Bortezomib- and Thalidomide-Induced Peripheral Neuropathy (PN) in Multiple Myeloma (MM): Clinical and Molecular Analysis of 474 Patients Treated with Thalidomide-Dexamethasone (TD) or Bortezomib-TD (VTD)

Abstract 1821 Introduction: PN is an important complication of MM and its incidence has been further increased after the introduction of the novel agents thalidomide and bortezomib. In a phase 3 trial comparing TD with VTD as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation for previously untreated MM patients, the VTD arm was significantly superior over TD in terms of improved rates of complete or near-complete response (CR/nCR) (the primary study endpoint) and progression free survival (PFS). Toxicity of VTD and TD regimens, including PN, was a secondary study endpoint. Methods: We performed a subanalysis of the study to assess the frequency, reversibility, risk factors and molecular markers associated with treatment-emergent PN. PN was graded by use of National Cancer Institute9s Common Toxicity Criteria (NCI CTCAE) version 3.0. Since grade 1 PN could be misinterpreted and does not interfere with the daily activities, only patients who developed PN of at least grade 2 were evaluated. A total of 474 patients (of whom, 236 randomized to the VTD arm and 238 to TD) were stratified according to the development or not of grade ≥2 neurological adverse events (NAEs). Gene expression profiles (GEP) of pre-treatment CD138+ bone marrow plasma cells (BMPCs) were analyzed in a subset of 127 VTD-treated patients for whom biological samples taken at diagnosis were adequate for genomic analysis. GEP experiments were performed using the Affymetrix HG-U133 Plus 2.0 platform and class comparison of groups of array was done with one-way ANOVA Partek Genomic Suite (version 6.4). Results: Occurrence of PN throughout the entire treatment program was significantly higher in the VTD arm compared with TD. In particular, the rate of grade ≥2 PN was 35% vs 10% (p p NRN1 (involved in the axonal regeneration), GSTM1 (involved in the detoxification of electrophilic compounds by conjugation with glutathione), DCTN1 (whose mutations are associated in specific types of disease-associated axonal degeneration). GeneGO® pathway analysis of differentially expressed genes showed enrichment for genes mainly implicated in the regulation of cytoskeleton rearrangement and the axonal guidance: indeed, several genes, which are involved in the signal transfer from semaphorin and ephrin to the cytoskeletal and motor proteins resulted differentially expressed in patients who developed grade ≥2 PN ( SEMA6A , SEMA4B , ACTA2 , EPHA5 , NEB ). Conclusions: Although VTD incorporated into double ASCT was associated with a higher incidence of grade ≥2 PN compared with TD, the probability of complete resolution or improvement to at least grade 1 was comparable in both VTD- and TD-treated groups. Importantly, NAEs did not adversely affect the rate of CR/nCR, and TTP and PFS. No relationship between development of PN and both patient demographics and disease characteristics was observed. Conversely, GEP analysis of BMPCs from patients with VTD-induced PN showed the significant deregulated expression of genes involved in the nervous system function. Disclosures: Off Label Use: Bortezomib and Thalidomide as induction therapy prior to and consolidation therapy after double autologous stem-cell transplantation in newly diagnosed multiple myeloma. Tosi: Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Baccarani: Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Bristol-Mayers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Boccadoro: Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria. Cavo: Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees.