3628 Cereblon (CRBN) Gene Polymorphisms Predict Clinical Response and Progression-Free Survival in Multiple Myeloma Patients Treated with Lenalidomide: A Pharmacogenetic Study of Immense Consortium Molecular Pharmacology, Drug Resistance – Lymphoid and Other Diseases Program: Oral and Poster Abstracts Type: Poster Session: 605. Molecular Pharmacology, Drug Resistance – Lymphoid and Other Diseases: Poster III Monday, December 8, 2014, 6:00 PM-8:00 PM North Building, Hall E (Moscone Center) Elzbieta Iskierka-Jazdzewska, MD1*, Anna Stepien, MSc2*, Federico Canzian, PhD3*, Alessandro Martino, PhD4*, Daniele Campa, PhD3*, Angelika Stein4*, Malgorzata Krawczyk-Kulis, MD, PhD5*, Malwina Rybicka, MD, PhD5*, Slawomira Kyrcz-Krzemien, MD, PhD6*, Aleksandra K. Butrym, MD, PhD7*, Grzegorz Mazur, MD, PhD8*, Artur J. Jurczyszyn, MD, PhD9*, Daria Zawirska, MD, PhD10*, Norbert Grzasko, MD, PhD11*, Waldemar Tomczak, MD, PhD12*, Edyta Subocz, MD, PhD13*, Marzena Watek, MD14*, Marcin Pasiarski, MD, PhD15*, Marcin Rymko, MD, PhD16*, Malgorzata Calbecka, MD, PhD16*, Agnieszka Druzd-Sitek, PhD17*, Jan Walewski, MD, PhD18, Marcin Kruszewski, MD, PhD19*, Malgorzata Razny, MD, PhD20*, Jan M Zaucha, MD, PhD21, Marek Dudzinski, MD, PhD22*, Pawel Gaj, PhD23*, Krzysztof Warzocha, MD, PhD24* and Krzysztof Jamroziak, MD, PhD25* Department of Hematology, Medical University, Lodz, Poland Laboratory of Clinical and Transplant Immunology and Genetics, Copernicus Memorial Hospital, Lodz, Poland 3German Cancer Research Center (DKFZ), Heidelberg, Germany 4German Cancer Research Center, Heidelberg, Germany 5Dept. of Hematology and BMT, Silesian Medical University Hospital SPSKM, Katowice, Poland 6Dept of Hematology and BMT, Silesian Medical University Hospital SPSKM, Katowice, Poland 7Department of Haematology, Blood Neoplasms and Bone Marrow Transplantation, Medical University, Wroclaw, Poland 8Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland 9Cracow University Hospital, Krakow, Poland 10Medical University, Krakow, Poland 11Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland 12Medical University, Lublin, Poland 13Dept. of Hematology, Military Institute of Medicine, Warsaw, Poland 14Department of Hematology, Holycross Cancer Center, Kielce, Poland 15Holycross Cancer Center, Kielce, Poland 16Department of Hematology, Copernicus Hospital, Torun, Poland 17Maria Sklodowska-Curie Memorial Institute and Oncology Centre Warsaw, Warsaw, Poland 18Department of Lymphoid Malignancies, The Maria Sklodowska-Curie Memorial Institute and Oncology Centre, Warsaw, Poland 19Department of Hematology, University Hospital, Bydgoszcz, Poland 1 2 Dept of Haematology, Rydygier Memorial Hospital, Krakow, Poland Department of Haematology, Sea Hospital in Gdynia, Gdynia, Poland 22Rzeszow Regional Hospital, Rzeszow, Poland 23Department of Immunology, Center for Biostructure Research, Medical University, Warsaw, Poland 24Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland 25Institute of Hematology and Transfusion Medicine, Warsaw, Poland 20 21 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 progressionfree 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. 3421 The International Multiple Myeloma Research (IMMEnSE) Consortium: Genetics of Multiple Myeloma Risk and Prognosis Myeloma: Biology and Pathophysiology, excluding Therapy Program: Oral and Poster Abstracts Type: Poster Session: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster II Sunday, December 7, 2014, 6:00 PM-8:00 PM West Building, Level 1 (Moscone Center) Federico Canzian, PhD1*, Katia Beider, Ph.D.2*, Gabriele Buda, MD3, Felipe de Arriba de la Fuente4*, Marek Dudzinski, MD, PhD5*, Charles Dumontet, MD, PhD6, Ramon Garcia-Sanz7*, Hiroshi Handa, MD, PhD8, Krzysztof Jamroziak, MD, PhD9*, Manuel Jurado, MD10,11, Artur J. Jurczyszyn, MD, PhD12*, Stefano Landi, MD, PhD13*, Fabienne Lesueur, PhD14*, Herlander Marques15*, Joaquín MartínezLópez, MD, PhD16*, Victor Moreno17*, Hirokazu Murakami, MD, PhD18, Arnon Nagler, MD2, Mario Petrini, MD, PhD19, Rui