Abstract: Introduction: IgM-secreting myeloma is rare, encompassing about 1% of all the myeloma cases. Given its rarity, the characteristics and survival of these patients have not been extensively studied. Therefore, we carried out a multicenter retrospective study in patients with IgM myeloma. Methods: The study protocol was reviewed and approved by the Institutional Review Board of each participating institution. Clinical data were gathered and included age, sex, hemoglobin, calcium, LDH, estimated glomerular filtration rate (GFR), presence of lytic bone lesions, International Staging System score, cytogenetic abnormalities, final outcome and overall survival (OS) time. OS was defined as the time in months from diagnosis to last follow-up or death. The Chi-square and the rank-sum tests were used to compare categorical and continuous variables, respectively. The Kaplan-Meier method was used to estimate OS and the log-rank waas used to compare groups. The Cox proportional-hazard regression method was used to fit univariate and multivariate survival models, reported as hazard ratio (HR) with 95% confidence intervals (CI). All reported p-values are two-sided, and were considered significant if less than 0.05. Results: A total of 159 patients with IgM myeloma from 20 centers from Europe, USA and Latin America were included in this analysis. Patients were diagnosed between 1996 and 2015. The median age at diagnosis was 65 years (range 37-86 years) with a male predominance (68%). The median serum IgM level was 2510 mg/dl (range 27-12,100 mg/dl) with 25% of patients having a serum IgM within normal limits but an IgM monoclonal spike detectable in serum electrophoresis. Hemoglobin levels 〈 10 g/dl were seen in 49 patients (32%), serum calcium was elevated in 24 (16%), estimated GFR of 60 ml/min or less in 56 (37%), lytic lesions were detected in 86 (58%), and serum LDH was elevated in 28 (24%). ISS scores of 1, 2 and 3 were seen in 53 (36%), 63 (43%) and 31 (21%) of patients, respectively. Although immunohistochemistry and/or flow cytometry data were limited, CD20 expression was seen in 15/26 (58%) and cyclin D1 in 10/15 (67%) patients. The most common cytogenetic abnormalities were t(11;14) in 26/67 (39%), del13q in 25/76 (33%) and del17p in 6/76 (8%) patients. 149 patients (94%) received at least one line of systemic therapy for myeloma of which 13 (9%) received rituximab as part of initial therapy. After a median follow-up of 47 months, 74 patients (47%) have died. The median OS was 62 months (95% CI 51-79 months). Cause of death was known in 38 patients, and the most common was myeloma progression (74%). IN the univariate analysis, prognostic factors associated with a worse OS were age (HR 1.03, 95% CI 1.01-1.06; p=0.01) and ISS score (ISS 2: HR 1.43, 95% CI 0.83-2.48; p=0.2, and ISS 3: HR 3.03, 95% CI 1.54-5.98; p=0.001, using ISS 1 as reference group), while male sex was associated with a better OS (HR 0.56, 95% CI 0.34-0.90; p=0.02). Hemoglobin, calcium, estimated GFR and lytic lesions were not associated with OS. In the multivariate analysis, male sex was associated with a better OS (HR 0.57, 95% CI 0.35-0.95; p=0.03) and ISS with worse OS (ISS 2: HR 1.57, 95% CI 0.89-2.74; p=0.12, and ISS 3: HR 2.76, 95% CI 1.38-5.55; p=0.004, using ISS 1 as reference group). Conclusion: Patients with IgM myeloma apparently present with similar clinical characteristics as patients with non-IgM myeloma. Pathologically, CD20 and cyclin D1 expression is common. The most common cytogenetic abnormalities identified were t(11;14) and del13q. Survival does not appear shorter than non-IgM myeloma patients, and the ISS appears to have similar prognostic value. Disclosures Castillo: Millennium: Research Funding; Janssen: Honoraria; Otsuka: Consultancy; Biogen: Consultancy; Abbvie: Research Funding; Pharmacyclics: Honoraria. Ghobrial:Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Noxxon: Honoraria; Amgen: Honoraria. Hájek:Celgene: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; BMS: Honoraria; Takeda: Consultancy. Hungria:International Myeloma Foundation Latin America: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Consultancy; Roche: Consultancy; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau. Reagan:Alexion: Honoraria; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees. Spicka:Janssen Cilag: 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, Research Funding; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria. Gertz:Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria; Annexon Biosciences: Research Funding.

