ALBERT

Description: 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 (

Description: 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.

Description: Background: Combination of fludarabine, cyclophosphamide and rituximab (FCR) is the current gold standard for physically fit patients (pts) with chronic lymphocytic leukemia (CLL). Nevertheless, many CLL patients cannot tolerate this intensive regimen owing to advanced age and/or serious comorbidities. Combination protocols based on dose-reduced fludarabine demonstrated promising results in pilot studies. Therefore, the Czech CLL Study Group initiated Project Q-lite, an observational study to assess efficacy and safety of low-dose FCR regimen used in elderly/comorbid patients with CLL/SLL. Updated results including progression-free survival (PFS), overall survival (OS) and multivariate analysis are presented. Patients and Methods: Between March 2009 and July 2012, a total of 207 pts with active disease (CLL, n=196, SLL, n=11) were treated by low-dose FCR at 16 centers cooperating within Czech CLL Study Group. Dose reductions of chemotherapy compared to full-dose FCR were: 50% of fludarabine (12 mg/m2 i.v. or 20 mg/m2 orally on days 1-3) and 60% of cyclophosphamide (150 mg/m2 i.v./p.o. on days 1-3). Rituximab was administered in standard schedule (375mg/m2 i.v. day 1 in 1st cycle, 500mg/m2 i.v. day 1 from 2nd cycle). Treatment was repeated every 4 weeks; antimicrobial prophylaxis with sulfamethoxazol/trimethoprim and aciclovir or equivalents was recommended. The basic characteristics are summarized in Table 1. Results: Based on intention-to-treat principle, the overall response rate / complete responses including clinical CR (without bone marrow biopsy) and CRi were 81/37% in 1st line and 63/30% in relapsed/refractory (R/R) disease. Serious (CTCAE grade III/IV) neutropenia was frequent (56 and 50%) but grade III/IV infections were only 15 and 18%. The most common causes of death were CLL progression and infections. At the median follow-up of 25 months, median progression-free survival (PFS) for previously untreated and R/R patients was 28 and 15 months; median overall survival (OS) has not been reached in previously untreated pts (75 % at 30 months) and was 30 months in R/R pts. Multivariate analysis identified del 11q, del 17p, bulky lymphadenopathy (1st line) and del 17p (R/R) as independent predictors of shorter PFS; absence of therapeutic response was the only factor associated with shorter OS (both in 1st line and R/R pts). Conclusions: Low-dose FCR appears to be an effective treatment for elderly/comorbid patients with CLL/SLL in first-line as well as R/R setting. Toxicity was acceptable and manageable. In historical comparison, efficacy of low-dose FCR compares favourably with chlorambucil monotherapy and is similar to obinutuzumab-chlorambucil combination from German CLL11 study. Interestingly, neither CIRS score nor creatinine clearance were predictive of PFS/OS. The study is registered at www.clinicaltrials.gov (NCT02156726). Fig 1. Fig 1. Disclosures Smolej: Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Travel grants, Travel grants Other; GlaxoSmithKline: Consultancy, Honoraria, Travel grants, Travel grants Other; Roche: Consultancy, Honoraria, Research Funding, Travel grants Other. Brychtova:Roche: Travel grants Other. Doubek:Roche: Consultancy; GlaxoSmithKline: Research Funding; Janssen: Consultancy. Spacek:Roche: Consultancy, Travel grants Other. Belada:Celgene: Research Funding; Roche: Consultancy, Research Funding, Travel grants, Travel grants Other; GlaxoSmithKline: Research Funding. Motyckova:Roche: Travel grants Other. Prochazka:Roche: Honoraria, Travel grants Other; Takeda: Speakers Bureau. Kozak:Roche: Honoraria, Travel grants Other.

Description: Introduction: Revised prognostic scoring system R-ISS (standard ISS plus cytogenetic changes) has been introduced as a possible tool for evaluation of patients with multiple myeloma. This system is based on pooled data from various clinical trials but has not been validated in patients´ population outside the clinical trial setting. Aim: To evaluate clinical relevance of R-ISS in real life population of multiple myeloma patients. Methods: Registry of monoclonal gammopathies (RMG) was established in 2007 and has become one of the flagship projects of the Czech Myeloma Group. The registry collects prospective data from patients with myeloma and other gammopathies (https://trials.cba.muni.cz/trialdb2/interface_forms/login_rmg.asp). Registry is regularly monitored and data are validated by an external monitor. Data from registry were retrieved to identify patients in whom all above mentioned parameters were available. These patients were then stratified according to R-ISS and TTP and OS were calculated as primary endpoints. Results: 555 patients (260 females, 295 males, median age 66 years) with multiple myeloma who had full set of necessary data available were identified. Median follow-up of this cohort was 22.2 months. 97 17.5% (97/555) patients were R-ISS stage I, 55.7% 309/555 were R-ISS stage II and 26.8% (149/555) patients were R-ISS III. Median overall survival was not reached for stage I, 3.9 years for stage II and 2.5 years for stage III. The differences were statistically significant (p

