Credit: Esther Dyson
Combining the proteasome inhibitor ixazomib with lenalidomide and dexamethasone shows promise for treating patients with newly diagnosed multiple myeloma (MM), according to researchers.
In a phase 1/2 study, the all-oral combination produced a 92% overall response rate and a 27% complete response rate.
Drug-related adverse events occurred in 100% of patients, with events of grade 3 or higher occurring in 63% of patients.
These results appear in The Lancet Oncology. The study was funded by Millennium Pharmaceuticals, the company developing ixazomib.
“Ixazomib is an investigational, oral proteasome inhibitor with promising anti-myeloma effects and low rates of peripheral neuropathy,” said study author Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota.
“While it is well known that a combination of bortezomib, lenalidomide, and dexamethasone is highly effective in treating newly diagnosed multiple myeloma, we wanted to study the safety, tolerability, and activity of ixazomib in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma.”
Dr Kumar and colleagues enrolled 65 patients—15 for phase 1 and 50 for phase 2 of the study—who were newly diagnosed with MM and 18 years of age or older. Patients had measurable disease, ECOG performance status of 0 to 2, and no grade 2 or higher peripheral neuropathy.
They received ixazomib (on days 1, 8, and 15) plus lenalidomide at 25 mg (on days 1 to 21) and dexamethasone at 40 mg (on days 1, 8, 15, and 22) for up to twelve 28-day cycles, followed by maintenance therapy with ixazomib alone.
In phase 1, patients received escalating doses of ixazomib, from 1.68 mg/m2 to 3.95 mg/m2, to establish the recommended dose for phase 2. The researchers established 2.97 mg/m2 as the maximum-tolerated dose and recommended the phase 2 dose be 2.23 mg/m2. This was converted to a 4.0 mg fixed dose based on population pharmacokinetic results.
Adverse events
The researchers said the combination was well tolerated, and most toxic effects were managed through dose modifications.
All patients reported at least one treatment-emergent adverse event, and 75% reported at least one treatment-emergent event that was grade 3 or higher.
Fifty-seven percent of patients had adverse events that led to dose reductions, including 53% of patients in the dose-escalation cohort and 58% of patients in the phase 2 cohort.
The most common adverse events resulting in dose reductions included skin and subcutaneous tissue disorders (20%), fatigue (14%), diarrhea (8%), peripheral neuropathy not elsewhere classified (8%), insomnia (6%), and increased body weight (6%). Five patients had adverse events leading to treatment discontinuation.
Two patients in the phase 2 cohort died while on study. One patient died of respiratory syncytial viral pneumonia that was thought to be treatment-related. The other patient died from cardiorespiratory arrest, which was considered not related to treatment.
Response and survival rates
Of the 64 response-evaluable patients, 92% responded to treatment. Fifty-eight percent had a partial response or better, and 27% had a complete response.
Responses deepened with an increasing number of treatment cycles. In the 25 patients continuing with maintenance therapy, 5 (20%) had an improvement in the depth of response during this phase.
The median duration of response has not been reached, but patients maintained responses for up to 2 years.
At last follow-up, 9 patients had progressed or died. The estimated 1-year progression-free survival was 88%, and 2-year progression-free survival was 67%.
The median overall survival has not been reached, but the estimated 1-year overall survival was 94%.
“The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone was generally well-tolerated and appeared active in patients with newly diagnosed multiple myeloma,” Dr Kumar said. “Our results support the development of a phase 3 trial studying this combination for multiple myeloma.”
