Abstract: 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 : & lt;3.5/3.5-5.5/ & gt;5.5 g/L), albumin levels ( & lt;3.5/≥3.5 g/L), line of therapy (3-13), prior exposure to pomalidomide/carfilzomib, refractory status (none/double/triple/quadruple), andincidence of thrombocytopenia (defined as platelet counts & lt;150.000 per µL) as covariates. Predicted PFS and OS curves for the RMG cohort were derived from the multivariate model. 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.

Abstract: 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.

Abstract: Monoclonal gammopathy of undetermined significance ( MGUS ) is a premalignant condition with a risk of malignant conversion. Patients and methods With the aim to estimate the cumulative risk MGUS progression to hematologic malignancies, we analyzed a nationwide population‐based cohort of 1887 MGUS patients from the Czech Registry of Monoclonal Gammopathies ( RMG ) between 2007 and 2013. Results During the follow‐up period (median 4 years; range 0.6‐34.8), progression to hematologic malignancies was observed in 8.6% (162 of 1887) of patients. Factors associated with progression were as follows: M‐protein concentration ≥1.5 g/ dL , pathological sFLC ( 〈 0.26 or 〉 1.65) ratio, bone marrow plasma cells ( BMPC s) in cytology 〉 5%, immunoparesis, age ≥69 years, and the level of serum hemoglobin at baseline 〈 12.0 g/ dL . Combining these factors, we propose a new risk model ( CMG model). The risk of progression at 10 years was 1.6%, 16.9%, 22.9%, 39.4%, and 52.3%, respectively, if 0 (reference group), one, two, three, or four to five risk factors are present ( P 〈 .001) with HR 63 times higher compared to the reference MGUS group. Conclusion The new CMG model was established with an advantage for better identification of MGUS patients at low risk.

Abstract: 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.

Abstract: 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 〈 0.001). Median TTP had similar dynamics (14.5 vs. 11.0 vs. 10.0 months; p= 〈 0.001). Altogether, 55.5% (416/750) of patients were pre-treated with thalidomide, while other patients were pre-treated with only conventional cytotoxic agens. Between these two groups we found differences in the achievement of treatment response: sCR+CR (8% vs. 14.1%; p =0.007), median TTP (11.0 vs. 15.0 months; p = 0.001) and median OS from the start of treatment with bortezomib (28.2 vs. 36.5 months; p = 0.001). Autologous stem cell transplantation after treatment with bortezomib was performed in 13.9% (104/750) of patients with positive effect on survival compared to patients without autologous stem cell transplantation (median OS 42.4 vs. 31.2 months; p = 0.007, median TTP 19.4 vs. 11.4 months; p 〈 0.001). Conclusion: Our results show that bortezomib is one of the highly effective drugs for patients with RRMM. In current practice, the benefit (measured TTP) is 10–14 months, according to severity of the disease with a favorable impact on overall survival even in heavily pretreated patients. Implementation of autologous stem cell transplantation in relapsed disease following bortezomib treatment had a beneficial effect on overall survival. Acknowledgments: This work was supported by IGA NT 12130–4 and IGA NT 12215–4 grants. Disclosures: Maisnar: Janssen Cilag: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer (Schering): Honoraria. Hajek:Merck: 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; Janssen Cilag: Honoraria.

Abstract: 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 〈 0.001, n=139), respectively. The CMG model was validated on 240 SMM patients from Heidelberg published in 2013. The risk of progression from SMM to MM at 2 years was 5.3%, 7.5%, 44.8% and 81.3% if 0, 1, 2 or 3 risk factors were present, respectively (p 〈 0.001) (Figure 1) with HR of 4.2 ([0.5-36.1]; p=0.189), 21.5 ([2.9-159.1] ; p= 0.003, HR 38.6 [4.7- 317.7]; p 〈 0.001, n=113). 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.