ALBERT

Description: Introduction: Great progress achieved in treatment of multiple myeloma (MM) over the past decade changed overall perception of importance of minimal residual disease (MRD) assessment. Since new drugs induce deep responses, MRD must be evaluated using sensitive techniques, such as allele specific PCR (ASO-PCR), next-generation sequencing (NGS) or flow cytometry. MM is a genetically heterogeneous cancer of plasma cells characterized by multiple focal lesions in the bone marrow (BM). Hence, a single-site biopsy can create a sampling bias. In spite of this, BM samples are typically used for MRD analysis, but currently an alternative approach called liquid biopsies, which utilizes body fluids for analysis of various molecules and cells, is intensively studied. Cell-free DNA (cfDNA) as one type of the molecule which can be analyzed using liquid biopsy approach showed promising results previously. In our study, patient-specific, clonotypic rearrangement of immunoglobulin heavy chain (IgH) gene, identified in bone marrow samples, was used for qPCR analysis of cfDNA samples from peripheral blood. We demonstrate that dynamics and quantity of patient-specific, clonotypic IgH rearrangement found in cfDNA can predict the outcomes and response of MM patients. Methods: Total of 45 patients enrolled in the study. Samples of BM were collected at diagnosis, and CD138+ cell fraction was sorted using magnetic activated cell sorting. At diagnosis and at three-month intervals, samples of peripheral blood (PB) were collected for cfDNA extraction and analysis until a patient reached complete remission (CR). If CR was not reached, samples were collected for 24 months after diagnosis. Two more samples of PB were collected (CR+3, CR+6) if patients reached CR. Patient-specific VDJ rearrangement was identified using previously described PCR method from genomic DNA extracted from CD138+ cell fraction; based on the results, patient-specific primers and probes were designed for use in ASO-qPCR. Obtained data were evaluated by absolute and relative frequencies of categorical variables and median (minimum-maximum) of quantitative variables. Results: First, we assessed time to CR. Patients were classified according to the quantity of cfDNA measured at time of diagnosis into three groups: negative, PNQ (= positive non-quantifiable) and positive. As PNQ had a similar profile to negative-classified samples (in K-M plot), PNQ were grouped together with negative results except extremely high values (〉 5, n = 2) which were reclassified from PNQ to positive group. The Kaplan-Meier estimates at 12 months were reported and supplemented by the 95% confidence interval derived using Greenwood formula. The results show that significantly higher number of patients classified as negative or PNQ with quantity 〈 5 have reached CR in contrast to patients classified as positive or PNQ with quantity 〉 5. The same trend applies to association of quantity of tumor-specific cfDNA with time to CR where Cox proportional-hazards model was adopted. Patients classified as negative or PNQ with quantity 〈 5 have significantly increased chance of achieving CR (2.7 times) in comparison to patients classified as positive or PNQ with quantity 〉 5. Conclusion: Our results demonstrate that MM patient-specific cfDNA fragments are released into the bloodstream and that patients either with no or very few DNA fragments have a higher chance of achieving better treatment response eventually. Work was supported by grant AZV 17-29343A Disclosures Hajek: Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Description: 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.

Description: 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

Description: Background : Outcomes reported in real-world practice versus controlled clinical trials show markedly shorter treatment durations, progression free survival (PFS) and overall survival (OS). Understanding effectiveness of therapeutic regimens in routine practice is critical for treating physicians as well as for regulatory and reimbursement authorities. We have performed a real-world comparison of two regimens, ixazomib, lenalidomide and dexamethasone (IRD) triplet and lenalidomide and dexamethasone (Rd) doublet in patients with relapsed and/or refractory multiple myeloma (RRMM) treated in seven Czech and one Slovak hematology-oncology centers. Patients and methods: Between 3/2015 and 5/2017, 344 patients with RRMM were treated with either IRD (N=127) or RD (N=217). Patients selected for both cohorts had the same inclusion and exclusion criteria. Patient baseline characteristics were well balanced. The data were collected through the Czech Registry of Monoclonal Gammopathies (RMG), which is an international database gathering data from patients with monoclonal gammopathies within Central Europe. Results: The median follow-up in the IRD vs RD arm was 20.8 vs 15.5 months, respectively. Median PFS in pts with 1-3 prior lines for the IRD cohort was 23.1 months (95% CI 11.8-34.5 months) and 11.6 months (95% CI 8.4-11.8 months) for the RD cohort favoring the all-oral triplet (p=0.001). The median PFS for all patients including 4+ line of therapy was 17.5 months (95% CI 10.3-24.7) in the IRD cohort versus 11.5 months (95% CI 8.6-14.3) in the RD group (p=0.005). Median OS for pts with 1-3 prior lines for IRD cohort was not reached, and was 27.1 months (95% CI 23.1-31.1 months) in the RD cohort (p=0.002). Median OS for all patients, including 4+ lines of treatment was 36.6 months in the IRD vs 26.0 months in the RD cohort (p=0.008). The PFS benefit of IRD over RD was observed in most of the assessed subgroups; in younger pts ≤65 years with hazard ratio (HR) 0.58, in pts 66-75 years HR 0.64. There was a trend towards better PFS in patients with lower ISS stage; ISS1 HR 0.53, ISS2 HR 0.58 and ISS3 the HR was 0.87. Patients in the 1st relapse (HR 0.53) benefited most from the IRD, followed by the 2nd relapse (HR 0.58), 3rd relapse (HR 0.90) and pts relapsing after 4+ therapies (HR 0.88). The PFS benefit of IRD regimen was observed in pts regardless of previous stem cell transplantation; transplant-eligible patients HR 0.51 and transplant-ineligible HR 0.71. Patients who did not benefit from the triplet regimen were those over 75 years of age and pts with the presence of extramedullary disease. The IRD treatment was well tolerated. The safety profile was concordant with previously reported data. Conclusions: This RMG comparative cohort analysis shows PFS benefit of all-oral IRD regimen over RD in the real world setting, and confirms growing evidence that long term outcomes with IRD triplet are comparable with phase 3 TOURMALINE-MM1 trial. Our analysis also shows an overall survival benefit of IRD over RD treatment. Patients older than 75 years, with 4+ lines of therapy and presence of extramedullary disease did not profit from addition of ixazomib to RD doublet.Additional data with larger patient populations confirming RWE effectiveness are warranted. With support of AZV 17-29343A, NV18-03-00500, FNOl 00098892, IGA-LF-2019-001, PROGRES Q40/08, MH CZ-DRO (UHHK, 00179906) Disclosures Minarik: Celgene: Consultancy, Honoraria, Research Funding; Amgen, BMS, Janssen-Cilag, Takeda: Consultancy, Honoraria. Straub:Amgen, Takeda, Celgene: Consultancy. Spicka:Celgene: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Sanofi: Consultancy. Skacel:Millennium Pharmaceuticals, Inc., subsidiary of Takeda Pharmaceutical Company Limited: Employment. Maisnar:Janssen, Amgen, Celgene, Takeda, BMS: Consultancy, Honoraria.