Description: Abstract 1872 Background: Bortezomib (Velcade) is one of the most effective treatment options in the treatment of relapsed or refractory multiple myeloma (RRMM). In the Czech Republic, it has been available since 2004. Registry of monoclonal gammopathy (RMG) of the Czech Myeloma Group contains information of more than 90% of patients in the Czech Republic treated with novel drugs.Aims: The aim of this retrospective analysis was to verify the therapeutic efficacy and safety of bortezomib in the treatment of RRMM in the Czech Republic. Methods: Before inclusion to RMG, all persons signed the informed consent form. In total, 1469 MM patients treated with bortezomib were evaluated from the RMG between June 2004 and December 2011.A total of 51.5% (750/1469) RRMM patients were analyzed with follow-up ≥6 months from the start of first administration of bortezomib. 30.6% (450/1469) patients with newly diagnosed MM were excluded from the analysis as well as 18.2% (267/1469) with a short follow-up. Evaluation of treatment response was performed according to the IMWG criteria. Median patient age was 65 years (range 33.9–88.1), median time since starting therapy was 21.5 months (range 6.1– 86.2), median number of previous treatments was 3.0 (range 1.0–8.0). In total, 92% (690/750) patients finished treatment of bortezomib (cycles length 21–28 days with application on days 1, 4, 8,11 or 1, (4), 8, 15 for frail patients). Median number of bortezomib cycles delivered was 6 (0.5–15.5). Results: Assessment of therapeutic response was possible in 92% (690/750) of treated patients. Overall response (ORR) in 57.5% (397/690) patients including 3% sCR, 8% CR, 20.3% VGPR, 26.2% PR. Stable disease was confirmed in 11.4% (79/690) patients and 22.5% (155/690) patients had progressive disease. In 50.1% of responders, first response (≥MR; defined as a ≥25% decrease in the serum MIg) occurred within the first cycle. At the second cycle, 24.2% of responders started to respond. Median time to progression (TTP) for all responders was 12.4 months. Median overall survival after starting bortezomib therapy (OS) was 32.3 months for all responders. Altogether, 692 adverse events (AEs) were documented. The most frequent AEs were: anemia in 62% of patients (462/750); severity of anemia was distributed as follows: 33.3% (250/750) cases of grade 1, 28.3% (212/750) cases of grade 2. Thrombocytopenia grade 3 and 4 was seen in 21.5% (161/750) of patients. Pre-existing peripheral neuropathy (PNP) grade 1–2 was presented in 25.1% (191/750) of patients at the start of bortezomib treatment. After treatment of bortezomib, PNP could be documented in 59.3% (445/750) cases with 16% (71/445) cases of grade 3 and 0.7% (3/445) cases of grade 4 PNP. In subanalysis, groups of patients were compared with relapsed patients who were treated with bortezomib in the second, third or greater-line of therapy. Among these three groups, there were significant differences in the evaluation of ORR (59.8% vs. 53.4% vs. 46.8%, p=0.022), as well as the sCR+CR was dependent on the number of previous treatment lines (15.6% vs 7.3% vs. 1.4%; p

Description: Background:Subcutaneous (SC) application of bortezomib has been recently introduced as a new application route in multiple myeloma (MM) patients. The results of an international randomized phase III trial confirmed that SC application of bortezomib is not inferior to intravenous (IV) route, with similar response rates and improved toxicity profile. Our aim was to confirm the results on a larger cohort of patients treated with IV or SC bortezomib in 2-year period within the Czech Myeloma Group. Patients and methods: We performed a retrospective analysis of 262 patients with MM treated with bortezomib based regimens during 2012-2013 in the Czech Republic. In total, there were 177 patients in the IV arm and 85 patients in the SC arm. Patients undergoing high-dosed chemotherapy followed by autologous stem cell transplantation (ASCT) were assessed separately (N = 99). There were 164 patients treated in the first line setting and 98 patients in relapse/progression of MM. The patients received up to eight 28-day cycles of bortezomib-based regimen with bortezomib dose 1.3mg/m2. The regimens used were following: CVD (cyclophosphamide, bortezomib, dexamethasone) in 58.2%/60.0%, VD (bortezomib, dexamethasone) in 10.7%/9.4%, BDD (bortezomib, doxorubicin, dexamethasone) in 9.6%/14.2%, VMP (bortezomib, melphalan, prednisone) in 6.0%/9.0%, bortezomib monotherapy in 1.1%/1.2%, BBD (bortezomib, bendamustine, dexamethasone) in 1.1%/2.4%, BP (bortezomib, prednisone) in 0%/1.6%, and other in 13.6%/2.4%. In order to reduce neurological toxicities, most of the patients received bortezomib once weekly. In both IV and SC arms we assessed the demographics and baseline characteristics, response rates and toxicities. For statistical estimation we used Mann-Whitney U test and Chi-square test at p 〈 0.05. Results:There were mild differences in the age and gender between IV and SC arms (median age 71.3 vs 67.9 years, p = 0.024; M/F ratio 1.4:1 vs 0.6:1, p = 0.007), other variables were without significant difference, including laboratory parameters (M-protein, hemoglobin, thrombocyte count, serum calcium level, albumin, creatinine, beta-2-microglobulin, lactate dehydrogenase, CRP), line of chemotherapy (first line, second line, third line and fourth and higher line) and therapeutic regimen used. Patients received median of 6 cycles in the IV group and 5 cycles in the SC group. The rates of response were similar in both, IV and SC arms with overall response rate (ORR) 71.7% vs 70.7%, complete remissions (CR) including stringent complete remissions (sCR) in 13.9% vs 8.6%, very good partial remissions (VGPR) in 30.8% vs 34.5% and partial remissions (PR) in 27% vs 27.6%. Toxicities were present in most patients (up to 99%), prevailing grade 1-2 toxicities, 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% patients 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% (p = 0.782). Conclusions: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. Supported by the grants IGA MZ CR NT 14393, NT 12215-4/2011, NT 14400, NT12451-5, NT 12215-4, and the grant MSM0021622434. Disclosures No relevant conflicts of interest to declare.

Description: 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.

Description: 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