Abstract: Background: Cereblon (CRBN), a subunit of cullin 4-based E3 ubiquitine ligase complex, has been characterized as the main immunomodulatory drugs (IMiDs), thalidomide, lenalidomide and pomalidomide, binding protein that is crucial for their antiproliferative and immunomodulatory properties. Several recent reports have suggested that CRBN gene and protein expression or alternative splicing affect sensitivity to IMiDs in multiple myeloma (MM). It can be speculated that CRBN expression level, alternative splicing or CRBN-E3 ubiquitine ligase substrate specificity in MM and microenvironment cells may be partially determined by inherited genetic background including functional single nucleotide polymorphisms (SNPs). Aim: The objective of this study was to verify whether naturally occurring SNPs in CRBN encoding CRBNgene (locus chromosome 3p26.2) may influence outcome of lenalidomide-based therapy in patients with MM. Methods: We genotyped 14 tagging SNPs in CRBN gene in 169 Polish Caucasian patients with refractory/relapsed MM treated with lenalidomide-based therapy. Among these patients 151 (89%) received lenalidomide/dexamethasone (Len-Dex) regimen while the remaining patients were treated with lenalidomide-based three drug combinations. Genomic DNA samples were collected and genotyped in the context of the IMMEnSE consortium. The influence of CRBNallelic variants on probability to achieve clinical response (at least partial response, PR) to lenalidomide-based therapy, achievement of complete response (CR), duration of progression-free survival (PFS) and overall survival (OS) were tested in regard to established clinical and laboratory predictive factors using logistic regression and proportional-hazards regression models. For all genotyped SNPs co-dominant, dominant and recessive inheritance modes were tested. Results: We found that carriers of minor alleles of two studied SNPs, namely CRBN rs1714327G 〉 C and CRBN rs1705814T 〉 C significantly associated with lower probability of achievement of clinical response (≥PR) to lenalidomide-based therapy using dominant inheritance model (OR=0.25, 95%CI 0.10-0.63; p=0.0033, Bonferroni corrected p=0.019 and OR=0.21, 95%CI 0.07-0.61; p=0.0041, Bonferroni corrected p=0.024, respectively). Moreover, in concordance with these findings one of these two SNPs, namely CRBN rs1705814T 〉 C, was also significantly associated with shorter PFS in the analyzed group of lenalidomide treated MM patients (OR=2.49; 95%CI 1.31-4.74; P=0.0054, Bonferroni corrected p=0.032). In contrast, none of the tested allelic variants of CRBN showed significant influence on OS. Conclusions: Taken together, our observations suggest that selected germline CRBN SNPs (rs1714327G 〉 C and rs1705814T 〉 C) affect lenalidomide efficacy in relapsed/refractory MM. Further studies are needed to explain functional mechanisms underlying these associations as well as to establish whether CRBN genetic variants may be useful as potential biomarkers for IMiDs-based therapy. Acknowledgments: This work was supported by the grants of Polish Young Heamatologists Club and Polish Myeloma Consortium. The work of Pawe³ Gaj was supported by a grant from the European Commission 7th Framework Programme: FP7-REGPOT-2012-CT2012-316254-BASTION Disclosures No relevant conflicts of interest to declare.

