3628 Cereblon (CRBN) Gene Polymorphisms Predict Clinical

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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