Manuel Reis, MD, PhD20*, Rafael Rios21*, Juan Sainz22*, Zofia SzemrajRogucka, MD, PhD9*, Annette Juul Vangsted, M.D.23*, Judit Varkonyi24*, Ulla Vogel, MD, PhD25*, Marzena Watek, MD26* and Daniele Campa, PhD13* Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany Hematology Division, Chaim Sheba Medical Center, Tel Hashomer, Israel 3Section of Hematology. AOUP, Pisa, Italy 4Hospital Morales Meseguer, Murcia, Spain 5Rzeszow Regional Hospital, Rzeszow, Poland 6Université Claude Bernard Lyon I, INSERM UMR 1052 / CNRS 5286, Lyon, France 7Hospital Universitario de Salamanca, Salamanca, Spain 8Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Maebashi, Japan 9Medical University of Lodz, Lodz, Poland 10Servicio Hematología-Hemoterapia, Hospital Virgen de las Nieves, Granada, Spain 11Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain 12Cracow University Hospital, Krakow, Poland 13University of Pisa, Pisa, Italy 14INSERM U900, Institut Curie, Paris, France 15Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal 16Department of Hematology, Hospital Universitario 12 de Octubre, Madrid, Spain 17IDIBELL- Catalan Institute of Oncology and University of Barcelona, Barcelona, Spain 18School of Health Sciences, Faculty of Medicine, Gunma University, Maebashi, Japan 19Santa Chiara, University of Pisa, Pisa, Italy 20University of Minho, Braga, Portugal 21Hematology department, Virgen de las Nieves University Hospital, Granada, Spain 1 2 Hematology department, Virgen de las Nieves University Hospital,, granada, Spain Department of Hematology,, Righospitalet and Roskilde Hospital, Copenhagen University, Copenhagen, Denmark 24Semmelweis University, Budapest, Hungary 25National Research Centre for the Working Environment, Copenhagen, Denmark 26Department of Hematology, Holycross Cancer Center, Kielce, Poland 22 23 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 Controls Median age Control type (5th-95th percentile) (5th-95th percentile) 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 Disclosures: No relevant conflicts of interest to declare. 2044 Type 2 Diabetes-Related Variants Influence on the Risk of Developing Multiple Myeloma: Results from the Immense Consortium Myeloma: Biology and Pathophysiology, excluding Therapy Program: Oral and Poster Abstracts Type: Poster Session: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster I Saturday, December 6, 2014, 5:30 PM-7:30 PM West Building, Level 1 (Moscone Center) Juan Sainz, PhD1,2*, Carmen Belén Lupiańez1,2*, Daniele Campa, PhD3,4*, Gabriele Buda, MD5, Hernan Jose Moreno, MD6, Marek Dudziński, PhD7*, Charles Dumontet, MD, PhD8, Ramón GarcíaSanz, MD, PhD9*, Krzysztof Jamroziak, MD, PhD10,11*, Artur J. Jurczyszyn, MD, PhD12*, Stefano Landi, MD, PhD4*, Fabienne Lesueur, PhD13*, Herlander Marques, MD, PhD14*, Joaquín Martínez-López, MD, PhD15*, Victor Moreno, MD, PhD16*, Mario Petrini, MD, PhD17, Rui Manuel Reis, MD, PhD14,18*, Zofia Szemraj-Rogucka, MD, PhD10*, Annette Juul Vangsted, MD, PhD19*, Judit Varkonyi, MD, PhD20*, Ulla Vogel, MD, PhD21*, Marzena Wątek, MD, PhD22*, Federico Canzian, PhD3* and Rafael Rios, MD1,2* GENYO. Centre for Genomics and Oncological Research: Pfizer / University of Granada / Andalusian Regional Government, PTS, Granada, Spain 2Virgen de las Nieves University Hospital, Granada, Spain 3German Cancer Research Center (DKFZ), Heidelberg, Germany 4University of Pisa, Pisa, Italy 5Section of Hematology. AOUP, Pisa, Italy 6Hospital Morales Meseguer, Murcia, Spain 7 Rzeszow Regional Hospital, Rzeszow, Poland 8Université Claude Bernard Lyon I, INSERM UMR 1052 / CNRS 5286, Lyon, France 9Department of Haematology, University Hospital of Salamanca, Salamanca, Spain 10Medical University of Lodz, Lodz, Poland 11Institute of Hematology and Transfusion Medicine, Warsaw, Poland 12Cracow University Hospital, Krakow, Poland 13INSERM U900, Institut Curie, Mines ParisTech, Paris, France 14University of Minho, Braga, Portugal 15Doce de Octubre Hospital, Madrid, Spain 16IDIBELL - Catalan Institute of