Abstract: Background. Thalidomide is one of the most prescribed regimens upfront in eNDMM, e.g. elderly myeloma, essentially as melphalan-prednisone-Thalidomide (MPT). Several options are offered at 1st and 2nd relapse to patients initially exposed to Thalidomide with either bortezomib or lenalidomide-based therapy. On the other hand, the second most prescribed drug in elderly myeloma upfront is Bortezomib, primarily as Bortezomib-melphalan-prednisone (VMP), the 2nd standard of care upfront in Multiple Myeloma (MM) ineligible for transplantation. Interestingly, lenalidomide is the drug of choice at first relapse in the vast majority of cases in most countries where lenalidomide is approved at first relapse and beyond. In this situation, it is likely that the patients would not receive thalidomide throughout the disease course of myeloma. We sought to analyse whether patients not exposed to thalidomide upfront, and that were solely exposed to the 2 drugs, bortezomib-based regimen and lenalidomide-based therapy would have a lower survival than patients exposed to all 3 drugs, e.g. thalidomide, lenaldiomide and bortezomib. Method. A total of 145 patients were recruited in this multicentric study, 46,2% were in the thalidomide upfront exposed arm and 53,8% had never been exposed to thalidomide. Patients were required to be aged ≥65 years, NDMM treated with either thalidomide upfront or never been exposed to thalidomide upfront or later in the myeloma disease course. If not exposed to thalidomide, the patients were to have received bortezomib upfront and lenalidomide first relapse or vice versa. In the thalidomide group, all patients had MPT initially for a median of 8 cycles (range 3 - 12), at a median dose of thalidomide of 100mg/day (50-200), with 11% dose reduction. In the non-exposed thalidomide group, all patients had bortezomib upfront, patients received Vd, VCd or VMP upfront; lenalidomide was then given at first relapse to all patients. The median dose administered of bortezomib was 1.3mg/m², for a median of 5 cycles (2-9). Results. Overall, the median age was 73 years (range, 65 - 85), with 35% aged 〉 75. The M/F ratio was 1.1, 38% were ISS 3, the median b2m was 5.5mg/L, 26% had an ECOG score ≥ 2, 42% had renal insufficiency, 11% had elevated LDH, 8% presence of plasmacytoma, and 14% had adverse FISH (del17p, t(4;14) and or t(14;16)). There was no difference in patients' characteristics across studied groups, according to exposure or not to thalidomide. With a median follow-up of 5 years, 60% have died overall; 69% in the thalidomide exposed group versus 52% in the thalidomide non-exposed group (p=0.027). The median OS of thalidomide exposed patients was 55.7 months (46;65) versus 44 months (35;53) in the thalidomide non exposed patients (p=0.079). In the thalidomide exposed group, the median PFS of the thalidomide, bortezomib then lenalidomide lines were 27 months (24;30), 11 months (8;13) and 13 months (10;15). In the thalidomide non-exposed group, the median PFS of bortezomib then lenalidomide lines were 17 months (13;21) and 13 months (6;20). We then studied the survival of patients from onset of first relapse in the thalidomide exposed group, e.g. upon treatment with bortezomib, followed by lenalidomide at subsequent relapse, 22.5 months (10;34) compared to patients in the thalidomide non-exposed group that received bortezomib upfront and lenalidomide at first relapse, 44 months (35;53), p=0.005. Conclusion. Overall, thalidomide exposed versus non exposed groups had similar OS, while OS was significantly lower in the thalidomide exposed patients at first relapse onset versus in the thalidomide non exposed patients from diagnosis. This data seems to recommend use of bortezomib- and lenalidomide-based regimens as early as possible in the myeloma disease course, but not to abandon thalidomide. Study of the impact of thalidomide in the post bortezomib, lenalidomide and pomalidomide era might thus be important to study and optimize. Disclosures Karlin: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Legros:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Garderet:Bristol-Myers Squibb: Consultancy. Hulin:Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Stoppa:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Moreau:Janssen: Other: Adboard; Novartis: Other: Adboard; Takeda: Other: Adboard; Amgen: Other: Adboard; Celgene: Honoraria, Other: Adboard. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Zweegman:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. MACRO:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Terpos:Janssen: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Research Funding. Leleu:LeoPharma: Honoraria; Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Chugai: Honoraria.

Abstract: Background: The initial therapies for multiple myeloma have changed significantly in the recent years with routine incorporation of combinations containing IMiDs and proteasome inhibitors. However, patients with MM invariably relapse after their initial treatment and undergo successive therapies for continued control of their disease. The increasing access to new therapies for treatment of relapsed disease has led to improved survival of patients with MM. Many recent phase 3 trials have studied the impact of new agents on outcome of patients with MM who are relapsing after the initial lines of therapy for relapsed disease. However, the natural history of relapsed myeloma earlier in the course of relapsed disease has not been studied in detail. Patients and methods: We designed a global, multicenter, retrospective study to examine the current treatment approaches for initial relapses in MM and patient outcomes following application of successive treatment regimens. Patients with multiple myeloma who experience a first relapse between January 1, 2007 and December 31, 2011 were identified at participating sites. Clinical