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

Cancer Sci. 2021 Dec;112(12):5011-5019. doi: 10.1111/cas.15158. Epub 2021 Oct 26.


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.

Keywords: HLA; Japanese; bortezomib; multiple myeloma; peripheral neuropathy.

Publication types

  • Clinical Trial, Phase II
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Bortezomib / administration & dosage*
  • Bortezomib / adverse effects
  • Female
  • Gene Frequency
  • Genotyping Techniques / methods*
  • HLA Antigens / genetics*
  • Humans
  • Japan
  • Male
  • Melphalan / administration & dosage*
  • Melphalan / adverse effects
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / epidemiology
  • Pneumonia / chemically induced
  • Pneumonia / epidemiology
  • Prednisolone / administration & dosage*
  • Prednisolone / adverse effects
  • Skin Diseases / chemically induced
  • Skin Diseases / epidemiology
  • Treatment Outcome


  • Antineoplastic Agents
  • HLA Antigens
  • Bortezomib
  • Prednisolone
  • Melphalan