1790 Genetic Associations with Therapy Response in the HOVON-65/GMMG-HD4 Trial in
Patients with Multiple Myeloma
Oral and Poster Abstracts
Poster Session: Myeloma - Biology and Pathophysiology, excluding Therapy Poster I
Saturday, December 5, 2009, 5:30 PM-7:30 PM
Hall E (Ernest N. Morial Convention Center)
Poster Board I-812
Sophie L Corthals1*, Hartmut Goldschmidt2*, David C Johnson3*, Henk Lokhorst4*, Yvonne de Knegt1*, Sonja
Zweegman5, Bronno van der Holt6*, Dirk Hose2, Marie Jose Kersten7*, Edo Vellenga8, Brian G M Durie9, Gareth J
Morgan3* and Pieter Sonneveld1
1Erasmus University Medical Center, Rotterdam, Netherlands
2University of Heidelberg, Heidelberg, Germany
3Institute of Cancer Research, London, United Kingdom
4University Medical Center, Utrecht, Netherlands
5VU University Medical Center, Amsterdam, Netherlands
6HOVON Data Center, Rotterdam, Netherlands
7Academic Medical Center, Amsterdam, Netherlands
8Department of Hematology, University Medical Center Groningen, Groningen, Netherlands
9Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA
Multiple Myeloma (MM) is a plasma cell malignancy, characterized by
significant heterogeneous disease progression and response to therapy. It is
very likely that genetic polymorphisms of genes involved in drug absorption,
distribution, metabolism and excretion may affect a patient's response to
therapy.
To explore whether genetic variation is associated with therapeutic outcome
in the Dutch-German HOVON-65/GMMG-HD4 trial, a custom-built molecular
inversion probe (MIP) based single nucleotide polymorphism (SNP) chip,
designed by "Bank on a Cure" (BOAC)) was used, containing 3404 SNPs
selected in "functional regions" within 983 genes representing cellular
functions and pathways that may influence disease response, toxicities,
complications, and survival. In the HOVON-65/GMMG-HD4 trial patients
were treated with either 3 induction cycles of
Vincristine/Adriamycin/Dexamethason (VAD, arm A) or 3 cycles of
Bortezomib in combination with Doxorubicin and Dexamethason (PAD, arm
B) after which response to treatment was determined. In 189 out of the
initial 40% of patients (n=350) being included in the HOVON-65/GMMG-HD4
trial germ-line DNA was collected. To explore SNP associations with
treatment response, an analysis was performed on both treatment arms
separately and a comparison was made between good responders (CR,
VGPR) (VAD n=17; PAD n=50) and patients who responded less well (PR or
less) (VAD n=67; PAD n=55). A Cochran-Armitage trend test was applied on
both data sets using the program PLINK. To account for multiple testing we
carried out label swapping procedures.
The association analysis identified highly significant SNPs uniquely
associated with VAD or bortezomib treatment response. The 3 most
significant SNPs associated with CR/VGPR on VAD are rs2725362 in WRN
(p=8.0x10-4; Odds Ratio (OR)=4.13, 95% confidence interval (CI)=1.71-
9.97) rs891507 in ABCB8 (p=1.2x10-3; OR=4.44, 1.81-10.88) and rs755622
in MIF (p=1.4x10-3; OR=4.35, 1.79-10.55). Different SNPs were associated
with CR/VGPR on PAD: rs2293616 in SLC15A2 (p=5.0x10-4; OR=0.43, 0.25-
0.75), rs1062372 in PMS2 (p=9.0x10-4; OR=0.31, 0.15-0.66) and rs90925
in LTA (p=1.0x10-3; OR=0.41, 0.22-0.75). Pathway analyses showed that
the two sets of associated SNPs were enriched for genes involved in DNA
repair, immune response/inflammation and drug metabolism. In addition,
overlapping SNP associations in the ADME genes (drug absorption,
distribution, metabolism, and excretion) ABCC1, CYP2C9, ABCC4 and ABCA1
were seen in both treatment arms.
Our findings demonstrate a trend of genetic polymorphisms associated with
treatment response. Genetic variations were found that were uniquely
associated with each treatment. The associations found will be validated in
an independent dataset.
Disclosures: Off Label Use: Use of Bortezomib in first line treatment of multiple myeloma. Goldschmidt:
Johnson and Johnson: Research Funding, Speakers Bureau. Sonneveld: Johnson and Johnson: Research Funding,
Speakers Bureau.