Ninlaro (ixazomib) is an oral prescription therapy that Takeda developed to treat multiple myeloma. Doctors prescribe it in combination with Revlimid (lenalidomide) and the corticosteroid dexamethasone for people with myeloma who have undergone at least one prior treatment.
The U.S. Food and Drug Administration approved the trio therapy — Ninlaro, Revlimid, and dexamethasone, or NRD — in 2015 following the results of the Phase 3 TOURMALINE-MM1 clinical trial (NCT01564537), which enrolled 722 participants. That same trial led the European Medicines Agency (EMA) to grant conditional marketing authorization for the NRD combination in 2016.
How does Ninlaro work?
Ninlaro is a proteasome inhibitor. It works by targeting cellular components called proteasomes that are necessary to break down and recycle damaged proteins inside cells. A functioning proteasome can help repair damaged proteins. This can promote cancer cell growth.
The inhibition of proteasomes using treatments such as Ninlaro ensures that cells cannot repair damaged proteins. Protein damage is often the result of aggressive cell division in cancer cells. That then results in their accumulation, causing the death of cancer cells.
Ninlaro in clinical trials
Researchers demonstrated the safety and efficacy of Ninlaro in treating myeloma in several clinical trials.
A Phase 2 study (NCT02046070) that ended in 2018 aimed to determine the safety and patients’ response rate to Ninlaro in combination with cyclophosphamide and dexamethasone (ICd). It enrolled 148 newly diagnosed multiple myeloma (NDMM) patients, older than 65, who had not received prior therapy and were ineligible for autologous hematopoietic stem cell transplantation (AHSCT). These are transplants involving a patient’s own cells. Participants tolerated ICd well with no late-onset toxicity.
Ongoing clinical trials
The TOURMALINE-MM1 trial, still ongoing, showed a very good overall response rate (ORR) of 78% in participants who received Ninlaro, compared with 72% among those who received a placebo. The results also showed a partial response rate of 48% in the Ninlaro group versus 39% in the placebo group. Treatment with Ninlaro led to significantly longer progression-free survival (PFS) in the treatment group compared with the placebo group — about 20.6 months versus 14.7 months — the study found. Researchers expect to complete this study, conducted at 24 sites across the U.S. and Canada, at the end of March 2021.
A Phase 3 study (NCT01850524) known as TOURMALINE-MM2 also is currently underway at 148 locations across the globe. That trial is examining the safety and efficacy of the NRD combination in 705 NDMM patients who are not eligible for AHSCT. It is investigating the PFS of patients who received NRD compared with those who received Revlimid and dexamethasone plus a placebo. Top-line results, presented at the Society of Hematologic Oncology (SOHO) 2020 annual meeting, recently held online, showed a 13.5-month increase in median PFS for patients who received NRD versus the combination with placebo. These results were not statistically significant, however, so the study did not meet its primary endpoint. The PFS was significantly better in the Ninlaro treatment group when the data was focused only on patients with the prespecified high-risk forms of the disease. The data also showed positive trends for patients on the Ninlaro combination treatment compared with the placebo combination in other categories, including response to treatment and time to progression. Researchers estimate that this trial will reach completion in February 2021.
Another Phase 3 clinical trial (NCT02181413), this one called TOURMALINE-MM3, also is ongoing and involves 656 participants at 178 sites. Expected to be completed in June 2025, this study is seeking to determine the effect of Ninlaro maintenance therapy among people with NDMM following AHSCT. Initial results have shown that Ninlaro reduced disease progression by 28% in these patients. However, about 42% of the enrolled participants reported adverse effects.
TOURMALINE-MM4, one other Phase 3 clinical trial (NCT02312258), will run until October 2024. This trial, currently underway at 278 locations worldwide with an actual enrollment of 706, is assessing the efficacy of Ninlaro as maintenance therapy in NDMM patients who have responded to initial therapy and have not undergone AHSCT. Preliminary results have shown that Ninlaro prolonged PFS compared with the placebo.
The dosing cycle for NRD — which can be taken at home — lasts about four weeks. Patients take Ninlaro on the starting day of the week for three weeks, along with Revlimid and dexamethasone. It may take up to one month from the onset of the regimen for the first response to become evident.
The side effects of Ninlaro include thrombocytopenia (low platelet counts), gastrointestinal problems, nerve problems swelling, and skin and liver problems. The nerve problems may comprise weakness, pain, numbness, and a burning sensation in the hands and feet.
Pregnant or breastfeeding women should not use Ninlaro.
Last updated: Oct. 19, 2020
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