and laboratory data pertaining to the time of diagnosis and from the time of individual relapses up to and including the third relapse will be obtained from the clinical records. The first date of treatment with an anti-myeloma regimen for first disease relapse was termed time zero (T0). Results: Three hundred and fifteen patients were enrolled; median age at diagnosis was 59 years (range: 35 - 86), 59% were male. Patients were enrolled from North America (33%), Europe (35%) or Asia (32%). The patients were diagnosed between 1997 and 2011 and the median time to T0 from diagnosis was 23.9 months (range: 0.8 - 131.9 months). An IMiD (thalidomide or lenalidomide), bortezomib or alkylator (melphalan or cyclophosphamide) was part of the initial therapy in 63%, 36% and 51% of patients, respectively; 93 (33%) patients had stem cell transplantation as part of initial treatment. The median follow up from the study entry was 56 months; 117 were alive at the time of data extraction. A second line, third line and fourth line of treatment were recorded in 307, 163 and 84 patients respectively. An IMiD (thalidomide, lenalidomide, or pomalidomide), proteasome inhibitor (bortezomib or carfilzomib) or alkylator (melphalan or cyclophosphamide) was part of the therapy for first relapse in 50%, 59% and 33% of patients, respectively. The responses to the regimens after T0, the TTNT, PFS and OS to each line of therapy are provided in the Table. Conclusion: The current study provides an assessment of the current treatment approaches used for initial treatment of MM and the salvage treatment options utilized. The study again demonstrates the progressively shorter duration of disease control with each successive treatment regimen, reflecting ongoing development of drug resistance. The overall survival of over 3 years from the time of therapy for first relapse highlights the impact of the newer therapies that have been introduced for this disease. Table. Treatment outcomes after initial relapse Endpoint 2nd line therapyN=307 3rd line therapyN=163 4th line therapyN=84 Partial response or better Median in Months (95% Confidence Interval) Overall Survival 36.1 (30.2, 42.4) 18.4 (14.5, 26.8) 12.6 (10.4, 19.0) Progression-Free Survival 13.4 (11.8, 15.8) 8.3 (6.5, 11.2) 6.4 (5.0, 8.1) Time to Next Treatment 15 (12,17) 9.8 (7.4, 12.0) 6.6 (5.8, 8.7) Figure 1. Figure 1. Disclosures Kumar: Onyx: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dimopoulos:Novartis: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Onyx: Honoraria; Celgene: Honoraria. Leleu:Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; TEVA: Honoraria; Novartis: Honoraria; BMS: Honoraria; Pierre Fabre: Honoraria; LeoPharma: Honoraria; Chugai: Honoraria. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen Cilag, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy.

Abstract: We established the IMMEnSE (International Multiple Myeloma rESEarch) consortium, to increase our understanding of the genetic determinants of multiple myeloma (MM) risk, response to therapy and survival. At present we have DNA samples of over 3200 MM cases and 3000 healthy controls from 10 countries, mainly in Europe. For the majority of the cases clinical data on known prognostic factors, therapy outcome and survival have been also collected. We already performed several association studies in the context of the IMMEnSE consortium. In particular, associations were found between MM risk and SNPs in the ABCB1 gene, which encodes for an efflux pump that has a key role in protecting cells from chemical damage (rs10264990: odds ratio (OR) =0.79, 95% confidence interval (CI) 0.68-0.91; p=0.001, and rs17327442: OR=1.99; 95%CI 1.32-3.02; p=0.001). We also investigated the 8q24 region, which has been shown to harbor multiple loci of susceptibility to various cancers, and found an association between a SNP mapping in this region and MM risk (rs2456449: OR=1.37; 95%CI 1.12-1.68; p=0.0022). In addition, IMMEnSE cases and controls were also genotyped for three MM risk SNPs from the first genome-wide association study (GWAS), and the association of two of them (rs4487645 on chromosome 7p15.3 and rs6746082 on chromosome 2p23.3) was confirmed. Finally, SNPs of key telomere-related genes were genotyped and telomere length was measured in MM cases and controls, and a pleiotropic and functional variant of the TERT gene was found to be associated with reduced MM risk (rs2242652: OR=0.81; 95%CI 0.72-0.92; p=0.001). A suggestive association between longer telomeres and increased MM risk was also found (ptrend=0.01). We will study new SNPs emerging as promising candidates from ongoing GWAS on MM risk and survival, as well as SNPs of key genes involved in the pathogenesis of MM. Finally, we plan to study methylation status of key genes involved in MM etiology, and mitochondrial copy number. The role of all these factors will be investigated in relation to MM risk and prognosis. Collection of samples and data of MM cases and controls is ongoing, as well as of subjects with monoclonal gammopathy of undetermined significance (MGUS). Table 1. MM cases and healthy controls collected in the IMMEnSE consortium Country Cases Median age(5th-95th percentile) Controls Median age(5th-95th percentile) Control type Italy 232 63 (46-78) 237 59 (42-76) General population Poland 1,286 63 (42-82) 200 68 (43-79) Blood donors Spain 322 64 (46-82) 1,131 66 (43-84) Hospitalized subjects France 642 57 (37-68) 191 48 (18-63) Blood donors Portugal 70 68 (45-82) 100 58 (53-79) Blood donors Hungary 148 68 (34-90) 105 74 (55-87) Hospitalized subjects Denmark 348 56 (43-65) 1,000 63 (52-73) Blood donors Israel 109 60 (41-77) 95 - Blood donors Canada 62 58 (42-70) - - - Japan 51 66 (47-84) - - - Total 3,270 63 (37-84) 3,059 63 (18-92) Figure 1 Centers involved in IMMEnSE Figure 1. Centers involved in IMMEnSE Disclosures No relevant conflicts of interest to declare.

