HLA genotyping in Japanese patients with multiple myeloma receiving bortezomib: An exploratory biomarker study of JCOG1105 (JCOG1105A1)

Abstract

Bortezomib (Btz) shows robust efficacy in patients with multiple myeloma (MM); however, some patients experience suboptimal responses and show specific toxicities. Therefore, we attempted to identify specific HLA alleles associated with Btz‐related toxicities and response to treatment. Eighty‐two transplant‐ineligible patients with newly diagnosed MM enrolled in a phase II study (JCOG1105) comparing two less intensive melphalan, prednisolone, plus Btz (MPB) regimens were subjected to HLA typing. The frequency of each allele was compared between the groups, categorized based on toxicity grades and responses to MPB therapy. Among 82 patients, the numbers of patients with severe peripheral neuropathy (PN; grade 2 or higher), skin disorders (SD; grade 2 or higher), and pneumonitis were 16 (19.5%), 15 (18.3%), and 6 (7.3%), respectively. Complete response was achieved in 10 (12.2%) patients. Although no significant HLA allele was identified by multiple comparisons, several candidates were identified. HLA‐B*40:06 was more prevalent in patients with severe PN than in those with less severe PN (odds ratio [OR] = 6.76). HLA‐B*40:06 and HLA‐DRB1*12:01 were more prevalent in patients with SD than in those with less severe SD (OR = 7.47 and OR = 5.55, respectively). HLA‐DRB1*08:02 clustered in the group of patients with pneumonitis (OR = 11.34). Complete response was achieved in patients carrying HLA‐DQB1*03:02, HLA‐DQB1*05:01, and HLA‐DRB1*01:01 class II alleles. HLA genotyping could help predict Btz‐induced toxicity and treatment efficacy in patients with MM, although this needs further validation.

Immunodiagnosis — the promise of personalized immunotherapy

“…CD8+ T cell dependent killing of cancer cells requires appropriate presentation of tumor antigens by MHC, which in humans is human leukocyte antigen (HLA) molecules, resulting in at least three kinds of biomarkers: specific HLA genotype for certain cancer type ( 115 ), some kind of HLA alleles having strong antigen presentation ability ( 116 ), and high HLA diversity which could provide a large library and are more likely to have appropriate HLA ( 117 ). An exploratory study of multiple myeloma patients treated with bortezomib found some HLA alleles as candidates, as patients carrying HLA-DQB1*03:02, HLA-DQB1*05:01, and HLA-DRB1*01:01 class II alleles are more likely to get a complete response ( 115 ). In 1535 advanced cancer patients treated with ICIs, the HLA-B44 supertype is associated with extended survival, whereas the HLA-B62 supertype was associated with poor outcomes ( 116 ).…”