Description: Introduction: The International Myeloma Working Group (IMWG) consensus aimed to provide recommendations for the optimal use of positron emission tomography-computed tomography (PET/CT) in patients with multiple myeloma (MM) and other plasma cell disorders, including smouldering multiple myeloma (SMM) and solitary plasmocytoma (Cavo M et al., Lancet Oncol. 2017). Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common pre-malignant disorders, in which the probability of progression to MM or other lymphoproliferative disorders is 1% per year (Kyle RA. Blood 2003). MGUS patients have an increased risk of developing hematologic and non-hematologic malignancies (Mailankody S, et al. Blood. 2011; Gregersen H et al., Am J Hematol. 2000). Data for the role of ¹⁸F-FDG PET/CT in diagnostic relevance in newly MGUS patients are still limited. We think, that using ¹⁸F-FDG PET/CT imaging in newly MGUS patients may be useful in early detection of other serious pathologies, not only in predicting progression of MGUS to active MM. Patients and methods: We prospectively analyzed the diagnostic relevance of ¹⁸F-FDG PET/CT in 390 newly MGUS patients . All MGUS patients were diagnosed and monitored at the Department of Internal Hematology and Oncology in Brno, Czech Republic from January 2010 to December 2016. The diagnosis of MGUS was made according to updated 2010 International Myeloma Working Group diagnostic criteria (Kyle RA et al., Leukemia 2010). Imaging scans were reviewed by a radiologist and a nuclear medicine physician. The aim of this analysis was to evaluate the benefit of ¹⁸F-FDG PET/CT in early detection of other serious illnesses in newly MGUS patients. This study did not focuse on the MGUS patients re-classified as MM. Patients underwent ¹⁸F-FDG PET/CT within 6 months of MGUS diagnosis. At the time of ¹⁸F-FDG PET/CT imaging the patients showed no specific symptoms indicative of later diagnosed serious illnesses. Results: A total of 390 newly diagnosed MGUS patients were evaluated, and by IMWG definition had no lytic lesions on skeletal survey. On ¹⁸F-FDG PET/CT, presence of focal or diffuse areas of detectable increased tracer uptake on at least two consecutive slices was recorded in 36 (9.2%) of MGUS patients. The most frequent pathology was lymphadenopathy (3.8%), followed by thyreopathy (2.1%), rheumatologic diseases (1.8%) and others solid tumors (1.3%). Primary malignancy was confirmed by biopsy in 17 (4.4%) patients. This included 12 (3.1%) patients with lymphoproliferative diseases and 3 (0.8%) patients with colon cancers. In 1 case prostate and thyroid cancer was diagnosed. On ¹⁸F-FDG PET/CT focal lymph nodes abnormalities were detected in 15 (3.8%) evaluable patients. Twelve (3.1%) patients were reclassified as having lymphoproliferative diseases. Among the remaining 3 patients with lymph nodes abnormalities 1 patient was detected with Sjögren's syndrome, 1 patient with sarcoidosis, and 1 patient with reactive lymphadenopathy ,without detection of malignant cells after biopsy. None of the patients had symptoms typical for lymphoproliferative diseaseas at the time of ¹⁸F-FDG PET/CT imaging. Thyreopathy was the second most common pathology in our study, observed in 8 (2.1%) patients. In 1 patient thyroid carcinoma was diagnosed; among the remaining 7 (1.8%) patients with focal thyreoid abnormalities nontoxic struma was found. All patients' thyroid hormones tested within the normal range at the time of ¹⁸F-FDG PET/CT imaging. Rheumatologic diseases were the third most common pathology, occurring in 7 (1.8%) of all scanned patients. Specifically, there were 4 (1.1%) patients with rheumatoid arthritis, 2 (0.5%) patients with polymyalgia rheumatica and 1 patient with giant-cell temporal arteritis. In 1 patient thymoma and schwannoma of the femoral nerve were identified. For all these patients, all diseases were early-onset without typical symptoms. Summary: In conclusion, using newer sensitive imaging tool we detected 36 (9.2%) patients with serious pathologies before the first symptoms. Therefore we believe, that ¹⁸F-FDG PET/CT imaging can be recommended to be done not only in all MGUS patients with suspected SMM or active MM, but also for early identification of other serious pathologies. Disclosures No relevant conflicts of interest to declare.

Description: 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.