Abstract: The aim of the multi-centre observational study was to evaluate the efficacy of lenalidomide (len) therapy in patients (pts) with resistant or relapsed MM as well in pts who continued treatment with len due to complications from the earlier lines of the therapy. The study involved 306 pts, 153 women and 153 men, aged 26-89 years (mean 60,5); on the onset of lenalidomide therapy 115 pts (38,8 %, Cohort 1, C1) were diagnosed with resistant MM, 135 pts (44,1%, Cohort 2, C2) had relapse of the disease, and 56 (18,3 %, Cohort 3, C3 ) len was instituted as continuation therapy due to polyneuropathy. In Stage I, II and III according to Durie - Salmon staging system there were 36, 88 and 182 pts respectively; 23 pts developed renal failure. 179 pts had IgG myeloma, 78 – IgA, 31pts were diagnosed with light chain disease, 13 – with non-secretory myeloma, 3- IgM, 2 -IgD and 196 with kappa light chain disease. Prior to len therapy the pts received 1-9 treatment lines (mean:3); 83 pts underwent megachemiotherapy. Average time from diagnosis to start of len treatment was 47 months (1-230). In 284 (92,8%) pts, len was administered at the dose of 25mg p.o , on days 1-21, in the remaining 22 (7,2%) pts (14, 3, 5 pts respectively) at the dose of 15mg, 10mg or 5 mg for 21 days, and dexamethasone (dx) at the dose of 20 mg on days 1-4, 8-11. 28 pts received only len at the dose of 25 mg for 21 days; individual pts were administered len with bortezomib or bendamustin and dexamethasone. The cycles were repeated every 28 days. All the pts were administered aspirin 75mg as the prophylaxis of deep vein thrombosis. Therapeutic response was evaluated on the basis of modified criteria of the European Group for Blood and Marrow Transplantation in all pts. At the time of the assessment 32 (10,45% ) pts have completed 1-2 cycles, 48 (15,7%) 3-4 cycles, the others 6 and more. The response rate was highest in pts continuing treatment, significantly higher than in resistant and relapsed myeloma. The response rate in group 1 and 2 was comparable 68,7% i 85,7%.(tabl ) respectively.ResponseResistant MM n=115 (C1);Relapsed MM n=135 (C2);Treatment continuation n=56 (C3);Total (n=306)CR/sCR10 (8,7 %)13 (9,6 %)15 (26,8 %)38VGPR11 (9,6 %)19 (14,1%)19 (33,9 %)49PR58 (50,4%)70 (51,9 %)16 (28,6 %)144SD29 (25,2 %)21 (15,6 %)3 (5,3 %)53PD7 (6,1 %)12 (8,9 %)3 (5,3 %)22Response:79 (68,7%)102 (85,7%)50 (89,2%)No response:36 (31,3%)33 (27,7%)6 (10,%)PC1:C2 =0,2266PC1:C3=0,0033PC2:C3=0,0321 The percentage of all responses was significantly higher in pts without renal insufficiency compared to those with renal failure (224/283 vs. 11/23) p= 0,0006, and in the group of pts whose serum beta-2-microglobulin was 〈 3.5 mg/L compared to those with beta-2-m 〉 3.5 mg/L 89/112 vs 45/68 p=0,0316. There were no significant differences in response to len, depending on the number of previous lines of treatment 1 vs. 〉 1, stage ISS, and underwent or no megachemotherapy. The median TTP was 14.0 months in pts who responded to treatment with len and dx (CR, nCR, VGPR, PR). The TTP in pts with disease stabilization, or disease progression was significantly shorter (p = 0.0000), median 5.0 months. The median TTP was 9.0 months in pts with resistant MM, 8.0 months in pts with relapsed MM, and was significantly shorter (p = 0.00007) compared with median TTP in pts continuing treatment (16.50 months). The median OS was 15.0 months in pts who responded to treatment with len and dx (CR, nCR, VGPR, PR), and it was significantly longer (p = 0.00000) than the median OS in pts with disease stabilization, or disease progression (median 8.0 months). In pts with resistant MM median OS was 10.50 months, in pts with relapsed MM -11.0 months, and were significantly