Management of adverse events associated with ixazomib plus lenalidomide/dexamethasone in relapsed/refractory multiple myeloma

Br J Haematol. 2017 Aug;178(4):571-582. doi: 10.1111/bjh.14733. Epub 2017 May 9.


The oral proteasome inhibitor ixazomib is approved in the United States, European Union and other countries, in combination with oral lenalidomide and dexamethasone (Rd), for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on the global, randomised, double-blind, placebo-controlled Phase III TOURMALINE-MM1 study of ixazomib-Rd (IRd) versus placebo-Rd in patients with relapsed/refractory multiple myeloma. IRd resulted in a significant improvement in progression-free survival versus placebo-Rd (median: 20·6 vs. 14·7 months; hazard ratio 0·74). Common toxicities observed more commonly with IRd versus placebo-Rd were thrombocytopenia, nausea, vomiting, diarrhoea, constipation, rash, peripheral neuropathy, peripheral oedema and back pain; these were generally grade 1/2 in severity except for thrombocytopenia (19% vs. 9% grade 3/4), which appeared manageable and reversible, with no differences between arms in significant bleeding or dose discontinuations. No cumulative toxicities were observed, indicating the potential feasibility of long-term IRd treatment. Safety data from TOURMALINE-MM1 are reviewed and guidance for managing clinically relevant adverse events associated with IRd is provided. Most toxicities were manageable with supportive care and dose delays or reductions as needed. Clinicians should be aware of and understand these potential side effects to optimise and prolong patient benefit.

Keywords: dosing; ixazomib; multiple myeloma; proteasome inhibitor; toxicity.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Boron Compounds / administration & dosage
  • Boron Compounds / adverse effects
  • Dexamethasone / administration & dosage
  • Dexamethasone / adverse effects
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Eruptions / etiology
  • Drug Eruptions / therapy
  • Follow-Up Studies
  • Glycine / administration & dosage
  • Glycine / adverse effects
  • Glycine / analogs & derivatives
  • Hematologic Diseases / chemically induced
  • Hematologic Diseases / therapy
  • Humans
  • Lenalidomide
  • Leukocyte Count
  • Male
  • Middle Aged
  • Multiple Myeloma / drug therapy*
  • Nausea / chemically induced
  • Nausea / therapy
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / therapy
  • Platelet Count
  • Thalidomide / administration & dosage
  • Thalidomide / adverse effects
  • Thalidomide / analogs & derivatives
  • Vomiting / chemically induced
  • Vomiting / therapy


  • Boron Compounds
  • Thalidomide
  • ixazomib
  • Dexamethasone
  • Lenalidomide
  • Glycine