Development of Bortezomib Induced Peripheral Neuropathy (BiPN) In Multiple Myeloma: Incidence and Molecular Characterization In Newly Diagnosed Patients Treated with Bortezomib

Bortezomib, a proteasome inhibitor with activity in multiple myeloma (MM) achieves high response rates in newly diagnosed patients. Bortezomib induced peripheral neuropathy (BiPN) affects 15% (grade 3–4) to 40% (grade 1–4) of patients. BiPN frequently is the dose-limiting toxicity which requires dosing adjustments, and significantly influences the quality of life. The pathogenesis of BIPN and the background for the individual differences of susceptibility are largely unknown.

This project was designed to obtain insight in the molecular characteristics underlying BiPN in MM patients.

We investigated the susceptibility to BiPN in 369 patients who were included in a large prospective, randomized, phase III trial (HOVON65/GMMG-HD4) of bortezomib (PAD) versus conventional vincristine (VAD) based induction treatment. The study integrated inherited genetic background as well as the gene expression profile of the myeloma in patients who were closely monitored for BiPN. Genetic variation associated with BiPN was analyzed using a custom-built molecular inversion probe (MIP) based single nucleotide polymorphism (SNP) chip, designed by “Bank on a Cure” (BOAC), containing 3404 SNPs selected in “functional regions” within 983 genes that represent cellular functions and pathways. Gene expression profiles were analyzed in purified myeloma plasma cells (PCs) using Affymetrix 133 Plus 2.0 array and integrated with SNP profiles for an association analysis with BiPN. We used vincristine induced peripheral neuropathy (ViPN) in VAD-treated patients as a reference. Pathway analysis was performed using significant genes (FDR<.05) or significant SNPs (permuted P<.05).

Analysis of myeloma gene expression profiles and SNP data of patients with early onset BiPN (within one treatment cycle) showed an association of genes involved in apoptosis, in nervous system development and in response to oxidative stress. Among the top upregulated genes in myeloma PCs were two enzyme coding genes, RHOBTB2, involved in drug induced apoptosis and CPT1C, involved in mitochondrial dysfunction. Ingenuity pathway analyses revealed enrichment of genes involved in the canonical pathway AMPK signaling including CPT1C, CKM and PIK3CG. AMPK signaling stimulates signaling pathways that replenish cellular ATP supplies in response to low glucose, hypoxia, ischemia, or heat shock, which may be triggered in response of myeloma cells to bortezomib. Significant SNPs (permutated P<.01) in the same patients were located in apoptosis gene caspase 9, ALOX12, and IGF1R. Pathway analysis of these associated genes revealed enrichment of genes involved in cell death, DNA repair and nervous system development and function. The molecular profile of late onset BiPN (developing after 2–3 bortezomib cycles) was characterized by genes involved in nervous system development, inflammation and DNA repair. The highest association was found with SOD2 and MYO5A expression by myeloma PCs, involved in nervous system development and function, and SNPs in inflammatory genes MBL2 and PPARD and in DNA repair genes ERCC3, ERCC4, ATM, BRCA1, EXO1 and MRE11A. In contrast, early onset ViPN was characterized by cell cycle and proliferation genes, i.e. GAGE7, GAGE12I, GAGE2C, GAGE6 and GAGE4 expression in MMPC, and SNPs in BRCA1, ERBB2, and CCNA2, known to be involved in cell cycle and proliferation. In addition, SNPs in absorption, distribution, metabolism, and excretion (ADME) genes i.e. a group of 11 intronic SNPs in DPYD and 9 SNPs in the ABC transporter ABCC1 were associated with late onset ViPN.

We identified molecular factors which are associated with BiPN in newly diagnosed multiple myeloma patients. First, apoptosis genes contribute to early BiPN, whereas genes involved in inflammatory pathways and DNA repair contribute to the development of late BiPN, indicating that distinct genetic factors are involved in the development of early and late onset BiPN. Second, myeloma-related factors and host genetic background interactively contribute to the development of BiPN. Comparison between BiPN and ViPN learned that genetic factors involved in the development of PN are involved in different molecular mechanisms. This investigation strongly suggests an interaction between myeloma-related factors and host genetic background in the development of bortezomib induced peripheral neuropathy.

Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees; Ortho Biotec: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Ortho Biotec: Research Funding; Chugai Pharma: Research Funding; Amgen: Research Funding. Sonneveld:Ortho Biotech: Consultancy; Ortho Biotech: Research Funding; International Myeloma Foundation: Research Funding.