Postmarketing Surveillance Study Finds Ixazomib Safety Profile Acceptable in RRMM

Real-world evidence from Japan found ixazomib has an acceptable safety profile in patients with relapsed/refractory multiple myeloma (RRMS).

Results of an all-case postmarketing surveillance study conducted in Japan found ixazomib has an acceptable safety profile for patients with relapsed/refractory multiple myeloma (RRMM) in clinical practice. Findings were published in Internal Medicine.

In Japan, approximately 5.9 to 6.2 people per 100,000 develop MM each year, the authors explained, noting prognoses have improved in recent decades. “At present, the Japanese Society of Hematology practical guidelines recommend the use of proteasome inhibitors (PIs) and immunomodulatory drugs, and these agents have contributed to the significant improvement in the survival of patients with MM,” they said.

Based on findings from the TOURMALINE-MM1 (MM1) study which found ixazomib—in conjunction with lenalidomide-dexamethasone (LenDex)—led to longer progression-free survival compared with LenDex plus a placebo, the PI with LenDex was approved in Japan in 2017.

Due to the limited number of Japanese patients included in the MM1 study, the researchers sought to evaluate the safety profile of ixazomib plus LenDex among patients with RRMM in clinical practice.

In MM1 “the frequency of serious adverse events (SAEs) was similar in those who received ixazomib vs placebo (47% and 49%), whereas grade 3/4 thrombocytopenia and rash occurred more frequently among patients who received ixazomib than among those who received placebo (19% vs 9% and 36% vs 23%, respectively),” the authors wrote.

All patients who received ixazomib in Japan between May 24 and September 24, 2017, were included in the current observational analysis. Starting doses, dose modifications, adverse events (AEs) and other factors were observed from the start of treatment until the sixth treatment cycle or discontinuation.

SAEs were defined as any AE that was life-threatening or leading to death, hospitalization, or permanent impairment of a bodily function. “AEs for which a causal relationship to ixazomib was at least considered possible (ie, the relationship could not be ruled out), as deemed by the investigating physician, were defined as adverse drug reactions (ADRs),” the researchers said. These included “thrombocytopenia (including decreased platelet count), severe (grade ≥3) gastrointestinal disorders (diarrhea, nausea, vomiting, etc), skin disorders, peripheral neuropathy (including sensory and motor), and infection.”

A total of 741 patients were included in the final analysis, and patients had a median age of 71 (rnage, 35-92) years. Around 39% of patients were at least 75 years old, and 89.3% of patients had received prior PIs. In addition, 6.2% of patients had liver dysfunction and 39.5% had kidney dysfunction.

Approximately 62% of the patients discontinued treatment on or before the sixth cycle, with AEs and insufficient efficacy being listed as the most common causes of discontinuation, the authors wrote.

Analyses revealed:

  • ADRs occurred in 572 (77.2%) patients, with the most common being thrombocytopenia (49.9%), diarrhea (29.2%), and nausea (12.4%)
  • Serious ADRs occurred in 193 (26%) patients, and the most common were thrombocytopenia (9.9%) and diarrhea (5.9%)
  • Thrombocytopenia, severe gastrointestinal disorders, infections, skin disorders, and peripheral neuropathy were prespecified as ADRs of clinical importance; the frequencies of these ADRs (grade 3) were 28.5%, 9.4%, 7.4%, 2.2%, and 1.3%, respectively
  • Treatment discontinuation was most common with thrombocytopenia and severe gastrointestinal disorders (49 and 43 patients, respectively)
  • Eleven patients died due to ADRs (16 events); 28 died as the result of disease progression

Additional ADRs included decreasing neutrophil count, decreasing white blood cell count, pneumonia, anemia, fatigue, loss of appetite, and herpes zoster, and all were consistent with those reported in the MM1 study.

The researchers hypothesized more patients experienced thrombocytopenia in the current analysis as some individuals had platelet counts below 75,000/mm3 to begin with; these patients were not eligible for MM1 inclusion. In addition, the proportion of older patients was greater in the current study than in the previous trial, and patients reported a higher number of prior PIs than those enrolled in MM1.

Dose reduction or interruption rates in the current study were consistent with data from MM1.

Overall, findings were consistent with the safety profile of ixazomib observed in the clinical study in combination with LenDex in patients with RRMM, the authors wrote, noting “it should be kept in mind that thrombocytopenia is an expected ADR, as indicated in the ixazomib package insert.”

The nonblinded, nonrandomized, noncontrolled nature of this analysis mark limitations, and the researchers were unable to detect any long-term ADRs. “The ADRs observed in this postmarketing surveillance were similar to those reported in the MM1 study despite patients in this study being older and heavily pretreated,” they said.

“Thrombocytopenia was frequent, and this should be managed with appropriate dose modification or interruption if warranted. Gastrointestinal symptoms require appropriate prophylaxis and symptomatic therapy for continuous treatment,” they concluded.

The study was funded by Takeda Pharmaceutical Company Limited, which manufactures ixazomib.


Kakimoto Y, Hoshino M, Hashimoto M, Hiraizumi M, Shimizu K, Chou Y. Safety profile of ixazomib in patients with relapsed/refractory multiple myeloma in Japan: an all-case post-marketing surveillance. Intern Med. Published online October 12, 2021. doi:10.2169/internalmedicine.7768-21

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