Ixazomib Appears Ineffective Following Progression on Other Proteosome Inhibitor Regimens in R/R Multiple Myeloma

Although well tolerated, ixazomib (Ninlaro) did not appear to be an effective replacement for bortezomib (Velcade) or carfilzomib (Kyprolis) following progression on a regimen containing the agents in patients with relapsed/refractory multiple myeloma and didn’t overcome resistance to other proteosome inhibitors, according to findings from a phase 1/2 trial (NCT02206425) published in Experimental Hematology.

The overall response rate (ORR) was 12.8% and the clinical benefit rate (CBR) was 17.9%. As their best response, Seventeen patients had progressive disease as their best response. Additionally, 15 patients had stable disease. The ORR was slightly higher in patients who received 4 mg of ixazomib at 15.0% compared with 12.8% in the overall population. Similar findings were reported for CBR at 25.0% vs 17.9%, respectively. The median PFS was 2.1 months, the median duration of response was 0.9 months, and the median overall survival was 34.2 months. A partial response was observed in 5 patients and 2 had a minimal response.

“In this phase 1/2 study, ixazomib showed little clinical benefit as a subsequent therapy for [patients with relapsed/refractory multiple myeloma] who had progressed while on the same combination regimen with another [proteasome inhibitor]. Specifically, substitution of bortezomib or carfilzomib with ixazomib in a subsequent line of therapy following resistance to one of these [proteasome inhibitors] in the prior line otherwise using the same combination resulted in few responses,” investigators of the study wrote.

A total of 46 patients enrolled on the study, with a median age of 67.5 years and the majority of whom were male (60.9%). Patients had received a median of 5 lines of prior therapy, and the median time since diagnosis was 32.5 months. Of the patients who completed 1 cycle of treatment, 39 completed at least 1 cycle of treatment and were evaluable for response. Within the evaluable population, 19 patients started treatment with 3 mg of ixazomib, and 20 patients were given 4 mg.

During phase 1 of the trial, 3 different ixazomib combination therapies were evaluated in 21 patients without an established maximum tolerated dose. In these patients, there were no dose limiting toxicities, and the maximum tolerated dose was not identified for these treatment combinations.

In total, 23.9% of patients experienced at least 1 grade 3 serious adverse effect (SAE), and 37.0% experienced at least 1 grade 3 AE.

The most common grade 3 or higher AEs included hyponatremia (8.7%), dyspnea (8.7%), anemia (8.7%), and thrombocytopenia (6.5%). The most frequent SAEs were grade 3 hyponatremia (4.3%) and pneumonia (4.3%). Grade 4 and 5 SAEs included respiratory failure, candida esophagitis, hypovolemic shock, myocardial infraction, and sepsis, all which occurred in 1 patient each.

During the study, 1 patient died because of respiratory failure due to myocardial infraction, watershed infarct stroke, and encephalopathy. Investigators determined this death may be related to the treatment. Due to an AE, 1 patient was removed from the study.

Reference

Daniely D, Forouzan E, Spektor TM, et al. A phase 1/2 study of ixazomib in place of bortezomib or carfilzomib in a subsequent line of therapy for patients with multiple myeloma refractory to their last bortezomib or carfilzomib combination regimen. Exp Hematol. Published Online April 10, 2022.doi:10.1016/j.exphem.2022.04.003