Republic: Employment. Diels:Johnson & Johnson: Employment, Equity Ownership. Besson:Janssen: Employment. Ito:Janssen: Employment, Equity Ownership.