shorter (p = 0.00077) comparing to pts continuing treatment (18.0 months). Summary Lenalidomide with dexamethasone is an orally administrated and effective both in resistant and relapsed patients as well as maintenance therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract: Background. Bortezomib-melphalan-prednisone (VMP) and melphalan-prednisone-Thalidomide (MPT) are the 2 standards of care upfront in Multiple Myeloma (MM) ineligible for transplantation, along with Bendamustine-prednisone in a very limited indication in Europe. These regimens are based on an alkylator plarform, to which cyclophosphamide might replace melphalan in some countries. For patients initially exposed to Thalidomide several options are offered at first relapse with bortezomib or lenalidomide-based therapy and vive versa at subsequent relapses. For patients initially exposed to bortezomib, either they are retreated with a bortezomib-based regimen or receive a lenalidomide-based therapy, but these patients often have never been exposed to thalidomide throughout their myeloma disease history. We hypothesized that patients that will receive the 3 agents, thalidomide first followed by bortezomib and lenalidomide at subsequent relapses, will have a prolonged survival compared to patients that had bortezomib-based first followed by lenalidomide at subsequent relapses but never been exposed to thalidomide upfront. We sought to understand the prognostic impact of receiving versus being spared from Thalidomide in elderly MM newly diagnosed. Method. A total of 76 patients were recruited, 37% had receive thalidomide and 63% never been exposed to thalidomide. Patients were required to be aged ≥65 years, NDMM treated with either thalidomide upfront or never been exposed to thalidomide upfront or later in the myeloma disease course. Response rate was determined according to IMWG. All survival endpoints were evaluated using Kaplan-Meier estimates and compared with the log-rank test. Results. Overall, the median age was 73 years (range, 65 - 85), with 46% aged 〉 75. The m:f ratio was 1.2, 49% of the patients were ISS 3, the median b2m was 4.5mg/L, 33% had an ECOG score ≥ 2, 47% renal insufficiency, 11% had elevated LDH, 8% presence of plasmacytoma, and 11% had adverse FISH (del17p, t(4;14) and or t(14;16)). There was no difference between the 2 studied groups, according to exposure or not to thalidomide. In the thalidomide group, all patients had MPT initially for a median of 8 cycles (range 3 – 12), at a median dose of thalidomide of 100mg/day (50-200), 11% dose reduction, an ORR of 79%, a median PFS of 30 months (CI95% 27;32). In the bortezomib group upfront, patients received Vd, VCd or VMP upfront. The median dose administered of bortezomib was 1.3mg/m², for a median of 5 cycles (2-9). The ORR was 67%, a median PFS of 17 months (CI95% 13;20) with 44% at 2-years PFS. With a median follow-up of 5 years, 93% had relapse, 47% have died. We then sought to compare the OS according to whether the patients were exposed to thalidomide. Interestingly, the median OS of the thalidomide group was 4 years (CI95% 3;5) versus 5 years for the group with no exposition to thalidomide (3.5;6), p=ns. The estimated 6-years OS was 32% and 44% for the 2 groups, respectively. Conclusion. The sequence of bortezomib-based regimen upfront followed by lenalidomide with no exposure to thalidomide in transplant ineligible patients appeared to be slightly superior to the sequence including-based regimen upfront followed by bortezomib and lenalidomide at subsequent relapses. This data needs to be confirmed in a larger study, but it seems that thalidomide could be spared for elderly NDMM that receive bortezomib-based and lenalidomide-based regimens