Oncology and University of Barcelona, Barcelona, Spain 17Santa Chiara, University of Pisa, Pisa, Italy 18Barretos Cancer Hospital, Barretos, Brazil 19Roskilde Hospital, Copenhagen University, Roskilde, Denmark 20Semmelweis University, Budapest, Hungary 21National Research Centre for the Working Environment, Copenhagen, Denmark 22Holycross Cancer Center, Kielce, Poland 1 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 CDKN2A2Brs2383208G/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 nondiabetogenic 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. Table 1. Demographical characteristics of IMMEnSE cases and controls. CASES Region* CONTROLS Gender Mean Age Gender Mean Age Control type M/F (Total) (± STD) M/F (Total) (± STD) 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) Hungary 49/87 (136) 65.83±11.19 50/51 (101) 73.18±10.10 Hospitalized subjects 60.88±07.88 Blood donors Denmark 163/112 (275) 55.20±07.32 276/211 (487) 43.26±11.84 General population Total 61.06±10.57 942/916 53.56±16.45 715/705 (1420) (1858) 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 ADRA2A rs10885122 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 rs5219 KCNQ1 rs2237897 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. 3481 Subcutaneous Bortezomib, Melphalan and Prednisone in Elderly Newly Diagnosed Multiple Myeloma Patients Myeloma: Therapy, excluding Transplantation Program: Oral and Poster Abstracts Type: Poster Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II Sunday, December 7, 2014, 6:00 PM-8:00 PM West Building, Level 1 (Moscone Center) Charles Herbaux, MD1*, Cristina M. Joao, MD, PhD2*, Alexia Plocque3*, Valentine Richez4*, Francesca Gay, MD5*, Loic Renaud1*, Laurence Legros, MD6*, Laurent Garderet, MD7, Souhila Ikhlef, MD8*, Brigitte Pegourie, MD9*, Martine Escoffre-Barbe, MD10*, Bruno Royer, MD11*, Laurent Voillat, MD12*, Cyrille Hulin, MD13*, Anne Banos, MD14*, Eric G. Voog, MD15, Lionel Karlin16*, Anne-Marie Stoppa, MD17, Lotfi Benboubker, MD, PhD18*, Sonja Zweegman, MD PhD19, Eva De Jongh20*, Niels Abildgaard, MD21, Katell Le Dű22*, Artur J. Jurczyszyn, MD, PhD23*, Philippe Moreau, MD24*, Thierry Facon, MD25, Denis Caillot, MD26*, Evangelos Terpos27 and Xavier Leleu, MD, PhD28 Service des Maladies du Sang, Hopital Claude Huriez, CHRU Lille, Lille, France Hematology department, Instituto Portuguęs de Oncologia de Lisboa, Lisbon, Portugal 3 CHU de Dijon, Dijon, France 4hematology Department, CHU Nice, Nice, France 5Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy 6CH de l'Archet, Nice, France 7Hematology, Centre Hospitalier Universitaire Hopital St-Antoine, Paris, France 8Division of Hematology - Oncology and Nuclear Medicine, Hospital and Unversity Saint Antoine, Paris, France 9Hôpital A.Michallon, CHU Grenoble, Grenoble, France 10Hematology, CHU Rennes, Rennes, France 11hematology, CHU Amiens, Amiens, France 12 Hematology, Hospital, Chalons sur Saone, France 13Service d’Hématologie, CHU Nancy – Brabois, Vandoeuvre, France 14Groupe Francophone des Myelodysplasies (GFM), Bayonne, France 15Hematology Department, Le Mans, Le Mans, France 16 Immuno-Hematology Unit, Paris, France 17 Hématologie Clinique, Institut Paoli Calmettes, Marseille, France 18CHU Tours Hopital Bretonneau, Tours, France 19Dept. of Hematology, VUMC, Amsterdam, Netherlands 20VUMC, Amsterdam, Netherlands 21Hematology, Odense University Hospital, Odense C, Denmark 22Centre Jean Bernard, Clinique Victor Hugo, Le Mans, France 23Cracow University Hospital, Krakow, Poland 24University Hospital of Nantes, Nantes, France 25Hôpital Claude Huriez, Centre Hospitalier Régional Universitaire de Lille, Lille, France 26 Hematology Department, CHU de Dijon - Hospital `Le Bocage`,, Dijon, France 27Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece 28Hopital Claude Huriez, CHRU Lille, Lille, France 1 2 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-melphalanprednisone 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.
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