with possibly an improvement of OS in this latter group with a prolonged follow up. Disclosures Gay: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Background. Bortezomib-melphalan-prednisone (VMP) is a standard of care upfront in Multiple Myeloma (MM) ineligible for transplantation, where bortezomib was given twice weekly intra veinously. Based on the VISTA study, the median TTP was 24.0 months, the median OS 56.4 months, the ORR (IMWG) 71% and the CR rate 30%. This regimen was then improved with a weekly administration of bortezomib starting at cycle 1 (called Palumbo design) or cycle 2 (called Mateos design). In the once-weekly schedule, the median PFS was 33.1 months, the median OS was not reached, the ORR 85% and the CR rate 30%. Recently, subcutaneous bortezomib was approved in association to dexamethasone in relapsed MM that proved non-inferior to standard intravenous administration in terms of efficacy, with an improved safety profile, particularly with regard to the rate of neuropathy. As a consequence, physicians have switched to Bortezomib subcutaneous administration in the VMP regimen in many countries. We aimed to study the impact of subcutaneous bortezomib in the VMP regimen (VscMP) in elderly MM newly diagnosed (NDMM). Method. A total of 40 patients were recruited for the current study. Patients were required to be aged ≥65 years, NDMM treated with subcutaneous Bortezomib, Melphalan and Prednisone. Patients had VscMP either according to VISTA schedule or to Palumbo (weekly) schedule. Response rate was determined according to IMWG. All survival endpoints were evaluated using Kaplan-Meier estimates and compared with the log-rank test. Results. The median age was 79 years (range, 67 - 90), with 28 patients (70%) aged 〉 75 and 18 patients (45%) aged 〉 80. The m:f ratio was 1.2, 77% of the patients were ISS 2 or 3, 32% had an ECOG score ≥ 2, and 10% had adverse FISH (del17p and/or t(4;14)). 15 patients were treated in the VISTA schedule and 25 in the weekly schedule (Palumbo design). No patients have had Mateos design. For the cohort as a whole, the median TTP was 32 months, the median OS is not reached with 81% 5-years estimate, the ORR 75% and the CR rate 17,5%; that demonstrated that subcutaneous bortezomib is non-inferior to IV data reported in historical studies for the VMP regimen. Similarly, there was not much difference in terms of efficacy between patients that had bortezomib subcutaneous weekly versus twice a week: weekly: the median OS is not reached, the ORR 80% and the CR rate 13%; twice a week: the median OS is not reached, the ORR 84% and the CR rate 20%. With regards to the safety profile of VMP given with bortezomib subcutaneous, it seemed to offer an improved safety profile: 12.5% of grade 3 or 4 hematologic toxicity versus 47% in the literature. It does not seem to be any difference in neurological toxicity, with 5% of grade ≥2 peripheral neuropathy in our study, as to the VISTA study. Interestingly, we have seen no clear difference in terms of safety profile between the two schedule designs, VMP twice a week versus weekly using bortezomib sub cutaneous, which tend to confirm the improved safety profile of VMP with bortezomib used subcutaneously. Conclusion. The use of subcutaneous bortezomib in the standard of care bortezomib-melphalan-prednisone regimen in elderly MM newly diagnosed had comparable efficacy than the intravenous administration. Importantly, the subcutaneous administration is associated to improved safety profile in comparison with previously published data. This dataset might encourage the use of the twice weekly subcutaneous bortezomib in the VMP regimen for patients considered fit. Disclosures No relevant conflicts of interest to declare.

Abstract: Type 2-diabetes (T2D) is thought to be a relevant risk factor for multiple myeloma (MM), but the relationship between both traits is still not well understood. Thus, we decided to conduct a population-based case-control study in a population of 1420 MM patients (705 women and 715 men) and 1858 controls (916 women and 942 men) to evaluate whether 58 genome-wide association studies (GWAS)-identified common variants for T2D influence the risk of developing MM. Logistic regression analyses showed that carriers of the KCNQ1rs2237892T allele or CDKN2A-2Brs2383208G/G, IGF-1rs35767T/T and MADDrs7944584T/T genotypes had an increased risk of MM (OR=1.32, 95%CI 1.01-1.71, P=0.039; OR=1.86, 95%CI 1.12-3.11, P=0.016; OR=2.13, 95%CI 1.35-3.37, P=0.001 and OR=1.33, 95%CI 1.06-1.67, P=0.014, respectively) whereas those carrying the KCNJ11rs5215C, KCNJ11rs5219T and THADArs7578597C alleles or the FTOrs8050136A/A and LTArs1041981C/C genotypes showed a decreased risk for the disease (OR=0.85, 95%CI 0.73-0.99, P=0.38; OR=0.84, 95%CI 0.72-0.99, P=0.034; OR=0.81, 95%CI 0.68-0.98, P=0.032; OR=0.78, 95%CI 0.64-0.95, P=0.013; and OR=0.76, 95%CI 0.58-0.99, P=0.042, respectively). The associations of these T2D-related variants with an increased or decreased risk of MM were due to non-diabetogenic alleles, which suggests a non-diabetogenic mechanism underlying the effect of these variants to determine the risk of the disease. A gender-stratified analysis also revealed a significant gender effect modification for ADAM30rs2641348, and NOTCH2rs10923931 SNPs (Pinteraction=0.001 and 0.0004 and Phet=0.19 and 0.60, respectively), which also underlies the importance of considering gender as a factor modifying the risk for MM. Men harbouring the ADAM30rs2641348C and NOTCH2rs10923931T alleles had a decreased risk of MM (OR=0.71, 95%CI 0.54-0.94, P=0.015 and OR=0.66, 95%CI 0.50-0.86, P=0.0019) whereas an opposite but not significant effect was observed in women. Finally, SNP-SNP interaction analysis revealed overall significant two- and three-locus interaction models to increase the risk of MM (FAM148Brs11071657-KCNJ11rs5219, and SLC30A8rs13266634-KCNJ11rs5219-FTOrs8050136; P=0.01 and 0.001, respectively) whereas a significant four-locus model was also found to increase the risk of MM in men (FADS1rs174550-TSPAN8rs7961581-PROX1rs340874-KCNJ11rs5219, P=0.001). Although further studies in independent populations are warranted to replicate these findings, these results suggest that TD2-related variants may influence the risk of developing MM, likely through non-diabetogenic mechanisms. Abstract 2044. Table 1. Demographical characteristics of IMMEnSE cases and controls. CASES CONTROLS Region* Gender M/F (Total) Mean Age (± STD) Gender M/F (Total) Mean Age (± STD) Control type Italy 117/107 (224) 62.60±9.90 127/105 (232) 58.75±10.92 General population Poland 173/198 (371) 62.35±10.39 124/226 (350) 50.68±19.43 Blood donors Spain 139/133 (272) 63.06±11.04 218/192 (410) 63.12±11.94 Hospitalized subjects France 42/33 (75) 55.80±9.04 95/89 (184) 44.07±15.22 Blood donors Portugal 32/35 (67) 65.79±11.16 52/42 (94) 60.88±07.88 Blood donors Hungary 49/87 (136) 65.83±11.19 50/51 (101) 73.18±10.10 Hospitalized subjects Denmark 163/112 (275) 55.20±07.32 276/211 (487) 43.26±11.84 General population Total 715/705 (1420) 61.06±10.57 942/916 (1858) 53.56±16.45 Table 2. Selected type-2 diabetes-related polymorphisms Gene name dbSNP rs# Gene name dbSNP rs# ADAM30 rs2641348 JAZF1 rs864745 ADAMTS9 rs4607103 KCNJ11 rs5215 ADCY5 rs11708067 rs5219 ADRA2A rs10885122 KCNQ1 rs2237897 ARAPI, CENTD2 rs1552224 rs2074196 BCL11A rs10490072 rs2237892 CDC123 rs12779790 rs2237895 CDKAL1 rs7754840 KCNQ1OT1 rs231362 CDKN2A-2B rs564398 LTA rs1041981 rs10811661 MADD rs7944584 rs2383208 MCR4 rs12970134 COL5A1 rs4240702 MTNR1B rs1387153 CRY2 rs11605924 NOTCH2 rs10923931 DCD rs1153188 PKN2 rs6698181 EXT2 rs1113132 PPARG rs1801282 FADS1 rs174550 PRC1 rs8042680 FAM148B rs11071657 PROX1 rs340874 FLJ39370 rs17044137 RBMS1 rs7593730 FTO rs8050136 SLC2A2 rs11920090 G6PC2 rs560887 SLC30A8 rs13266634 GCK rs1799884 TCF2 rs7501939 GCKR rs1260326 TCF7L2 rs7903146 HHEX rs1111875 TCF7L2 rs12255372 HMGA2 rs1531343 THADA rs7578597 HNF1A, TCF1 rs7957197 TP53INP1 rs896854 IGF1 rs35767 TSPAN8 rs7961581 IGF2BP2 rs4402960 VEGFA rs9472138 IL13 rs20541 WFS1 rs734312 IRS1 rs2943641 rs10010131 Disclosures No relevant conflicts of interest to declare.